Number 66 - March 2015
Hormones
and the heart
66
Heart
and
Metabolism
Heart and Metabolism a Servier publication
Editor in Chief Mario Marzilli, MD, PhD, Italy
Editorial Board Luis Henrique W. Gowdak, MD, PhD, Brazil
Derek J. Hausenloy, PhD, UK
Graham Jackson, MB (Hons), UK
Gary D. Lopaschuk, PhD, Canada
Michael Marber, MB (BS), PhD, UK
Published by Les Laboratoires Servier
Publication Director/
Directeur de Ia Publication Laurence Alliot, PharmD, France
Editorial project coordinator Brigitte Oget-Chevret
brigitte.oget-chevret@fr.netgrs.com
Correspondence to Servier International
Brigitte Oget Chevret
50 rue Carnot
92284 Suresnes Cedex
France
Aim and Scope Heart and Metabolism is a quarterly journal focusing on the
management of cardiovascular diseases. Its aim is to inform
cardiologists and other specialists about the newest findings
on the role of metabolism in cardiac disease and to explore
their potential clinical implications.
Each issue includes an editorial, followed by articles on a key
topic. Experts in the field explain the metabolic consequences
of cardiac disease and the multiple potential targets for pharmacotherapy in ischemic and nonischemic heart disease.
Website www.heartandmetabolism.com
Heart and Metabolism is indexed in EMBASE, and SCOPUS, and PASCAL/INISTCNRS until issue 65.
Design Studio DTC - Servier
Layout Bleu Banquise
Printed in France
© 2015 by Les Laboratoires Servier
ISSN 1566-0338
All rights reserved throughout the world and in all languages.
No part of this publication may be reproduced, transmitted,
or stored in any form or by any means either mechanical or
electronic, including photocopying, recording, or through an
information storage and retrieval system, without the written
permission of the copyright holder.
Opinions expressed do not necessarily reflect the views of
the publishers, editors, or editorial board. The authors, editors, and publishers cannot be held responsible for errors or
for any consequences arising from the use of the information
contained in this journal.
00-00-0000 / PEFC Certified / This publication is from sustainably managed forests and controlled sources. / www.pefc.org
Contents
EDITORIAL
Hormones and the heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
G. Jackson
ORIGINAL ARTICLES
Thyroid, aldosterone, and cardiovascular disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
C. Vlachopoulos, D. Terentes-Printzios
Testosterone and cardiovascular disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
T. Hugh Jones
Measuring myocardial salvage: hormone cardioprotection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
D. J. Hausenloy
Testosterone and the heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
C. C. K. Ho, H. M. Tan
Effects of trimetazidine on hormones and the heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
V. Sansoy, K. Kılıçkesmez
CASE REPORT
Erectile dysfunction and lower urinary tract symptoms should trigger a metabolic
screen and cardiovascular risk estimation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
M. Kirby
REFRESHER CORNER
Evaluation of metabolic syndrome and male sexual dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
J. J. Heidelbaugh, M. M. Miner
HOT TOPICS
Testosterone replacement therapy: cardiovascular benefits and possible risks . . . . . . . . . . . . . . . 37
G. Hackett
GLOSSARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
G. D. Lopaschuk
1
Editorial - Graham Jackson
Heart Metab. (2015) 66:2
Hormones and the heart
Graham Jackson, MB (Hons), FRCP, FACC, FESC; St. Thomas’ Hospital, London, UK
Correspondence: Graham Jackson, Petersfield, Bishop’s Walk, Croydon, Surrey, CR0 5BA,
United Kingdom
E-mail: gjcardiol@talk21.com
T
he effect of hormones on the heart usually
relates to tachycardias such as thyroid overactivity, bradycardias such as thyroid underactivity, and arrhythmias such as adrenaline excess. In this
edition of Heart and Metabolism, we focus on the
hormone “of the moment”—testosterone. We know
that in chronic conditions testosterone depletion is
quite common, eg, affecting nearly 50% of type 2
diabetics. The question has always surrounded the
safety of replacing testosterone in those who are
hypogonadal. Recently, the replacement of testosterone has been thought to increase cardiovascular
risk. This has caused considerable consternation as
the bulk of preceeding trials suggested the opposite.
So, it was particularly interesting to read a systemic
review and meta-analysis of cardiovascular risk associated with testosterone replacement therapy (TRT).1
further reinforced by the Vlachopoulos et al paper,
where they found that a low plasma testosterone
in hypertensive patients was associated with an
increased risk of major cardiac events.4
This report from a well-recognised unit does not
support a causal link between TRT and adverse
cardiovascular risk events.1 Similarly, the European
Medicines Agency (EMA) could find no evidence that
TRT in hypogonadal men increased cardiovascular
risk.2 In an editorial, Wu reviewed the position of TRT
and the absence of cardiovascular risk, but more
information was needed with regard to benefit.3
REFERENCES
Wu’s reassurance that there is no obvious disadvantage in using TRT is alluded to by Professor Hugh
Jones in his paper featuring in this edition of Heart
and Metabolism, and even raises the possibility that
TRT reduces mortality. The body of evidence, as
discussed in this issue, is very much in favour of TRT
improving quality and possibly quantity of life. This is
2
My personal approach is, if the patient is hypogondal
and there are no contraindications, to replace testosterone to normal levels (>12 nmol/L). Furthermore,
there is increasing evidence that testosterone may be
important with regard to reducing abdominal obesity,
which in turn should therefore decrease cardiovascular risk further.5
Therefore, whilst there is a degree of confusion, we
hope that this issue of Heart and Metabolism will
help to clarify the position of TRT as a hormone that
benefits the heart. L
1.Corona G, Maeroli E, Rastrelli G, et al. Cardiovascular risk associated with testosterone-boosting medications: a systemic review and meta-analysis. Expert Opin Drug Saf. 2014:13:13271351.
2.
European Medicines Agency. PRAC review does not confirm increase in heart problems with testosterone medicines.
http://www.ema.europa.eu/docs/en_GB/document_library/
Referrals_document/Testosterone_31/Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/
WC500175213.pdf. Updated October 10, 2014. Accessed
February 2, 2015.
3.Wu FCW. Caveat emptor: does testosterone treatment reduce
mortality in men? J Clin Endocrinol Metab. 2012;97:18841886.
4.
Vlachopoulos C, Ioakeimidis N, Terentes-Printzios D, et al.
Plasma total testosterone and incident cardiovascular events
in hypertensive patients. Am J Hypertens. 2013;26:373-381.
5.Traish AM. Testosterone and weight loss: the evidence. Curr
Opin Endocrinal Diabetes Obes. 2014;21:313-322.
Original Article
Heart Metab. (2015) 66:3-6
Thyroid, aldosterone, and
cardiovascular disease
Charalambos Vlachopoulos, MD; Dimitrios Terentes-Printzios, MD
Hypertension Unit and Peripheral Vessels Unit, First Department of Cardiology, Athens Medical School,
Hippokration Hospital, Athens, Greece
Correspondence: Charalambos Vlachopoulos, MD, 24 Profiti Elia str, Athens 14575, Greece
E-mail: cvlachop@otenet.gr
Abstract
The endocrine and cardiovascular systems have essential pathophysiological links. As expected, dysfunction of one leads to harmful consequences to the other. Thyroid hormones and aldosterone are
two examples of this close association. Dysfunction of the thyroid gland is usually suspected due to
cardiovascular symptoms, such as those related to increased blood pressure and rhythm disturbances.
Thyrotropin, also known as thyroid-stimulating hormone, is the initial screening test used. Importantly,
even subclinical forms of thyroid dysfunction can affect cardiovascular prognosis. Similarly, increased
levels of aldosterone are implicated in several cardiovascular disorders, such as hypertension and heart
failure. Blockade of aldosterone in these conditions leads to improved prognosis. Contrary to some other
chronic diseases, endocrine dysfunction can be reversed or at least adequately managed in order to
improve cardiovascular health and reduce cardiovascular events. For these reasons, it is of paramount
importance for the cardiologist to work hand in hand with the endocrinologist in such patients. L Heart
Metab. 2015;66:3-6
Keywords: aldosterone; cardiovascular disease; heart failure; hormone; thyroid
E
ndocrine function is a cornerstone in both
cardiovascular physiology and cardiovascular
disease.1 As expected, endocrine disorders,
either in the form of overt hypofunction/hyperfunction
or even in their subclinical form, have essential effects
on the cardiovascular system. Two endocrine glands
associated mostly with cardiovascular physiology are
the thyroid and the adrenal gland. There is a large
number of clinical studies that have explored the effect
of these two glands and their secreted hormones on
cardiovascular health. The scope of this review is to
investigate the main cardiovascular alterations that
are related to the thyroid hormones and aldosterone
in cases of endocrine dysfunction. Additionally,
we comment on the cardiovascular therapeutic
opportunities offered by these hormones for improvement of cardiovascular health and prognosis.
Thyroid and cardiovascular disease
Thyroid hormones, triiodothyronine (T3) and thyroxine
(T4), are produced in the thyroid gland in a molar ratio of approximately 1 to 7. Every enzymatic step in
the synthesis and secretion of T4 and T3 is regulated
by thyrotropin, also known as thyroid-stimulating hormone (TSH). The TSH test is the appropriate initial
screening for thyroid dysfunction in several cardiovascular clinical entities and risk factors known to be affected by thyroid disease such as hypertension, atrial
fibrillation, and dyslipidemia.2
3
Vlachopoulos and Terentes-Printzios
Thyroid, aldosterone, and cardiovascular disease
Heart Metab. (2015) 66:3-6
Abbreviations
ARR: aldosterone-to-renin ratio; RAAS: renin-angiotensin-aldosterone system; T3: triiodothyronine; T4: thyroxine; TSH: thyrotropin/thyroid-stimulating hormone
The effects of thyroid hormones on the cardiovascular system are the most clinically useful and sensitive
signs of thyroid dysfunction. Regarding pathophysiology, thyroid dysfunction has essential cardiovascular
consequences in myocardial contractility, peripheral
hemodynamics, and heart rate (Figure 1).2 Thyroid
Systemic vascular resistance
Tissue thermogenesis
↑ 15% to 20%
T4
T4
T3
Changes in
pulmonary pressure
↑ Preload
↑ Cardiac output
30% to 50%
↓ Diastolic blood pressure
T3
Renin-angiotensinaldosterone axis
↑ Cardiac
chronotropy and inotropy
↓ Afterload
Fig. 1 Effects of thyroid hormones on cardiovascular function.
Abbreviations: T3, triiodothyronine; T4, thyroxine.
Modified from reference 2: Danzi et al. Med Clin North Am. 2012;96(2):257268. © Elsevier Inc.
hormones, in addition to their direct effects on cardiovascular function, also have indirect effects mediated
through the autonomic nervous system, renin-angiotensin-aldosterone system (RAAS), and renal function,
and resultant changes in vasoreactivity, arterial stiffness, and atherosclerosis.3 The importance of vascular
function and especially aortic stiffness as assessed by
pulse wave velocity is high, as arterial stiffness is an
independent and strong predictor of cardiovascular
prognosis and all-cause mortality.4,5
Hyperthyroidism
Cardiovascular symptoms are often the principal clinical elements of patients with hyperthyroidism. Palpitations are common in most patients, resulting from
increases in cardiac contractility. Heart rate increase
is caused by an increase in sympathetic tone and a
decrease in parasympathetic stimulation. Heart rate
4
increase during exercise is exaggerated. Many patients with hyperthyroidism experience exercise intolerance and exertional dyspnea.
Systolic hypertension is common in hyperthyroid
patients. This elevation in systolic pressure may result
from the combined effect of increased preload and
cardiac output, as well as of increased arterial stiffness. Consequently, left ventricular hypertrophy has
been associated with the hyperthyroid state. Furthermore, in the long term, hyperthyroidism is also associated with diastolic dysfunction. In severe, untreated
cases, it may even lead to heart failure.6 Increased
rates of pulmonary hypertension have been observed
in hyperthyroidism.
Sinus tachycardia is the most common rhythm
alteration in patients with hyperthyroidism. However,
atrial fibrillation is the most clinically important arrhythmia of hyperthyroidism. The prevalence of atrial
fibrillation ranges from 2% to 20% and increases progressively with age. Symptomatic treatment of atrial
fibrillation includes β-blockers that can rapidly alleviate symptoms of hyperthyroidism in contrast to the
mainstay treatment for hyperthyroidism that requires
a longer period of time to restore the euthyroid state.
Anticoagulation in patients with hyperthyroidism and
atrial fibrillation is controversial.
A small percentage of hyperthyroid patients can
present with angina-like chest pain that could imply
myocardial ischemia due to increase in cardiac work
or even a form of vasospastic angina. Even in its subclinical form, hyperthyroidism is associated with an
increased risk of coronary heart disease events and
mortality, especially when levels of TSH are below
0.10 mIU/L.7
Hypothyroidism
The cardiovascular features of hypothyroidism are
more subtle and less conspicuous. Bradycardia, diastolic hypertension, and narrow pulse pressure are all
typical. Changes in cardiovascular function and hemodynamics caused by hypothyroidism are entirely
opposite to those of hyperthyroidism (Table I).2 Furthermore, hypothyroidism also produces increases in
total cholesterol and low-density lipoprotein cholesterol analogous to the rise in TSH level. The serum
creatine kinase level is substantially elevated in up
to 1 out of 3 patients with hypothyroidism. Pericardial effusion may also be a consequence of hypo-
Heart Metab. (2015) 66:3-6
Vlachopoulos and Terentes-Printzios
Thyroid, aldosterone, and cardiovascular disease
thyroidism. Plausible mechanisms are a decrease in
lymphatic clearance function and an increase in the
volume of distribution of albumin. Prolongation of QT
interval can also be observed.
As expected, exacerbation of cardiovascular risk
factors, such as hypertension, hypercholesterolemia,
and increased homocysteine, with hypothyroidism can
lead to atherosclerosis and eventually overt cardiovascular disease. Hypothyroidism, even in the form of a
subclinical condition, is associated with coronary heart
disease events and mortality, particularly in those patients with a TSH concentration of 10 mIU/L or greater.8
Hormone replacement treatment with levothyroxine in patients older than 50 years with known or suspected coronary artery disease should be cautiously
initiated following the combined assessment by both
a cardiologist and an endocrinologist.
Aldosterone and cardiovascular disease
Aldosterone is a mineralocorticoid hormone that is
produced from cholesterol in the zona glomerulosa
of the adrenal cortex by a series of enzymatic reactions.9 The RAAS regulates aldosterone synthesis
mainly by angiotensin II, which binds to the angiotensin II type I receptor on cells of the zona glomerulosa.
Other regulatory factors include serum sodium and
potassium levels and adrenocorticotropic hormone.
Mineralocorticoid hormones work to maintain normal
sodium and potassium concentrations, and to maintain normal volume status. Renin secretion responds
principally to changes in intravascular volume.
Measurements, signs, and symptoms
Hyperaldosteronism
Primary hyperaldosteronism is a group of clinical
entities in which aldosterone production is disproportionally high, resulting in inhibition of the RAAS.9
Hypertension is the hallmark clinical characteristic of
hyperaldosteronism.10 The prevalence of hyperaldosteronism is reported as up to 1% to 5% of patients
with hypertension, and 5% to 20% of patients with
resistant hypertension.1 Potassium depletion is also
a hallmark of hyperaldosteronism. Screening for hyperaldosteronism is made by measuring plasma aldosterone and plasma renin activity, and calculating
an aldosterone-to-renin ratio (ARR). Patients with a
positive ARR (ARR >20 with aldosterone >15 ng/dL)
should be further evaluated.
Hyperaldosteronism causes pathologic cardiac
remodeling and has been implicated in left ventricular
hypertrophy, diastolic dysfunction, and cardiac fibrosis. Increased aldosterone levels have been shown
to cause endothelial dysfunction and promote inflammation, while aldosterone-mediated vascular fibrosis
leads to increased arterial stiffness. Finally, hyperaldosteronism has been associated with impaired glucose
tolerance and decreased insulin sensitivity. These
deleterious effects could partly explain the detrimental effect of primary aldosteronism on cardiovascular
mortality, even in treated patients.11
In myocardial infarction and heart failure, aldosterone levels are elevated and contribute to maladaptive cardiovascular remodeling via direct effects on
collagen deposition and consequential cardiovascu-
Normal
Hyperthyroid
Hypothyroid
Isovolumic relaxation time (ms)
60-80
25-40
>80
Heart rate (bpm)
72-84
88-130
60-80
Cardiac output (L/min)
5.8
>7.0
<4.5
Hemodynamics
Blood volume (% of normal)
100
105.5
84.5
Systemic vascular resistance (dyn•s•cm−5)
1500-1700
700-1200
2100-2700
Signs, symptoms, findings of tests
Palpitations, atrial fibrillation
Bradycardia
Anginal chest pain
Increased serum cholesterol
Exercise intolerance,
exertional dyspnea
Decreased endurance,
fatigue
Systolic hypertension,
cardiac hypertrophy,
pulmonary hypertension,
heart failure
Impaired cardiac
contractility, impaired
diastolic function
Table I Cardiovascular symptoms, signs, and hemodynamics in different thyroid states.
Abbreviations: ms, milliseconds; bpm, beats per minute.
Modified from reference 2: Danzi et al. Med Clin North Am. 2012;96(2):257-268. © Elsevier Inc.
5
Vlachopoulos and Terentes-Printzios
Thyroid, aldosterone, and cardiovascular disease
lar fibrosis. Many studies have shown that aldosterone blockade ameliorates these deleterious effects.
Two large randomized clinical studies, the Randomized Aldactone Evaluation Study (RALES) and the
Eplerenone Post–Acute Myocardial Infarction Heart
Failure Efficacy and Survival Study (EPHESUS), confirmed the beneficial effect of aldosterone blockade
and introduced aldosterone antagonists in the treatment of heart failure.12 However, the beneficial effects
of aldosterone blockade in diastolic dysfunction and
heart failure are controversial and probably minimal.13
Finally, despite the fact that studies have shown a
beneficial effect of mineralocorticoid receptor blockade when added to standard therapy on proteinuria
in patients with diabetic nephropathy, hyperkalemia
still remains an important issue.14
Conclusion
Both thyroid hormones and aldosterone have essential effects on the cardiovascular system. Imbalance
of their levels leads to disturbance in the homeostasis of the cardiovascular system. Importantly, most of
these deleterious hormone-mediated cardiovascular
effects can be reversed or managed with the proper
regulation or blockade of these hormones. Therefore,
it is important for both endocrinologists and cardiologists to apply a global approach in the assessment of
such patients. L
REFERENCES
1. Rhee SS, Pearce EN. The endocrine system and the heart: a
review. Rev Esp Cardiol. 2011;64(3):220-231.
6
Heart Metab. (2015) 66:3-6
2.
Danzi S, Klein I. Thyroid hormone and the cardiovascular system. Med Clin North Am. 2012;96(2):257-268.
3.
Grais IM, Sowers JR. Thyroid and the heart. Am J Med.
2014;127(8):691-698.
4.Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of
cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol. 2010;55(13):1318-1327.
5.
Vlachopoulos C, Aznaouridis K, Terentes-Printzios D, Ioakeimidis N, Stefanadis C. Prediction of cardiovascular
events and all-cause mortality with brachial-ankle elasticity
index: a systematic review and meta-analysis. Hypertension.
2012;60(2):556-562.
6.Gencer B, Collet TH, Virgini V, et al; Thyroid Studies Collaboration. Subclinical thyroid dysfunction and the risk of heart failure
events: an individual participant data analysis from 6 prospective cohorts. Circulation. 2012;126(9):1040-1049.
7.
Collet TH, Gussekloo J, Bauer DC, et al; Thyroid Studies Collaboration. Subclinical hyperthyroidism and the risk
of coronary heart disease and mortality. Arch Intern Med.
2012;172(10):799-809.
8.Rodondi N, den Elzen WP, Bauer DC, et al; Thyroid Studies
Collaboration. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA. 2010;304(12):13651374.
9.Garg R, Adler GK. Aldosterone and its cardiovascular effects.
In: Robertson D, Williams GH, eds. Principles of Clinical and
Translational Science. London, UK: Elsevier; 2008.
10.Xanthakis V, Vasan RS. Aldosterone and the risk of hypertension. Curr Hypertens Rep. 2013;15(2):102-107.
11.Reincke M, Fischer E, Gerum S, et al; German Conn’s RegistryElse Kröner-Fresenius-Hyperaldosteronism Registry. Observational study mortality in treated primary aldosteronism: the German Conn’s registry. Hypertension. 2012;60(3):618-624.
12.Funder JW. Aldosterone, hypertension and heart failure: insights from clinical trials. Hypertens Res. 2010;33(9):872-875.
13.Edelmann F, Wachter R, Schmidt AG, et al; Aldo-DHF Investigators. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial. JAMA.
2013;309(8):781-791.
14.Rossing K, Schjoedt KJ, Smidt UM, Boomsma F, Parving HH.
Beneficial effects of adding spironolactone to recommended
antihypertensive treatment in diabetic nephropathy: a randomized, double-masked, cross-over study. Diabetes Care.
2005;28(9):2106-2112.
Original Article
Heart Metab. (2015) 66:7-12
Testosterone and cardiovascular
disease
T. Hugh Jones, MD, FRCP
Robert Hague Centre for Diabetes and Endocrinology, Barnsley Hospital and Department of Human Metabolism,
The Medical School, University of Sheffield, Sheffield, UK
Correspondence: Professor T. Hugh Jones, Robert Hague Centre for Diabetes and Endocrinology, Barnsley Hospital NHS
Foundation Trust, Gawber Road, Barnsley, S75 2EP, United Kingdom
E-mail: hugh.jones@nhs.net
Abstract
Low levels of endogenous circulating testosterone in men in community-based epidemiological studies
are associated with an increased risk of mortality from all causes, with some studies identifying a link
with cardiovascular (CV) disease. Testosterone deficiency is associated with several CV risk factors
including central obesity, dyslipidemia, hypertension, and insulin resistance. Testosterone replacement
therapy (TRT) in men with hypogonadism, when carefully replaced to the normal range, has been
shown to improve some risk parameters including waist circumference, total and low-density lipoprotein
cholesterol, lipoprotein(a), insulin resistance, and hyperglycemia. TRT does slightly lower high-density
lipoprotein cholesterol in some trials; the clinical significance of this effect is not known. Beneficial
effects of TRT have demonstrated reduced exercise-induced cardiac ischemia in men with chronic
stable angina and improved functional exercise capacity, and Vo2max in men with moderate chronic
cardiac failure. Evidence from well-conducted trials where TRT achieves normal testosterone values
and meta-analysis of the studies have not identified any increased risk of major CV events. Some recent
studies have shown increased CV risk, but have major flaws in design and either over- or under-treated
patients. Clearly only a large, long-term, placebo-controlled randomized clinical trial may provide the
definitive answer. The benefits of TRT on quality of life and sexual function are very important to the
majority of men with hypogonadism. Furthermore, two retrospective studies have reported that TRT
can reduce mortality in hypogonadal men with and without type 2 diabetes. Careful diagnosis, titration
of testosterone dose to maintain levels within the mid-normal range, and long-term safety monitoring
are key to the reduction in complications. L Heart Metab. 2015;66:7-12
Keywords: cardiovascular; diabetes; heart; testosterone
S
exual dysfunction has been identified as a
biomarker for the presence of cardiovascular
(CV) disease, which may predate the onset of
a future CV event. Erectile dysfunction (ED) may be
the first symptom of CV disease.1 It is well recognized
that CV risk reduction by improvement in lifestyle (diet,
exercise, and cessation of smoking) and control of
hypertension, cholesterol, and diabetes can reduce
CV events. ED is one of a triad of sexual symptoms
found in male hypogonadism with reduced, or loss of,
libido and morning erections accounting for the other
two.2,3 Between 20% to 30% of men with ED have
7
Jones
Testosterone and cardiovascular disease
hypogonadism. There is good evidence that low levels of circulating testosterone have a high prevalence
in men with CV disease, metabolic syndrome, and
type 2 diabetes.4,5
Low testosterone may merely be a biomarker of
illness secondary to the chronic inflammatory state
of atherosclerosis. Accumulating evidence has demonstrated that low testosterone levels are associated
with an increased risk of death and that higher endogenous testosterone may protect against major
CV events.6-10 There is evidence, mainly from animal
studies, that testosterone deficiency may promote
atherogenesis, whereas replacement can ameliorate the disease.11 Testosterone replacement therapy
(TRT) has been shown to improve exercise-induced
cardiac ischemia, cardiac failure, and may improve
mortality. However, some recent retrospective studies have raised concerns over testosterone therapy
increasing CV events, although these are heavily
flawed, whereas the majority of studies and metaanalyses have not supported this. This short review
will discuss current clinical aspects of testosterone
deficiency and replacement therapy.
Epidemiology
The majority of community-based population studies
have reported that low testosterone levels (in particular <12 nmol/L) are associated with an increased allcause mortality risk.6 Several of these studies have
shown that the most common cause of mortality is
CV disease.6 In disease-specific populations, which
include men with proven CV disease by coronary
angiography (Figure 1), and in type 2 diabetes, low
testosterone increases mortality risk two-fold.12,13 Two
studies support an effect of low testosterone on an
increased risk of CV events. The MrOS study from
Sweden has demonstrated that men in the upper
quartile of testosterone levels have lower CV events
8
than those in the lower three quartiles combined.9 Another study found that there was a “J-shaped” curve
with a reduced frequency of CV events in the midnormal range.10 The Health in Men (HIM) study from
Australia reported that there was a reduced risk of
all-cause mortality in the mid-to-higher normal range
compared with low and high levels representing a “U”
shaped curve.8 Additionally, this study found that CV
mortality was decreased in men with dihydrotestosterone levels in the high-normal range. This knowledge that testosterone deficiency is associated with
an increased risk of CV mortality is supported by the
findings that men receiving androgen deprivation
therapy (ADT) for prostate cancer have increased frequency of CV events and death.14
The reasons as to why testosterone deficiency is
associated with CV disease and mortality have not
been fully established. Low testosterone may be a
biomarker as a consequence of ill health. Chronic
inflammatory disorders, which include atherosclerosis, may suppress the hypothalamic-pituitary-testicular axis, thus lowering testosterone levels. However,
there is evidence that testosterone deficiency is associated with major CV risk factors.5 These include
central adiposity, dyslipidemia, insulin resistance, hyperglycemia, and a proatherogenic cytokine profile.
Hypogonadism has an increased prevalence in men
with type 2 diabetes and hypertension as well as CV
disease.4,5
1.000
0.975
Bio-T > 2.6 nmol/L
Cumulative survival
Abbreviations
ADT: androgen deprivation therapy; BMI: body mass
index; CHF: chronic heart failure; CV: cardiovascular; ED:
erectile dysfunction; FDA: Food and Drug Administration;
HDL: high-density lipoprotein; LDL: low-density lipoprotein; LP(a): lipoprotein(a); MACE: major adverse cardiovascular events; PDE5: phosphodiesterase type 5; TRT:
testosterone replacement therapy
Heart Metab. (2015) 66:7-12
0.950
0.925
Bio-T < 2.6 nmol/L
0.900
0.875
Log rank, P<0.007, HR 2.2 (1.2-3.9)
0
500
1000
1500
200
2500
3000
3500
Survival time
Fig. 1 Kaplan-Meier survival curve of cardiovascular (CV) mortality
based on baseline bioavailable testosterone (bio-T). The solid line
represents patients with CV disease and a baseline bio-T below the
normal range (<2.6 nmol/L). The broken line represents men with CV
disease and a bio-T in the normal range (>2.6 nmol/L).
Abbreviation: HR, hazard ratio.
From reference 12: Malkin CJ et al. Heart. 2010;96(22):1821-1825. © 2010,
BMJ Publishing Group Ltd and the British Cardiovascular Society.
Heart Metab. (2015) 66:7-12
Carotid intima-media thickness (CIMT) is increased in men with low testosterone.5 One study
showed that after a 4-year follow-up, progression of
CIMT was greatest in men with testosterone levels in
the lower tertile.15 Animal studies have demonstrated
that testosterone deficiency leads to an increased risk
of lipid streak formation within aortic and coronary arteries.11 Testosterone supplementation ameliorates
the deposition of lipid. This raises the question as to
whether or not TRT may have an atheroprotective effect.
Pathogenesis
The European Male Aging Study (EMAS) has demonstrated that obesity and comorbidities are the major
promoters for the suppression of testosterone deficiency, with aging accounting for a lesser effect.16 Evidence supports a bidirectional mechanism between
obesity and testosterone status.4 Hypogonadism is
well known to increase body fat and reduce muscle
mass. This is evident in men with Klinefelter’s syndrome who may present with a female distribution of
body fat (eunuchoid habitus). Furthermore, men with
low testosterone in epidemiological studies have an
increased risk of developing the metabolic syndrome
and type 2 diabetes, independent of obesity at baseline.4
Obesity is considered to be a proinflammatory
state as adipocytes secrete adipocytokines, which include tumor necrosis factor-α (TNFα), interleukin-1β
(IL-1β), interleukin-6 (IL-6), and leptin. These adipocytokines act upon the hypothalamus to inhibit pulsatile gonadotropin-releasing hormone (GnRH) release
leading to the suppression of luteinizing hormone
and then testosterone secretion from the testes.4 In
addition, the aromatase activity correlates positively
with the degree of visceral fat, leading to more rapid
breakdown of testosterone to estradiol, lowering circulating testosterone levels further. The testosteronedeficient state enhances the uptake of triglycerides
into adipocytes and promotes the relative increase
in fat cells derived from stem cells compared with
muscle cells. This bidirectional relationship between
fat and testosterone metabolism is known as the
hypogonadal-obesity-adipocytokine hypothesis (Figure 2).17,18 The greater the fat deposition, the greater
the breakdown of testosterone. Adipocyte aromatase
activity increases further, eventually leading to a hy-
Jones
Testosterone and cardiovascular disease
pogonadal state. Weight reduction and exercise may
break the cycle, but hypogonadism can be associated with lack of motivation and therefore a poor response to lifestyle changes.
Angina
Testosterone therapy was first shown to relieve symptoms of angina in 1939 with several case report studies finding that the majority of men and also women
responded. More recently, these observations have
been confirmed in placebo-controlled studies over
periods between 1 and 12 months. Testosterone
therapy improves time to 1 mm ST depression on
exercise testing in men with chronic stable angina,
either when administered acutely or over several
months.11,19 Importantly, the lower the baseline testosterone level the greater the reduction in ischemia.19
Evidence strongly supports a role of testosterone as
a rapid-acting arterial vasodilator in the coronary arteries as well as in other systemic vessels, including
mesenteric and pulmonary vascular beds.11 In particular, one study in which testosterone was given
directly into coronary arteries in men undergoing routine angiography showed testosterone significantly increased coronary artery diameter and coronary blood
flow within a period of 2 to 5 minutes.20 In vitro experi-
Fig. 2 Hypogonadal-obesity-adipocytokine hypothesis.
Abbreviation: IL, interleukin, TNF, tumor necrosis factor.
From reference 17: Rao PM et al. Nat Rev Endocrinol. 2013;9:479-493.
© 2013, Nature Publishing Group.
9
Jones
Testosterone and cardiovascular disease
ments have shown that testosterone may promote
vessel dilation by blocking L-calcium channels at the
nifedipine binding site.11 Other sites of action include
inhibiting potassium channels and intracellular, storeoperated calcium release, increasing the expression
of β1-adrenergic receptors as well as upregulating the
response to noradrenaline and acetylcholine.11 Conversion of testosterone to estradiol may also lead to
a vasodilatory response, but there is a direct effect of
testosterone and its metabolite dihydrotestosterone
(DHT) that is endothelium independent.11
Chronic heart failure
Chronic heart failure (CHF) is commonly caused by
coronary artery disease. CHF significantly impacts
quality of life, causes cachexia, and has a high mortality rate that is worse than several forms of cancer. Low
testosterone is common in men with CHF and is likely
to occur as a consequence of chronic inflammation
resulting from atherosclerosis, heart failure, and/or the
cachectic state. Supraphysiological levels of testosterone promote the retention of extracellular water and if
patients with hypogonadism are overtreated, then this
can lead to an exacerbation of cardiac failure. Unlike
older formulations, transdermal administration of testosterone replacement can be carefully titrated and
replace testosterone to within the mid-normal range.
There have been a small number of trials of up
to 12 months that have reported a beneficial effect
of TRT in men with moderate CHF.21,22 Testosterone
improved functional exercise capacity, Vo2max, and, in
one-third of men, improvement in New York Heart Association class in the 12-month study. Furthermore,
in the 12-month study blood pressure and left ventricular length did not deteriorate, whereas there was
worsening of these parameters in the placebo population. This suggests that testosterone may possibly
retard progression of left ventricular dysfunction.
Testosterone replacement therapy and
cardiovascular risk factors
The major clinical indication for TRT is to improve the
symptoms of hypogonadism, which primarily include
sexual dysfunction. However, there have been several studies that have reported beneficial effects on
certain CV risk factors, which include central adiposity, total and low-density lipoprotein (LDL) cholesterol,
10
Heart Metab. (2015) 66:7-12
lipoprotein(a) (Lp[a]), and insulin resistance, as well
as suppressing serum levels of proinflammatory cytokines.4,5
Visceral adiposity, as assessed by waist circumference, waist-hip ratio, and computed tomography
(CT)/magnetic resonance imaging (MRI) scanning, in
hypogonadal men is significantly decreased by TRT.11
Furthermore, several trials have reported a reduction
in fat mass and an increase in lean mass supported
by a fall in serum leptin when this has been measured.
The corresponding rise in muscle bulk may explain
why most studies have not shown changes in body
mass index (BMI). A longer-term observational study
has shown a gradual improvement in waist circumference and BMI over a period of 3 years.23
TRT consistently lowers total cholesterol by 0.25 to
0.5 mmol/L.5 Some studies have demonstrated falls
in LDL cholesterol and/or triglycerides, whereas some
have not. The effect of TRT on high-density lipoprotein
(HDL) cholesterol is less clear, with small decreases,
no change, or increases. The explanation for these alterations in HDL are not clear, however commentators
have suggested that as a result of reverse cholesterol
transport, increased shuttling of cholesterol from lipid
laden tissues back to the liver may lead to the fall in
concentration. Further work needs to examine and exactly determine the biological and indeed clinical relevance, if any, of these phenomena. Lp(a) correlates
positively with CV risk and research has shown that
TRT significantly lowers levels of this lipoprotein. No
studies, however, have been performed to determine if
suppression of Lp(a) improves CV outcomes.
TRT does decrease insulin resistance in hypogonadal men with metabolic syndrome and/or type 2
diabetes.4,24 Insulin resistance is considered to be an
intermediate CV risk factor as it does lead to hyperglycemia, hypertension, dyslipidemia, as well as endothelial dysfunction and a proinflammatory serum
cytokine profile. TRT suppresses TNFα, IL-1β, and
IL-6, and raises IL-10, an antiatherogenic cytokine.25
Whether or not there is an overall benefit of TRT
on CV risk in men when replaced to the normal physiological range is unknown.
Testosterone replacement therapy and
cardiovascular safety
There has been some recent controversy over whether or not TRT increases the risk of adverse CV events
Heart Metab. (2015) 66:7-12
as a result of two retrospective studies26,27 and one
trial that used high doses of testosterone in elderly
men.28 Many clinical trials (including several randomized controlled trials), clinical use of TRT over more
than 70 years, and other meta-analyses have not unmasked any increased risk. Indeed a meta-analysis of
studies in men with metabolic syndrome and type 2
diabetes has shown reduced risk.29
Both retrospective trials have received heavy criticism due to flawed study design and analysis. The
Vigen et al study compared two groups; those receiving TRT and those who did not. There was a complicated statistical analysis using over 50 variables,
which changed a positive effect of TRT with lower CV
events to an adverse result. Furthermore, there was
no evidence that all patients were carefully diagnosed
with hypogonadism and, once on treatment, 17.6%
received only one prescription. The mean testosterone level on treatment in those who continued was
subtherapeutic. Later, the authors also admitted that
they had included a significant number of females in
their analysis. Comments and responses to the Vigen
et al paper are discussed in the Journal of the American Medical Association.30-35
The Finkle et al study using data on 55 000 testosterone prescriptions in California compared reporting of myocardial infarction in the first 3 months with
either the same patients in the 12 months prior to the
prescription or a cohort of men receiving phosphodiesterase type 5 (PDE5) inhibitors.27 They reported an
increased risk of myocardial infarction on TRT compared with the other group. No data were given on
whether hypogonadism was diagnosed before initiation of therapy or if testosterone levels had been
performed, nor testosterone levels on treatment. The
comparator groups were not appropriate. Use of nitrates associated with more severe CV disease are
contraindicated with PDE5 inhibitors, so the latter
group would potentially have been a healthier cohort
in respect to preexisting disease.
A recent systematic review and meta-analysis of
randomized placebo-controlled clinical trials (testosterone treated, n=3016; placebo, n=2747) did not
detect any increased risk of major adverse CV events
(MACE) in those men on TRT.29 Other meta-analyses
have been limited by not having a defined end point
of MACE and have used a wide definition of CV-related episodes.36 The US Food and Drug Administration
(FDA) have stated that “these studies do not provide
Jones
Testosterone and cardiovascular disease
conclusive evidence of increased risk associated with
the use of testosterone therapy.” Recently a large
study of 6355 testosterone treated men did not show
an increased risk of myocardial infarction.37
Many experts in the field have called for a large,
well-powered clinical trial to determine whether or
not TRT has adverse or beneficial effects on CV outcomes. This has now been recognized by the FDA.
Conclusion
Erectile dysfunction and testosterone deficiency are
independent biomarkers for the presence and severity of CV disease, metabolic syndrome, and type
2 diabetes. Each biomarker could potentially raise
awareness as an early marker of atherosclerosis. Hypogonadism requires careful diagnosis preferably by
an experienced clinician in this area. Quality of life is
very important to many people and TRT may achieve
an improvement. The decision to treat with TRT
should be discussed with patients with regards to
benefit and risks. Only a longer-term trial will provide
answers to whether or not there is an effect, positive
or negative, on patients. L
REFERENCES
1.Jackson G, Boon N, Eardley I, et al. Erectile dysfunction and
coronary artery disease prediction: evidence-based guidance
and consensus. Int J Clin Pract. 2010;64(7):848-857.
2.
Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone
therapy in men with androgen deficiency syndromes: an
Endocrine Society clinical practice guideline. J Clin Endocrinol
Metab. 2010;95(6):2536-2559.
3.Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment and monitoring of late-onset hypogonadism in males. Int
J Androl. 2009;32(1):1-10.
4.Wang C, Jackson G, Jones TH, et al. Low testosterone associated with obesity and the metabolic syndrome contributes to
sexual dysfunction snd cardiovascular disease risk in men with
type 2 diabetes. Diabetes Care. 2011;34:1669-1685.
5.Jones TH. Testosterone deficiency: a risk factor for cardiovascular disease? Trends Endocrinol Metab. 2010;21(8):496-503.
6.Muraleedharan V, Jones TH. Testosterone and mortality. Clin
Endocrinol. 2014;81:477-487.
7.Hyde Z, Norman PE, Flicker L, et al. Low free testosterone
predicts mortality from cardiovascular disease but not other
causes: the health in men study. J Clin Endocrinol Metab.
2012;97:179-189.
8.Yeap BB, Alfonso H, Chubb SAP, et al. In older men an optimal
plasma testosterone is associated with reduced all-cause mortality and higher dihydrotestosterone with reduced ischemic
heart disease mortality, while estradiol levels do not predict
mortality. J Clin Endocrinol Metab. 2014;99:E9-E18.
9.Ohlsson C, Barrett-Connor E, Bhasin S, et al. High serum
testosterone is associated with reduced risk of cardiovascular
events in elderly men. The MrOS (Osteoporotic Fractures in Men)
study in Sweden. J Am Coll Cardiol. 2011;58(16):1674-1681.
11
Jones
Testosterone and cardiovascular disease
10.
Soisson V, Brailly-Tabard S, Helmer C, et al. A J-shaped
association between plasma testosterone and risk of ischemic
arterial event in elderly men: The French 3C cohort study.
Maturitas. 2013;75:282-288.
11.
Kelly DM, Jones TH. Testosterone: a vascular hormone in
health and disease. J Endocrinol. 2013;217:R47-R71.
12.Malkin CJ, Pugh PJ, Morris PD, Asif S, Jones TH, Channer KS.
Low serum testosterone and increased mortality in men with
coronary heart disease. Heart. 2010;96(22):1821-1825.
13.Muraleedharan V, Marsh H, Kapoor D, Channer KS, Jones TH.
Testosterone deficiency is associated with increased mortality
and testosterone replacement improves survival in men with
type 2 diabetes. Eur J Endocrinol. 2013;169:725-733.
14.Levine GN, D’Amico AV, Berger P, et al. Androgen-deprivation
therapy in prostate cancer and cardiovascular risk. A science
advisory from the American Heart Association, American
Cancer Society, and American Urological Association
Endorsed by the American Society for Radiation Oncology.
Circulation. 2010;121:833-840.
15.Muller M, van den Beld AW, Bots ML, Grobbe DE, Lamberts
SW, van der Schouw YT. Endogenous sex hormones and
progression of atherosclerosis in elderly men. Circulation.
2004;109:2074-2079.
16.Wu FC, Tajar A, Pye SR, et al. Hypothalamic-pituitary-testicular
axis disruptions in older men are differentially linked to age and
modifiable risk factors: the European Male Aging Study. J Clin
Endocrinol Metab. 2008;93:2737-2745.
17.Rao PM, Kelly DM, Jones TH. Testosterone and insulin resistance in the metabolic syndrome and T2DM in men. Nat Rev
Endocrinol. 2013;9:479-493.
18.Kelly DM, Jones TH. Testosterone: a metabolic hormone in
health and disease. J Endocrinol. 2013;217:R25-R45.
19.English KM, Steeds RP, Jones TH, Diver MJ, Channer KS.
Low-dose transdermal testosterone therapy improves angina
threshold in men with chronic stable angina: A randomized, double-blind, placebo-controlled study. Circulation.
2000;102:1906-1911.
20.
Webb CM, McNeill JG, Hayward CS, de Zeigler D,
Collins P. Effects of testosterone on coronary vasomotor
regulation in men with coronary heart disease. Circulation.
1999;100:1690-1696.
21.Malkin CJ, Pugh PJ, West JN, van Beek EJ, Jones TH, Channer
KS. Testosterone therapy in men with moderate severity heart
failure: a double-blind randomized placebo controlled trial. Eur
Heart J. 2006;27(1):57-64.
22.Caminittti G, Volterrani M, Iellamo F, et al. Effect of long-acting
testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex
sensitivity in elderly patients with chronic heart failure a
12
Heart Metab. (2015) 66:7-12
double-blind, placebo-controlled, randomized study. JACC.
2009;54:919-927.
23. Saad F, Haider A, Doros G, Traish A. Long-term treatment of
hypogonadal men with testosterone produces substantial and
sustained weight loss. Obesity. 2013;21:1975-1981.
24.Jones TH, Arver S, Behre HM, et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or
metabolic syndrome (the TIMES2 Study). Diabetes Care.
2011;34(4):828-837.
25.Malkin CJ, Pugh J, Jones RD, Kapoor D, Channer KS, Jones
TH. The effect of testosterone replacement on endogenous
inflammatory cytokines and lipid profiles in hypogonadal men.
J Clin Endocrinol Metab. 2004;89:3313-3318.
26.
Vigen R, O’Donnell CI, Baron A, et al. Association of
testosterone therapy with mortality, myocardial infarction,
and stroke in men with low testosterone levels. JAMA.
2013;310:1829-1836.
27.Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of
non-fatal myocardial infarction following testosterone therapy
prescription in men. PLoS One. 2014;9:1-7.
28.Basaria S, Coviello AD, Travison TG, et al. Adverse events
associated with testosterone administration. N Engl J Med.
2010;363(2):109-122.
29.
Corona G, Maseroli E, Rastrelli G, et al. Cardiovascular
risk associated with testosterone-boosting medications: a
systematic review and meta-analysis. Expert Opin Drug Saf.
2014;13(10):1327-1351.
30.
Morgentaler A, Trais A, Kacker R. Deaths and cardiovascular events in men receiving testosterone. JAMA.
2014;311(9):961-962.
31. Jones TH, Channer KS. Deaths and cardiovascular events in
men receiving testosterone. JAMA. 2014;311(9):962-963.
32. Katz J, Nadelberg R. Deaths and cardiovascular events in men
receiving testosterone. JAMA. 2014;311(9):963.
33. Riche DM, Baker WL, Koch CA. Deaths and cardiovascular events in men receiving testosterone. JAMA.
2014;311(9):963-964
34. Dhindsa S, Batra M, Dandona P. Deaths and cardiovascular
events in men receiving testosterone. JAMA. 2014;311(9):964.
35. Ho PM, Baron AE, Wierman ME. Deaths and cardiovascular events in men receiving testosterone. JAMA.
2014;311(9):964-965.
36.Xu L, Freeman G, Cowling BJ, Schooling CM. Testosterone
therapy and cardiovascular events among men: a systematic
review and meta-analysis of placebo-controlled randomized
trials. BMC Med. 2013;11:108.
37. Baillargeon J, Urban RJ, Kuo YF, et al. Risk of myocardial
infarction in older men receiving testosterone therapy. Ann
Pharmacol. 2014;48:1138-1144.
Original Article
Heart Metab. (2015) 66:13-18
Measuring myocardial salvage:
hormone cardioprotection
Derek J. Hausenloy, MD, PhD
The Hatter Cardiovascular Institute, Institute of Cardiovascular Science, University College London, London
WC1E 6HX, UK; The National Institute of Health Research University College London Hospitals Biomedical
Research Centre, London W1T 7DN, UK; National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169609, Singapore; Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore, Singapore 169857, Singapore
Correspondence: Prof Derek J. Hausenloy, The Hatter Cardiovascular Institute, University College London,
67 Chenies Mews, London, WC1E 6HX, United Kingdom
E-mail: d.hausenloy@ucl.ac.uk
Abstract
Ischemic heart disease (IHD) is the leading cause of death and disability worldwide. For patients presenting
with an acute ST-segment elevation myocardial infarction (STEMI) the treatment of choice is timely reperfusion by primary percutaneous coronary intervention (PPCI). However, the process of reperfusion can in itself
independently induce myocardial injury and cardiomyocyte death—a phenomenon that has been termed
“myocardial reperfusion injury” and that contributes to up to 50% of the final myocardial infarction (MI) size.
Therefore, novel cardioprotective therapies are required to protect the heart against myocardial reperfusion
injury in order to reduce MI size, preserve myocardial function, and prevent the onset of heart failure. In
this regard, a number of hormones have been reported in preclinical animal studies and early clinical trials
to reduce MI size when administered at the time of reperfusion. Assessing the cardioprotective efficacy of
a novel therapy requires the measurement of the area at risk (AAR) of MI and MI size, as this allows the
calculation of myocardial salvage, which is a more sensitive measure of cardioprotection than absolute MI
size reduction as it takes into account the AAR. Cardiac magnetic resonance imaging (MRI) is an important
imaging modality for assessing myocardial salvage in reperfused STEMI patients. The recent availability
of hybrid simultaneous positron emission tomography (PET)/MRI will allow one to investigate the effects
of novel cardioprotective therapies in the reperfused heart on cardiac metabolism, fibrosis, angiogenesis,
apoptosis, and inflammation, providing new insights into the pathophysiology of acute MI and the post-MI
remodeled heart. In this article, we review the emerging role of cardiac MRI to assess myocardial salvage of
novel cardioprotective therapies such as hormones. L Heart Metab. 2015;66:13-18
Keywords: acute myocardial infarction; cardiac MRI; cardioprotection; myocardial reperfusion injury;
myocardial salvage; PET/MRI
I
schemic heart disease (IHD) is the leading cause
of death and disability worldwide, one major
manifestation of which is an acute ST-segment
elevation myocardial infarction (STEMI). For these
patients, the treatment of choice is timely myocardial reperfusion using primary percutaneous
coronary intervention (PPCI). However, the process
of reperfusion can in itself induce cardiomyocyte
death—a phenomenon that has been termed
“myocardial reperfusion injury.”1 There is currently no
effective therapy for preventing myocardial reperfusion injury, making it a neglected therapeutic target.
Furthermore, although the mortality from an acute
STEMI appears to be decreasing, the incidence of
13
Hausenloy Measuring myocardial salvage: hormone cardioprotection
Abbreviations
AAR: area at risk; IHD: ischemic heart disease; MRI:
magnetic resonance imaging; MI: myocardial infarction;
PET: positron emission tomography; PPCI: primary percutaneous coronary intervention; STEMI: ST-segment
elevation myocardial infarction
patients going on to develop heart failure is actually
increasing.2 Therefore, novel therapies are required
to prevent myocardial reperfusion injury, reduce
myocardial infarction (MI) size, and preserve cardiac
function, thereby preventing the onset of heart
failure.3,4 In this respect, experimental animal and
early clinical studies have reported beneficial effects
in terms of myocardial salvage with several different
hormones administered at the time of myocardial
reperfusion.5-7 The ability to assess the cardioprotective efficacy of novel therapies requires the in
vivo measurement of the area of myocardium at risk
of MI (the area at risk or AAR) and MI size. In this
regard, T2-weighted cardiac magnetic resonance
imaging (MRI) can quantify the size of the AAR by
detecting areas of myocardial edema, an approach
that has been used to measure myocardial salvage
in clinical cardioprotection studies. In this article, we
highlight myocardial reperfusion injury as a neglected
therapeutic target, review the therapeutic potential
of hormones as a novel cardioprotective therapy for
preventing reperfusion injury, and explore the role of
cardiac MRI for measuring myocardial salvage.
Heart Metab. (2015) 66:13-18
death had been fiercely contested in the past. This
was due to an inability to directly demonstrate reperfusion inducing the death of cardiomyocytes that
were viable at the end of ischemia.9,10 However, the
fact that therapeutic interventions have been reported in both animal and clinical studies to reduce MI
size when administered solely at the time of reperfusion has been accepted as indirect evidence for the
existence of myocardial reperfusion injury. Examples
of therapies that have been reported to reduce MI
size when given at reperfusion include a variety of
different hormones.
Hormones as novel cardioprotective therapies
A large number of hormones have been found in
animal MI studies to prevent myocardial reperfusion
injury and reduce MI size when exogenously administered at the time of myocardial reperfusion (Figure
2).7 These hormones mediate their cardioprotective
effect via a number of different cell-surface receptors
(including serine threonine, tyrosine kinase, G-protein
coupled, natriuretic, and cytokine receptors), which
activate a wide variety of intracellular cardioprotective
signaling cascades (including the cyclic guanosine
monophosphate–protein kinase G [cGMP-PKG],11
the reperfusion injury salvage kinase [RISK],5,6 and
the survivor activating factor enhancement [SAFE]12-14
pathways), many of which terminate on mitochondria,
MI size
Expected
MI size
in absence
of PPCI
Myocardial reperfusion injury: a neglected
therapeutic target
“Myocardial reperfusion injury” describes the myocardial injury and cardiomyocyte death that occurs
on reperfusing ischemic myocardium.1 In STEMI
patients reperfused by PPCI, the presence of myocardial reperfusion injury mitigates the benefits of
reperfusion in terms of myocardial salvage, contributing to up to 50% of the final MI size (Figure 1).1,8
There are four types of myocardial reperfusion injury, the first two of which are reversible and include
reperfusion arrhythmias and myocardial stunning.
The second two, which are irreversible and induce
cardiomyocyte death, are microvascular obstruction
and lethal reperfusion injury. The existence of lethal
reperfusion injury as an independent mediator of cell
14
MI size increase due
to reperfusion injury
Ischemia (0 to 12 hrs)
Chest pain
onset
Reperfusion (0 to 24 hrs)
Actual
MI size
after PPCI
Expected
MI size
for duration
of ischemia
Time
PPCI
Fig. 1 Myocardial reperfusion injury as a neglected therapeutic
target. This figure illustrates the effect of myocardial reperfusion
injury on myocardial infarction (MI) size in ST-segment elevation MI
(STEMI) patients presenting with chest pain and treated by primary
percutaneous coronary intervention (PPCI). Myocardial reperfusion
injury increases the MI size, such that actual MI size is larger than
expected for the duration of acute myocardial ischemia.
Modified from reference 8: Hausenloy DJ, Yellon DM. J Clin Invest.
2013;123(1):92-100. © 2013, American Society for Clinical Investigation.
Heart Metab. (2015) 66:13-18
an important target of cardioprotection (Figure 2).7
Only an overview of hormone cardioprotection can be
provided in this section; for a more comprehensive
account the reader is directed to extensive reviews of
this topic.5-7,12,13,15 A selected number of these cardioprotective hormones including atrial natriuretic peptide (ANP), insulin (glucose-insulin-potassium [GIK]
therapy), and exenatide (a glucagon-like peptide
1 [GLP-1] analogue) have been translated into the
clinical setting and have been reported to reduce MI
size when administered at the time of reperfusion in
STEMI patients receiving PPCI (Table I).16-21 Ongoing
clinical cardioprotection STEMI studies are currently
investigating the hormone melatonin and a number of
hormones (including erythropoietin16) that have failed
to have any beneficial effects in the clinical setting despite reduced MI size in animal studies (Table I).16-21
The reason for the failed translation of cardioprotec-
Hausenloy
Measuring myocardial salvage: hormone cardioprotection
tive therapies from bench to bedside has been extensively reviewed.4,22
The ability to assess the cardioprotective efficacy
of novel therapies administered at the time of myocardial reperfusion to prevent reperfusion injury requires the assessment of myocardial salvage, as this
is a more sensitive measure of cardioprotection than
absolute MI size reduction. Cardiac MRI has recently
been shown to quantify myocardial salvage in clinical
cardioprotection studies.
Assessing myocardial salvage using cardiac MRI
Following an acute coronary artery occlusion, the
amount of myocardium at risk of infarction (or AAR)
is a major determinant of MI size. Therefore, it is essential to take this into account when assessing the
ability of a novel cardioprotective therapy to limit MI
Fig. 2 Signaling pathways underlying hormone cardioprotection at reperfusion. Simplified scheme illustrating the intracellular signaling
pathways underlying the cardioprotection elicited by hormones investigated in animal studies and translated into the clinical setting (*).
Exogenously administered hormones will bind to their respective receptor on the cardiomyocyte cell surface, activating a variety of signaling
cascades, including the reperfusion injury salvage kinase (RISK; Raf-Mek1/2-Erk1/2 and PI3K-Akt), survivor activating factor enhancement (SAFE; JAK-STAT), and cyclic guanosine monophosphate–protein kinase G (cGMP-PKG) pathways, which then terminate on either
mitochondria (where mitochondrial permeability transition pore [mPTP] opening is inhibited) and the sarcoplasmic reticulum (where sarco/
endoplasmic reticulum Ca2+-ATPase [SERCA] is inhibited), thereby inducing cardioprotection.
Abbreviations: Akt, protein kinase B; ANP, atrial natriuretic peptide; BAD, Bcl-2-associated death promoter; eNOS, endothelial nitric oxide synthase; GF, growth
factor; GIK, glucose-insulin-potassium therapy; GLP-1, glucagon-like peptide 1; GSK, glycogen synthase kinase; JAK, janus kinase; KATP, adenosine triphosphate–
sensitive potassium channel; NO, nitric oxide; PKC, protein kinase C; ROS, reactive oxygen species; sGC, soluble guanylyl cyclase; STAT, signal transducer and
activator of transcription. Modified from reference 7: Hausenloy DJ, Yellon DM. Cardiovasc Res. 2009;83(2):179-194. © 2014, Oxford University Press.
15
Hausenloy Measuring myocardial salvage: hormone cardioprotection
size. This is especially important in patients presenting with an acute STEMI, in whom the size of the AAR
can vary from 5% to 40% of the left ventricular (LV)
volume from patient to patient depending on the site
of the acute coronary artery occlusion. Myocardial
salvage, which takes into account the AAR, is a more
sensitive measure of cardioprotective efficacy than
absolute reduction in MI size, meaning that a smaller
number of patients is required in clinical trials investigating novel cardioprotective therapies. Myocardial
salvage, which is calculated by subtracting MI size
from the AAR, represents the amount of myocardium
salvaged by the novel cardioprotective therapy (Figure 3). When normalized to the AAR, the myocardial
salvage index is the proportion of the AAR that has
been salvaged by the novel cardioprotective therapy
(Figure 3).
The ability to assess myocardial salvage in the
clinical setting requires a reliable and robust in vivo
measure of the AAR. In this regard, cardiac MRI has
emerged as a potential approach for achieving this.
Cardiac MRI has recently been reported to be beneficial in patients presenting with an acute coronary
syndrome, as it can measure LV volumes and function, detect regional wall motion abnormalities, and
exclude LV thrombus.23,24 Furthermore, a unique
characteristic of cardiac MRI is its ability to tissue
characterize the different components of the infarct.
For reperfused STEMI patients, cardiac MRI can be
Heart Metab. (2015) 66:13-18
safely performed in the first week to quantify both the
AAR and the MI size, thereby enabling the calculation
of myocardial salvage. Cardiac MRI performed in the
first week of hospital admission has been shown to
retrospectively quantify the AAR in STEMI patients.
This relies on the ability of T2-weighted cardiac MRI
to detect myocardial edema, a marker of reversible
myocardial ischemic reperfusion injury within the AAR
(Figure 3).25-27 There have, however, been several is-
Fig. 3 Measuring myocardial salvage by cardiac magnetic resonance imaging (MRI). Myocardial salvage, calculated by the area
at risk (AAR) minus the myocardial infarction (MI) size, is a sensitive
measure of cardioprotection that can be measured by cardiac MRI
as shown in this representative short-axis left ventricle (LV) slice.
The area of increased T2 values corresponds to the AAR (left) and
the area of late gadolinium enhancement (right) depicts the MI. In
this case, the myocardial salvage (percentage of LV area salvaged
by the novel cardioprotective therapy) is 22% (35% to 13%), and
the myocardial salvage index (proportion of AAR salvaged by the
novel cardioprotective therapy) equals 0.63 (22%/35%).
sues with using T2-weighted cardiac MRI to measure the AAR in reperfused STEMI patients including
imaging artifacts, low signal-to-noise ratio, and the
cardioprotective therapy reducing the circumferen-
Hormone
n
Treatment protocol
Results
Notes
Erythropoietin (EPO)16
51
High dose EPO (2 x 50 000 IU
by IV bolus—one prior to PPCI
and a further dose 24 hours
later)
Failure to reduce MI size or improve
myocardial salvage; increased
incidence of MVO
A number of large studies have
confirmed that EPO is not
beneficial; some studies find it
may be harmful
Insulin (GIK therapy)17
357
12-hour IV GIK infusion
administered in the ambulance
Reduced MI size and less inhospital mortality and cardiac arrest
Inconclusive results in previous
clinical studies with GIK therapy
Atrial natriuretic peptide
(ANP)18
569
72-hour IV infusion of
Carperitide (an ANP analogue)
Reduced MI size by 15% (72 hour
AUC CK) and 2.0 % increase in
LVEF
Glucagon-like peptide
(GLP-1)19
21
72-hour IV infusion of GLP-1
Increased LVEF and less regional
wall motion abnormalities
Glucagon-like peptide
(GLP-1) analogue20
107
6-hour IV infusion of exenatide
(a GLP-1 analogue) started 15
minutes “prior” to PPCI
Increased MSI (0.62 to 0.71) at 90
days by cardiac MRI
Reduced MI size by 23% of AAR at
90 days by cardiac MRI
Melatonin21
40
Melatonin Intracoronary 10 mL
0.1 mg/mL and intravenously
49 mg
Currently recruiting primary end
point MI size and myocardial
salvage on cardiac MRI at 4 days
Only patients with severe LV
impairment were included
Table I Hormone cardioprotection at reperfusion in ST-segment elevation myocardial infarction (STEMI) patients.
Abbreviations: AUC, area under the curve; CK, creatine kinase; GIK, glucose-insulin-potassium; IU, international units; IV, intravenous; LV, left ventricle; LVEF,
left ventricular ejection fraction; MI, myocardial infarction; MRI, magnetic resonance imaging; MSI, myocardial salvage index; MVO, microvascular obstruction; n,
number; PPCI, primary percutaneous coronary intervention. Data from references 16-21.
16
Heart Metab. (2015) 66:13-18
tial extent of myocardial edema (and therefore the
measured AAR).27,28 The very recent availability of
hybrid simultaneous PET/MRI provides the opportunity to simultaneous relate changes in cardiac metabolism (myocardial 18F-fluorodeoxyglucose [18FDG]
uptake) to constituents of the reperfused myocardial
infarction. It allows the PET and MRI images to be
acquired simultaneously with the patient in the same
position on the scanner table, facilitating accurate
coregistration of fused images, and precise voxelby-voxel comparison images of cardiac anatomy
and metabolism.29-32 Using this technique, we have
recently demonstrated impaired glucose metabolism
as evidenced by reduced myocardial 18FDG uptake
within the AAR that corresponds to that delineated by
T2-mapping cardiac MRI imaging (unpublished data,
Figures 4 and 5). The relationship between the colocalized areas of myocardium with impaired glucose
metabolism (imaged by PET) and edema (imaged by
T2 mapping) in reversibly injured myocardium within
Hausenloy
Measuring myocardial salvage: hormone cardioprotection
the AAR is unclear and needs further investigation.
With the availability of novel tracers for detecting hypoxia, apoptosis, fibrosis, inflammation, and angiogenesis, hybrid PET/MRI of the heart should provide
unique insights into the pathophysiology of acute MI
and subsequent post-MI LV remodelling. This should
result in the identification of novel cellular and molecular targets for treating MI and heart failure.
Summary and conclusion
Despite optimal therapy, the morbidity and mortality in patients presenting with a STEMI remains significant. One neglected therapeutic target for which
there is currently no effective therapy is “myocardial reperfusion injury,” which refers to the cardiomyocyte death that occurs on reperfusing acutely
ischemic myocardium and that has been reported
to reduce MI size by 50%. As such, novel cardioprotective therapies are required to target myocardial
reperfusion injury to limit MI size, preserve cardiac
function, and prevent the onset of heart failure. In
this regard, certain hormones have been reported
in animal studies and initial clinical trials to reduce
MI size when administered at the onset of reperfusion through the activation of established intracellular cardioprotective signaling pathways. Cardiac
MRI has emerged as a potential noninvasive imaging
1
2
3
4
LGE-CMR
18
FDG-PET
T2 mapping
CMR
Fusion
Fig. 4 Hybrid simultaneous positron emission tomography/
magnetic resonance imaging (PET/MRI) of left anterior descending (LAD) coronary artery myocardial infarction (MI). This figure
shows representative long-axis fused 18F-fluorodeoxyglucose
(18FDG)-PET/MRI images (left-sided panels) and late gadolinium
enhancement (LGE; right-sided panels; white arrows) cardiac MRI
images of a patient presenting with a transmural MI (containing
microvascular obstruction; yellow arrows) within the LAD coronary
artery territory. There is an area of markedly reduced myocardial
uptake of glucose, which spatially matches the distribution of LGE
(left-sided panels; red arrows).
Fig. 5 Positron emission tomography/magnetic resonance
imaging (PET/MRI) of transmural and subendocardial myocardial
infarction (MI).This figure shows representative short-axis images
of late gadolinium enhancement (LGE) cardiac MRI (showing
MI), 18F-fluorodeoxyglucose
(18FDG)–PET (showing reduced
myocardial FDG uptake in areas of MI and the area at risk [AAR]),
T2-mapping MRI (increased T2 values within the AAR), and fused
FDG-PET:LGE MRI in two patients with subendocardial MI ([1] and
[2], with significant myocardial salvage) and two with transmural MI
([3] and [4], with minimal myocardial salvage).
17
Hausenloy Measuring myocardial salvage: hormone cardioprotection
technique for quantifying myocardial salvage, permitting the assessment of the cardioprotective efficacy of novel therapies targeted against reperfusion
injury. The recent availability of hybrid simultaneous
PET/MRI should provide important insights into the
pathophysiology of acute MI and post-MI remodeling, enabling the identification of novel therapeutic
targets for cardioprotection. L
The author would like to thank Dr Steven White, Dr Heeraj Bulluck,
Dr Leon Menezes, Professor Ashley Groves, all staff and patients
at the Hatter Cardiovascular Institute and the Heart Hospital, and
the University College London Department of Nuclear Medicine. REFERENCES
1.Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl
J Med. 2007;357(11):1121-1135.
2.
Chen J, Hsieh AF, Dharmarajan K, Masoudi FA, Krumholz
HM. National trends in heart failure hospitalization after acute
myocardial infarction for Medicare beneficiaries: 1998-2010.
Circulation. 2013;128(24):2577-2584.
3.Ovize M, Baxter GF, Di Lisa F, et al. Postconditioning and protection from reperfusion injury: where do we stand? Position
paper from the Working Group of Cellular Biology of the
Heart of the European Society of Cardiology. Cardiovasc Res.
2010;87(3):406-423.
4.Hausenloy DJ, Erik BH, Condorelli G, et al. Translating cardioprotection for patient benefit: position paper from the Working
Group of Cellular Biology of the Heart of the European Society
of Cardiology. Cardiovasc Res. 2013;98(1):7-27.
5.Hausenloy DJ, Yellon DM. New directions for protecting the
heart against ischaemia-reperfusion injury: targeting the
Reperfusion Injury Salvage Kinase (RISK)-pathway. Cardiovasc
Res. 2004;61(3):448-460.
6.Hausenloy DJ, Yellon DM. Reperfusion injury salvage kinase
signalling: taking a RISK for cardioprotection. Heart Fail Rev.
2007;12(3-4):217-234.
7.
Hausenloy DJ, Yellon DM. Cardioprotective growth factors.
Cardiovasc Res. 2009;83(2):179-194.
8.Hausenloy DJ, Yellon DM. Myocardial ischemia-reperfusion injury:
a neglected therapeutic target. J Clin Invest. 2013;123(1):92-100.
9.Piper HM, Garcia-Dorado D, Ovize M. A fresh look at reperfusion injury. Cardiovasc Res. 1998;38(2):291-300.
10.
Piper HM, Garcia-Dorado D. Prime causes of rapid cardiomyocyte death during reperfusion. Ann Thorac Surg.
1999;68(5):1913-1919.
11.
Garcia-Dorado D, Agullo L, Sartorio CL, Ruiz-Meana M.
Myocardial protection against reperfusion injury: the cGMP
pathway. Thromb Haemost. 2009;101(4):635-642.
12.Lacerda L, Somers S, Opie LH, Lecour S. Ischaemic postconditioning protects against reperfusion injury via the SAFE
pathway. Cardiovasc Res. 2009;84(2):201-218.
13.Lecour S. Activation of the protective Survivor Activating Factor
Enhancement (SAFE) pathway against reperfusion injury:
Does it go beyond the RISK pathway? J Mol Cell Cardiol.
2009;47(1):32-40.
14.Lecour S. Multiple protective pathways against reperfusion injury: a
SAFE path without Aktion? J Mol Cell Cardiol. 2009;46(5):607-609.
15.
Hausenloy DJ, Lecour S, Yellon DM. RISK and SAFE
pro-survival signalling pathways in ischaemic postconditioning: Two sides of the same coin. Antioxid Redox Signal.
2011;14(5):893-907.
18
Heart Metab. (2015) 66:13-18
16.Ludman AJ, Yellon DM, Hasleton J, et al. Effect of erythropoietin as an adjunct to primary percutaneous coronary
intervention: a randomised controlled clinical trial. Heart.
2011;97(19):1560-1565.
17.Selker HP, Beshansky JR, Sheehan PR, et al. Out-of-hospital
administration of intravenous glucose-insulin-potassium
in patients with suspected acute coronary syndromes:
the IMMEDIATE randomized controlled trial. JAMA.
2012;307(18):1925-1933.
18.Kitakaze M, Asakura M, Kim J, et al. Human atrial natriuretic
peptide and nicorandil as adjuncts to reperfusion treatment for
acute myocardial infarction (J-WIND): two randomised trials.
Lancet. 2007;370(9597):1483-1493.
19.Nikolaidis LA, Mankad S, Sokos GG, et al. Effects of glucagonlike peptide-1 in patients with acute myocardial infarction
and left ventricular dysfunction after successful reperfusion.
Circulation. 2004;109(8):962-965.
20.Lonborg J, Vejlstrup N, Kelbaek H, et al. Exenatide reduces
reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J. 2012;33(12):1491-1499.
21.
ClinicalTrials.gov. The Effect of Melatonin on Ischemiareperfusion Injury Following Acute Myocardial Infarction.
ClinicalTrials.gov Identifier: NCT01172171. https://clinicaltrials.
gov/ct2/show/NCT01172171?term=NCT01172171&rank=1.
Accessed October 1, 2014.
22.
Schwartz LL, Kloner RA, Arai AE, et al. New horizons in
cardioprotection: recommendations from the 2010 national
heart, lung, and blood institute workshop. Circulation.
2011;124(10):1172-1179.
23.Lockie T, Nagel E, Redwood S, Plein S. Use of cardiovascular
magnetic resonance imaging in acute coronary syndromes.
Circulation. 2009;119(12):1671-1681.
24.Kim HW, Farzaneh-Far A, Kim RJ. Cardiovascular magnetic
resonance in patients with myocardial infarction: current and
emerging applications. J Am Coll Cardiol. 2009;55(1):1-16.
25.Aletras AH, Tilak GS, Natanzon A, et al. Retrospective determination of the area at risk for reperfused acute myocardial
infarction with T2-weighted cardiac magnetic resonance
imaging: histopathological and displacement encoding with
stimulated echoes (DENSE) functional validations. Circulation.
2006;113(15):1865-1870.
26.
Giri S, Chung YC, Merchant A, et al. T2 quantification for
improved detection of myocardial edema. J Cardiovasc Magn
Reson. 2009;11(1):56.
27.White SK, Frohlich GM, Sado DM, et al. Remote ischemic conditioning reduces myocardial infarct size and edema in patients
with ST-segment elevation myocardial infarction. JACC
Cardiovasc Interv. 2014;pii:S1936-8798(14)01073-01075.
28.
Thuny F, Lairez O, Roubille F, et al. Post-conditioning
reduces infarct size and edema in patients with ST-segment
elevation myocardial infarction. J Am Coll Cardiol.
2012;59(24):2175-2181.
29.
Ibrahim T, Nekolla SG, Langwieser N, et al. Simultaneous
positron emission tomography/magnetic resonance imaging
identifies sustained regional abnormalities in cardiac metabolism and function in stress-induced transient midventricular
ballooning syndrome: a variant of Takotsubo cardiomyopathy.
Circulation. 2012;126(21):e324-e326.
30.Schlosser T, Nensa F, Mahabadi AA, Poeppel TD. Hybrid MRI/
PET of the heart: a new complementary imaging technique
for simultaneous acquisition of MRI and PET data. Heart.
2013;99(5):351-352.
31.Nensa F, Poeppel TD, Beiderwellen K, et al. Hybrid PET/MR
imaging of the heart: feasibility and initial results. Radiology.
2013;268(2):366-373.
32.Rischpler C, Nekolla SG, Dregely I, Schwaiger M. Hybrid PET/
MR imaging of the heart: potential, initial experiences, and
future prospects. J Nucl Med. 2013;54(3):402-415.
Original Article
Heart Metab. (2015) 66:19-23
Testosterone and the heart
Christopher C. K. Ho, MD, MS, MFSTEd, FICS, FRCSEd, FRCS, FECSM1;
Hui Meng Tan, MBBS, FRCSEd, FRCS2,3
1
Department of Surgery, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia;
2
Department of Primary Care, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia;
3
Department of Urology, Sime Darby Medical Centre, Subang Jaya , Petaling Jaya, Malaysia
Correspondence: Tan Hui Meng, Department of Urology, Sime Darby Medical Centre,
Subang Jaya, Petaling Jaya, Malaysia
E-mail: perandro@hotmail.com
Abstract
Testosterone has generated a lot of interest and controversies lately. There are epidemiological studies
showing the correlation of low testosterone level with poor health in men. Low testosterone predicts
an increase in all-cause mortality. Testosterone replacement therapy (TRT) has been shown to improve
mortality in men with testosterone deficiency. Normalization of testosterone levels has been shown to be
beneficial to the heart. Besides the direct effect on the heart, TRT has also been shown to have a positive
effect on the metabolic parameters (metabolic syndrome) that indirectly affect the heart. L Heart Metab.
2015;66:19-23
Keywords: cardiovascular; metabolic syndrome; testosterone
T
estosterone levels in men have been shown
to decrease gradually with age. This decline
is about 2% per year, but in healthier men,
the decline is attenuated. The exact prevalence of
testosterone deficiency is controversial. In a study
involving more than 10 000 men, 80% were found
to have symptoms of testosterone deficiency.1 In
another study done in the primary care setting, where
a total of 2162 men >45 years old were sampled,
the prevalence of testosterone levels of less than
300 ng/dL (8.4 nmol/L) was 38.7%.2 In the US, less
than 10% of men with low testosterone received
testosterone replacement therapy (TRT). A total of
50% of older men with type 2 diabetes mellitus have
testosterone deficiency. As a consequence, in the
US where the prevalence of type 2 diabetes mellitus
is expected to increase over the next 20 years, the
health impact of testosterone deficiency syndrome
will cost the US economy up to 500 billion US
dollars.3
The rise in the usage of TRT has generated a lot of
interests and controversies. Many studies have been
done and the role of testosterone and its effect on the
cardiovascular system is a hot issue at the moment.
This review aims to address some of these issues.
Testosterone level and its association with the heart
There are some epidemiological studies that have
shown the correlation between testosterone and
cardiovascular disease. In over 40 epidemiological studies conducted so far, no one has found any
association between high testosterone levels and
cardiovascular disease. In contrast, many found an
association between low testosterone levels and cardiovascular disease. These include studies on carotid
artery atheroma and peripheral arterial disease.
Seventeen prospective cohort or nested casecontrolled studies have also examined the relationship between testosterone levels and cardiovascular
19
Ho and Tan
Testosterone and the heart
Abbreviations
BMI: body mass index; HDL: high-density lipoprotein;
SHBG: sex hormone–binding globulin; TRT: testosterone replacement therapy
morbidity and mortality. In ten of these studies, there
was no correlation between baseline testosterone
levels and subsequent development of fatal or nonfatal coronary heart disease, cerebrovascular disease, or heart failure after adjustment for confounders, during observation periods of 5 to 31 years.
Weak correlations of high androgen levels with cardiovascular mortality were observed in two studies.
Conversely, two studies reported significant correlations between low baseline testosterone levels and
cardiovascular deaths, and two others between low
baseline testosterone and progression of carotid
artery intima-media thickness, or between low testosterone and an increased incidence of stroke or
transient ischemic events. However, two other prospective studies were unable to confirm the correlations with intima-media thickness progression, and
with an increased risk of stroke. Lastly, the Caerphilly study found a positive association of the cortisol/testosterone ratio with chronic heart disease
incidence and mortality.4-7
Recent evidence has proven that men with lower
levels of testosterone are more prone to developing
coronary artery disease.8 This was shown after only
taking into account bioavailable testosterone levels,
as compared with older studies that did not do this.
Bioavailable testosterone includes both free testosterone and testosterone bound loosely to albumin.
Testosterone, which is bound to sex hormone–
binding globulin (SHBG), is biologically inactive.
There is also evidence that the lower the levels of
testosterone, the more severe the degree of coronary artery disease.9 This could be due to its effect
on the carotid intima-media thickness. Various studies have shown the inverse relationship between
endogenous testosterone levels and intima-media
thickness of the carotid arteries, abdominal aorta,
and thoracic aorta.10 This suggests that those with
low testosterone levels are more prone to developing atherosclerosis.
Besides coronary artery disease, testosterone levels have also been studied in congestive heart failure.
Studies have shown that men with congestive heart
20
Heart Metab. (2015) 66:19-23
failure have significantly reduced total and free testosterone levels. As the severity of congestive heart
failure worsens, the levels of both total testosterone
and estimated free testosterone lower correspondingly. In fact, it was shown that reduced levels of total
and estimated free testosterone were both predictors
of increased mortality in men with congestive heart
failure.11
Metabolic syndrome, which is comprised of insulin resistance, hypertension, dyslipidemia, and visceral obesity, is associated with an increased risk of
cardiovascular disease (relative risk, 2.35).12 Testosterone levels are also known to affect metabolic syndrome. Low testosterone levels have been shown to
correlate with worsening type 2 diabetes and obesity.
In fact, not only are the total testosterone levels lower
in diabetics, the free testosterone and the testosterone bound to SHBG are also lower. This means that
total testosterone in diabetics is not entirely caused
by the reduction in levels.13
At the moment, the evidence for testosterone
levels and dyslipidemia is poor. Most of the studies
done were cross-sectional studies based on small
sample size.14,15 Therefore, the results are inconclusive. However, the relationship between testosterone
levels and obesity is quite established. It has been
shown that the odds ratio for having hypogonadism
was significantly higher in obese men, and there was
a statistically significant negative correlation between
total testosterone level and body mass index (BMI).2
In terms of mortality, studies have consistently shown
that lower levels of endogenous bioavailable testosterone are associated with higher rates of all-cause
and cardiovascular mortality.5,16
Testosterone replacement therapy: a new approach
for the heart
TRT may be beneficial to the heart. There are a few
ways that testosterone, through its effect on other parameters (components of metabolic syndrome), may
improve cardiovascular health.
Testosterone replacement therapy in obesity
As discussed earlier, low testosterone levels are associated with obesity. This could be because adipose
tissue is rich with the aromatase enzyme, which converts testosterone to estrogen. Studies have shown
Heart Metab. (2015) 66:19-23
Ho and Tan
Testosterone and the heart
that TRT decreases fat mass and BMI.13 Testosterone
is believed to cause a reduction in abdominal adiposity by inducing lipolysis. Besides that, testosterone
also activates the enzyme 11-hydroxysteroid dehydrogenase in adipose tissue, which transforms glucocorticoids into their inactive form.17
Long-term testosterone therapy for up to 6 years
has been shown to result in significant and sustained
improvements in weight. In a study by Haider et al,
TRT caused a decrease of waist circumference by
11.56 cm and weight decline by 17.49 kg (15.04%).18
What is more interesting to note is that the reduction
in waist circumference with testosterone undecanoate in more than 500 hypogonadal men appears to
be superior when compared with data published for
other drugs, in combination with lifestyle and behavioral interventions.19
controlled trials showed that triglyceride values improved in those given TRT, but no specific difference
was found in cholesterol levels between the TRT and
control groups.24
Testosterone replacement therapy in diabetes
mellitus and glycemic control
It is widely known that lifestyle modifications, along
with diet, exercise, and weight loss, are able to reduce insulin resistance, and therefore, prevent the
progression to overt diabetes. However, the addition of TRT to lifestyle interventions has been
shown to improve the glycemic control better and,
in fact, is able to reverse the metabolic syndrome
in 52 weeks.20 The combination of TRT and lifestyle
modifications is also able to increase insulin sensitivity, reduce fatty liver, and improve muscle mass,
compared with placebo and lifestyle modifications
alone.13,25
There is also strong evidence that TRT in diabetic
men improves the homeostatic model of insulin resistance, hemoglobin A1c, and fasting plasma glucose.20
How it does this is still controversial, although it is
believed to be mediated partly by its effect on visceral
fat. Besides that, testosterone is also believed to be
involved in promoting glucose utilization by stimulating glucose uptake, glycolysis, and mitochondrial oxidative phosphorylation. Testosterone also increases
Glut4 in cultured skeletal muscle cells. Glut4, in turn,
facilitates glucose transportation into the cell.21
The effects of TRT on diabetic men with hypogonadism go beyond glycemic control. In a study by
Muraleedharan et al,22 mortality was increased in
the low testosterone group (17.2%) compared with
the normal testosterone group (9%; P=0.003). TRT
(mean duration 41.6±20.7 months; n=64) was associated with an 8.4% reduced mortality compared with
19.2% (P=0.002) in the untreated group (n=174).
Testosterone replacement therapy and
hyperlipidemia
TRT has beneficial effects on lipids as well. In a 5-year
study on the effects of TRT, an improvement in lipid
profile (total/high-density lipoprotein (HDL) cholesterol
ratio, -2.9±1.5; P<0.0001) was shown.23 However, a
meta-analysis and systemic review on randomized
Testosterone replacement therapy and hypertension
The positive effect of TRT on blood pressure has
also been documented. A study by Francomano et
al showed an improvement in both systolic and diastolic blood pressure (-23±10 and -16±8 mm Hg;
P<0.0001) over 5 years.23 However, a meta-analysis
of randomized controlled trials did not show any significant difference in the blood pressure between TRT
and the control.24
Testosterone replacement therapy and lifestyle
Testosterone replacement therapy and myocardium
Besides its effects on metabolic syndrome, TRT has
a direct effect on the heart as well. It has been found
to improve myocardial ischemia in men with coronary artery disease. In fact, TRT has been shown to
increase time to angina in stress tests.26 Both acute
and chronic testosterone therapy improved myocardial ischemia independent of the method of administration. It is hypothesized that testosterone promotes
coronary vasodilation by its action on the calcium
and potassium channels on the surface of vascular
smooth muscle cells.
TRT has also been demonstrated to shorten the
corrected QT (QTc) interval by augmenting the activity
of slowly activating delayed rectifier potassium channels, while simultaneously slowing the activity of Ltype calcium channels.27 This stabilizes the heart.
21
Ho and Tan
Testosterone and the heart
Testosterone replacement therapy and mortality
TRT was associated with decreased risk of death
(hazard ratio [HR], 0.61; 95% confidence interval
[95% CI], 0.42-0.88; P=0.008). In fact, TRT is able
to reduce mortality by 50% in men with low testosterone (testosterone <300 ng/dL) as compared with
those not receiving TRT.28 The key is to achieve optimal testosterone levels with TRT and not to go overboard with supra-normal testosterone levels. Yeap
et al have also shown that the greatest benefits are
seen with testosterone levels in the third quartile.29
They concluded that optimal androgen levels are a
biomarker for survival because older men with midrange levels of testosterone and dihydrotestosterone
had the lowest death rates from any cause.
Conclusion
Testosterone levels have been shown to be associated positively with metabolic syndrome and cardiovascular diseases (Figure 1). TRT, on the other hand,
has also shown positive outcomes in terms of metabolic parameters and cardiovascular outcomes, but
the long-term effects are not known. So far, all the
studies published were small and short-term. The
two controversial papers, which raised the alarm on
TRT, showed that more needs to be done to allay our
fears on TRT.30,31
Despite the obvious benefits of TRT on the heart,
caution needs to be heeded, especially in men with
severe heart problems and those above 75 years
of age. In frail elderly men, it is not advisable to use
high-dose TRT. The administration of TRT requires
Fig. 1 An illustration of how testosterone deficiency may affect the
heart directly, or indirectly through the metabolic syndrome.
22
Heart Metab. (2015) 66:19-23
close monitoring. Lifestyle changes are also needed
to complement the benefit of TRT. When men are appropriately diagnosed, treated, and monitored, TRT
is relatively safe and beneficial. Indeed, the ongoing
Testosterone Trial in Older Men (NCT00799617) will
provide important guidance to older men who meet
current recommendations for TRT. L
REFERENCES
1.Trinick TR, Feneley MR, Welford H, Carruthers M. International
web survey shows high prevalence of symptomatic testosterone deficiency in men. Aging Male. 2011;14:10-15.
2.Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C.
Prevalence of hypogonadism in males aged at least 45 years:
the HIM study. Int J Clin Pract. 2006;60(7):762-769.
3.Moskovic DJ, Araujo AB, Lipshultz LI, Khera M. The 20-year
public health impact and direct cost of testosterone deficiency
in U.S. men. J Sex Med. 2013;10(2):562-569.
4.Vikan T, Johnsen SH, Schirmer H, Njølstad I, Svartberg J.
Endogenous testosterone and the prospective association
with carotid atherosclerosis in men: the Tromsø study. Eur J
Epidemiol. 2009;24(6):289-295.
5.Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab.
2008;93:68-75.
6.Yeap BB, Hyde Z, Almeida OP, et al. Lower testosterone levels
predict incident stroke and transient ischemic attack in older
men. Clin Endocrinol Metab. 2009;94(7):2353-2359.
7.Smith GD, Ben-Shlomo Y, Beswick A, Yarnell J, Lightman S,
Elwood P. Cortisol, testosterone and coronary heart disease:
prospective evidence from the Caerphilly study. Circulation.
2005;112:332-340.
8.Akishita M, Hashimoto M, Ohike Y, et al. Low testosterone level
as a predictor of cardiovascular events in Japanese men with
coronary risk factors. Atherosclerosis. 2010;210:232-236.
9.Li L, Guo CY, Jia EZ, et al. Testosterone is negatively associated with the severity of coronary atherosclerosis in men. Asian
J Androl. 2012;14:875-878.
10.Fu L, Gao QP, Shen JX. Relationship between testosterone
and indexes indicating endothelial function in male coronary
heart disease patients. Asian J Androl. 2008;10:214-218.
11.
Anker SD, Banasiak W, Poole-Wilson PA, Ponikowski
P. Anabolic deficiency in men with chronic heart failure:
prevalence and detrimental impact on survival. Circulation.
2006;114:1829-1837.
12.Mottillo S, Filion KB, Genest J, et al. The metabolic syndrome
and cardiovascular risk a systematic review and meta-analysis.
J Am Coll Cardiol. 2010;56(14):1113-1132.
13.Corona G, Monami M, Rastrelli G, et al. Type 2 diabetes mellitus and testosterone: a meta-analysis study. Int J Androl.
2010;34:528-540.
14.Agledahl I, Skjaerpe PA, Hansen JB, Svartberg J. Low serum
testosterone in men is inversely associated with non-fasting
serum triglycerides: the Tromso Study. Nutr Metab Cardiovasc
Dis. 2008;18:256-262.
15.
Vaidya D, Dobs A, Gapstur SM, et al. The association of
endogenous sex hormones with lipoprotein subfraction profile
in the multi-ethnic study of atherosclerosis. Metabolism.
2008;57:782-790.
16.
Araujo AB, Dixon JM, Suarez EA, Murad MH, Guey LT,
Wittert GA. Endogenous testosterone and mortality in men: a
systemic review and meta-analysis. J Clin Endocrinol Metab.
2011;96:3007-3019.
17.Oskui PM, French WJ, Herring MJ, Mayeda GS, Burstein S,
Heart Metab. (2015) 66:19-23
Kloner RA. Testosterone and the cardiovascular system: a
comprehensive review of the clinical literature. J Am Heart
Assoc. 2013;2(6):e000272.
18.Haider A, Yassin A, Doros G, Saad F. Effects of long term testosterone therapy on patients with “diabesity”: results of observational studies of pooled analyses in obese hypogonadal men
with type 2 diabetes. Int J Endocrinol. 2014;2014:683515.
19.Saad F, Haider A, Doros G, Traish A. Long-term treatment of
hypogonadal men with testosterone produces substantial and
sustained weight loss. Obesity. 2013;21(10):1975-1981.
20.Heufelder AE, Saad F, Bunck MC, Gooren L. Fifty-two-week
treatment with diet and exercise plus transdermal testosterone
reverses the metabolic syndrome and improves glycemic
control in men with newly diagnosed type 2 diabetes and
subnormal plasma testosterone. J Androl. 2009;30:726-733.
21.
Grossmann M. Testosterone and glucose metabolism in
men: current concepts and controversies. J Endocrinol.
2014;220(3):R37-R55.
22.Muraleedharan V, Marsh H, Kapoor D, Channer KS, Jones
TH. Testosterone deficiency is associated with increased
risk of mortality and testosterone replacement improves
survival in men with type 2 diabetes. Eur J Endocrinol.
2013;169(6):725-733.
23.Francomano D, Lenzi A, Aversa A. Effects of five year treatment
with testosterone undecanoate on metabolic and hormonal
parameters in ageing men with metabolic syndrome. Int J
Endocrinol. 2014;2014:527470.
24.
Cai X, Tian Y, Wu T, Cao CX, Li H, Wang KJ. Metabolic
effects of testosterone replacement therapy on hypogonadal
men with type 2 diabetes mellitus: a systematic review and
meta-analysis of randomized controlled trials. Asian J Androl.
Ho and Tan
Testosterone and the heart
2014;16(1):146-152.
25.Hoyos CM, Yee BJ, Phillips CL, Machan EA, Grunstein RR,
Liu PY. Body compositional and cardiometabolic effects of
testosterone therapy in obese men with severe obstructive
sleep apnoea: a randomised placebo-controlled trial. Eur J
Endocrinol. 2012;167:531-541.
26.English KM, Steeds RP, Jones TH, Diver MJ, Channer KS.
Low-dose transdermal testosterone therapy improves angina
threshold in men with chronic stable angina: a randomized, double-blind, placebo-controlled study. Circulation.
2000;102:1906-1911.
27.Charbit B, Christin-Maitre S, Demolis JL, Soustre E, Young
J, Funck-Brentano C. Effects of testosterone on ventricular repolarization in hypogonadic men. Am J Cardiol.
2009;103:887-890.
28.
Shores MM, Smith NL, Forsberg CW, Anawalt BD,
Matsumoto AM. Testosterone treatment and mortality in
men with low testosterone levels. J Clin Endocrinol Metab.
2012;97(6):2050-2058.
29.Yeap BB, Alfonso H, Chubb SA, et al. In older men an optimal
plasma testosterone is associated with reduced all-cause mortality and higher dihydrotestosterone with reduced ischemic
heart disease mortality, while estradiol levels do not predict
mortality. J Clin Endocrinol Metab. 2014;99(1):E9-E18.
30.
Vigen R, O’Donnell CI, Barón AE, et al. Association of
testosterone therapy with mortality, myocardial infarction,
and stroke in men with low testosterone levels. JAMA.
2013;310:1829-1836.
31.Finkle WD, Greenland S, Ridgeway GK, et al. Increasing risk of
non-fatal myocardial infarction following testosterone therapy
prescription in men. PLoS ONE. 2014;9(1):e85805.
23
Original Article
Heart Metab. (2015) 66:24-26
Effects of trimetazidine on hormones
and the heart
Vedat Sansoy, MD, FESC; Kadriye Kiliçkesmez, MD
Department of Cardiology, Institute of Cardiology, University of Istanbul, Istanbul, Turkey
Correspondence: Vedat Sansoy, MD, Professor of Cardiology, Institute of Cardiology, University of Istanbul, Haseki,
34096, Istanbul, Turkey
E-mail: vedat.sansoy@gmail.com
Abstract
Trimetazidine is a well-known, clinically effective antianginal agent recommended by guidelines for
the treatment of stable angina pectoris. There is also substantial evidence for its benefit in patients
with heart failure. Natriuretic peptides are markers of myocardial load and findings from recent studies
suggest that trimetazidine treatment has a positive effect on this neurohormonal pathway in patients
with ischemic heart disease or heart failure. L Heart Metab. 2015;66:24-26
Keywords: angina pectoris; cardiac metabolism; coronary artery disease; heart failure; natriuretic peptides
C
oronary artery disease (CAD) and congestive heart
failure (CHF) represent two major public health
problems that impair quality of life and reduce
longevity. The impairment of cardiac function in chronic
CAD and CHF is related to left ventricular remodeling,
a pathologic process by hemodynamic overload and
neurohormonal activation.1 The heart exerts an endocrine function where both atria and ventricles are able to
produce cardiac natriuretic hormones. The activation or
deactivation of the cardiac natriuretic hormone system
is almost always the result of one or more physiological
or pathological changes. Atrial natriuretic peptide (ANP)
and brain natriuretic peptide (BNP) are secreted from
the heart as a result of direct wall stress, to protect the
human body from volume overload2 and also to inhibit
the renin-angiotensin system, endothelin secretion, and
sympathetic activity.3 Measurement of plasma concentrations of natriuretic peptide is now increasingly being
used as a tool for clinical diagnosis and prognosis in
patients with CHF and CAD.4
Trimetazidine’s mechanism of action
In the heart, adenosine-5’-triphosphate (ATP) is
produced primarily by the metabolism of free fatty
24
acids (FFAs) and carbohydrates.5 FFA oxidation provides more energy, but it is associated with increased oxygen consumption. Trimetazidine is a partial inhibitor of the β-oxidation enzyme long-chain
3-ketoacyl coenzyme A thiolase (3-KAT) activity,
the final enzyme in the FFA β-oxidation pathway
(Figure 1).6,7 It increases pyruvate dehydrogenase
Lactate
Glucose
Free fatty acids
GLYCOLYSIS
Cytosol
Lactate
Pyruvate
Fatty Acyl-CoA
CPT-I
Outer mitochondrial
membrane
Inner mitochondrial
membrane
NAD+ + CoA
PDH
NADH
Acetyl-CoA
Mitochondrial
matrix
Citric
acid
cycle
Fatty Acyl-Carnitine
CAT
CPT-II
Fatty Acyl-CoA
Fatty acid
-oxidation
NAD+ + CoA
Trimetazidine
Fig. 1 Diagram illustrating the site of action of trimetazidine and
various cardiac metabolic modulators.
Abbreviations: CAT, carnitine-acylcarnitine translocase; CoA, coenzyme A;
CPT, carnitine palmitoyltransferase; NAD+, nicotinamide adenine dinucleotide
(oxidized); NADH, nicotinamide adenine dinucleotide (reduced); PDH, pyruvate dehydrogenase.
From reference 7: Sabbah HN, Stanley WC. Heart Fail Rev. 2005;10(4):281288. © 2006, Springer Science and Business Media, LLC.
Heart Metab. (2015) 66:24-26
Abbreviations
ANP: atrial natriuretic peptide; ATP: adenosine-5’triphosphate; BNP: brain natriuretic peptide; CAD:
coronary artery disease; CHF: congestive heart failure; FFA: free fatty acids; NYHA: New York Heart Association
activity and the metabolic rate of glucose.8 This results in decreased oxygen consumption, hydrogen
ion production, intracellular acidosis, and reduced
calcium ion accumulation. Trimetazidine reduces
myocardial injury caused by free radicals, therefore
modulates the inflammatory response. In this way,
trimetazadine protects the whole myocardium against necrotic and apoptotic cell death and reduces
the remodeling process.
Trimetazidine in coronary artery disease
Existing data support the use of drugs that optimize
cardiac energy metabolism such as trimetazidine for
the treatment of patients with CAD.9,10 The VASCO
study is the largest randomized controlled study conducted with trimetazidine. Patients with stable angina
receiving 50 mg of atenolol were randomized to the
addition of trimetazidine MR 70 mg or 140 mg, or placebo for a 12-week period. In the cohort of all chronic
stable angina patients, trimetazidine significantly improved total exercise duration compared with baseline
and placebo.11 Recent European Society of Guidelines on stable angina pectoris recommended that
trimetazidine may be used as an add-on drug after
β-blockers.12
Major metabolic changes occur during the early
hours of myocardial infarction and during ischemia/
reperfusion. FFA concentrations are greatly increased, and exert a toxic effect on the myocardium.
This effect determines increased membrane damage, endothelial dysfunction, tissue inflammation, and
decreased cardiac function. Trimetazadine reduces
ischemia/reperfusion damage folowing ischemia and
preserves myocardial contractile function.13 Decreasing plasma FFA concentrations and cardiac fatty
acid oxidation, together with the stimulation of glucose and lactate uptake, might reduce these detrimental effects.14 Demirelli et al assessed the impact
of treatment with trimetazadine in patients with non–
ST segment elevation myocardial infarction undergo-
Sansoy and Kiliçkesmez
Effects of trimetazidine on hormones and the heart
ing percutaneous coronary intervention.15 Forty-five
patients were randomly assigned to receive either
placebo or trimetazidine. In patients on trimetazadine
at 1-month follow-up, a considerable improvement
in left ventricular end-diastolic volume was reported
and BNP levels decreased compared with patients
on placebo. The authors concluded that the beneficial effects of percutaneous coronary intervention (PCI)
may be reinforced with a combination of PCI and trimetazidine treatment.
Trimetazidine in heart failure
Natriuretic peptide is used in the diagnosis, monitoring, and prognosis of patients with congestive heart
failure.16 Its concentration falls in patients with decompensated heart failure after treatment, suggesting that
measurement of plasma natriuretic peptide may be
helpful in titrating therapy.17 The plasma measurement
of natriuretic peptide is also used in the diagnosis and
prognosis of patients with CAD. Increased natriuretic
peptide was found to be related to ischemia.18
Trimetazidine has documented effects on improving the left ventricular function, exercise tolerance,
and New York Heart Association (NYHA) class. A
recent study demonstrated that short-term trimetazidine treatment in patients with ischemic cardiomyopathy improves exercise tolerance and reduces plasma level of BNP. The study involved 50 patients with
ischemic cardiomyopathy; 25 patients were assigned
to receive conventional treatment plus trimetazidine,
while the remaining 25 patients constituted the control group. After a 6-month follow-up, both groups achieved an insignificant reduction in NYHA class. The
group receiving trimetazidine demonstrated a considerable reduction in BNP levels and cardiac troponin
T, while the control group showed increased plasma
BNP levels, with no significant changes in cardiac troponin T levels. Trimetazidine administration also resulted in a significant improvement in exercise tolerance
assessed with a 6-minute walk test, however, it was
not associated with a significant improvement in left
ventricular systolic function, at baseline, and after 1
month and 6 months, respectively.19 Fragasso et al
obtained similar results in 55 patients with heart failure
and left ventricular dysfunction of various etiologies.20
Zhang et al presented a meta-analysis on the use of
trimetazidine in CHF patients.21 Sixteen randomized
25
Sansoy and Kiliçkesmez Effects of trimetazidine on hormones and the heart
studies were evaluated, with 884 patients in the study
group. This meta-analysis demonstrated that the use
of trimetazidine was associated with improved left
ventricular ejection fraction, increased exercise tolerance, reduced NYHA class, decreased left ventricle
volume and plasma BNP levels, and a reduced rate of
cardiovascular hospitalizations.
ANP, another biomarker of heart failure, appears
to be noninferior to BNP for diagnosis of acute heart
failure and also has prognostic value in patients with
CHF.22 The rise in ANP secretion can be reversed by
successful treatment of heart failure. Morgan et al,
using an experimental heart failure model, additionally
demonstrated that treatment with trimetazadine over
a 12-week period reduced the levels of ANP.23
Conclusion
In conclusion, trimetazidine is a well-known, clinically
effective drug for the treatment of stable angina pectoris. Evidence for its benefit in patients with heart failure
is also substantial. Considering natriuretic peptides to
be a marker of myocardial load, findings from recent
studies suggest that trimetazidine treatment has a positive effect on this neurohormonal pathway in patients
with ischemic heart disease or heart failure. L
REFERENCES
1.Cohn JN, Ferrari R, Sharp N. Cardiac remodeling-concepts
and clinical implications: a consensus paper from an international forum on cardiac remodeling. J Am Coll Cardiol.
2000;35(3):569-582.
2.de Bold AJ, Bruneau BG. Natriuretic peptides. In: Fray JCS,
Goodman MH, eds. Handbook of Physiology, Section 7: The
Endocrine System, Volume III: Endocrine Regulation of Water
and Electrolyte Balance. Oxford, UK: Oxford University Press;
2000:377-409.
3.Brunner-La Rocca HP, Kaye DM, Woods RL, et al. Effects of
intravenous brain natriuretic peptide on regional sympathetic
activity in patients with chronic heart failure as compared
with healthy control subjects. J Am Coll Cardiol. 2001;
37(5):1221-1227.
4.Maisel A, Mueller C, Adams K Jr, et al. State of the art: using
natriuretic peptide levels in clinical practice. Eur J Heart Fail.
2008;10(9):824-839.
5.
Lopaschuk GD, Belke DD, Gamble J, Itoi T, Schonekess
BO. Regulation of fatty acid oxidation in the mammalian
heart in health and disease. Biochem Biophys Acta. 1994;
1213(3):263-276.
6.Kantor PF, Lucien A, Kozak R, Lopaschuk GD. The antianginal
drug trimetazidine shifts cardiac energy metabolism from fatty
acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res.
2000;86(5):580-588.
26
Heart Metab. (2015) 66:24-26
7.Sabbah HN, Stanley WC. Metabolic therapy for heart disease:
impact of trimetazidine. Heart Fail Rev. 2005;10(4):281-288.
8.Fantini E, Demaison L, Sentex E, Grynberg A, Athias P. Some
biochemical aspects of the protective effect of trimetazidine on
rat cardiomyocytes during hypoxia and reoxygenation. J Mol
Cell Cardiol. 1994;26(8):949-958.
9.
Szwed H, Sadowski Z, Elikowski W, et al. Combination
treatment in stable effort angina using trimetazidine and
metoprolol: results of a randomized, double-blind, multicentre
study (TRIMPOL II). TRIMetazidine in POLand. Eur Heart J.
2001;22(24):2267-2274.
10.Sellier P, Broustet JP. Assessment of anti-ischemic and antianginal effect at trough plasma concentration and safety of
trimetazidine MR 35 mg in patients with stable angina pectoris:
a multicenter, double-blind, placebo-controlled study. Am J
Cardiovasc Drugs. 2003;3(5):361-369.
11.Vitale C, Spoletini I, Malorni W, Perrone-Filardi P, Volterrani M,
Rosano GM. Efficacy of trimetazidine on functional capacity
in symptomatic patients with stable exertional angina—the
VASCO- angina study. Int J Cardiol. 2013;168(2):1078-1081.
12.Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC
guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary
artery disease of the European Society of Cardiology. Eur Heart
J. 2013;34(38):2949-3003.
13.Stanley WC. Partial fatty acid oxidation inhibitors for stable
angina. Expert Opin Investig Drugs. 2002;11(5):615-629.
14.Barsotti A, Di Napoli P. Trimetazidine and cardioprotection during ischemia-reperfusion. Ital Heart J. 2004;5(suppl 2):29S-36S.
15.Demirelli S, Karakelleoglu S, Gündogdu F, et al. The impact of
trimetazidine treatment on left ventricular functions and plasma
brain natriuretic peptide levels in patients with non-ST segment
elevation myocardial infarction undergoing percutaneous coronary intervention. Korean Circ J. 2013;43(7):462-467.
16.Gardner RS, Ozalp F, Murday AJ, et al. N-terminal pro-brain
natriuretic peptide. A new gold standard in predicting mortality in patients with advanced heart failure. Eur Heart J.
2003;24(19):1735-1743.
17.Jourdain P, Jondeau G, Funck F, et al. Plasma brain natriuretic peptide-guided therapy to improve outcome in heart
failure: the STARS-BNP Multicenter Study. J Am Coll Cardiol.
2007;49(16):1733-1739.
18.Jernberg T, Stridsberg M, Venge P, Lindahl B. N-terminal pro
brain natriuretic peptide on admission for early risk stratification
of patients with chest pain and no ST-segment elevation. J Am
Coll Cardiol. 2002;40(3):437-445.
19.Di Napoli P, Di Giovanni P, Gaeta MA, D’Apolito G, Barsotti A.
Beneficial effects of trimetazidine treatment on exercise tolerance and B-type natriuretic peptide and troponin T plasma
levels in patients with stable ischemic cardiomyopathy. Am
Heart J. 2007;154(3):602.e1-e5.
20.Fragasso G, Rosano G, Baek SH, et al. Effect of partial fatty
acid oxidation inhibition with trimetazidine on mortality and morbidity in heart failure: results from an international multicenter
retrospective cohort study. Int J Cardiol. 2013;163(3):320-325.
21.Zhang L, Lu Y, Jiang H, et al. Additional use of trimetazidine in
patients with chronic heart failure: a meta-analysis. J Am Coll
Cardiol. 2012;59(10):913-922.
22.Masson S, Latini R, Carbonieri E, et al. The predictive value of
stable precursor fragments of vasoactive peptides in patients
with chronic heart failure: data from the GISSI-heart failure
(GISSI-HF) trial. Eur J Heart Fail. 2010;12(4):338-347.
23.Morgan EE, Young ME, McElfresh TA, et al. Chronic treatment with trimetazidine reduces the upregulation of atrial
natriuretic peptide in heart failure. Fundam Clin Pharmacol.
2006;20(5):503-505.
Case Report
Heart Metab. (2015) 66:27-31
Erectile dysfunction and lower urinary
tract symptoms should trigger a
metabolic screen and cardiovascular
risk estimation
Mike Kirby, MBBS, LRCP, MRCS, FRCP
Visiting Professor, Faculty of Health and Human Sciences, Centre for Research in Primary and Community Care
(CRIPACC), University of Hertfordshire, UK; Visiting Professor, The Prostate Centre, London, UK; Editor in Chief,
Primary Care Cardiovascular Journal, Warwickshire, UK; Visiting Professor of Primary Care, Institute of Diabetes
for Older People (IDOP), Beds and Herts Postgraduate Medical School, Luton, UK
Correspondence: Professor Mike Kirby, The Cottage, 30 Wedon Way, Bygrave, Baldock, Herts,
SG7 5DX, United Kingdom
E-mail: kirbym@globalnet.co.uk
Abstract
The UK has made great strides in reducing death from cardiovascular disease (CVD), but there is still
room for improvement compared with other Western European Countries. CVD accounts for approximately one-third of all deaths in men and women in the UK. Half of these deaths are related to coronary
heart disease (CHD), which is the most common cause of premature death in those under the age of
75 years. Atherosclerotic changes in the coronary arteries eventually lead to CHD, and nine key risk
factors have been well recognized. Erectile dysfunction (ED) is an independent risk factor and provides
a window of opportunity to identify early CVD. ED and lower urinary tract symptoms (LUTS) share
underlying pathophysiological etiological mechanisms and will often drive men to consult. This provides
the opportunity to consider what burden of CVD risk factors the patient carries, and to perform an
appropriate metabolic screen. L Heart Metab. 2015;66:27-31
Keywords: cardiovascular disease; erectile dysfunction; lower urinary tract symptoms; metabolic
syndrome; lifestyle
T
he UK has made great strides in reducing death
from cardiovascular disease (CVD), but there
is still room for improvement compared with
other Western European Countries.1 CVD accounts
for approximately one-third of all deaths in men and
women in the UK. Half of these deaths are related
to coronary heart disease (CHD), which is the most
common cause of premature death in those under
the age of 75 years.2
Atherosclerotic changes in the coronary arteries
eventually lead to CHD, and nine key risk factors have
been well recognised.3 In 2001, we raised the question “Is erectile dysfunction a marker for cardiovascular disease?”4 and recently highlighted the importance of the co-diagnosis of erectile dysfunction (ED)
and lower urinary tract symptoms (LUTS).5
The link between ED and LUTS was brought home
by the multinational survey of the aging male (MSAM)
27
Kirby
ED and LUTS should trigger a metabolic screen and cardiovascular risk estimation
Abbreviations
CHD: coronary heart disease; CVD: cardiovascular
disease; ED: erectile dysfunction; LUTS: lower urinary
tract symptoms; PDE5: phosphodiesterase type 5;
PSA: prostate-specific antigen
Base: total sample
100
Net reduction of stiffness
No, I cannot get an erection
90
83
70
70
50
27
30
14
10
25
12
2
2
Age cohort
45
5
33
17
50-59 years
7
45
52
64
40
50
53
0
M
Mo ild
de
ra
te
Se
ve
re
20
LUTS
severity
49
53
40
0
57
50
41
43
6
12
19
0
M
Mo ild
de
ra
te
Se
ve
re
In %
60
70
65
89
60-69 years
16
20
31
44
0
M
Mo ild
de
ra
te
Se
ve
re
80
83
allow the identification of at-risk men who require
further cardiovascular evaluation.18 Therefore, a multidisciplinary collaborative approach is encouraged
and the screening net should be cast as widely as
possible.
It is important to recognise that ED is an independent marker of increased CVD, over and above the
conventional risk factors.19 It has been well demonstrated in a systematic review and meta-analysis that
lifestyle intervention together with cardiovascular risk
factor reduction improves erectile function.20 In addition to this, factors associated with decreased risk of
LUTS include increased physical activity, moderate
alcohol intake, and increased vegetable consumption,21 and LUTS can also be improved by means of
lifestyle changes.22,23
Case history
70-79 years
Fig. 1 Erectile dysfunction according to age and severity of lower
urinary tract symptoms (LUTS) using the Danish Prostate Symptom
Score Sex (DAN-PSSsex) questionnaire.
From reference 6: Rosen R et al. Eur Urol. 2003;44:637-649. © 2003,
Elsevier BV.
study (Figure 1).6 Many large epidemiological studies
using well-powered multivariate analyses consistently
provide overwhelming evidence of a link between ED
and LUTS.7,8 The pathogenic mechanisms underlying
the relationships between ED and LUTS have been
the subject of several recent reviews.7,9-11 The underlying mechanisms include the alteration of the nitric
oxide–cyclic guanosine monophosphate pathway;
enhancement of the Rho-kinase (ROCK) signalling;
autonomic hyperactivity; and pelvic atherosclerosis,
secondary to endothelial dysfunction. Additional contributing factors may include chronic inflammation12
and sex steroid ratio imbalance.13
Two meta-analyses have clearly shown that ED
predicts CVD events and all-cause mortality.14,15 Because ED and LUTS are very common worldwide
clinical problems, enquiring about these symptoms
in middle-aged men who have no cardiac symptoms
provides a window of opportunity to identify those
with underlying CVD. This is important, as it has been
well demonstrated in two significant studies that ED
can precede a cardiac event by between an average
of 2 to 5 years.16,17
This has also been emphasised in the Princeton
III Consensus, showing that ED is a marker of increased CVD risk and the identification of ED may
28
Heart Metab. (2015) 66:27-31
Initial visit
Background
A 60-year-old scientist and company director attended with some concern regarding perineal discomfort
that had been present for two weeks. There had been
a past history of prostatitis 15 years previously, but
he had been prescribed no treatment for this. He had
undertaken a company medical 14 years previously,
when it was noted that he had an elevated cholesterol
of 6 mmol/L and triglycerides (TG) of 2.61 mmol/L.
He was advised to deal with this by means of diet and
exercise. He gave a history of ED for the previous 5
years, which had been treated with on-demand Cialis
and Viagra, neither of which he had found particularly
helpful. His urinary symptoms included frequency,
some morning urgency, getting up once at night, and
a rather poor flow rate.
On direct questioning, his general health appeared to be good. He had a history of some acid
reflux, but no cardiac symptoms. His exercise level was low to moderate, in terms of playing tennis
once per week with occasional walks. He was a
nonsmoker and consumed 15 to 20 units of alcohol
per week. He was not taking any medication. There
was a family history of type 2 diabetes in his father
and brother. In his personal history, he had experienced pericarditis at the age of 24 and a Bell’s palsy
in 2009.
Heart Metab. (2015) 66:27-31
Kirby
ED and LUTS should trigger a metabolic screen and cardiovascular risk estimation
Initial clinical examination and investigations
Clinical examination revealed height 181 cm, weight
91 kg, waist circumference 98 cm, and blood pressure 150/92 mm Hg. His heart was normal and all peripheral pulses were present. There were no abdominal
bruits and the chest was clear. There were no abnormal swellings in the abdomen. Digital rectal examination revealed a nontender and nodular prostate, which
felt to be about 30 g. This was subsequently confirmed
to be 31 g on the transrectal ultrasound report (Table
I). The abdominal ultrasound showed some features
suggesting fatty liver infiltration. His urinary investigation findings are summarized in Table II.
The electrocardiogram (ECG), renal function, and
liver function were normal. His cholesterol profile was:
cholesterol 6.6 mmol/L, high-density lipoprotein (HDL)
• Prostate measures 31 mL in volume.
• There is periurethral calcification and focal echogenic areas in the
central gland, which could be due to previous prostatitis.
• There is very early central benign prostatic hypertrophy change
and an early medium lobe enlargement.
• The peripheral zone is relatively uniform in reflectivity.
• The gland vascularity is within normal limits.
• The seminal vesicles are symmetrical and normal in appearance.
Conclusion: There are some areas of prostate that would suggest previous episodes of prostatitis, but no definite current active
inflammatory changes seen. The bladder and upper tracts appear
normal.
Table I Transrectal ultrasound results.
Voided volume
Maximum flow rate
Average flow rate
Residual urine
IPSS
IIEF
441 mL
14.7 mL/sec
7.7 mL/sec
190 mL
22 (severe symptoms)
14 (moderate to severe erectile dysfunction)
Table II Results of urinary investigations and IPSS/IIEF scores after
initial visit.
Abbreviations: IIEF, International Index of Erectile Function; IPSS, International
Prostate Symptom Score.
Central obesity Plus any two of the following:
Raised blood pressure
Raised triglyceride level
Reduced high-density lipoprotein cholesterol
Raised fasting plasma glucose 1.3 mmol/L, low-density lipoprotein (LDL) 4.6mmol/L,
TG 1.5 mmol/L. HbA1c 43 mmol/mol (6.1%) and fasting plasma glucose 5.8 mmol/L. Fibrinogen was 4.5
g/L (normal range 1.5 to 4). Testosterone was 17.8
nmol/L, prostate-specific antigen (PSA) 3.09 mcg/L,
free PSA 0.52 mcg/L, and free/total PSA ratio 17.8.
Occult blood tests were negative
This patient had the features of metabolic syndrome (Table III),24 with an increased waist circumference, raised blood pressure and blood glucose, and
dyslipidemia.
Using the Joint British Societies recommendations
on the prevention of Cardiovascular Disease (JBS3)
risk calculator, his heart age was 74 years. He had a
17% 10-year risk of a cardiovascular event, with a life
expectancy of 83 years. The calculator predicted that
he would gain 3 extra years of life and his 10-year risk
would reduce to 5.3% if his risk factors were suitably
adjusted, giving him a life expectancy of 86 years.
At the time the patient was seen, the threshold for intervention with statins was a 20% 10-year risk, but having ED in addition to his current risk factors put this man
at high risk of having underlying and future CVD. He
was, however, reluctant to take statins due to adverse
reports of side effects that he had read in the media.
It was decided that, to further evaluate his potential CVD risk, he would undertake a computed tomography coronary calcium scan, which was duly performed. This showed a total calcium score of 585 (left
marginal artery, 0; left anterior descending artery, 319;
left circumflex artery, 0; and right coronary artery, 266),
putting him in the 80th-centile range for age and gender. There was no abnormality identified in the lungs.
This man therefore had a high burden of coronary
artery calcification for his age and an exercise stress
echo was performed. On standard Bruce protocol,
the patient achieved 89% maximum predicted heart
rate (MPHR) and 13.4 metabolic equivalents (METs)
Waist circumference: ≥94 cm for Europid men; ≥80 cm for Europid women; with ethnicity specific values
for other groups*
Systolic ≥130 or diastolic ≥85 mm Hg, or taking medication for previously diagnosed hypertension
≥150 mg/dL (1.7 mmol/L) or taking medication for this specific lipid abnormality
<40 mg/dL (1.03 mmol/L) in men, <50 mg/dL (1.29 mmol/L) in women, or taking medication for this
specific lipid abnormality
≥ 100 mg/dL (5.6 mmol/L), or previously diagnosed type 2 diabetes. If >5.6 mmol/L or 100 mg/dL,
oral glucose tolerance test is strongly recommended, but is not necessary to define presence of the
syndrome
Table III International Diabetes Federation (IDF) definition of the metabolic syndrome.
*If body mass index is >30 kg/m², central obesity can be assumed and waist circumference need not be measured.
Modified from reference 24: International Diabetes Federation. http://www.idf.org/metabolic-syndrome. © 2006, International Diabetes Federation.
29
Kirby
ED and LUTS should trigger a metabolic screen and cardiovascular risk estimation
of workload. He did not have any chest pain and no
ischemic ECG changes. Left ventricular wall motion
was normal both before and after exercise. He therefore had a negative exercise stress echocardiogram.
Management
He agreed to take statin therapy and was started on
atorvastatin 40 mg. He was also recommended a
Mediterranean-style diet and provided with a twicedaily exercise programme. Regarding the ED and
LUTS, he was started on daily Tadalafil (phosphodiesterase type 5 [PDE5] inhibitor) at a dose of 5 mg.
In summary, this man presented with LUTS, ED, and
some perineal discomfort, possibly related to previous
prostatitis. Clinical examination and subsequent investigations confirmed that he had the metabolic syndrome
and this, combined with a history of ED, gave him a significant risk of having underlying CVD. This was subsequently confirmed on a coronary calcium scan and he
was started on statin therapy (atorvastatin 40mg daily),
aiming for a reduction of 50% in the lipid profile. He was
provided with a diet and exercise programme. He was
asked to check his own blood pressure at home.
In addition to the statin therapy, he was prescribed daily Tadalafil 5 mg, which has the benefit of
treating both his ED and his LUTS. PSA levels were to
be carefully followed up
Three-month review
Repeat clinical examination, investigation, and score
results at 3-month review are summarized in Table IV.
Parameter
3-month review
Initial visit
Weight
85 kg 91 kg
Waist circumference
97 cm 98 cm
PSA
2.33 mcg/L
3.09 mcg/L
HbA1c
6.1% (43 mmol/mol) No change
Cholesterol
3.1 mmol/L
6.6 mmol/L
HDL
1.4 mmol/L
1.3 mmol/L
LDL
1.3 mmol/L
4.6 mmol/L
BP
132/84 mm Hg
150/92 mm Hg
IIEF2414
IPSS10 22
JBS3 heart age
61 years
74 years
Table IV Examination and investigation results at 3-month review
compared with initial visit.
Abbreviations: BP, blood pressure; HDL, high-density lipoprotein; IIEF,
International Index of Erectile Function; IPSS, International Prostate Symptom
Score; JBS3, Joint British Societies recommendations on the prevention of
Cardiovascular Disease; LDL, low-density lipoprotein; PSA, prostate-specific
antigen.
30
Heart Metab. (2015) 66:27-31
At this 3-month review, he reported feeling very well,
and was eating a Mediterranean-style diet and walking
twice daily. Pelvic/perineal discomfort was no longer a
problem. He reported walking 10 000 steps per day using a pedometer. He had gained 3.1 life years.
This is a good response to daily PDE5 inhibitor
therapy relating to ED and LUTS, with a significantly
reduced risk of future CVD as the result of lifestyle
changes and statin therapy. L
REFERENCES
1.Murray CJL, Richards MA, Newton JN, et al. UK health performance: findings of the Global Burden of Disease Study 2010.
Lancet. 2013;381(9871):997-1020.
2.Townsend N, Wickramasinghe K, Bhatnager P, et al; British
Heart Foundation Health Promotion Research Group.
Coronary heart disease statistics: a compendium of health
statistics. London, UK: British Heart Foundation; 2012.
3.Yusef S, Hawken S, Ounpuu S, et al; INTERHEART Study
Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries
(the INTERHEART study): case-control study. Lancet.
2004;364(9438):937-952.
4.Kirby M, Jackson G, Betteridge J, et al. Is erectile dysfunction a marker for cardiovascular disease? Int J Clin Pract.
2001;155:614-618.
5.Kirby M, Chapple C, Jackson G, et al. Erectile dysfunction and
lower urinary tract symptoms: a consensus on the importance
of co-diagnosis. Int J Clin Pract. 2013;67(7):606-618.
6.Rosen R, Altwein J, Boyle P, et al. Lower urinary tract symptoms and male sexual dysfunction: the multinational survey of
the aging male (MSAM-7). Eur Urol. 2003;44(6):637-649.
7.Gacci M, Eardley I, Giuliano F, et al. Critical analysis of the
relationship between sexual dysfunctions and lower urinary
tract symptoms due to benign prostatic hyperplasia. Eur Urol.
2011;60(4):809-825.
8.Seftel AD, de la Rosette J, Birt J, Porter V, Zarotsky V, Viktrup
L. Coexisting lower urinary tract symptoms and erectile dysfunction: a systematic review of epidemiological data. Int J Clin
Pract. 2013;67(1):32-45.
9.MvVary KT. Erectile dysfunction and lower urinary tract symptoms secondary to BPH. Eur Urol. 2005;47:838-845.
10.
Kohler TS, McVary KT. The relationship between erectile
dysfunction and lower urinary tract symptoms and the role of
phosphodiesterase type 5 inhibitors. Eur Urol. 2009;55:38-48.
11.Andersson KE, de Groat WC, McVary K, et al. Tadalafil for
the treatment of lower urinary tract symptoms secondary to
benign prostatic hyperplasia: pathology and mechanism(s) of
action. Neurourol Urodyn. 20111;30:292-301.
12.
Panna G, Fibbi B, Amuchastegui S, et al. Human benign
prostatic hyperplasia stromal cells as inducers and targets
of chronic immuno-mediated inflammation. J Immunol.
2009;182:4056-4064.
13.Corona G, Maggi M. The role of testosterone in erectile dysfunction. Nat Rev Urol. 2010;7:46-56.
14.Vlachopoulos CV, Terentes-Printzios DG, Ioakeimidis NK, et
al. Prediction of cardiovascular events and all-cause mortality
with erectile dysfunction: A systematic review and metaanalysis of cohort studies. Circ Cardiovasc Qual Outcomes.
2013;6:1-11.
15.Dong JY, Zhang YH, Qin LQ. Erectile dysfunction and risk of
cardiovascular disease: meta-analysis of prospective cohort
studies. J Am Coll Cardiol. 2011;58(13):1378-1385.
Heart Metab. (2015) 66:27-31
Kirby
ED and LUTS should trigger a metabolic screen and cardiovascular risk estimation
16.Hodges LD, Kirby M, Solanki J, et al. The temporal relationship
between erectile dysfunction and cardiovascular disease. Int J
Clin Pract. 2007;61(12):2019-2025.
17.Jackson G. Erectile dysfunction: a marker of silent coronary
artery disease. Eur Heart J. 2006;27(22):2613-2614.
18.
Nehra A, Jackson G, Miner M, et al. The Princeton III
Consensus recommendations for the management of erectile
dysfunction and cardiovascular disease. Mayo Clin Proc.
2012;87(8):766-778.
19.
Bohm M, Baumhakel M, Teo K, et al. Erectile dysfunction
predicts cardiovascular events in high-risk patients receiving telmisartan, ramipril, or both: The ONgoing Telmisartan
Alone and in combination with Ramipril Global Endpoint
Trial/Telmisartan Randomized AssessmeNt Study in ACE
iNtolerant subjects with cardiovascular Disease (ONTARGET/
TRANSCEND) Trials. Circulation. 2010;121(12):1439-1446.
20.Gupta BP, Murad MH, Clifton MM, et al. The effect of lifestyle
modification and cardiovascular risk factor reduction on erectile dysfunction: a systematic review and meta-analysis. Arch
Intern Med. 2011;171(20):1797-1803.
21.Parsons JK. Lifestyle factors, benign prostatic hyperplasia and
lower urinary tract symptoms. Curr Opin Urol. 2011;21:1-4.
22.Maserejian NN, Kupelian V, Miyasato G, et al. Are physical
activity, smoking and alcohol consumption associated with
lower urinary tract symptoms in men or women? Results
from a population based observational study. J Urol.
2012;188(2):490-495.
23.Parsons JK, Messer K, White M, et al. Obesity increases and
physical activity decreases lower urinary tract symptom risk in
older men: the Osteoporotic Fractures in Men study. Eur Urol.
2011;60(6):1173-1180.
24.
International Diabetes Federation. IDF worldwide definition
of the metabolic syndrome. http://www.idf.org/metabolicsyndrome. Accessed August 23, 2014.
31
Refresher Corner
Heart Metab. (2015) 66:32-36
Evaluation of metabolic syndrome
and male sexual dysfunction
Joel J. Heidelbaugh, MD1; Martin M. Miner, MD2
Clinical Professor, Departments of Family Medicine and Urology, University of Michigan Medical School,
Ann Arbor, MI, USA;
2
Clinical Associate Professor, Departments of Family Medicine and Urology, Warren Alpert School of Medicine,
Brown University, Men’s Health Center, The Miriam Hospital, 164 Summit Ave, Providence, RI, USA
1
Correspondence: Joel J. Heidelbaugh, Ypsilanti Health Center, 200 Arnet Suite 200, Ypsilanti, Michigan, 48198, USA
E-mail: jheidel@umich.edu
Abstract
Cardiovascular disease and erectile dysfunction are commonly encountered disorders in men of
advancing age that share a common pathophysiologic pathway with endothelial dysfunction. Metabolic
syndrome and its various components play pivotal roles in the development of both cardiovascular
disease and erectile dysfunction. The evaluation and management of cardiovascular risk in men with
vasculogenic erectile dysfunction, but no known underlying cardiovascular disease, can include exercise stress testing, determining the coronary artery calcium score, and measuring carotid intima-media
thickness. Knowledge of potential underlying increased cardiometabolic risks can alert the clinician
toward appropriate risk stratification and evaluation to minimize future coronary events. L Heart Metab.
2015;66:32-36
Keywords: cardiometabolic risk; erectile dysfunction; male sexual dysfunction; metabolic syndrome
C
ardiovascular disease (CVD) is a leading cause
of death in men worldwide. Erectile dysfunction
(ED) is a common disorder in men as they age
that often leads them to engage in medical care in
the absence of underlying and unknown cardiovascular disease or risk equivalents. Several risk factors
overlap for the development of both CVD and ED
including advancing age, smoking, metabolic syndrome (MetS), sedentary lifestyle, abdominal obesity,
visceral adiposity, insulin resistance, hypertension,
hyperlipidemia, and type 2 diabetes mellitus.1-5
Research over the last decade has discovered
common pathophysiologic links between CVD and
ED including endothelial dysfunction,6 patterns of
32
systemic inflammation,7 and low serum total testosterone.8 A population-based, longitudinal study of
ED and future risk of CVD determined that when accounting for common cardiovascular risk factors, ED
is associated with a 45% to 80% increased risk of
coronary artery disease (CAD).9-11
The Princeton III Consensus Recommendations,12
which serve as an evidence-based guideline for the
management of CVD and ED, have created a platform upon which clinicians can risk stratify men to
establish the presence of vasculogenic ED and the
volume of subclinical atherosclerotic burden. Novel
criteria have emerged in understanding the relationship between MetS and ED relative to the prediction
Heart Metab. (2015) 66:32-36
Abbreviations
CAD: coronary artery disease; CIMT: carotid intimamedia thickness; CVD: cardiovascular disease; ED:
erectile dysfunction; EST: exercise stress testing; HDL:
high-density lipoprotein; MetS: metabolic syndrome;
NO: nitric oxide
of CVD events that may not be discovered by the traditional Framingham Risk Score risk stratification.
The metabolic syndrome
MetS is commonly defined by a cluster of overlapping
factors including dyslipidemia (eg, elevated triglycerides and apolipoprotein B [apoB]–containing lipoproteins, low levels of high-density lipoprotein [HDL]
cholesterol), hypertension, and deregulated glucose
homeostasis) that directly increase the risk of coronary heart disease and other forms of cardiovascular
atherosclerotic disease. In addition to the many clinical implications of MetS, there are still no universally
accepted pathogenic mechanism(s) or consensus diagnostic criteria. The most current definition of MetS
incorporates the International Diabetes Federation
(IDF) and American Heart Association/National Heart,
Lung, and Blood Institute (AHA/NHLBI) definitions and
requires a patient to have any three of the following five
conditions13: (i) waist circumference >40 inches in men
and >35 inches in women; (ii) triglycerides >150 mg/
dL; (iii) HDL <40 mg/dL; (iv) blood pressure >135/85
mm Hg; and (v) fasting glucose >100 mg/dL.
ED has been causally linked to multiple aspects of
the MetS including overall CVD risk, type 2 diabetes
mellitus, hypertension, and visceral adiposity.14-19 Several interrelated mechanisms have been proposed to
explain the observed relationship between the MetS
and ED. The most commonly suggested mechanism
is a low serum testosterone level, which has been
shown to be associated with both moderate and severe degrees of ED via diminished nitric oxide (NO)
synthesis.20 Increasing α-adrenergic activity has been
linked to several established aspects of the MetS and
could explain the link between the MetS and ED.21
Cardiovascular evaluation of erectile dysfunction
Evaluation of subclinical CVD in men at low to intermediate risk via noninvasive testing for underlying cardio-
Heidelbaugh and Miner
Evaluation of metabolic syndrome and male sexual dysfunction
vascular disease provides a useful strategy in identifying CAD in men with ED, MetS, and type 2 diabetes
mellitus.22,23 ED and CVD, specifically CAD, have the
common denominator of endothelial dysfunction. Several studies have determined that ED may precede a
clinically significant CAD event by a period estimated
between 2 and 5 years and at an average of 3 years.24,25
Reported symptoms of ED also have the ability to predict the likelihood of an acute coronary syndrome as
well as increased mortality, suggesting the rupture of
an asymptomatic coronary plaque. Figure 1 provides
an algorithm for the evaluation and management of
cardiovascular risk in men with vasculogenic erectile
dysfunction, but no known cardiovascular disease recommended for the primary care physician.26
Exercise stress testing
A prospective trial of 65 men with physical ED and no
symptoms of CAD were screened for CVD via exercise stress testing (EST) and multidetector computed
tomography, which aims to detect subclinical plaque
formation that may be at risk of rupture and that does
Vasculogenic erectile dysfunction patient
with no known cardiovascular disease
Initial risk stratification*
Low risk
(≤5%)
High risk
(≥20%)
Intermediate risk
(>5% to <20%)
Exercise stress testing
Normal
Consider carotid intima-media
thickness, ankle-brachial index,
or coronary artery calcium scoring
Abnormal
Normal
Risk factor
management
Risk factor
management;
consider emerging
prognostic markers
(eg, testosterone)
Abnormal
Risk factor
management;
refer to
cardiologist
Fig. 1 Evaluation and management of cardiovascular risk in men
with vasculogenic erectile dysfunction, but no known cardiovascular
disease recommended for the primary care physician. *Based on
the Framingham Risk Score.
Modified from reference 26: Miner M et al. Am J Med. 2014;127(3):174182. © 2014, Elsevier Inc.
33
Heidelbaugh and Miner Evaluation of metabolic syndrome and male sexual dysfunction
not have a significant luminal stenosis to negatively influence the EST.27 In three men, the exercise electrocardiogram was borderline abnormal and in 62 men
it was normal. CT calcium was present in 53 men
(score range 5 to 1671) and noncalcified plaque was
present in seven men. Thus, the estimated window
of 2 to 5 years between ED and a clinically significant
CAD event offers an opportunity for aggressive risk
factor reduction, and should, thus, be a routine component in any cardiovascular risk calculator.
Carotid intima-media thickness
Carotid intima-media thickness (CIMT) has been proposed as a possible measurement of determination
of risk for ED. The American College of Cardiology
Foundation (ACCF)/AHA,22 and, more emphatically,
the Society for Heart Attack Prevention and Eradication Task Force,28 support assessment during evaluation of patients at intermediate risk for underlying
CVD. One trial found that 50% of 136 asymptomatic
subjects (mean age, 57±11 years) with no history of
vascular events and a Framingham Risk Score less
than 10% had CIMT ≥75th percentile.29 The challenge
with interpreting this data is the assumed extrapolation to ED as a risk factor for CVD. Another study of
32 men with MetS compared with 29 healthy controls
yielded a higher prevalence and severity of ED in men
with MetS, as scores on the International Index of
Erectile Dysfunction (IIEF-5) correlated inversely with
CIMT.30
Coronary artery calcium scoring
Coronary artery calcium (CAC) scoring has been validated prospectively in several trials as a predictor of
CVD. A recent review of four major trials concluded
that CAC is the strongest marker for clinical risk prediction and is the most likely to positively predict future clinical cardiovascular outcomes.31 CAC scores
are considered more accurately predictive of CVD
outcomes compared with CIMT measurements and
have been shown to be independently predictive of
mortality in men less than 45 years of age and in the
elderly via a cohort study of over 44 000 subjects.32
One trial, which consisted of EST and CAC scoring in
20 men aged 39 to 69 years with ED and no cardiac
symptoms or known underlying CVD, yielded CAC
scores of >50 in 11 men, all of whom were found to
34
Heart Metab. (2015) 66:32-36
have angiographic evidence of CAD on coronary CT
angiography, nine of whom had normal ESTs.33 The
authors concluded that ED is a bona fide predictor of
subclinical, non–flow-limiting CAD that was not detectable via EST, and that CAC coupled with coronary
CT angiography may help detect subclinical CAD in
men with normal ESTs.
Testosterone and the metabolic syndrome
Increasing evidence supports the notion that testosterone supplementation can have a positive effect in
men with MetS and ED. The Princeton III Consensus
Recommendations from 2012 posit that testosterone
levels should be measured in all men with physical
ED.12 This statement is in contrast with the American College of Physicians guideline from 2009 that
neither recommend for or against hormonal testing
and/or treatment in men with ED.34 The TIMES2 study
(Testosterone replacement In hypogonadal Men with
Either metabolic Syndrome or type 2 diabetes), a
large randomized trial, demonstrated that 6 to 12
months of transdermal testosterone replacement
therapy significantly improved insulin resistance and
glycemic control in hypogonadal men with diabetes.35
A meta-analysis of five randomized controlled trials
determined that men who received testosterone replacement therapy for an average of 58 weeks demonstrated significant benefit in the reduction of fasting
serum glucose, insulin, and triglyceride levels as well
as waist circumference.36 It was noted, however, that
testosterone replacement therapy, in this meta-analysis, was not found to have an appreciable improvement in HDL, blood pressure, or body mass index.
Conclusion
Growing evidence supports the relationship between
MetS and ED. Additional research will further investigate biomarkers relative to visceral adiposity, testosterone, dyslipidemia, and other inflammatory and
endocrine factors that place men at increased risk of
a hopefully reversible metabolic disease. Clinicians in
both primary and specialty care require the inquisitiveness to investigate each male patient’s risks and
offer appropriate evidence-based risk stratification.
We recommend the following metabolic investigation
in men with ED, in conjunction with the 2013 atherosclerotic cardiovascular disease (ASCVD) Risk Esti-
Heart Metab. (2015) 66:32-36
mator37 (in conjunction with the AHA and AAC) to determine 10-year and lifetime ASCVD risk (myocardial
infarction and cardiovascular accident) for men aged
40 to 59 years:
• Abdominal waist circumference.
• Blood pressure and heart rate.
• Fasting serum insulin and glucose levels.
•Baseline renal function (serum blood urea nitrogen
and creatinine).
• Fasting serum lipid profile.
• Morning serum total testosterone level.
• Serum high-sensitivity C-reactive protein.
• Serum 25-hydroxyvitamin D.
Men’s health specialists are uniquely poised to educate their male patients on both cardiometabolic risk
factors as well as lifestyle strategies to reduce risk.
Engaging men to understand the link between MetS
and ED can serve as a powerful motivating factor in
promoting such changes. L
REFERENCES
1.
Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ,
McKinlay JB. Impotence and its medical and psychosocial
correlates: results of the Massachusetts Male Aging Study. J
Urol. 1994;151:54-61.
2.
Hatzimouratidis K, Amar E, Eardley I, et al. Guidelines on
male sexual dysfunction: erectile dysfunction and premature
ejaculation. Eur Urol. 2010;57:804-814.
3.Guay A, Jacobson J. The relationship between testosterone
levels, the metabolic syndrome (by two criteria), and insulin
resistance in a population of men with organic erectile dysfunction. J Sex Med. 2007;4:1046-1055.
4.Seftel AD, Sun P, Swindle R. The prevalence of hypertension,
hyperlipidemia, diabetes mellitus and depression in men with
erectile dysfunction. J Urol. 2004;171:2341-2345.
5.Sun P, Swindle R. Are men with erectile dysfunction more likely
to have hypertension than men without erectile dysfunction? A
naturalistic national cohort study. J Urol. 2005;174:244-248.
6.Guay AT. ED2: erectile dysfunction = endothelial dysfunction.
Endocrinol Metab Clin North Am. 2007;36:453-463.
7.
Vlachopoulos C, Aznaouridis K, Ioakeimidis N, et al.
Unfavourable endothelial and inflammatory state in erectile
dysfunction patients with or without coronary artery disease.
Eur Heart J. 2006;27:2640-2648.
8.
Yassin AA, Akhras F, El-Sakka AI, Saad F. Cardiovascular
diseases and erectile dysfunction: the two faces of the coin of
androgen deficiency. Andrologia. 2011;43:1-8.
9.Inman BA, St Sauver JL, Jacobson DJ, et al. A populationbased, longitudinal study of erectile dysfunction and future
coronary artery disease. Mayo Clin Proc. 2009;84:108-113.
10.
Ponholzer A, Temml C, Obermayr R, Wehrberger C,
Madersbacher S. Is erectile dysfunction an indicator for
increased risk of coronary heart disease and stroke? Eur Urol.
2005;48(3):512-518.
11.
Thompson IM, Tamgen CM, Goodman PJ, Probstfield JL,
Moinpour CM, Coltman CA. Erectile dysfunction and subsequent cardiovascular disease. JAMA. 2005;294:2996-3002.
12.
Nehra A, Jackson G, Miner M, et al. The Princeton III
Consensus recommendations for the management of erectile
Heidelbaugh and Miner
Evaluation of metabolic syndrome and male sexual dysfunction
dysfunction and cardiovascular disease. Mayo Clin Proc.
2012;87(8):766-778.
13.Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International
Diabetes Task Force on Epidemiology and Prevention; National
Heart, Lung, and Blood Institute; American Heart Association;
World Heart Federation; International Atherosclerosis Society;
and International Association for the Study of Obesity.
Circulation. 2009;120:1640-1645.
14.Kupelian V, Shabsigh R, Araujo AB, O’Donnell AB, McKinlay
JB. Erectile dysfunction as a predictor of the metabolic syndrome in aging men: results from the Massachusetts male
aging study. J Urol. 2006;176:222-226.
15.Tomada N, Tomada I, Botelho F, Cruz F, Vendeira P. Are all
metabolic syndrome components responsible for penile
hemodynamics impairment in patients with erectile dysfunction? The role of body fat mass assessment. J Sex Med.
2011;8:831-839.
16.
Aslan Y, Sezgin T, Tuncel A, Tekdogan UY, Guler S, Atan
A. Is type 2 diabetes mellitus a cause of severe erectile
dysfunction in patients with metabolic syndrome? Urology.
2009;74:561-564.
17.
Bal K, Oder M, Sahin AS, et al. Prevalence of metabolic
syndrome and its association with erectile dysfunction among
urologic patients: metabolic backgrounds of erectile dysfunction. Urology. 2007;69:356-360.
18.Jackson G. Sexual response in cardiovascular disease. J Sex
Res. 2009;46:233-236.
19.Al-Hunayan A, Al-Mutar M, Kehind EO, Thalib L, Al-Ghorory M.
The prevalence and predictors of erectile dysfunction in men
with newly diagnosed with type 2 diabetes mellitus. BJU Int.
2007;99:130-134.
20.Reilly CM, Zamorano P, Stopper VS, Mills TM. Androgenic
regulation of NO availability in rat penile erection. J Androl.
1997;18:110-115.
21.Chen CJ, Kuo TB, Tseng YJ, Yang CC. Combined cardiac
sympathetic excitation and vagal impairment in patients
with non‑organic erectile dysfunction. Clin Neurophysiol.
2009;120:348-352.
22.Greenland P, Alpert JS, Beller, GA, et al. 2010 ACCF/AHA
guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology
Foundation/American Heart Association Task Force on
Practice Guidelines. Circulation. 2010;122:e584-e636.
23.Gazzaruso C, Giordanetti S, De Amici E, et al. Relationship
between erectile dysfunction and silent myocardial ischemia in
apparently uncomplicated type 2 diabetic patients. Circulation.
2004;110:22-26.
24.Montorsi P, Ravagnani PM, Galli S, et al. Association between
erectile dysfunction and coronary artery disease. Role of
coronary clinical presentation and extent of coronary vessels
involvement: the COBRA trial. Eur Heart J. 2006;27:2632-2639.
25.
Baumhakel M, Bohm M. Erectile dysfunction correlates
with left ventricular function and precedes cardiovascular
events in cardiovascular high-risk patients. Int J Clin Pract.
2007;61:361-366.
26.Miner M, Nehra A, Jackson G, et al. All men with vasculogenic
erectile dysfunction require a cardiovascular workup. Am J
Med. 2014;127(3):174-182.
27.Jackson G. Erectile dysfunction and asymptomatic coronary
artery disease: frequently detected by computed tomography
coronary angiography but not by exercise electrocardiography.
Int J Clin Pract. 2013;67(11):1159-1162.
28.Naghavi M, Falk E, Hecht HS, et al. From vulnerable plaque
to vulnerable patient—Part III: executive summary of the
Screening for Heart Attack Prevention and Education (SHAPE)
Task Force report. Am J Cardiol. 2006;98:2H-15H.
29.Naqvi TZ, Mendoza F, Rafii F, et al. High prevalence of ultrasound detected carotid atherosclerosis in subjects with low
35
Heidelbaugh and Miner Evaluation of metabolic syndrome and male sexual dysfunction
Framingham risk score: potential implications for screening
for subclinical atherosclerosis. J Am Soc Echocardiogr.
2010;23:809-815.
30.Unal M, Aksoy DY, Aydin Y, et al. Carotid artery intima-media
thickness and erectile dysfunction in patients with metabolic
syndrome. Med Sci Monit. 2014;20:884-888.
31.Barth AS, Abd TT, Blumenthal RS, et al. Comparative effectiveness of risk markers for cardiovascular risk assessment in
intermediate-risk individuals: coronary artery calcium vs “the
rest”. Curr Cardiovasc Imaging Rep. 2013;6:203-210.
32.Tota-Maharaj R, Blaha MJ. Coronary artery calcium for the prediction of mortality in young adults <45 years old and elderly
adults >75 years old. Eur Heart J. 2012;33:2955-2962.
33.Jackson G, Padley S. Erectile dysfunction and silent coronary
artery disease: abnormal computed tomography coronary
angiogram in the presence of normal exercise ECGs. Int J Clin
Pract. 2008;62:973-976.
36
Heart Metab. (2015) 66:32-36
34.Qaseem A, Snow V, Denberg TD, et al. Hormonal testing and
pharmacologic treatment of erectile dysfunction: a clinical
practice guideline from the American College of Physicians.
Ann Intern Med. 2009;151(9):639-649.
35.Jones TH, Arver S, Behre HM, et al. Testosterone replacement in hypogonadal men with Type 2 diabetes and/or
metabolic syndrome (the TIMES2 study). Diabetes Care.
2011;34(4):828-837.
36.
Corona G, Monami M, Rastrelli G, et al. Testosterone and
metabolic syndrome: a meta-analysis study. J Sex Med.
2011;8(1):272-283.
37.
2013 Prevention Guidelines ASCVD Risk Estimator.
Cardiosource. American College of Cardiology. http://
cardiosource.org/science-and-quality/practice-guidelinesand-quality-standards/2013-prevention-guideline-tools.aspx.
Accessed August 11, 2014.
Hot Topics
Heart Metab. (2015) 66:37-40
Testosterone replacement therapy:
cardiovascular benefits and possible
risks
Geoffrey Hackett, MD
Professor of Men’s Health, Heartlands Hospital, Birmingham, UK; Bedfordshires and Hertsfordshire Postgraduate
Medical School, Bedfordshire, UK
Correspondence: Geoffrey Hackett, MD, Holly Cottage Clinic, Fisherwick, Lichfield, WS14 9JL, United Kingdom
E-mail: geoff.hackett@virgin.net
R
ecent guidelines suggest that a level of
total testosterone less than 8 nmol/L or
free testosterone less than 180 pmol/L in
conjunction with bothersome symptoms requires
testosterone replacement therapy (TRT), whereas
total testosterone greater than 12 nmol/L or free
testosterone greater than 225 pmol/L does not.
Between these levels, a trial therapy for a minimum
of 6 months should be considered based on symptoms without defining what constitutes a satisfactory response.1,2
Effect of low testosterone on surrogate markers for
cardiovascular risk
Low testosterone and increased mortality
The effects of testosterone replacement therapy on
cardiovascular mortality
There is increasing evidence from multiple long-term
studies that testosterone deficiency syndrome (TDS)
is associated with increased cardiovascular and allcause mortality, especially in populations with established cardiovascular disease and type 2 diabetes.
Haring et al3 looked at the data in terms of several
models and found that, even after strict adjustment
for comorbidities, there was a consistent link between mortality risk and testosterone level throughout the studies, but that this did not prove causation
(Table I).4-9
The EMAS group (European Male Aging Study)10
recently reported 4.3-year follow-up data on 2599
men aged 40 to 79 years and concluded that men
with a baseline total testosterone ≤8 nmol/L and sexual symptoms had a 3-fold increased mortality and
a 5-fold increased risk of cancer death. The authors
concluded that there are a small number of men with
low testosterone at considerable risk of early death.
Several of the above studies have shown reductions in
waist circumference, visceral fat, and body mass index
(BMI). There is a high level of evidence that TRT improves
insulin resistance and reduces HbA1c by approximately
0.89% by 18 months in men with poorly controlled diabetes.11 There is also a high level of evidence for reductions in total cholesterol, weight, BMI, visceral fat, and
improvement in lean muscle mass.12
A prospective recent study of 587 men with type 2
diabetes involved a 5.8-year follow-up. Low testosterone was defined as total testosterone <10.4 nmol/L.
The mortality rate was 20% in the untreated group,
9.1% in the normal group independent of comorbidities and therapies, and 8.6% in the treated group.13
A retrospective US study involved 1031 men with
372 undergoing TRT. The cumulative mortality was
21% in the untreated group vs 10% in the treated
group (P=0.001) with the greatest effect in younger
men and those with type 2 diabetes.14
A recent retrospective US study was conducted
on 8709 men15 with baseline total testosterone of
10.4 nmol undergoing coronary angiography. In the
cohort of 7486 patients not receiving testosterone
therapy, 681 died, 420 had myocardial infarctions,
and 486 had strokes. Among the 1223 patients receiving testosterone therapy, 67 died, 23 had myo-
37
Hackett
Testosterone replacement therapy
Heart Metab. (2015) 66:37-40
Abbreviations
ED: erectile dysfunction; EMAS: European Male Aging
Study; TDS: testosterone deficiency syndrome; TRT:
testosterone replacement therapy
cardial infarctions, and 33 had strokes. At first sight,
these results would suggest benefit, but a complex
statistical analysis reversed the trend and concluded that there was a greater risk in the TRT group.
There were concerns that 1132 patients experiencing
events were excluded because they were prescribed
TRT after the event, when surely these patients
should have been included in the untreated group.
The authors later conceded that this number should
have been 128 and conceded that 104 women had
been wrongly entered into the study.
The baseline total testosterone was 1 nmol/L lower
in the treated group and symptoms were not considered. Men were likely to be treated if they suffered from
erectile dysfunction (ED), an independent marker for
cardiac events. Only 60% had any record of a followup testosterone level, and in the men with a follow-up,
the mean treatment level was 10.2 nmol/L, suggesting
suboptimal therapy. The level of criticism of this paper
led to widespread demands for retraction.
Another recent US publication16 looked at prescribing data in men treated with TRT, but with no
data on blood results or symptoms. Coronary events
were assessed in the 12 months before and 3 months
after therapy, even though benefits would take much
longer. Curiously, a cohort of men taking phosphodiesterase type 5 inhibitors (PDE5 inhibitors) were considered to be the “control” group even though these
drugs have been shown to increase testosterone.
Although widely quoted in public media, the several
design flaws and statistical analyses have discredited
this paper.
The TOM study (Testosterone in Older Men with
mobility limitations)17 involved frail elderly men with
multiple comorbidities treated with 100 mg of testosterone gel, which was increased to 150 mg after 2
weeks. The treatment group had significantly greater
risk factors at baseline. The study was stopped prematurely due to 23 vs 5 adverse events for active vs
placebo (one death). Strangely, peripheral edema and
a rise in blood pressure were classified as cardiovascular events along with self-reported syncope.
Anderson et al analyzed data from 5695 men
(mean age 62) on TRT over a 5-year period on the
basis of levels of total testosterone achieved by therapy (Figure 1).18 They showed a significant reduction
in all-cause mortality where therapeutic levels were
achieved and no evidence of harm with levels in the
upper range. There was no reduction in the number
of myocardial infarctions or stroke. This suggests that
the major impact of TRT is on survival from events
rather than absolute numbers.18
Wang study ;
TT <8.0 nmol/L
(230 ng/dL)
Rancho
Bernardo
study6;
TT <8.36
nmol/L
(241 ng/dL)
Male Veterans
Study7;
TT <8.7
nmol/L
(250 ng/dL)
HIM8;
TT <10.41
nmol/L
(300 ng/dL)
EPIC9;
TT <12.5
nmol/L
(360 ng/dL)
34
69
82
98
241
474
Model 1, HR
(95% CI)
1.59
(0.83; 4.02)
1.96
(0.93; 3.63)
2.21
(1.26; 3.89)**
2.24
(1.41; 3.57)**
1.33
(0.93; 1.90)
1.28
(0.95; 1.72)
2.21
(1.40; 3.49)**
Model 2, HR
(95% CI)
2.12
(1.01; 4.46)*
2.08
(1.12; 3.86)*
2.33
(1.33; 4.12)**
2.10
(1.34; 3.29)**
1.28
(0.89; 1.84)
1.20
(0.88; 1.62)
2.26
(1.43; 3.59)**
Model 3, HR
(95% CI)
2.50
(1.18; 5.27)*
2.24
(1.21; 4.17)*
2.53
(1.43; 4.47)**
2.32
(1.38; 3.89)**
1.37
(0.95; 1.99)
1.28
(1.93; 1.75)
2.35
(1.47; 3.74)***
Model 4, HR
(95% CI)
2.68
(1.19; 6.04)*
2.13
(1.06; 4.26)*
2.56
(1.38; 4.76)**
1.92
(1.18; 3.14)**
1.11
(0.72; 1.69)
1.10
(0.78; 1.56)
2.25
(1.35; 3.75)**
Cut-off
for the
definition
of low TT
MMAS4;
TT <6.94
nmol/L
(200 ng/dL)
Low TT (n)
5
Age-specific
cut-off
<10th
percentile
Table I Association of low total testosterone (TT) levels with all-cause mortality by different cut-offs from recent studies. Model 1: adjusted for
age. Model 2: adjusted for age and WC. Model 3: adjusted for model 2, smoking (three categories), high-risk alcohol use, and physical activity.
Model 4: adjusted for model 3, renal insufficiency, and DHEAS.
Abbreviation: CI, 95% confidence interval; DHEAS, dehydroepiandrosterone sulfate; EPIC, European Prospective Investigation into Cancer; HIM, Hypogonadism
In Men study; HR, hazard ratio; MMAS, Massachusetts Male Aging Study; WC, waist circumference. *P=0.05, **P=0.01, ***P=0.001.
Modified from reference 3: Haring R et al. Eur Heart J. 2010;31:1494-1501. © 2010, the author.
38
Heart Metab. (2015) 66:37-40
Hackett
Testosterone replacement therapy
Testosterone and erectile dysfunction
Conclusions
ED is an established marker for future cardiovascular
risk and the major presenting symptom leading to a
diagnosis of low testosterone. Current guidelines suggest that all patients presenting with ED, irrespective
of age, should be screened for low testosterone, as
it is a potentially curable cause of ED, especially in
men without other comorbidities. National Institute for
Health and Care Excellence (NICE) guidelines and the
UK general practice contract19 have suggested that all
men with type 2 diabetes be assessed for ED annually;
increased demand for testosterone supplementation
will be a natural consequence of this correction of previous underdiagnosis and undertreatment.
Low levels of testosterone are manifested by ED, reduced sexual desire, and loss of morning erections. Increasing numbers of men are being diagnosed with ED
that requires treatment according to published guidelines. Increasing evidence shows that testosterone
deficiency is associated with increased cardiovascular
and all-cause mortality. Recent data suggest that testosterone replacement therapy may reduce cardiovascular mortality as well as improving multiple surrogate
markers for cardiovascular events. Specific clinical trials of testosterone replacement therapy are needed in
selected populations, but in the meantime, we must
treat patients based on the best current evidence. L
A
20
Event rate (%)
P<0.0001
P<0.0001
REFERENCES
P=0.06
16.7
15
P<0.0001
10
P=0.001
n=191
P=0.20
7.4
6.3
5.5
5
n=198
2.7
n=72
1.9
n=72
0
n=105
n=37
1 year
B
4
3 years
Low f/u T <212 ng/dL, 14% treated, n=1142
Normal f/u T 212-742 ng/dL, 100% treated, n=2634
High f/u T >742 ng/dL, 100% treated, n=1919
Event rate (%)
3
P=0.97
P=0.21
P=0.03
P=0.38
P=0.36
P=0.31
2.1
2
1.4
1.2
1
n=14
0
0.4
n=11
1 year
0.6
n=24
n=36
1.6
n=31
n=11
3 years
Fig. 1 Testosterone replacement therapy reduces major adverse
cardiovascular events and death, but not absolute rate of myocardial infarction and cerebrovascular accident. Cardiovascular
impact of testosterone therapy in 5695 men with low testosterone
levels. (A) Event rates of major adverse cardiovascular events and
death. (B) Event rates of major adverse cardiovascular events and
myocardial infarction.
Abbreviations: f/u, follow-up; T, testosterone.
Based on data from reference 18: Anderson et al. Circulation. 2014;130:A13220.
1.Wang C, Nieschlag E, Swerdloff RS, et al. Investigation, treatment, and monitoring of late-onset hypogonadism in males:
ISA, ISSAM, EAU, EAA, and ASA recommendations. Eur Urol.
2009;55:121-130.
2.
Nehra, A. Jackson G, Miner M, et al. The Princeton III
Consensus recommendations for the management of erectile
dysfunction and cardiovascular disease. Mayo Clin Proc.
2013;87:766-778.
3.Haring R, Volzke H, Steveling A, et al. Low serum testosterone levels are associated with increased risk of mortality in
a population-based cohort of men aged 20-79. Eur Heart J.
2010;31:1494-1501.
4.Tivesten A, Vandenput L, Labrie F, et al. Low serum testosterone and estradiol predict mortality in elderly men. J Clin
Endocrinol Metab. 2009;94:2482-2488.
5.Mazat L, Lafont S, Berr C, et al. Prospective measurements
of dehydroepiandrosterone sulfate in a cohort of elderly
subjects: relationship to gender, subjective health, smoking habits, and 10-year mortality. Proc Natl Acad Sci USA.
2001;98:8145-8150.
6.Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab.
2008;93:68-75.
7.Basaria S, Dobs AS. Testosterone making an entry into the
cardiometabolic world. Circulation. 2007;116:2658-2661.
8.Laaksonen DE, Niskanen L, Punnonen K, et al. Testosterone
and sex hormone-binding globulin predict the metabolic
syndrome and diabetes in middle-aged men. Diabetes Care.
2004;27:1036-1041.
9.Khaw KT, Dowsett M, Folkerd E, et al. Endogenous testosterone and mortality due to all causes, cardiovascular disease,
and cancer in men: European prospective investigation into
cancer in Norfolk (EPIC-Norfolk) Prospective Population Study.
Circulation. 2007;116:2694-2701.
10.Pye SR, Huhtaniemi IT, Finn JD, et al. Late-onset hypogonadism and mortality in aging men. J Clin Endocrinol Metab.
2014;99(4):1357-1366.
11. Hackett G, Cole N, Bhartia M, Kennedy D, Raju J, Wilkinson
P; BLAST Study Group. Testosterone replacement therapy
improves metabolic parameters in hypogonadal men with type
2 diabetes but not in men with coexisting depression: The
BLAST Study. J Sex Med. 2014;11(3):840:856.
39
Hackett
Testosterone replacement therapy
12.Traish AM, Haider A, Doros G, Saad F. Long-term testosterone
therapy in hypogonadal men ameliorates elements of the
metabolic syndrome: an observational, long-term registry
study. Int J Clin Pract. 2013;68(3):314-329.
13.Muraleedharan V, Marsh H, Kapoor D, Channer KS, Jones
TH. Testosterone deficiency is associated with increased
risk of mortality and testosterone replacement improves
survival in men with type 2 diabetes. Eur J Endocrinol.
2013;169(6):725-733.
14.Shores M, Smith NL, Forsberg CW, Anawalt BD, Marsumoto
AM. Testosterone treatment and mortality in men with low
testosterone levels. J Clin Endocrin Metab. 2012;97(6):20502058.
15.
Vigen R, O’Donnell CI, Baron AE, et al. Association of
testosterone therapy with mortality, myocardial infarction,
40
Heart Metab. (2015) 66:37-40
and stroke in men with low testosterone levels. JAMA.
2013;310(17):1829-1836.
16.Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of
non-fatal myocardial infarction following testosterone therapy
prescription in men. PLoS One. 2014;9:e85805.
17.Basaria S, Coviello AD, Travison TG, et al. Adverse events
associated with testosterone administration. New Eng J Med.
2010;363(2):109-122.
18. Anderson JL, May HT, Lappé DL, Blair TL, Le VT, Muhlestein
JB. Cardiovascular impact of testosterone therapy in men
with low testosterone levels [abstract 13220]. Circulation.
2014;130:A13220.
19.Home P, Mant J, Diaz J, Turner C; Guideline Development
Group. Management of type 2 diabetes: summary of updated
NICE guidance. BMJ. 2008;336:1306-1308.
Glossary
Drugs affecting testosterone
Drugs affecting testosterone are any medication/agent
that influences circulating testosterone levels and
includes antihypertensives, and agents such as statins
(ie, atorvastatin and simvastatin) and spironolactone,
which decrease testosterone levels, whereas the ovulation inducer clomiphene increases testosterone levels.
Erectile dysfunction
Erectile dysfunction is a form of sexual dysfunction
that involves an inability of the penis to maintain an
erection during sexual activity. Erectile dysfunction
is commonly treated with phosphodiesterase type
5 inhibitors such as sildenafil (Viagra), which prevent
the breakdown of cyclic guanosine monophosphate
and relaxes smooth muscle cells in the blood vessels
supplying the corpus cavernosum of the penis.
Follicle-stimulating hormone
Follicle-stimulating hormone (FSH) is a heterodimeric
glycoprotein consisting of α and β subunits, and has
a molecular weight of 28-29 kDa. FSH is synthesized
and released by gonadotrophs in the anterior pituitary
in response to stimulation by gonadotropin-releasing
hormone, itself released from hypothalamic neurons
into the capillary networks of the hypothalamic median
eminence and lower infundibular trunk. In males, FSH
stimulates Sertoli cells in the testis, which are critical
to germ-cell development. In females, it acts on the
ovaries to stimulate follicle development and is the
main hormone controlling estrogen secretion.
Hormones
Hormones are chemical substances classically
released from ductless cells into the circulation (can
also be released into the interstitial fluid), and elicit
effects at target cells. These effects may occur at distant target cells, nearby cells (paracrine), or the same
cell (autocrine). Hormones regulate and coordinate
biological functions via cell-to-cell communication and
thus contribute to the maintenance of homeostasis.
Luteinizing hormone
Luteinizing hormone (LH) is a heterodimeric glycoprotein consisting of α and β subunits, and has a
molecular weight of 28-29 kDa. LH is synthesized
and released by gonadotrophs in the anterior pituitary
in response to stimulation by gonadotropin releasing
hormone, itself released from hypothalamic neurons
into the capillary networks of the hypothalamic median
Heart Metab. (2015) 66:41
eminence and lower infundibular trunk. In males, LH
stimulates Leydig cells in the testis to produce testosterone. In females, LH causes ovulation, the formation
of the corpus luteum, and stimulation of the ovaries to
produce estrogen and progesterone.
Pituitary gland
The pituitary gland is a pea-sized endocrine gland
consisting of three lobes (anterior, intermediate, and
posterior) that protrudes from the bottom of the hypothalamus of the brain, and synthesizes and secretes
a number of hormones that control/regulate growth
(human growth hormone), blood pressure (vasopressin), sexual reproduction (FSH and LH), and pregnancy
(oxytocin).
Prostate-specific antigen
Prostate-specific antigen (PSA) is a member of the
kallikrein (KLK)-related peptidase family, and is also
known as KLK3. PSA is a serine protease synthesized
in prostate cells as 261 amino acid preproprotein,
which is subsequently processed to a 244 amino acid
pro-PSA. Pro-PSA is processed via cleavage of a
seven amino acid peptide to yield mature/active PSA,
which circulates as an 80-90 kDa complex with α-1antichymotrypsin. PSA is widely used as a tumour
marker, as cancerous prostate tissue releases up to
10-fold greater amounts when compared with normal
and benign hyperplastic prostate tissue, despite similar levels of overall expression.
Testosterone
Testosterone is an anabolic steroid hormone (derived
from cholesterol). In males, testosterone is required for
the development of secondary sexual characteristics
and spermatogenesis. In the bloodstream, the majority of testosterone is tightly bound to sex hormonebinding globulin (SHBG), weakly bound to albumin (and
other proteins), or freely circulating. Only a minor fraction of testosterone in the circulation is free/nonprotein
bound. Testosterone that is not bound to SHBG (ie,
albumin bound and free testosterone) is considered to
be bioavailable. Several algorithms have been developed to calculate free testosterone concentration. If
the circulating concentration of SHBG (nmol/L) and
total testosterone (nmol/L) is measured, an estimate
of circulating free testosterone concentration (nmol/L)
can be calculated as follows:
[Free testosterone] =
[Total Testosterone] (6.11 – 2.38 log10 [SHBG])
In the next issue:
Cardiac biomarkers in ACS
EDITORIAL
M. Marber
ORIGINAL ARTICLES
Using biomarkers to obtain mechanistic insight and guide management in acute
coronary syndrome
K. C. Wollert
Incorporating high-sensitivity cardiac troponin assays into clinical practice:
these assays are your friend
S. Love, Y. Sandoval, F. S. Apple
High biomarkers, but normal angiogram: what next?
S. C. A. M. Bekkers, M. W. Smulders
What can we learn from metabolomics?
F. Baig, M. Mayr
Trimetazidine effects on cardiac biomarkers in
acute coronary syndrome
J. J. Dalal
CASE REPORT
Number 67 - July 2015
Elevated cardiac troponin in a patient with coronary
artery disease: why look harder?
A. Maznyczka, N. Varma, L. Foote, R. Williams,
D. D’Cruz, V. O. Puntmann
REFRESHER CORNER
Defining acute myocardial infarction
K. M. Eggers
Cardiac biomarkers
in ACS
HOT TOPICS
Metabolic markers in predicting acute
cardiovascular events
A. Huqi
G. D. Lopaschuk
67
15 VA 1031 BA
GLOSSARY