REVIEW
Acute Myocardial Infarction in Young
Individuals
Rajiv Gulati, MD, PhD; Atta Behfar, MD, PhD; Jagat Narula, MD, PhD;
Ardaas Kanwar; Amir Lerman, MD; Leslie Cooper, MD;
and Mandeep Singh, MD, MPH
Abstract
Globally, cardiovascular disease remains a major cause of adverse outcomes in young individuals,
unlike its decline in other age groups. This group is not well studied and has a unique risk profile with
less traditional cardiovascular risk factors compared with older populations. Plaque rupture still remains the most common etiology of myocardial infarction, but unique syndromes such as plaque
erosion, coronary microvascular dysfunction, spontaneous coronary artery dissection, and coronary
spasm related to drug use are more prevalent in this age group. Such diversity of diagnosis and
presentation, along with therapeutic implications, underscore the need to study the profile of
myocardial infarction in young persons. We searched PubMed for articles published from 1980 to 218
using the terms acute myocardial infarction, young, plaque rupture, plaque erosion, spontaneous
coronary artery dissection (SCAD), coronary vasospasm, variant or Prinzmetal angina, drug-induced
myocardial infarction, myocarditis, coronary embolism, microvascular dysfunction, MINOCA, and
myocardial infarction in pregnancy and reviewed all the published studies. With the data from this
search, we aim to inform readers of the prevalence, risk factors, presentation, and management of
acute myocardial infarction in young patients and elaborate on special subgroups with diagnostic and
therapeutic challenges. We also outline a parsimonious method designed to simplify management of
these complex patients.
ª 2019 Mayo Foundation for Medical Education and Research
For editorial
comment, see
page 29
From the Department of
Cardiovascular Medicine,
Mayo Clinic, Rochester, MN
(R.G., A.B., A.L., M.S.);
Department of Medicine/
Cardiology, Mount Sinai
Hospital, New York, NY
(J.N.); University of Minnesota, Minneapolis, MN (A.K.);
and Department of Cardiovascular Medicine, Mayo
Clinic, Jacksonville, FL (L.C.).
136
M
ortality from cardiovascular diseases (CVDs) has declined from
2003 to 2013. However, more
than 2000 Americans die of CVD daily, and
a significant proportion of them are younger
than 65 years of age.1 Although the incidence
of acute coronary syndrome (ACS) has
decreased in older populations, younger
men and women who present with acute
myocardial infarction (MI) have not had
similar declines (especially men) in cardiovascular events.2 Most studies have used an
age cutoff of 40 to 45 years to define young patients with CVD. For this review, we will use
an arbitrary cutoff of 55 years or younger to
define young. This demarcation is important
because the risk factor profile of the younger
population is unique, women in general are
premenopausal or perimenopausal, traditional atherosclerotic cardiovascular risk
n
Mayo Clin Proc. 2020;95(1):136-156
factors are less common compared with older
populations, and, importantly, age-related
multimorbidity, frailty, and poor cognition
are encountered less frequently. Cardiovascular disease, however, remains a major cause of
morbidity and mortality among young individuals globally, even as significant strides
are made in improvement in diagnosis and
therapeutics.3 Current challenges include
atypical and delayed presentation, nonadherence to treatment, and syndromes unique to
this age group. For example, spontaneous
coronary artery dissection (SCAD), vasospastic angina, MI with intact fibrous cap,
and cocaine/methamphetamine use are more
prevalent in the younger age group.
Such diversity of diagnosis and presentation, along with the therapeutic implications,
underscore the need to study the profile of MI
in young persons. We searched PubMed for
Mayo Clin Proc. n January 2020;95(1):136-156 n https://doi.org/10.1016/j.mayocp.2019.05.001
www.mayoclinicproceedings.org n ª 2019 Mayo Foundation for Medical Education and Research
ACUTE MYOCARDIAL INFARCTION IN YOUTH
articles published from 1980 to 2018 using
the terms acute myocardial infarction, young,
plaque rupture, plaque erosion, spontaneous
coronary artery dissection (SCAD), coronary
vasospasm, variant or Prinzmetal angina,
drug-induced myocardial infarction, myocarditis, coronary embolism, microvascular
dysfunction, MINOCA, and myocardial
infarction in pregnancy and reviewed all the
published studies. With the data from this
search, this review aims to inform readers of
the prevalence, risk factors, presentation,
and management of MI in young individuals
and also elaborate on special subgroups with
diagnostic and therapeutic challenges. Most
data are derived from large prospective registries, but readers will find many important
studies with small numbers of enrolled patients, especially among the descriptions of
uncommon etiologies of MI.
Myocardial infarction in young individuals can be grouped into 5 categories: (1)
MI related to traditional cardiovascular risk
factors similar to those in older individuals,
(2) use of recreational drugs such as cocaine
and methamphetamine, (3) MI due to
SCAD, myocarditis, or coronary embolism
(CE), (4) MI due to atheromatous coronary
artery disease (CAD) but without critical coronary stenosis, and (5) coronary vasospasm.
PREVALENCE
Overall, prevalence estimates vary because
the clinical profile of atherosclerotic and nonatherosclerotic phenotypes is poorly defined.
This lack of definition is especially true for patients who present with MI with nonobstructive coronary arteries (MINOCA) because
angiography-based differentiation without
routine intracoronary imaging and nonuniform work-up have led to poor identification
of nonplaque mechanisms.4 There are also
limited data on the incidence of MI in young
patients. The Framingham Heart Study’s 10year follow-up data revealed that the incidence of MI was 12.9, 38.2, and 71.2 per
1000 in men and 2.2, 5.2, and 13.0 per 1000
in women in the age groups of 30 to 34, 35
to 44, and 45 to 54 years, respectively
(Figure 1).5 Of 708 MIs among 5127 participants, more than 25% were silent, and the
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n
ARTICLE HIGHLIGHTS
d
d
d
d
This review informs readers of the prevalence and risk factors
of myocardial infarction in young individuals.
It elaborates on the syndromes unique to younger individuals
presenting with myocardial infarction, such as spontaneous
coronary artery dissection.
It gives a simple diagnostic strategy that rests on detection of
thrombus on coronary angiography.
It summarizes the prevalence of myocardial infarction and gives
simple vignettes that will heighten suspicion of the syndrome.
proportion of unrecognized MIs was higher
in women.
MI Related to Traditional Cardiovascular
Risk Factors in Patients With Atherosclerotic
CAD
Plaque rupture accounts for approximately
60% to 65% of cases of MI in young individuals, and similar to older individuals, it is
the most common cause of MI in this age
group (Figure 2).6 In the United States, each
year more than 30,000 women younger than
55 years are hospitalized with a diagnosis of
MI.7 Hospitalization rates, characteristics of
patients, and short-term survival were studied
in a Nationwide Inpatient Sample of 230,684
hospitalizations from 2001 to 2010. Hospitalization rates for MI did not decline over the
study period (Figure 1).2 Compared with
men, younger women (who represented
25% of MIs) had higher comorbidity, stayed
longer in the hospital, and had higher inhospital mortality (Figure 3). Similar findings
were noted in another study from British
Columbia.8 The authors observed significant
declines in both 30-day mortality and hospital
admissions for MI; however, younger women
had higher mortality and hospital readmissions, underscoring our need to focus on
this subgroup.2 The Framingham coronary
risk score and prevalence of MI were assessed
in adults between 35 and 54 years who participated in the National Health and Nutrition
Examination Survey (NHANES) during 2 periods, 1988-1994 and 1999-2004. For MI, the
gap between men and women narrowed
https://doi.org/10.1016/j.mayocp.2019.05.001
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MAYO CLINIC PROCEEDINGS
recently (2.5% vs 0.7% in 1988-1994 and
2.2% vs 1.0% in 1999-2004 [both P<.01]).9
The authors also noted an increase in the Framingham coronary risk score in young
women (3.0% vs 3.3% in NHANES 19881994 and NHANES 1999-2004, respectively
[P¼.02]).9,10
Recreational Drug Use and Psychosocial
Factors
Obtaining a good drug history is paramount in
younger patients presenting with MI. In the
NHANES-3 survey of 10,085 adults between
18 and 45 years of age, frequent cocaine use
accounted for 25% of nonfatal MIs.11 In the
Cocaine Associated Chest Pain (COCHPA)
study, MI with cocaine use was seen in 6%.12
A lower incidence of MI associated with
cocaine use was observed with different presenting symptoms and diagnostic criteria for
MI.13 Rates of MI associated with cocaine use
range between 0.7% and 6%, and a careful history of cocaine intake must be obtained.14,15
One study reported an average age of 38 years
in 130 patients presenting with MI associated
with the use of cocaine.16 Case series or casecontrol studies have described young patients
with MI who used amphetamines, oral contraceptives (especially with smoking),17,18 or
marijuana.19 Among 3882 patients with MI
studied by Mittleman et al,19 124 (3.2%)
used marijuana in the preceding year. Its use
was associated with an almost 5-times higher
risk of MI over baseline, especially within the
first hour after use. In the CARDIA (Coronary
Artery Risk Development in Young Adults)
study,20 3617 young adults had a 15-year
follow-up. Following adjustment of risk factors, the authors did not find an association between use of marijuana and risk of CVD.
However, another study of 1913 adults who
had survived acute MI found that during 3.8
years of follow-up, use of marijuana was associated with higher mortality.21
The role of psychosocial stress is poorly
recognized and underappreciated, and a
Incidence and Prevalence of MI in Young Individuals
Framingham data
Nationwide inpatient sample
600
500
400
300
200
100
0
Men
Women
AMI rates/100,000 patient-years
Incidence of MI/1000
80
60
40
20
0
30-34
35-44
600
500
400
300
200
100
0
45-54
Age (y)
A
600
500
400
300
200
100
0
AMI rate (30-34 years)
Black men
White men
Black women
White women
2001 2003 2005 2007 2009
AMI rate (35-39 years)
2001 2003 2005 2007 2009
AMI rate (45-49 years)
2001 2003 2005 2007 2009
600
500
400
300
200
100
0
600
500
400
300
200
100
0
AMI rate (40-44 years)
2001 2003 2005 2007 2009
AMI rate (50-54 years)
2001 2003 2005 2007 2009
B
FIGURE 1. A, Ten-year follow-up data in younger patients enrolled in the Framingham Heart Study5 demonstrating higher incidence
of myocardial infarction (MI) in men, especially beyond age 45 years. The incidence in the corresponding age brackets in women was
approximately one-fifth to one-seventh that of men (see text). B, Myocardial infarction trends in men and women 30 to 54 years old
from the Nationwide Inpatient Sample (2001-2010). Comorbidity increased in both sexes during the study period. Women had
higher in-hospital mortality but also significant decline compared with men. AMI ¼ acute myocardial infarction. Adapted from J Am
Coll Cardiol,2 with permission from the American Heart Association, Inc.
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ACUTE MYOCARDIAL INFARCTION IN YOUTH
MI Due SCAD, Myocarditis, and CE
SCAD is initiated by intimal disruption or
intramural hematoma and is not due to underlying atherosclerosis, iatrogenic causes,
or trauma (Table 1).26 It is commonly seen
in younger women with a paucity of known
cardiac risk factors. Recent series suggest
that up to 1% to 4% of all cases presenting
with ACS may be caused by SCAD and occur
in younger women (<50 years).27-32 SCAD is
also an important etiology in MI related to
pregnancy. In a Mayo Clinic registry, 54 of
323 women with SCAD were pregnant or
were 12 weeks or less postpartum.33 Only 4
occurred during pregnancy, and most events
occurred
within
the
first
month
postpartum.26,28,34,35
The prevalence of myocarditis varies, but a
recent meta-analysis reported it in 33% of patients (183 of 556) with MINOCA.36 The prevalence of myocarditis varies from 2% to 42% in
autopsy series37,38 and 9% to 16% by endomyocardial biopsy in adults with nonischemic
dilated cardiomyopathy.39,40 Coronary embolism is considered the cause of MI in 4% to
13% of cases.41-43 Mechanisms of CE are akin
to venous thromboembolism and can be delineated based on the Virchow triad (Figure 4). In
a study of de novo ST-segment elevation MI,
53 of 1232 patients (4.3%) had CE. These patients were not young but had no evidence of
coronary atherosclerosis.45 In the Young Adult
Myocardial Infarction and Ischemic Stroke
(YAMIS) Study, major venoarterial shunt was
found in 25% of 101 young patients (16-39
years) who survived an MI and stroke.46 Paradoxical embolism as the cause should be
considered in young adults in the presence of
additional hypercoagulable risk factors (pregnancy, ischemic stroke, factor V Leiden).47-49
MI Due to Atheromatous CAD Without
Critical Coronary Stenosis
Antemortem characterization of unruptured
plaque is now feasible with optical coherence
tomography (OCT) and intravascular
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Mechanisms of MI in Young Individuals
70
Patients with mechanism (%)
higher prevalence of depression, anxiety,
and hostility in younger patients likely contributes not only to addiction but to the
pathogenesis of acute and chronic CVD.22-25
Other
• Spasm
• SCAD
• Hypercoagulable state
• Thromboembolism
• Myocarditis
• Drug use
60
50
40
30
20
10
0
Plaque rupture
IFC
Other
FIGURE 2. Plaque-based mechanisms dominate
as the etiology for myocardial infarction (MI) in
young individuals. Only 10% to 11% of patients
have a nonplaque etiology such as spontaneous
coronary dissection (SCAD), coronary embolism, or coronary microvascular dysfunction.
Among plaque-based mechanisms, an intact
fibrous cap (IFC) or plaque erosion should be
considered, especially in younger women
without traditional cardiovascular risk factors
(with the exception of smoking).
ultrasound (IVUS).50-54 The classic demographic profile of such patients includes
younger women who are smokers but do
not have other cardiovascular risk factors
such as diabetes mellitus or hyperlipidemia
commonly seen in patients with plaque
rupture.55-57
The VIRGO (Variation in Recovery: Role of
Gender on Outcomes of Young AMI Patients)
registry enrolled young (18-55 years) patients
with MI between 2008 and 2012.4 Using
angiography-based classification, the investigators divided the cohort into those with revascularization or plaque of 50% or greater
(88.4%) or MINOCA (obstruction with plaque
<50%) or other etiologies (11.1%) (Figure 5).
Women had an almost 5 times higher incidence of MINOCA than men. A large majority
(224 of 299 patients [75%]) remained undefined, and a minority were categorized as
SCAD, coronary spasm, or embolization
(Figure 5), underscoring the need for a systematic approach and liberal imaging utilization
for better plaque characterization.
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MAYO CLINIC PROCEEDINGS
Recent MI Trends in Young
Nationwide inpatient sample
> Comorbidities
< AMI hospitalization rate
> Length-of-stay
Young women <55
years with AMI
Young men <55
years with AMI
> In-hospital mortality
Comorbidities
Women
Men
AMI hospitalization rate
Women
Men
Length-of-stay
Women
Men
In-hospital mortality
Women
Men
FIGURE 3. Acute myocardial infarction (MI) trends in young women and men from the Nationwide
Inpatient Sample from 2001-2010. Although young women with MI have higher multimorbidity, length of
stay, and in-hospital mortality compared with young men, the data indicate that over time, comorbidities
have increased in both sexes and women had a relative reduction in mortality. Adapted from J Am Coll
Cardiol,2 with permission from the American Heart Association, Inc.
CASPER (Coronary Artery Spasm in Patients
With Acute Coronary Syndrome) study, among
138 (of 488) patients with ACS who had no
demonstrable coronary disease, coronary
spasm was seen in approximately half (48.8%)
of those tested.61 Recent American Heart Association/American College of Cardiology/Heart
Rhythm Society guidelines acknowledged the
importance of coronary microvascular dysfunction as an etiology for sudden cardiac death.62
Coronary Vasospasm (Microvascular
Dysfunction)
The true prevalence of microvascular dysfunction in coronary arteries is unknown but depends on the population (higher in Asians),
timing (higher with ACS), and use of provocative testing (higher if routinely employed for
its detection) (Table 1).59 In 1089 patients
who underwent coronary angiography, coronary spasm was induced with ergonovine in
20% who had recent MI and in 15% who had
chest pain.60 The prevalence of coronary microvascular dysfunction increased with systematic
efforts in its detection. The frequency of epicardial and microvascular spasm was 33.4% and
24.2%, respectively, among 921 patients with
nonobstructive CAD in whom intracoronary
acetylcholine provocation was used.60 In the
RISK FACTORS
MI Related to Traditional Cardiovascular
Risk Factors in Patients With Atherosclerotic
CAD
In a large, multinational cohort study with
follow-up of 2 decades, the traditional
TABLE 1. Features of Spontaneous Coronary Artery Dissection and Coronary Artery Spasm
Spontaneous coronary artery dissection
1% to 4% Overall prevalence
d
2% to 4% Overall prevalence
d
Higher prevalence (up to 35%) in women <50 y
d
Higher prevalence with provocative testing (20%)
d
Important cause of sudden cardiac death
d
Higher prevalence in setting of acute coronary syndrome
d
Racial disparity, higher in Asians
d
d
140
Coronary artery spasm
d
Important consideration in pregnancy
and postpartum period
Look for fibromuscular dysplasia
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ACUTE MYOCARDIAL INFARCTION IN YOUTH
FIGURE 4. Anatomic and pathophysiologic mechanisms involved in coronary embolism are based on the Virchow triad for venous
thromboembolism. Careful attention to anatomic predisposition is required for accurate diagnosis. The criteria for diagnosis of
coronary embolism revolve around the absence of atherosclerosis, the presence of coronary thrombus (particularly at multiple locations), and concomitant systemic embolization. ASD ¼ atrial septal defect; DVT ¼ deep venous thrombosis; LV ¼ left ventricular;
PFO ¼ patent foramen ovale. From J Am Coll Cardiol Intv,44 with permission from Elsevier.
cardiovascular risk factors were equally predictive of mortality in young men compared
with older men.63 Similarly, among 7302
eligible young women without major electrocardiographic abnormalities or prevalent
CAD at baseline, the long-term (31-year)
risk of development of CAD and mortality
was higher in women with major coronary
risk factors.64 A similar risk factor profile
and association with outcomes was found
in the Framingham Heart Study and the
Nurses’ Health Study.65,66 These data underscore the importance of earlier interventions
to positively modify the risk factor profile
and lifestyle approaches in younger patients
presenting with MI.
The INTERHEART investigators provided
the most compelling global perspective on the
effect of risk factors associated with MI.67
Increased apolipoprotein B/apolipoprotein A1
ratio (odds ratio [OR], 3.25 [highest vs lowest
quintile]) smoking (OR, 2.87 [current vs
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never]), abdominal obesity (1.12 [highest vs
lowest tertile]), hypertension (OR, 1.91), diabetes mellitus (OR, 2.37), psychosocial issues
(OR, 2.67), eating fruits and vegetables daily
(OR, 0.70), regular alcohol use (OR, 0.91),
and regular physical exercise (OR, 0.86) were
factors significantly related to MI (P<.0001
for all risk factors and P¼.03 for alcohol).
The profile of risk factors in younger patients
presenting with MI mirrors those in the older
age group. Smoking and hyperlipidemia are 2
major risk factors accounting for almost
two-thirds of the population-attributable risk
for MI.
Recent national trends underscore the
growing epidemic of obesity (body mass
index [BMI], 30; calculated as weight in kilograms divided by height in meters
squared) in youth and young adults, with
current (2015-2016) age-standardized prevalence estimates of 42.8% among adults
between 40 and 59 years. These estimates
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MAYO CLINIC PROCEEDINGS
VIRGO Classification System
Angiographic evidence of plaque-mediated culprit lesion
Yes
n=2,425
No
n=366
Uncertain
n=11
Other defined mechanism
No
n=335
Yes
n=31
Obstructive CAD (≥50% stenosis)
No
n=238
Yes
n=90
O2 demand-supply imbalance
Yes
n=35
New
taxonomy
Universal
AMI
Uncertain
(prior PCI)
n=7
O2 demand-supply imbalance
No
n=55
Yes
n=88
No
n=150
Class I (n=2425)
plaque-mediated
culprit lesion
Class IIa (n=35)
obstructive CAD
O2 imbalance +
Class IIb (n=55)
obstructive CAD
O2 imbalance –
Class IIIa (n=88)
non-obstructive
CAD
O2 imbalance +
Class IIIb (n=150)
non-obstructive
CAD
O2 imbalance –
Class IV (n=31)
vasospasm;
SCAD; embolism;
takotsubo
Type I
Type II
Unclassified
Type II
Unclassified
Type I & type II
Class V (n=18)
indeterminate
Type I or
unclassified
FIGURE 5. The Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) study developed an
angiography-based classification of myocardial infarction in young patients. Importantly, most myocardial infarctions fall into class I or
plaque-mediated mechanism, and in only a minority could a clear nonplaque mechanism be identified (class IV). Classes II and III are
based on the presence or absence of significant obstructive coronary artery disease (CAD) and further subdivided based on the
presence or absence of oxygen (O2) supply-demand mismatch. PCI ¼ percutaneous coronary intervention; SCAD ¼ spontaneous
coronary artery dissection. From Spatz ES, Curry LA, Masoudi FA, et al. The Variation in Recovery: Role of Gender on Outcomes of
Young AMI Patients (VIRGO) Classification System: a taxonomy for young women with acute myocardial infarction. Circulation.
2015;132(18):1710-1718 (www.ahajournals.org/journal/circ),58 with permission from Wolters Kluwer Health Inc.
were significantly higher compared with the
36.2% noted in 2007-2008 in the same age
group and higher than the overall prevalence
of 39.6%.68 The association of obesity with
accelerated atherosclerosis was underscored
by the Pathobiological Determinants of
Atherosclerosis in Youth (PDAY) study in
which arteries, blood, and other tissue from
3000 persons (aged 15 to 34 years) was
examined and a significant correlation was
seen, especially in young men, between
obesity and fatty streaks, raised lesions in
the right coronary artery, and stenosis in
the left anterior descending artery.69 The
Framingham Heart Study’s 5209 participants
(aged 35 to 75 years) were followed up for
up to 44 years, and the age-adjusted relative
risk (RR) for CVD was increased among
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Mayo Clin Proc.
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both overweight men (RR, 1.46 [95% CI,
1.20-1.77]) and women (RR, 1.20 [95% CI,
1.03-1.41]) and obese men (RR, 1.46 [95%
CI, 1.20-1.77]) and women (RR, 1.64 [95%
CI, 1.37-1.98]).70 Obese patients not only
have earlier pathologic evidence and higher
RR for CVD but also experience earlier MI.
Among 111,847 patients with noneSTelevation MI included in the CRUSADE
(Can Rapid Risk Stratification of Unstable
Angina Patients Suppress Adverse Outcomes
With Early Implementation of the American
College of Cardiology/American Heart Association Guidelines) registry, mean patient
age at the time of MI was 58.7 years in the
most obese patients (BMI >40 kg/m2)
compared with the leanest patients (BMI
18.5 kg/m2).71 An excellent recent review
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ACUTE MYOCARDIAL INFARCTION IN YOUTH
summarizes the role of metabolically healthy
obesity, the obesity paradox, and various
lifestyle modifications for weight loss that
would be important in the management of
young obese individuals who present with
an MI.72
Recreational Drug Use and Psychosocial
Factors
The risk of MI associated with reactional
drug use and psychosocial factors is discussed in the Prevalence section.
MI Due to SCAD, Myocarditis, and CE
Spontaneous Coronary Artery Dissection. The
factor most commonly associated with SCAD
is fibromuscular dysplasia (FMD), seen in
25% to 86% of patients.27 Two recent series
described FMD in 50% (diagnostic iliac angiograms) to 72% of 168 patients with
SCAD.27,28 Other factors associated with
SCAD include pregnancy, connective tissue
disorder, hormones, systemic inflammatory
disorders (eg, Kawasaki disease, systemic
lupus erythematosus), precipitating events
(>50% recall a precipitating factor) akin to
that seen in patients with Takotsubo cardiomyopathy (ie, intense exercise or emotional
stress, cocaine, retching, vomiting).26,73
Coronary Embolism. In the study by Shibata
et al,42 the most common underlying disease
in patients with CE was atrial fibrillation
(73%), followed by cardiomyopathy (25%)
and valvular heart disease (15%). Less
frequent cardiac etiologies of CE included
infective endocarditis and tumors. The systemic disorders associated with CE include
antiphospholipid antibody syndrome, malignancy, and autoimmune disorders. No clear
etiology could be discerned in 26.4%.45
Myocarditis. Viral infections account for most
cases of myocarditis in North America and
Europe.74 Autoimmune myocarditis can
occur with sarcoidosis, scleroderma, or systemic lupus erythematosus. Immune-mediated
myocarditis can also be seen with drugs (eg,
penicillin, furosemide, phenytoin) or heart
transplant rejection. Toxic myocarditis is seen
with drugs (eg, amphetamine, anthracyclines,
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cocaine, cyclophosphamide, lithium), heavy
metals (copper or iron deposits), or snake bite.
MI Due to Atheromatous CAD Without
Critical Coronary Stenosis
Plaque rupture could not be demonstrated in
autopsy studies in approximately one-third of
cases of sudden death from ACS.57,75 Plaques
with an intact fibrous cap (without plaque
rupture) are seen more frequently in younger
women (especially smokers) without known
cardiac risk factors.76
Coronary Vasospasm (Microvascular
Dysfunction)
Multivariable predictors of microvascular
dysfunction in a study by Nakayama et al77
included previous MI (OR, 5.37), baseline
elevation of biomarkers (OR, 2.84), age
younger than 70 years (OR, 2.19), glomerular
filtration rate greater than 60 mL/min per
1.73 m2 (OR, 1.72), and lack of a traditional
cardiovascular risk profile. Such paucity of cardiovascular risk was also noted in the ParisSudden Death Expertise Center study, with
the exception of smoking and drug abuse.78
Smoking, older age, and higher levels of inflammatory markers (high-sensitivity C-reactive
protein) have also been noted to be significant
risk factors for coronary microvascular
dysfunction.79
CLINICAL PRESENTATION
Concordant with overall trends, two-thirds of
all MIs in young patients present with
noneST-elevation (Table 2).80 In general,
clinical presentation in young patients with
MI is indistinguishable from that of older patients, and most patients present with chest
pain due to plaque rupture. However, certain
differences are noteworthy. First, a history of
angina symptoms before MI is less common,
seen in approximately one-fourth of patients.81 Second, 69% of patients younger
than 45 years do not report chest pain before
MI.82,83 Third, the onset of symptoms is
within 1 week of MI.83,84 In addition, younger
women typically have longer delays in reporting symptoms and getting medical attention
in the setting of MI; possible reasons could
be varying prodromal symptoms, inaccurate
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TABLE 2. Clinical Presentation of Young Patients
With Myocardial Infarction
d
Two-thirds present with noneST-elevation
myocardial infarction
d
Chest pain characteristics similar to those in older
patients
d
Women have 5-times higher odds of having
myocardial infarction with nonobstructive
coronary artery disease
d
Look for drug use (cocaine) or source of
thromboembolism
d
Suspect myocarditis in patients with a history of
viral illness who present with worsening heart
failure or chest pain
assessment for personal cardiac risk,
competing and conflicting priorities affecting
their decision making, less consistent
response of the health care system to symptoms, and poor access to primary care.85 In
young patients who present with MI in the
setting of normal coronary arteries, recent
recreational drug use should be recorded
and signs of sympathetic overactivity should
be noted (sweating, mydriatic pupils,
tachycardia).
Clinical and family history of recurrent
arterial and/or venous thrombosis should be
diligently evaluated. Presenting symptoms of
myocarditis vary from dyspnea or chest pain
to life-threatening shock or arrhythmias, and
therefore, this diagnosis requires a high index
of suspicion.74 Two main presentations of
myocarditis are new or worsening congestive
heart failure or symptoms of chest pain akin
to those of ACS. Preceding viral illness (respiratory or gastrointestinal symptoms), younger
age, and inflammatory markers (high C-reactive protein level) can point to a diagnosis of
myocarditis (Table 3).36 Similar to other MIs,
patients with SCAD present with chest pain
(95.9%) and elevation of cardiac biomarkers
(26%-87% with ST-segment elevation MI).
Ventricular arrhythmia or sudden cardiac
death is the presenting symptom in 3% to
11% of patients.26
Vasospastic angina (Prinzmetal) typically
presents with ST-elevation MI without provocation, is associated with stress, cold, or hyperventilation, and is characterized by prompt
relief with sublingual nitroglycerine.86 A circadian variation is noted with this syndrome,
with most attacks occurring during the morning hours. Vasospastic angina typically affects
women smokers.87
DIAGNOSIS OF MI IN YOUNG PATIENTS
General Principles
The current classification for MI ignores patients with minimal or no CAD, and using
the Universal Definition of Myocardial Infarction,58 its etiology is still unclear in approximately 12% of women. Furthermore, patients
with different etiologies and varying severity
of atherosclerosis and left ventricular function
are combined, leading to management dilemmas and phenotypic heterogeneity. To
address the deficiencies in the current classification, using an inductive approach and
grouping patients with similar clinical
TABLE 3. Diagnosis of Myocarditis
Clinical presentation
Diagnostic criteria
d
Acute chest pain
d
Electrocardiographic, Holter monitoring, stress test
abnormalities (heart block, ST-T changes, ventricular
tachycardia/ventricular fibrillation)
d
New-onset (<3 mo) worsening dyspnea
d
Elevated troponin level
d
Subacute/chronic (>3 mo) worsening dyspnea
d
New regional wall motion abnormality, functional decline,
thrombus, increase in wall thickness, or pericardial effusion
d
Arrhythmia, syncope, or sudden death
d
Tissue characterization by cardiac magnetic resonance
imaging
d
Unexplained cardiogenic shock
Data from Eur Heart J.74
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ACUTE MYOCARDIAL INFARCTION IN YOUTH
characteristics, a novel VIRGO taxonomy classified 2802 young women with MI according
to the underlying pathophysiologic mechanisms: obstructive CAD (most common)
with or without supply-demand ischemia, no
obstructive CAD, or patients in whom a clear
mechanism is not related to plaque rupture.
This classification still is very complex to
follow and combines various disease mechanisms that require different management into
one class (eg, dissection, vasospasm, embolism). It also does not delineate distinct pathways that help clinicians with their
management (Figure 5).58
MI Related to Traditional Cardiovascular
Risk Factors
The most common etiology of MI in young
individuals is plaque rupture, which is seen
in almost 88% to 89% of patients and should
be suspected in those who smoke or have
hyperlipidemia, diabetes mellitus, or hypertension. We propose a simple diagnostic algorithm that will delineate most causes of
MI in young patients, Figure 6.
Recreational Drug Use and Psychosocial
Factors
A careful drug history is essential in young patients as it points to the right diagnosis, pathophysiology (coronary vasospasm), and
management (psychosocial support, counseling,). Depression can interfere with medication compliance, affect self-care, increase
ambulatory visits, and negatively impact health
status.88 Depressive symptoms can be associated with other mood disturbances (eg, anxiety) or substance abuse, which also are
associated with adverse cardiac outcomes.89
MI Due to SCAD, Myocarditis, and CE
Spontaneous Coronary Artery Dissection.
SCAD should be suspected in younger patients with MI, and diagnosis is confirmed by
coronary angiography. Presently, computed
tomographic angiography has insufficient
sensitivity for SCAD diagnosis.90-94 A careful
search for FMD in coronary and other vascular
territories should be done routinely. Intravascular imaging with OCT or IVUS can shed
some light on the mechanism of SCAD based
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on the presence or absence of identifiable
intimal tear. This differentiation may have
clinical implications as the risk of clinical
deterioration in patients with SCAD who are
managed conservatively is higher in those
with intramural hematoma without identifiable intimal tear and the highest risk of
worsening is noted within 6 days of presentation.95-103
Myocarditis. Diagnostic criteria for myocarditis include the presence of one clinical
(new-onset/worsening heart failure/ACS)
and one diagnostic (electrocardiography,
stress test, Holter monitoring, elevated biomarkers, and typical tissue characterization
by cardiac magnetic resonance imaging) criterion in the presence of normal coronary arteries (no significant coronary stenosis that
exceeds 50% or patients with preexisting
CVD) (Table 3). Twelve-lead electrocardiography, echocardiography, and cardiac magnetic resonance imaging are indicated before
endomyocardial biopsy in patients suspected
to have myocarditis. Among the 374 patients
enrolled in the Italian Multicenter Study on
Acute Myocarditis, late gadolinium enhancement was a significant predictor (OR, 2.73;
95% CI, 1.2-5.9; P¼.01) of adverse events
including mortality, hospitalization with
heart failure, resuscitated cardiac arrest, or
appropriate firing of implantable cardioverter-defibrillator.104
Coronary Embolism. Coronary embolism is
diagnosed with coronary angiography demonstrating angiographic thrombus, concomitant
CE in multiple locations/vessels, or evidence
of systemic embolization (Figure 4). Patients
should be screened for the source of embolic
material. Echocardiography is needed to identify left ventricular, left atrial, or appendage
thrombus, intracardiac shunt, or a patent foramen ovale. Coronary embolism is frequently
associated with systemic embolism, and other
sites (eg, abdomen, brain) should be screened.
MI Due to Atheromatous CAD Without
Critical Coronary Stenosis
Myocardial Infarction With Nonobstructive
Coronary Arteries. To diagnose patients
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Proportion of all MI
Suspect in patients with
Young patient with MI
Do coronary angiography
Commonest cause is
plaque rupture
88%
MINOCA/
nonatherosclerotic
11%
Smoking, dyslipidemia, diabetes mellitus,
hypertension, etc
Women without CV risk factors
~20%
Coronary vasospasm
17%
Recreational drug use
3%
Hypercoagulability
Atrial fibrillation, cardiomyopathy, infective
endocarditis
Antiphospholipid syndrome, cancer
3%
SCAD
Younger women with ACS, postpartum, FMD
3%
Myocarditis
50%-75%
Undefined
Viral illness preceding chest pain, heart
failure symptoms
Obtain drug history for cocaine and
methamphetamines, seek signs of
sympathetic overactivity
(sweating, dilated pupils, tachycardia)
FIGURE 6. Diagnosis of myocardial infarction (MI) in young individuals. Data are compiled from multiple
sources and reflect an approximation of the current prevalence of various causes of MI in young individuals. The most common cause of MI still is plaque rupture, accounting for around 88%. It should be
suspected in patients with traditional cardiovascular (CV) risk factors, most commonly smoking and
dyslipidemia. In 11% of patients, MI with nonobstructive coronary arteries (MINOCA) is observed. A
history of recreational drug use, especially cocaine, should be sought and signs of sympathetic overactivity
should be observed. Coronary embolism should be suspected in patients with atrial fibrillation, cancer, or
cardiomyopathy. Spontaneous coronary artery dissection (SCAD) should be included in the differential
diagnosis in young women, especially postpartum or with known fibromuscular dysplasia (FMD).
Myocarditis should be high in the index of suspicion if there is a history of viral illness. Patients with
MINOCA without any defined etiology should be encouraged to undergo further invasive testing to
exclude coronary vasospasm. ACS ¼ acute coronary syndrome.
with MI with no obstructive CAD, a good history, physical examination, electrocardiography, measurement of cardiac biomarkers,
echocardiography, and coronary angiography
with or without left ventricular angiography
are needed to identify various causes that
fall under the umbrella of MINOCA. Proposed diagnostic criteria for MINOCA
include Universal Definition of Myocardial
Infarction criteria, nonobstructive CAD on
angiography, and no overt cause of similar
presentation such as pulmonary embolism
or dissection.105 Many investigators include
myocarditis and Takotsubo syndrome in
MINOCA. For this review, we have not
included Takotsubo cardiomyopathy because
it principally affects older, usually postmenopausal, women. Recently, European
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guidelines to diagnose MINOCA required
clinical documentation of MI, the presence of
no significant obstruction (<50% stenosis) in
coronary arteries, and no specific etiology for
their acute presentation necessitating further
evaluation (Figure 7).105
Coronary Plaque Disease. For patients with
coronary plaque disease, antemortem imaging of plaque characteristics has allowed cardiologists with tools to base their
management decisions on plaque characteristics such as the presence or absence of plaque rupture. With the advent of OCT,
antemortem diagnosis of plaque erosion is
now feasible. It is based on patient demographic characteristics (young, women, minimal cardiovascular risk factors) and the
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ACUTE MYOCARDIAL INFARCTION IN YOUTH
presence of thrombus on angiography and is
aided by the absence of plaque rupture on
intracoronary imaging.76,106
Coronary Vasospasm/Microvascular
Dysfunction
Coronary microvascular dysfunction reflects
an endogenous hyperreactivity and may present de novo, as seen in patients with variant
angina, or in the context of exogenous vasospastic stimuli such as the use of stimulants
(cocaine, methamphetamine) or can be
induced in the cardiac catheterization laboratory with a stepwise increase in the doses
of intracoronary acetylcholine or ergonovine
(Figure 8).107 The test results are considered
abnormal if the patient’s symptoms and/or
electrocardiograpic changes can be reproduced with significant (90%) (focal/
diffuse) narrowing of epicardial coronary
arteries.
Pregnancy and MI
The population-based incidence of acute MI
in pregnancy was determined in California.108
The incidence of MI during pregnancy between 1991 and 2000 was 1 in 35,700 deliveries and increased during the study period.
Higher maternal mortality rates (7.3%) were
noted in patients who had MI during pregnancy, and multivariate predictors included
older maternal age. In a Nationwide Inpatient
Sample from 2000-2002, a higher incidence
of MI (6.2 in 100,000) was noted in pregnancy,109 and most MIs occurred during the
third trimester or during the early postpartum
period. Atherosclerosis is not very common,
and many pregnant women have SCAD (see
preceding Spontaneous Coronary Artery
Dissection section), microvascular dysfunction, thrombus, or coronary emboli as determined by 2 small studies.110,111 Presentation
is similar to other young patients, but a
higher incidence of ST-segment elevation MI
(75%) in the anterior wall (69%) is noted.
Treatment should be individualized based
on the needs and health of the mother and
child and requires a multidisciplinary
approach. Optimal care may include bare
metal stents and postponing delivery by 2 to
MI Without Obstructive CAD (MINOCA)
Clinical history, ECG, and cardiac biomarkers
Coronary angiography
LV angiography
Normal or regional wall
motion abnormalities with
“epicardial pattern”
Normal or regional wall
motion abnormalities with
“microvascular causes”
Epicardic causes
Microvascular causes
Coronary
artery plaque
Coronary
dissection
CAS
CMS
Takotsubo
syndrome
Myocarditis
Coronary
embolism
FIGURE 7. The diagnosis of myocardial infarction (MI) without obstructive coronary artery disease (CAD)
(MINOCA) rests on obtaining a good clinical history, electrocardiography (ECG), cardiac biomarkers, and
echocardiography. All these patients need to undergo coronary and left ventricular angiography. The potential
causes can be ascertained from the types of regional wall motion abnormality (epicardicdplaque-based,
coronary dissection, coronary artery spasm [CAS]; or microvasculardcoronary microvascular spasm [CMS],
Takotsubo syndrome, myocarditis, or coronary embolism). Adapted from Eur Heart J Acute Cardiovasc Care,105
with permission.
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FIGURE 8. Angiographic protocol for coronary microvascular dysfunction. Typical functional angiography demonstrating coronary flow
reserve (CFR) changes in an endothelial-dependent (CFRe) and endothelial-independent (CFRne) manner. The protocol, initiated with
diagnostic angiography and moving on to adenosine and acetylcholine (ACh) infusion, is depicted at the top of the figure. The angiogram
(far left) shows an example of vasoconstriction after the administration of ACh. Endothelial-independent CFR is assessed using blood
flow velocity profiles (average peak velocity [APV]) at rest and after adenosine infusion (bottom middle figure). Assessment of CFRe is
depicted on the far right with a normal pre-ACh reading consisting of a predominant diastolic component on the top. The lower right
figure shows a marked reduction in APV after the infusion of ACh indicative of poor microvascular recruitment of blood flow seen in
patients with microvascular disease. Arrows indicate range of doses that can be used for adenosine and acetylcholine. The dose for
acetylcholine is 106 mol/L to 104 mol/L. IC ¼ intracoronary; Microcirc [microcirc] ¼ microcirculation.
3 weeks after MI. During MI, measures
should be instituted to reduce cardiac workload (epidural anesthesia, left lateral position,
treatment of hypertension and tachycardia).
Aspirin and b-blocker use112,113 are safe in
pregnancy, but other drugs (statins/angiotensin-converting enzyme inhibitors/fibrinolytic therapy) either have been found to be
unsafe or have not been tested during pregnancy. Heparin is the anticoagulant of choice
(during stent placement) because it does not
cross the placenta. Bleeding may be more
problematic during longer-term heparin use.
The complication rates of MI are high in pregnant patients, and in one study 38% experienced heart failure/shock, 12% had
ventricular arrhythmias, and 20% had recurrent angina.110
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TREATMENT
MI Related to Traditional Cardiovascular
Risk Factors
The treatment of young patients with MI due
to plaque rupture should follow the current
guidelines. This process would require
guideline-directed medical management
and coronary revascularization, similar to
treatment for older individuals.
Recreational Drug Use and Psychosocial
Factors
Recreational drug use and psychosocial factors are important and need to be considered
in every young patient presenting with MI,
especially patients who lack traditional cardiovascular factors and those in whom
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ACUTE MYOCARDIAL INFARCTION IN YOUTH
coronary vasospasm is detected during coronary angiography. Once detected, these patients should be referred for further
counseling and treatment.
MI Due to SCAD, Myocarditis, and CE
Spontaneous Coronary Artery Dissection.
The management for SCAD remains uncertain because of the lack of randomized studies
of treatment outcomes or comparison between surgical or percutaneous revascularization. Observational data have indicated
healing of most lesions with spontaneous
dissection (70%-97%), with most healing
occurring by 35 days.27,35,94,114-116 Recurrent MI is observed early (<7 days) in 5% to
10% of patients and calls for extension of
inpatient monitoring. Indications for urgent
revascularization include left main coronary
artery involvement, ongoing chest pain, and
ischemia or any hemodynamic instability.
However, most patients with SCAD are
managed conservatively, especially if coronary blood flow is not compromised. Once
the ischemia resolves with conservative
management, angiographic resolution and
long-term outcomes are excellent.93 Routine
angioplasty and stent placement in patients
with SCAD are associated with worse outcomes because guidewires and balloons can
track the false lumen, thereby extending the
hematoma and dissection.27 The role of dual
antiplatelet therapy, statins, or systemic
anticoagulation has not been extensively
tested. Recent American Heart Association
consensus supports aspirin use for at least 1
year.26 In a study of 327 patients from Canada, b-blockers were beneficial and reduced
dissection recurrence in these patients (hazard ratio, 0.36), underscoring the need for its
routine administration.117
Myocarditis. Patients presenting with decompensated heart failure should be treated at centers with expertise in invasive monitoring,
catheterization, and endomyocardial biopsy.
These sick patients may require inotropic support, extracorporeal membrane oxygenators,
or left ventricular assist devices until recovery
of left ventricular function occurs or they
require cardiac transplant.118-120 If possible,
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cardiac transplant should be deferred because
many patients recover over time. Physical activity should be restricted for 6 months and
reassessed at that time, especially to allow
athletes to compete. Treatment with acyclovir,
ganciclovir, and valacyclovir for herpesvirus
and interferon beta for adenoviral or enteroviral infection can be considered.121,122 Highdose intravenous immunoglobulins are associated with improvement in heart function,121
but in the IMAC (Intervention in Myocarditis
and Acute Cardiomyopathy) randomized trial
of recent-onset dilated cardiomyopathy, immunoglobulins produced no benefit in 62
patients.123
Most immunosuppression trials have used
corticosteroids with or without cyclosporine
or azathioprine. The results were favorable in
giant cell or virus-negative myocarditis.
Immunosuppression was not helpful in
myocarditis of unknown etiology in the
Myocarditis Treatment Trial.39 In this trial,
111 patients with an ejection fraction of less
than 45% and histopathologically proven
myocarditis were randomized to receive either
routine treatment or immunosuppression (24
weeks) with prednisone and either cyclosporine or azathioprine. The change in the
ejection fraction at 28 weeks (primary end
point) and survival did not differ between the
2 groups. The usefulness of immunosuppression with cyclosporine and corticosteroids
was also demonstrated in patients with giant
cell myocarditis.124
Coronary Embolism. The initial treatment
of CE is indistinguishable from common garden variety of ACS and includes antiplatelet
therapyand anticoagulation with unfractionated heparin. If the diagnosis during coronary angiography is CE, thrombectomy is
performed for large thrombus burden, sometime aided by intracoronary glycoprotein IIb/
IIIa inhibitors or thrombolytic therapy.
Balloon angioplasty and coronary stents are
not required. We favor intravascular ultrasound or OCT for determining the underlying mechanism (e.g., plaque erosion). Oral
anticoagulation with warfarin or noval
newer anticoagulants need to be started
and continued for at least 3 months, longer
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TABLE 4. Diagnosis of Acute Myocardial Infarction in Young Individuals
Thrombus detected in coronary arteries
Without traditional cardiovascular
risk factors
Atherothrombotic culprit with cardiovascular risk factors
d
Culprit identified with evidence of atherosclerosis
in coronary and other vascular territories
d
Plaque erosion
d
Follow current ACC/AHA guidelines
d
Thromboembolic disease
d
Hypercoagulable state
ACC/AHA ¼ American College of Cardiology/American Heart Association.
if the risk factor for CE persists (e.g., atrial
fibrillation). In patients with atrial fibrillation, oral anticoagulation should be presecribed regardless of the CHADS-VASC
score. Sytematic search for potential precipitating factors need to be done once the acute
phase is over. There is no need for routine
thrombophilia screening, unless there is a
clinical suspicion.
MI Due to Atheromatous CAD Without
Critical Stenosis
If an intact fibrous cap of a coronary plaque is
detected in a patient presenting with MI, it portends a favorable prognosis.125 Typically, less
severe coronary stenosis is observed in patients
presenting without plaque rupture, and patients may benefit from aggressive anticoagulation and antiplatelet therapy with or without
catheter-based aspiration of thrombus without
routine stent deployment.126 Prati et al127
studied 31 patients presenting with STelevation MI who underwent OCT following
aspiration of thrombus. Of the patients
without significant obstructive plaque, 19
were treated with stents, whereas 12 were
treated with antiplatelet therapy alone. At 24month follow-up, no patients treated conservatively and one who received a stent needed
repeated revascularization; however, this conservative approach needs further investigation.
Coronary Vasospasm/Microvascular
Dysfunction
Coronary artery microvascular dysfunction
should be suspected in young patients with
MI who have normal findings on coronary
angiography or have minimal CAD (<50% stenosis). There are no protocols that are
routinely followed in such patients to detect
or induce microvascular dysfunction, leading
to underdiagnosis of microvascular dysfunction. Radico et al128 used fractional flow
reserve for indeterminate lesions and intracoronary acetylcholine to uncover coronary
microvascular dysfunction if an obvious etiology of ACS remained undetected. Exclusion of
other causes of MI in young patients is important (myocarditis, Takotsubo cardiomyopathy, or paroxysmal atrial fibrillationerelated
MI) before invasive investigations for the presence of coronary microvascular dysfunction
TABLE 5. Myocardial Infarction With Nonobstructive Coronary Arteries (<50% Stenosis)
Spontaneous coronary artery dissection
Premenopausal women
d
Premenopausal women
d
Coronary angiographic features include arterial
wall stain, diffuse narrowing, hazy and linear stenosis
d
Look for spontaneous spasm. If present, give
sublingual or intracoronary nitroglycerine
d
Use ultrasonography/optical coherence tomography
to define mechanism
d
Holter monitoring to identify ST elevation
with chest pain (Prinzmetal/variant angina)
d
Pressure/Doppler studies with intracoronary
acetylcholine to induce spasm and evaluate for
endothelial dysfunction on follow-up at 6-8 wk
d
150
Coronary microvascular dysfunction
d
Look for fibromuscular dysplasia
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ACUTE MYOCARDIAL INFARCTION IN YOUTH
TABLE 6. When the Initial Work-up for MINOCA is
Negative
Precipitating causes:
*Drug history (cocaine, methamphetamine,
marijuana)
*Preceding viral illness favors myocarditis
*Type II myocardial infarction due to supply/
demand mismatch
Cardiac MRI (late gadolinium enhancement):
*Subepicardial (myocarditis)
*Subendocardial (ischemia, dissection,
thromboembolism)
MINOCA ¼ myocardial infarction with nonobstructive coronary arteries; MRI ¼ magnetic resonance imaging.
are undertaken. The approach and its safety in
80 patients was demonstrated by Montone
et al.129
The treatment of patients with coronary
microvascular dysfunction should be guided
by the outcomes and the results of the invasive testing. Once detected, most patients
need basic CVD prevention (diet, exercise,
and weight loss) and long-term nitrates with
or without nondihydropyridine calciumchannel blockers. Their doses in isolation or
in combination can be gradually increased
to the maximum tolerated dose. b-Blockers
(especially nonselective), in general, are
avoided because they can exacerbate and prolong vasospasm. Nicorandil (a nitrate and potassium channel activator), magnesium,
antioxidants, rho kinase inhibitor, and statins
have been tried with some success in these
patients.130-132
FOLLOW-UP AND PROGNOSIS
The prognosis for young patients with MI is
not benign. The adverse cardiovascular
events are similar in patients presenting
with or without significant obstruction in
coronary arteries. Mortality is higher
compared with age- and sex-matched
controls.
Patients with SCAD typically have recurrent MI rates of 10% to 30% at 2 to 3 years.
The event rate at 5 years is between 15% and
37% and at 10 years is approximately
50%.28,117,133 In a report from Mayo Clinic,
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recurrence of SCAD was noted in 17% (15
of 87 patients) and 10-year recurrence was
estimated to be 29.4%.27
The detection of microvascular dysfunction can lead to significant adverse cardiac
events on follow-up. In one study, patients
with severe endothelial dysfunction had a
higher incidence of cardiac mortality, MI, or
revascularization.134 In another study, patients presenting with MI who had testingconfirmed microvascular dysfunction had
significantly higher all-cause (32.4% vs
4.7%; P¼.002) and cardiac (18.9% vs 0.0%;
P¼.005) mortality compared with patients
who had negative test results. In addition,
higher rates of hospital readmissions with
ACS and worse anginal symptoms were reported at 1 year in patients with microvascular dysfunction.129
In 50% of patients with resolution of
myocarditis over the ensuing 2 to 4 weeks,
12% to 25% may experience deterioration
and development of worsening congestive
heart failure that may further progress to
requiring cardiac transplant.74 Patients with
biopsy-proven giant cell myocarditis have a
poor prognosis.135
RECOMMENDATIONS
We recommend a systematic approach to
arriving at a correct diagnosis. Any young patient with confirmed MI should undergo coronary
angiography
to
identify
the
atherothrombotic culprit (Table 4 and
Figure 6). If risk factors (smoking, diabetes
mellitus, hyperlipidemia, hypertension, peripheral arterial disease) and angiographic features (thrombus, presence of atherosclerotic
disease elsewhere in the coronary vascular
bed) favor atherothrombotic disease, then we
recommend following the American Heart Association/American College of Cardiology
guidelines for medical management and/or
coronary revascularization with either percutaneous coronary intervention or surgery.
If thrombus is detected on angiography
in patients without traditional cardiovascular
risk factors and significant CAD, we recommend work-up for a hypercoagulable state
(deficiency in protein C and S factors, factor
V Leiden, oral contraceptives) and/or
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looking for a source of embolism (atrial
fibrillation, valvular [native or prosthetic],
left ventricular) and considering evaluation
for supportive evidence of thromboembolic
infarction in other end organs, such as cerebral or abdominal imaging. If thrombus is
present without risk factors (with the exception of smoking), a diagnosis of plaque
erosion should be considered (see subsequent discussion).
If no obvious thrombus is seen on coronary angiography, one should carefully
look for SCAD or coronary microvascular
dysfunction, especially in premenopausal
women (Table 5). If SCAD is recognized,
conservative management suffices in most
patients (see the section on SCAD). The
medical management of these patients includes b-blockers and baby aspirin.
In young patients with MI, spontaneous
coronary microvascular dysfunction should
be investigated thoroughly and the diameter
of the coronary vasculature with and
without intracoronary nitroglycerine should
be routinely measured, especially if coronary
angiographic findings are normal. If coronary microvascular dysfunction is identified,
these patients can be treated effectively with
oral nitrates and/or nondihydropyridine
calcium-channel blockers.
If coronary angiographic findings are inconclusive and no culprit is visible angiographically, we recommend ruling out any
precipitating cause such as drugs (cocaine,
methamphetamine, marijuana for coronary
spasm), hypercoagulable state (CE), preceding
viral illness (myocarditis), or supply-demand
mismatch (type II MI) (anemia, thyrotoxicosis).
Cardiac magnetic resonance imaging is an
important investigation because the late gadolinium enhancement in the subendocardium
suggests ischemic injury, whereas subepicardial
localization favors myocarditis or an infiltrative
disorder. Ischemic injury characteristics should
prompt a closer reexamination of the initial
diagnostic coronary angiogram for SCAD or
small missing branches and allows clinicians
to reevaluate and recalibrate their diagnosis
(Table 6).
If the diagnosis is still elusive, 2 procedures should be considered: (1) invasive
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provocation of microvascular dysfunction
and evaluation of endothelial function at 6
to 8 weeks of follow-up and (2) utilization
of IVUS/OCT to rule out plaque erosion, especially in cases of coronary lesions with angiographic thrombus. For better plaque
characterization, we favor OCT, which can
differentiate a ruptured from an intact fibrous
cap and a red from a platelet-rich thrombus
and can help guide conservative or invasive
management in these patients.136,137
CONCLUSION
This review focuses on the prevalence, risk
factors, unique syndromes, and overall profile of young patients presenting with MI.
We also discuss the management of important syndromes that are more prevalent in
the younger population. Lastly, we propose
a unique method that will help clinicians
stratify young patients with MI into different
diagnostic categories. This approach will be
of immense help in arriving at the right diagnosis and individualizing the treatment of
MI in young patients.
Abbreviations and Acronyms: ACS = acute coronary
syndrome; BMI = body mass index; CAD = coronary artery
disease; CE = coronary embolism; CVD = cardiovascular
disease; FMD = fibromuscular dysplasia; IVUS = intravascular
ultrasound; MI = myocardial infarction; MINOCA = MI with
nonobstructive coronary arteries; NHANES = National
Health and Nutrition Examination Survey; OCT = optical
coherence tomography; OR = odds ratio; RR = relative risk;
SCAD = spontaneous coronary artery dissection
Potential Competing Interests: Dr Behfar is a member of
the board of and has received grants (funds paid to his institution) from Rion LLC; has patents (planned, pending, or issued) from Rion LLC and Celyad; has received royalties
from Celyad; and has stock/stock options in Rion LLC.
The other authors report no competing interests.
Correspondence: Address to Mandeep Singh, MD, MPH,
Department of Cardiovascular Medicine, Mayo Clinic, 200
First St SW, Rochester, MN 55905 (singh.mandeep@
mayo.edu).
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