*
TO WHOM CORRESPONDENCE SHOULD BE ADDRESSED
Mitochondrial Cytopathies and Cardiac Disease
Neil Friedman, MBChB
Neurological Institute
Cleveland Clinic Foundation
© 2010
Key Points
•
The heart is metabolically very active, both in terms of energy production
and of energy utilization.
It is not surprising, therefore, that cardiac
dysfunction often accompanies mitochondrial disorders and that several
cardiac disorders have been associated with specific mitochondrial
defects.
•
Cardiac manifestations include arrhythmias as well as hypertrophic and,
less commonly, dilated or non-compaction cardiomyopathies.
•
There should be a high index of suspicion for potential cardiac
involvement in any patient with a diagnosed mitochondrial cytopathy.
•
Conversely, a possible mitochondrial basis should be suspected in
patients presenting with isolated, unexplained cardiac disease, or a
familial/genetic history of cardiac disease.
•
Antenatal onset may occur.
Heart Metabolism
o The average (adult) heart weighs about 250-300 grams (7-10
ounces) and consumes about 27 ml (1 ounce) of oxygen per
minute.
o To maintain myocardial contractility (keeping the heart beating), the
mitochondria in the cardiac cells (myocytes) utilize oxygen to
generate
energy
phosphorylation.
(ATP),
through
the
process
of
oxidative
o The myocytes contain high numbers of mitochondria (1000’s per
cell), which account for about 20-40% of the cell volume.
o In the fetal heart, glucose and lactate are the primary fuel sources
for energy production.
o After birth, fatty acids become the primary energy source and their
metabolism accounts for about 60% of the oxygen consumed at
rest and in the fasting state.
o The metabolism of glucose accounts for about 28% of oxygen
consumption and that of lactate for about 11%.
o During exercise, the heart’s dependence on fatty acids to generate
energy increases, whereas during myocardial ischemia (such as
angina or a heart attack) glucose becomes the main fuel.
o Under hypoxic (low oxygen) conditions, the breakdown of glucose
to pyruvate (through glycolysis) results in the formation of lactate
instead of acetyl CoA, which would normally enter the citric acid
cycle.
o Anaerobic glycolysis results in the production of two ATP molecules
only, instead of the 36 molecules generated through the process of
oxidative phosphorylation (under normal aerobic conditions).
o A normally contracting heart pumps oxygenated blood containing
nutrients and metabolites to meet the other organs’ metabolic and
energy requirements.
•
The interplay between mitochondrial disease and cardiac disease can be
considered at two levels. The heart may be involved as one component of
a multisystem mitochondrial cytopathy or it may be the principal or even
the only organ involved.
•
Mitochondrial cardiopathies may manifest as structural alterations, such
as dilated or hypertrophic cardiomyopathies or as a disturbance of heart
rate and/or rhythm, such as ventricular tachycardia, Wolff-Parkinson-White
syndrome, or heart block.
•
The clinical manifestations include heart failure, reduced exercise
tolerance, or death. Cardiac dysfunction may also give rise to failure of
other organs.
•
The frequency of cardiomyopathy in children with mitochondrial disease is
approximately 20-25%1,2 although some series have reported incidences
as high as 40%.14 Hypertrophic cardiomyopathy is more common than
dilated
cardiomyopathy.2,14
Left-ventricular
non-compaction
cardiomyopathy or left-ventricular hypertrabeculation cardiomyopathy is
an unusual cardiomyopathy so-named for the trabeculated or spongiform
appearance of the left ventricular wall. It is often associated with genetic
cardiac, non-cardiac, metabolic and neuromuscular disease, most
frequently mitochondrial cytopathies, especially Barth syndrome.14, 15
•
Well-recognized
mitochondrial
involvement include:
cytopathies
with
distinct
cardiac
o
Kearns-Sayre syndrome (KSS), which can cause third-degree
heart block;
o Leber’s hereditary optic neuropathy (LHON), which is often
accompanied by Wolff-Parkinson-White (WPW) syndrome (an
aberrant conduction defect);
o Myoclonic epilepsy with ragged red fibers (MERRF) which may be
associated with dilated cardiomyopathy and/or WPW syndrome.23
o Mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS), frequently associated with hypertrophic
cardiomyopathy,3, 17 or
o Barth syndrome, which typically causes left ventricular noncompaction cardiomyopathy.4
•
In some instances, there may be more than one manifestation of cardiac
disease in a specific syndrome: for example, His-ventricular (H-V) interval
prolongation or dilated cardiomyopathy can be seen in Kearns-Sayre
syndrome in addition to the “classical” heart block5; or hypertrophic
cardiomyopathy and/or, less commonly, WPW syndrome in MELAS.17,18
Cardiac Defects
•
Mitochondrial cardiopathies may be accompanied by alterations in
mitochondrial numbers, shape, and function and can be primary or
secondary.
•
Primary cardiomyopathies are due to mutations either in mitochondrial
DNA (mtDNA) or in nuclear DNA (nDNA). Except for 13 subunits encoded
by mtDNA, all other components of the respiratory chain complexes are
encoded for by nDNA.
•
A mitochondrial cytopathy is secondary when the primary insult affects
mitochondrial function either indirectly or through damage to the
mitochondrial genome.
For example, mitochondrial proliferate in
myocytes as a result of mtDNA deletions induced by free radicals
generated by altered oxidative phosphorylation in ischemic heart tissue
(heart tissue that isn’t getting enough blood). Another example is the
mtDNA depletion syndrome that may result from certain drug therapies,
such as zidovudine (AZT) therapy for HIV/AIDS.
•
Friedreich ataxia is a multisystemic genetic disorder (in this case due to a
trinucleotide repeat) that causes accumulation of iron in cardiac myocytes.
The result is hypertrophic cardiomyopathy.
•
Barth syndrome perhaps requires special mention.
Although this is a
systemic disorder, cardiac involvement is a key feature and is somewhat
specific due to the non-compaction or spongiform cardiomyopathy. Barth
syndrome is an X-linked disorder due to a mutation in the G4.5 gene
encoding the protein taffazin. Short stature and cyclic neutropenia are
other associated features. Arrhythmias may also occur.
•
Antenatal onset of cardiac disease (arrhythmias and/or cardiomyopathy)
may occur and is increasingly being reported.19, 20. 21, 22
•
Defects of Mitochondrial DNA
o Defects in mitochondrial DNA cause less than three percent of
dilated
and
an
even
smaller
percentage
of
hypertrophic
cardiomyopathies.
o The mtDNA-related cardiomyopathies usually result from mutations
affecting transfer RNAs (tRNAs).6,15
o Some rare mutations involve ribosomal RNA (rRNA).7
o Rare mtDNA causes of cardiomyopathy are missense mutations in
cytochrome b.8
o A recent report describes an apparently heart-specific mitochondrial
DNA depletion syndrome, a problem usually associated with
muscle or liver disease.9
•
Defects in Nuclear DNA
o Nuclear DNA (nDNA) encodes for many proteins involved in
mitochondrial
function,
including
mtDNA
replication
and
transcription factors, membrane proteins, and subunits of the
electron transport chain respiratory complexes.
o Defects in nDNA are likely to be more common causes of cardiac
disorder than mtDNA defects.
o Several defects in nDNA can cause infantile or early-onset
hypertrophic cardiomyopathy by affecting complex I (mutations
encoding for the NADH dehydrogenase ubiquinone flavorprotein—
or NDUF—subunits),10 complex IV (mutations of the SCO2 or
COX15 genes involved in the assembly of Complex IV),11,12,16 or
the adenine nucleotide translocator (ANT1) protein—which has
been demonstrated in mouse models.6
Nuclear subunits of
Complex III have also been implicated.13
o Cardiac involvement with mutations of the Twinkle (PEO1) gene, an
essential mitochondrion-specific helicase important in mtDNA
maintenance and mtDNA copy number is increasingly being
recognized.24
o Mutations resulting in enzyme deficiencies in the beta-oxidation
pathway of lipid metabolism (e.g. VLCAD, LCAD, MCAD and
SCAD)
and
in
cardiomyopathies.
the
transport
of
carnitine
often
cause
In this case, in addition to the reduced energy
production, the accumulation of fatty acids is also toxic to the
cardiac myocytes.
o Defects in the mitochondrial trifunctional protein (MTP), another
component of the beta-oxidation pathway, may result in dilated
cardiomyopathy.
o A recent animal study has shown the first gene mutation (Dnm1L)
involved in mitochondrial fission and remodeling to result in a
dilated cardiomyopathy in the mouse mutant Python phenotype.25
No human disease involving this gene or mechanism has yet been
described.
Clinical Manifestations
•
The clinical manifestations of cardiac involvement in mitochondrial disease
may be either “pure” cardiopathies or, more commonly, part of multisystemic mitochondrial cytopathies – which may include: short stature,
sensorineural hearing loss, diabetes mellitus, peripheral neuropathies, and
many more symptoms and signs.
•
The cardiac manifestations are similar to those caused by any other
medical or primary cardiac condition.
•
There are three main clinical groups – asymptomatic, arrhythmias, and
cardiomyopathies.
1. Asymptomatic – cardiac dysfunction is detected as part of a screening
evaluation of a patient with mitochondrial disease, or is found in an
asymptomatic family member.
2.
Arrhythmias
a. Symptoms: palpitations - tachycardia, bradycardia, or irregular
heart rate, syncope or pre-syncope, dizziness, pallor, shortness
of breath, chest pain or sudden death.
b. Signs: Irregular pulse rate, pallor, and/or sweating.
3. Congestive heart failure
a. Symptoms:
i. Arrhythmia (as above)
ii. Shortness of breath, dyspnea with effort, orthopnea, easy
fatigability.
iii. Failure-to-thrive, loss of appetite
iv. Swelling of feet and ankles
v. Chronic cough
b. Signs: Irregular pulse rate, weight loss or alternatively excessive
weight gain, elevated jugular venous pressure, edema,
hepatomegaly, displaced cardiac apex, and/or murmur.
Evaluation of Cardiac Disease
•
Evaluation:
1.
Clinical
2.
Fractionated creatine kinase (CK): elevation of the MM fraction may
indicate a concomitant underlying skeletal myopathy providing an
additional clue to a possible mitochondrial cytopathy (or other
primary genetic neuromuscular disorder).
3.
Special Investigations: will vary according to the nature of the
suspected underlying problem, but includes –
a. Electrocardiogram (ECG) – should be done in all patients
b. Echocardiogram (Echo) – should be done in all patients
c. Chest X-ray
d. Holter monitor
e. Stress test
f. Chest computed tomography (CT) scan or cardiac magnetic
resonant imaging (MRI) scan
g. Nuclear heart scans -radionuclide ventriculography (RNV) or
multiple gate acquisition scan (MUGA)
h. Heart catheterization
i. Electrophysiological studies (EPS) may be necessary for further
evaluation of some cases of arrhythmias
4.
Cardiac biopsy: in select instances, cardiac biopsy may be helpful
for the diagnosis of a mitochondrial cardiomyopathy.
Electron
microscopy may identify abnormalities in mitochondrial number,
shape or size.
5.
Screening of family members: first degree relatives of the index
case should be screened by ECG and echocardiogram for potential
sub-clinical involvement. This should include female carriers in the
case of X-linked inheritance and matrilinear relatives if mtDNA
mutations are suspected.
Treatment of Cardiac Disease
•
The treatment of cardiac disease is unrelated to its possible
mitochondrial nature, and is directed towards the underlying etiology
and symptoms.
1. Arrhythmias: treatment options will vary based on the type of
arrhythmia but may include a. Medication: anti-arrhythmic drugs
b. Defibrillation or cardioversion
c. Radiofrequency ablation
d. Pacemaker
e. Implantable cardioverter-defibrillator (ICD) device
2. Congestive heart failure: treatment options will vary but may include
–
a. Limitation of sodium intake
b. Medications: anti-arrhythmic drugs, diuretics, beta-blockers,
angiotensin-converting enzyme
(ACE) inhibitors, and/or
angiotensin receptor blockers (ARB)
c. Heart transplantation
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