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TITLE: Noncompaction Cardiomyopathy
ABSTRACT
Noncompaction cardiomyopathy (NC) is an uncommon type of genetic cardiomyopathy
that is characterized by trabeculations and recesses within the ventricular myocardium, most
commonly affecting the LV. Patients typically present with heart failure symptoms and also
often have concurrent diastolic and systolic dysfunction. In addition to developing heart failure,
these patients appear to also be at risk for thromboembolic events or arrhythmias including atrial
fibrillation or ventricular tachycardia. It is important to recognize this rare cause of heart failure
because early diagnosis may lead to a better prognosis. Moreover, the management of these
patients may differ from that of patients with other causes of cardiomyopathy. Diagnostic criteria
for NC is inconsistent with multiple diagnostic schemes, but imaging studies such as cardiac
MRI and Doppler studies are critical to perform. Similarly, there are no specific guidelines used
for managing patients with NC leaving clinicians to formulate treatment strategies based on
personal experience. The purpose of this case report is to use two case examples to illustrate
the spectrum of NC and to also review the diagnosis, prognosis and management plan for these
patients. We suggest the best way of treating NC patients is directly related to their presenting
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signs and symptoms. For most symptomatic patients, it is reasonable to consider initiating
angiotensin-converting enzyme inhibitors (ACEi), beta-blockers and an anticoagulant to prevent
thromboembolic events. Moreover, it is imperative that they receive adequate follow-up with
serial imaging.
KEYWORDS: Noncompaction, cardiomyopathy, heart failure
MANUSCRIPT TEXT
Case 1: A healthy, athletic 33-year-old woman presented to hospital for a cardiac workup after
her mother was recently diagnosed with dilated cardiomyopathy (DCM). Of note, her maternal
grandmother also had a diagnosis of DCM. The 33-year-old patient was asymptomatic at
presentation and had no history of cardiac disease. Her initial ECG showed left ventricular
hypertrophy (LVH) without any other abnormalities. An echocardiogram showed preserved left
ventricular function and signs of noncompaction cardiomyopathy. Subsequently, an MRI was
done showing prominent trabeculations and noncompaction in the inferior and lateral wall of the
left ventricle (LV). Her cardiopulmonary test showed a peak VO2 of 44.8 ml/kg/min and her BNP
level was 10pg/mL.
Case 2: A 25-year-old man with a past medical history of Hodgkin’s disease requiring
autologous stem cell transplant presented to hospital with heart failure symptoms such as
peripheral edema and dyspnea. Previous routine echocardiograms reported a preserved LV
function. At presentation he had New York Heart Association (NYHA) class II symptoms. His
initial echocardiogram demonstrated significant trabeculations in the LV in addition to having a
spongy appearance. A cardiac MRI demonstrated biventricular dilation with global thickening
and excess trabeculations in the LV plus a large left atrium. His left ventricular ejection fraction
(LVEF) was 36% and the end-diastolic volume was 177mL.
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Introduction:
The classification of cardiomyopathies has evolved over the past 50 years and continues
to grow due to the increased availability and accuracy of diagnostic techniques, molecular
knowledge and imaging capabilities. Common examples of cardiomyopathies include
hypertrophic cardiomyopathy, dilated cardiomyopathy and myocarditis. However, uncommon
causes of cardiomyopathy have recently been described including arrhythmogenic right
ventricular dysplasia, Tako-Tsubo cardiomyopathy and left ventricular noncompaction. While
uncommon, these conditions are important to consider when symptoms are not resolved with
usual therapies1. Patients often develop signs and symptoms of heart failure but the underlying
cause is drastically different. Furthermore, because these are rare diagnoses, the prevalence in
society may be underestimated; thus, challenging clinicians to develop better management
plans.
The rarity of NC presents not only a management dilemma, but also a diagnostic
dilemma. NC is an uncommon type of genetic cardiomyopathy that is characterized by
trabeculations and recesses within the ventricular myocardium, most commonly affecting the
LV1. The right ventricle is also affected in less than half of the cases2. Though the American
Heart Association has characterized this type of cardiomyopathy, the World Health Organization
still considers NC to be an “unclassified cardiomyopathy”3. This cardiomyopathy is usually
isolated but may be found in conjunction with other congenital heart defects4. Noncompaction is
usually described in the pediatric population and only a few case reports in the adult population
have been published in recent years5. There have been both familial and non-familial cases
reported in the literature and interestingly, familial recurrence seems to be more common in
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adult patients with NC than in pediatric
populations6.
Several genes have also been identified
that appear to be associated with NC.
Several differences between adults and children with NC are that adults often also have
Wolff-Parkinson-White syndrome and complete bundle branch blocks, while children
occasionally have concurrent dysmorphic features6-8. Regardless of the age at presentation, it
is largely accepted that the cause of NC cardiomyopathy stems from the disturbance of normal
compaction of the loose myocardial meshwork during fetal development7. Gradual “compaction”
of this spongy meshwork of fibers and intertrabecular recesses normally occurs between weeks
5 and 8 of embryonic life8.
Clinical Features:
The prevalence of NC is unknown but is reported to be 0.05% in the general population
based on echocardiographic studies9. Noncompaction affects both males and females equally.
Once thought to be a pediatric condition, presentation of symptoms may not occur in childhood
at all and adult presentations of NC are increasing. Patients typically present with heart failure
symptoms such as dyspnea, fatigue and lower limb edema. In a group of patients who
underwent coronary angiography, less than 10% had significant stenosis10. Diastolic
dysfunction in ventricular NC is present in most patients, and may be related to both abnormal
relaxation and restrictive filling caused by the numerous prominent trabeculae. The origin of
systolic dysfunction in NC is unclear, but subendocardial hypoperfusion and microcirculatory
dysfunction may play roles in ventricular dysfunction and arrhythmogenesis 8. In addition,
impaired microvascular function may account for the contractile dysfunction 8.
Other complications associated with NC are thromboembolic events or arrhythmias
including atrial fibrillation or ventricular tachycardia4. In one study of patients with isolated
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ventricular NC, the occurrence of thromboembolic events, including cerebrovascular accidents,
transient ischemic attacks, pulmonary emboli and mesenteric infarction, ranged from 21% to
38%. Embolic complications may be related to the development of thrombi in the extensively
trabeculated ventricle, depressed systolic function or the presence of atrial fibrillation. Atrial
fibrillation has been reported in over 25% of patients while ventricular tachyarrhythmias have
been reported in as many as 47% of NC patients8. Sudden cardiac death accounted for half the
deaths in a large series of patients with ventricular NC8.
An association between NC and neuromuscular disorders (NMDs) has also been
described, with as many as 82% of patients having some form of neuromuscular disorder 8.
Some examples of specific NMDs include dystrophinopathy, myotonic dystrophy 1 and Pompe's
disease10. In one study of NC patients, a specific NMD was diagnosed in 22% of the patients
while a NMD of unknown etiology was diagnosed in 42%10. Some patients may also have
dysmorphic facial features, again demonstrating the pediatric association of this condition2.
Diagnosis:
The diagnosis of NC is made most often with either echocardiography or MRI. A series
of echocardiographic features have been identified to aid in the diagnosis of NC. Several
researchers have laid out specific criteria to define NC (see Box 1)11. Some important findings
include: thick endocardial layer of the LV wall, deep trabeculations and recesses, and a thin
epicardial layer (see Fig 1). The likelihood of NC is increased if the end-systolic ratio of
noncompacted to compacted layers is greater than two. The location of the thickening is also
indicative of NC with the pathological areas usually limited to the mid-lateral, apical and midinferior areas. In a study, 61% of noncompaction muscle was confined to the apex of the LV
wall. Moreover, Doppler studies also demonstrate flow within the trabecular recesses 4,11. Lastly,
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hypokinesis was observed occasionally in noncompacted segments but this is a nonspecific
finding8.
Box 1: Criteria for Diagnosis of Noncompaction Cardiomyopathy11
Öechslin's criteria: maximum ratio of the thick endocardial layer to the thin compacted
epicardial layer of myocardium >2 at end-systole, the presence of myocardial spaces
and Doppler evidence of flow within them
Stöllberger's criteria: >3 coarse, prominent trabeculations apically towards the papillary
muscles that have equal echogenicity as the myocardium, move with it, are not
connected to the papillary muscles, and are surrounded by perfused intertrabecular
spaces in the ventricle
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Fig. 1: Echocardiogram of the left ventricle showing prominent trabeculation as shown by the
arrows.
MRI provides good correlation with echocardiography for localization and extent of
noncompaction and is useful in cases with poor echocardiographic image quality (see Fig 2).
Another potential advantage of MRI is the possibility of identifying subendocardial perfusion
deficits6. Positron emission tomography (PET) may be used to assess microcirculatory
dysfunction ultimately responsible for the wall motion abnormalities6.
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Fig 2: Cardiac MRI showing prominent trabeculations in the left ventricle as shown by the arrow.
The Canadian Cardiovascular Society has also recommended contrast echocardiography
to aid in the diagnosis of LV noncompaction, especially in the presence of suboptimal studies12.
In addition to echocardiographic findings, some typical ECG findings of NC include
bilateral ventricular hypertrophy, arrhythmias or isolated T-wave inversions3. Furthermore,
chest x-rays can demonstrate cardiomegaly or pulmonary congestion secondary to NC.
Genetic testing can provide additional information to aid in the diagnosis of this
condition3. The most frequently studied gene regarding NC is G4.5 located on Xq28. The
protein coded by this gene is taffazin and it is found in heart and muscle. Unfortunately, this
gene is found in only a small proportion of NC patients but the relative frequency in which NC is
found in families implies that elusive genes have not yet been discovered. Other genes that
have been identified in a few patients include alpha-dystrobrevin, ryanodine 2 receptor gene and
the cardiac specific gene CSX. One study also mapped a gene locus to chromosome 11p15.
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Animal studies are also ongoing and have identified mutations in the FKBP12 gene and Peg1 as
possible causes of NC3. In the majority of adult patients, NC appears to be an autosomal
dominant trait. Conversely, NC in children is usually associated with mutations in the G4.5 gene
located on the X chromosome. Other cardiomyopathies have also been mapped to this same
region including Barth syndrome and Emery-Dreifuss muscular dystrophy8.
NC is known to have familial causes leading to the importance of genetic testing such
that family members can be screened for this condition before becoming symptomatic. Because
of the rare nature of this condition, it is often misdiagnosed as another cardiovascular condition
with dilated cardiomyopathy, ischemic cardiomyopathy, valvular disease, arrhythmogenic right
ventricular dysplasia or cardiac metastases being common misdiagnoses8,9.
Prognosis:
Noncompaction carries a significant morbidity and mortality. Patients with more
trabeculations or with a ratio of noncompaction to compaction greater than 3 had higher
morbidity as defined by a worse NYHA functional class9. Öechslin et al. reported that certain
clinical characteristics were observed more frequently in NC non-survivors compared with
survivors, including higher LV diameter on presentation, NYHA class III-IV, permanent or
persistent atrial fibrillation and bundle branch block8. Due to the rarity of this condition, there are
no large studies looking at the patient’s outcomes but in a small study of 34 patients with NC,
more than half developed heart failure with 12% of patients needing a heart transplant and 35%
of patients died at 44 months follow-up4. The occurrences of systemic emboli, ventricular
arrhythmias and death were considerably lower in the largest pediatric series with NC when
compared with adults. Of note, however, nearly 90% of patients followed for 10 years developed
LV dysfunction8.
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Noncompaction is still a rare cause of heart failure being much less common than
coronary artery disease, dilated cardiomyopathy and valvular defects 13. The incidence of NC
may be comparable to that of hypertrophic cardiomyopathy13.
Treatment:
There are no accepted guidelines as to how to treat patients with NC. In patients who
developed symptoms of heart failure and had advanced heart failure symptoms, medical
treatment with ACEi, diuretics, beta-blockers appear to have favorable results9. With previous
studies showing a stabilization of LV function with beta-blockers (specifically carvedilol), patients
with depressed LV function should at least be on a beta-blocker14. There are also suggestions
of aspirin or anticoagulation therapy to decrease the risk of emboli; specifically we recommend
using either aspirin or warfarin3,8. Otherwise, digoxin is also a possibility but there are no
studies demonstrating its effectiveness in NC.
Other then medical management, invasive management for NC includes the use of
implantable cardioverter defibrillator (ICD) and cardiac transplantation. There is minimal
evidence suggesting that ICD use as a primary prevention strategy in NC patients is beneficial,
but given that patients with NC are predisposed to developing heart failure, thromboembolic
events, and arrhythmias, it is not unreasonable to consider the use of ICD in patients with
depressed LV function to decrease the risk of sudden cardiac death. There are many trials
describing the importance of ICD use including the SCD-HeFT and MADIT trials and we
propose using these as a basis for determining whether or not patients should receive an ICD.
For example, NC patients with an LV function of less than 35% or are suffering from NYHA II or
III symptoms should be considered for ICD implantation as noted in the SCD-HeFT trial15.
Moreover, ICDs and biventricular pacemakers may have a role in the treatment of NC patients
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with prolonged intraventricular conduction and ventricular
arrhythmias8.
The consideration for
cardiac transplantation is warranted if patients deteriorate clinically and LV function does not
improve or stabilize with maximum medical therapy as per currently accepted heart failure
treatment guidelines. Early consideration for transplantation may also be reasonable if patient’s
present acutely with NYHA III or IV symptoms or have comorbid cardiac abnormalities including
bicuspid aortic valves3,4,16.
With the potential for progression to critical endpoints and transplantation as a last resort,
regular follow-up is crucial. Because of the frequency of ventricular tachycardia and significant
risk of sudden cardiac death, assessment for atrial and ventricular arrhythmias by ambulatory
ECG monitoring should be performed annually8. Screening echocardiography of first-degree
relatives is also recommended. Furthermore, since there is an association between NC and
NMDs, patients should be referred to a neurologist8. Ultimately, the important issue is to ensure
regular follow-up with cardiac imaging with either echocardiography or cardiac MRI at each
annual appointment to monitor for any radiographical changes. It is also important to assess for
any signs of clinical deterioration at each visit.
Management:
Case 1: Patients with NC cardiomyopathy are rarely asymptomatic and this patient likely
represents a mild case of NC. Since the finding of NC was incidental and because the patient
was otherwise healthy with no symptoms suggestive of heart failure, the decision was made to
not initiate treatment. There is no evidence to suggest that initiating prophylactic treatment is of
any benefit. The management plan for this young woman is to have yearly follow-up with a
cardiac MRI, ECG and 24-hour Holter monitoring. The patient currently remains asymptomatic
and lives an active lifestyle.
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Case 2: In symptomatic patients medical management should be initiated. This patient was
started on several medications in lieu of his condition including ACE-inhibitors, beta-blockers
and warfarin. A dual-chamber ICD was also inserted. Over 5 years of follow-up, the patient
described feeling better after the ICD insertion and his dyspnea and fatigue has slowly
improved. The patient remains stable with reasonable exercise tolerance. He is being followed
yearly with repeat echocardiograms.
Conclusion:
Noncompaction cardiomyopathy is an uncommon condition that is often misdiagnosed. It
is important to recognize this rare cause of heart failure because early diagnosis may lead to a
better prognosis. Moreover, the management of these patients may differ from that of patients
with other causes of cardiomyopathy. There is a wide spectrum of patients presenting with NC
as was illustrated with our cases. There are no guidelines as to how to approach a patient with
NC but patients with reduced LV function should be treated according to well-established heart
failure guidelines16,17. In addition, other medications that should be strongly considered include
ACEi, beta-blockers and anticoagulative therapies.
Furthermore, since there is an association between NC and NMDs, patients should be
referred to a neurologist. It is important to recognize that patients with NC can present with a
wide spectrum of symptoms and that regular follow-up is very important. We recommend
annual follow-up with serial investigations and clinical assessments at each visit. Ultimately,
patients with NC may deteriorate and a discussion about cardiac transplantation should be
initiated to allow time for patients to comprehend their illness and current state.
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CONFLICTS OF INTEREST
There are no conflicts of interest.
REFERENCES
1
Maron B, Towbin J, Thiene G, Antzelevitch C, Corrado D, Arnett D, Moss A, Seidman C,
Young J. Contemporary Definitions and Classification of the Cardiomyopathies: An American
Heart Association Scientific Statement From the Council on Clinical Cardiology, Heart Failure
and Transplantation Committee; Quality of Care and Outcomes Research and Functional
Genomics and Translational Biology Interdisciplinary Working Groups; and Council on
Epidemiology and Prevention. Circulation 2006;113;1807-1816
2 Moric-Janiszewska E, Markiewicz-Loskot G. Genetic Heterogeneity of Left Ventricular
Noncompaction Cardiomyopathy. Clinical Cardiology 2008;31(5):201-204
3 Botto L. Left Ventricular Noncompaction. Orphanet encyclopedia Sept 2004
4 Weitzel N, Puskas F, Callahan V, Seres T. A Case of Left Ventricular Noncompaction.
Anesthesia and Analgesia 2009;108(4):1105-1106
5 Borges A, Kivelitz D, Baumann G. Isolated Left Ventricular Non-Compaction: Cardiomyopathy
with Homogenous Transmural and Heterogenous Segmental Perfusion. Heart 2003;89;21
6 Jenni R, Oechslin E, van der Loo B. Isolated ventricular non-compaction of the myocardium in
adults. Heart 2007;93:11–15
7 Ambardekar A, Krantz M. Case of Ventricular Noncompaction: The Crypts and the Blood.
Mayo Clinical Proceedings Aug 2008;83(8):866
8 Weiford B, Subbarao V, Mulhern K. Noncompaction of the ventricular myocardium. Circulation
2004;109;2965-2971
9 Espinola-Zavaleta N, Soto M, Castellanos L, Jativa-Chavez S, Keirns C. Non-compacted
cardiomyopathy: clinical-echocardiographic study. Cardiovascular Ultrasound 2006;4:35
10 Stollberger C, Winkler-Dworak M, Blazek G, Finsterer J. Cardiologic and neurologic findings
in left ventricular hypertrabeculation/noncompaction relating to echocardiographic indication.
Intern Journal of Card 119 (2007) 28–32
11 Finsterer J, Stollberger C. Definite, probable, or possible left ventricular hypertrabeculation
/noncompaction. Letter to the editor- Intern Journal of Card 123 (2008) 175–176
12 Honos G, Amyot R, Choy J, Leong-Poi H, Schnell G, Yu E. Contrast echocardiography in
Canada: Canadian Cardiovascular Society/Canadian Society of Echocardiography position
paper. Canadian Journal of Cardiology 2007;23(5):351-356
13 Kovacevic-Preradovic T, Jenni R, Oechslin E, Noll G, Seifert B, Jost C. Isolated Left
Ventricular Noncompaction as a Cause for Heart Failure and Heart Transplantation: A Single
Center Experience. Cardiology 2009;112:158-164
14
Wald R, Veldtman G, Golding F, Kirsh J, McCrindle B, Benson L. Determinants of Outcome in
Isolated Ventricular Noncompaction in Childhood. Am J Cardiol 2004;94:1581–1584
15 Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines for DeviceBased Therapy of Cardiac Rhythm Abnormalities: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee
to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers
and Antiarrhythmia Devices) developed in collaboration with the American Association for
Thoracic Surgery and Society of Thoracic Surgeons. J Am Coll Cardiol. May 27 2008;51(21):e162.
UTMJ ORIGINAL RESEARCH SUBMISSION
Page 13 of 14
M Luong
16
Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline update for the diagnosis
and management of chronic heart failure in the adult: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee
to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed
in collaboration with the American College of Chest Physicians and the International Society for
Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation
2005;112:e154-235
17 Arnold JMO, Liu P, Demers C, et al; Canadian Cardiovascular Society. Canadian
Cardiovascular Society consensus conference recommendations on heart failure 2006:
diagnosis and management. Can J Cardiol 2006;22:23-45.
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