Case Report

Noncompaction Cardiomyopathy and Stroke: Case Report and Literature Review Ashish Kulhari, MD, Nikhil Kalra, MD, and Cathy Sila, MD

Background: To describe a rare case of isolated noncompaction cardiomyopathy and stroke and to review the medical literature on noncompaction cardiomyopathy.

Methods: Retrospective chart review of the case was performed. Extensive literature review on etiology, clinical presentation, diagnosis, and management of noncompaction cardiomyopathy was also performed. Results: Our patient is a healthy 20-year-old woman who presented with sudden onset left face and arm weakness and hypesthesia. Magnetic resonance imaging (MRI) brain showed right middle cerebral artery (MCA) infarct. Magnetic resonance angiography head showed right MCA artery (M2) cutoff. MRI neck was nonsignificant. Echocardiogram was suggestive of noncompaction of left ventricle. Cardiac MRI confirmed the noncompaction of the left ventricle myocardium, which was thought to be the etiology of stroke. Patient was started on anticoagulation for secondary stroke prevention. Conclusions: Isolated left ventricular noncompaction cardiomyopathy (LVNC) is a rare form of primary genetic cardiomyopathy, which occurs because of the arrest of the process of compaction of ventricular myocardium during embryogenesis. Noncompaction cardiomyopathy is usually associated with other primary cardiac structural abnormalities like dysfunctional cardiac valves. In isolated noncompaction cardiomyopathy, there are no other primary cardiac structural abnormalities. The most common clinical features seen in LVNC include left ventricular systolic dysfunction, congestive heart failure, arrhythmias, and cardiac embolic events theorized to result from thrombus formation within the intertrabecular recesses. As it is a rare disease, evidence-based recommendations for preventing thromboembolic events in isolated left ventricular noncompaction have not been established. Key Words: Noncompaction—cardiomyopathy—stroke—atrial fibrillation—anticoagulation. Ó 2015 by National Stroke Association

Case Summary From the Department of Neurology, University Hospitals Case Medical Center, Cleveland, Ohio. Received February 16, 2015; accepted April 12, 2015. A.K. contributed to article design, drafting, and revision and figure selection. N.K. contributed to article drafting. C.S. contributed to study supervision and article editing. This is a nonfunded, nonsponsored study. All authors report that they have no disclosures. Address correspondence to Cathy Sila, MD, Department of Neurology, University Hospitals Case Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106. E-mail: [email protected] 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.04.014

A 20-year-old right-handed Caucasian female with history of migraines with aura, taking oral contraceptive pills, presented to emergency room with sudden onset of weakness and sensory loss on left face and arm accompanied with right frontal headache. Headache was different from her typical migraine attacks and was not associated with aura. Noncontrast computed tomography (CT) head was normal. Because of minor neurologic symptoms and possibility of complex migraine, intravenous tissue plasminogen activator was not given. Magnetic resonance imaging (MRI) of brain showed moderate-sized acute

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infarct in right middle cerebral artery territory (Fig 1, A). Magnetic resonance angiography head showed cutoff of the superior division of right middle cerebral artery (MCA) artery (Fig 1, B). Magnetic resonance angiography neck was nonsignificant. Fat sat MRI brain did not show any dissection. A transthoracic echocardiogram showed hypertrabeculated left ventricular apex with deep crypts suggestive of left ventricular noncompaction cardiomyopathy, ejection fraction of 55%, normal cardiac valves, normal-sized left atrium, no thrombus, and no patent foramen ovale (Fig 2, A). Patient had no signs or symptoms of heart failure. Given ejection fraction of 55% and lack of heart failure clinical features, she was classified as stage B heart failure. Cardiac MRI was done to confirm findings of echocardiogram. Cardiac MRI showed prominent trabeculations in the left ventricular mid and apical regions, which confirmed the diagnosis of isolated left ventricular compaction cardiomyopathy (Fig 2, B-D). Telemetry did not reveal any arrhythmia. Lipid panel, Hemoglobin A1c, Anti-nuclear antibody, Erythrocyte sedimentation rate, C-reactive protein were all within normal limits. Hypercoagulable work-up was negative. Given all the above findings and cortical infarct, final diagnosis was cardioembolic right MCA infarct due to left ventricular noncompaction cardiomyopathy. After discussion with cardiology, patient was started on lifelong anticoagulation with coumadin with goal international normalized ratio of 2-3. Genetic testing revealed a heterozygous novel variant in the lamin A/C gene. She followed up in cardiology and stroke clinic and was continued on anticoagulation for indefinite period.

Discussion

separated by sinusoids that connect to the left ventricular cavity. This spongy myocardium has a trabecular appearance. The ‘‘spongy’’ myocardium begins to ‘‘compact’’ and develop into mature musculature during weeks 5-8 of embryogenesis. The sinusoids shrink and eventually become capillaries in the coronary circulation. In LVNC, this process of ‘‘compaction’’ is arrested and there is persistence of these large trabeculations that are continuous with left ventricular cavity without any communication with epicardial circulation.1,2 The exact cause of the arrest of compaction is not known. Rare in any case, noncompaction is almost invariably associated with other congenial cardiac malformations but even rarer it can present as isolated LVNC.3 Although LVNC is primarily the disease of left ventricle, associated involvement of right ventricle has been described in past.2

Epidemiology Noncompaction cardiomyopathy, which was first found as an interesting autopsy finding in 1932, then became an echocardiographic curiosity 3 decades ago, has now become a rather common finding in living subjects with the introduction of various newer cardiovascular imaging modalities in addition to echocardiography, including cardiac MRI, cardiac CT, and contrast ventriculography.2 Prevalence of noncompaction cardiomyopathy in those adults who are referred for echocardiography for some clinical reason has been estimated between .01% and .27%.4-7 Prevalence in the entire population is estimated to be between .014% and 1.3%.8-10 The incidence is estimated between .05% and .25% per year.4 Males are more commonly affected than females. Prevalence in males has been reported around 56%-82%.3,4,11,12

Introduction Isolated left ventricle noncompaction (LVNC) is a rare primary genetic cardiomyopathy. During embryogenesis, early myocardium consists of the interconnecting fibers

Genetics Noncompaction cardiomyopathy can be inherited or develop sporadically as well. The most common pattern

Figure 1. (A) DWI MRI brain showing acute right MCA infarct. (B) Intracranial MRA showing cutoff at the superior division of right MCA artery. Abbreviations: DWI, diffusion-weighted imaging; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging.

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Figure 2. (A) Transthoracic echo and (B, C, D) cardiac magnetic resonance imaging (long axis, short axis, and lateral view, respectively) showing prominent trabeculations in myocardium.

of inheritance is autosomal dominant, although X-linked recessive, autosomal recessive, and mitochondrial inheritance can occur.4,13 There are various genetic mutations associated with LVNC. Some of the proteins encoded by the affected genes include LIM domain binding protein 3, a-dystrobrevin, tafazzin, lamin A/C, beta-myosin heavy chain, alpha-cardiac actin, cardiac troponin T, troponin I, cardiac myosin binding protein C, SCN5A, and tropomyosin.4 These genes encode for mitochondrial, sarcomeric, and cytoskeletal proteins among others. The lamin A/C (LMNA) protein is an inner nuclear membrane matrix protein.

Clinical Features Noncompaction cardiomyopathy is usually associated with other primary cardiac structural abnormalities like dysfunctional cardiac valves. In isolated noncompaction cardiomyopathy, there are no other primary cardiac structural abnormalities. The most common clinical features seen in LVNC include left ventricular systolic dysfunction, congestive heart failure, arrhythmias, and thromboembolic events. Table 1 outlines the demographics and the clinical features of the patients enrolled in the 4 biggest studies of noncompaction cardiomyopathy done so far. Left ventricular dysfunction is the most commonly reported clinical manifestation.3,4,11,12 It is thought that microcirculation in the subendocardial layer of the heart

is diminished, which leads to systolic dysfunction. In addition, diastolic dysfunction occurs because of abnormal relaxation of the hypertrabeculated heart wall.14 Atrial fibrillation, Wolf-Parkinson-White syndrome, and ventricular arrhythmias are commonly seen in LVNC patients.3,4,11,12 Thromboembolic events are also very common in LVNC. Two prospective LVNC case series in adult patients found 21%-24% risk of cerebral embolism during the follow-up period.4,11 Thromboembolism is theorized to result from atrial fibrillation, decreased systolic function, and intertrabecular thrombus formation.4,13,14

Diagnostic Tools Echocardiography is most commonly used to diagnose noncompaction cardiomyopathy. Trabeculations can be directly visualized on echocardiogram. There are a few standardized echocardiogram criteria, which are used to make the diagnosis of noncompaction cardiomyopathy (Table 2).4,11 Cardiac MRI is more sensitive as the apical and the lateral walls of heart are better visualized. Cardiac MRI has been found to have very high specificity,15 suggesting effectiveness of cardiac MRI as a confirmatory test after echocardiogram. However, there are no standardized criteria for diagnosis on cardiac MRI.16 Contrast-enhanced CT has additional ability to rule out coronary artery diseases,

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Table 1. Clinical features and demographics of the patients with noncompaction cardiomyopathy Patient characteristics

Chin et al3

Ritter et al4

Ichida et al12

Oechslin et al11

No. of patients Males (%) Median age at diagnosis (y) Age range (y) Follow–up (y) LV systolic dysfunction (%) Congestive heart failure (%) Atrial fibrillation (%) Ventricular thrombus (%) WPW syndrome (%) Ventricular tachycardia (%) Cerebral embolism (%)

8 63 7 .9-22.5 #5 63 63 — 25 13 38 25

17 82 45 18-71 #6 76 53 29 6 0 47 24

27 56 5 0-15 #17 60 30 — 0 15 0 0

34 74 40 16-71 #11 82 68 26 9 0 41 21

Abbreviations: LV, left ventricle; WPW, Wolff-Parkinson-White.

which makes it advantageous over echocardiography and cardiac MRI. Using specific criteria, contrast CT has been found to have a sensitivity of 100% and specificity of 95%.4 Left ventriculography can be used to diagnose LVNC in cases where the patient also has a low ejection fraction.

Management Management of LVNC is dependent on the clinical manifestations of the disease. Patients with systolic or diastolic heart failure and arrhythmias are treated with standard heart failure therapy and antiarrhythmics, respectively4,8 To reduce the risk of thromboembolism, anticoagulation is recommended, especially in those with history of thromboembolism, atrial fibrillation, or reduced ejection fraction.4,8,13 The risk of a thromboembolic event in LVNC is likely significant in adult populations. Two prospective LVNC case series in adult patients found 21%-24% risk of cerebral embolism during the follow-up period4,11 (Table 1). In pediatric patients, risk of embolism is less clear. Two pediatric case series observed a cerebral embolism rate Table 2. Echocardiogram criteria for diagnosis of noncompaction cardiomyopathy

1. The presence of prominent trabecular meshwork in myocardium which appears like thick spongy noncompacted myocardium. 2. The presence of thin normal appearing compacted myocardium. 3. Noncompacted myocardium is thicker than compacted myocardium (NC:C $2) during the end systolic phase of cardiac cycle. 4. Visualization of intertrabecular spaces perfusion from ventricular cavity.

of 0%-25%3,12 (Table 1). St€ ollberger et al17 explored the relationship between the predicted risk of stroke from atrial fibrillation scores (CHADS2 and CHA2DS2VASc) and stroke in LVNC patients. Scores were significantly higher in patients with stroke or embolism than without. This might help physicians in determining whether anticoagulation is necessary or not. There are multiple case reports and case series of LVNC-associated strokes.3,12,16,18-20 In most of these, patients were started on oral anticoagulation for secondary prophylaxis although there has not been any randomized control trial to determine significant benefit. The authors of one case report recommended starting oral anticoagulation only if there was thrombus found in the ventricle on imaging.16 Vitamin K antagonists should be considered over the newer oral anticoagulants such as dabigatran or rivaroxaban.21 Our patient had hypertrabeculated left ventricle with stage B heart failure and ischemic stroke, which puts her at higher risk of cardioembolic events in future. Given high risk of stroke recurrence, she was started on chronic oral anticoagulation for secondary prevention. Downside of starting her on chronic anticoagulation is that she is a young female with child bearing potential, teratogenic side effects of warfarin, and increased risk of intracerebral and extracerebral bleeding. Randomized control trials will be needed in the future to determine the most appropriate method to treat LVNC patients after stroke. However, because of the low incidence of the disease and difficulty in early detection, guidelines based off small case series and reports may be the only method to guide treatment in the near future.

References 1. Udeoji DU, Philip KJ, Morrissey RP, et al. Left ventricular non compaction cardiomyopathy. Ther Adv Cardiovasc Dis 2013;7:260-273.

NONCOMPACTION CARDIOMYOPATHY AND STROKE 2. Cheng TO. Left ventricular noncompaction cardiomyopathy: three decades of progress. Int J Cardiol 2014;174: 227-229. 3. Chin TK, Perloff JK, Williams RG, et al. Isolated noncompaction of left ventricular myocardium. A study of eight cases. Circulation 1990;82:507-513. 4. Ritter M, Oechslin E, S€ utsch G, et al. Isolated noncompaction of the myocardium in adults. Mayo Clin Proc 1997; 72:26-31. 5. Benjamin MM, Khetan RA, Kowal RC, et al. Diagnosis of left ventricular noncompaction by computed tomography. Proc (Bayl Univ Med Cent) 2012;25:354-356. 6. Ozkutlu S, Ayabakan C, Celiker A, et al. Noncompaction of ventricular myocardium: a study of twelve patients. J Am Soc Echocardiogr 2002;15:1523-1528. 7. Stollberger C, Finsterer J. Left ventricular hypertrabeculation/noncompaction. J Am Soc Echocardiogr 2004;17:91-100. 8. Aras D, Tufekcioglu O, Ergun K, et al. Clinical features of isolated ventricular noncompaction in adults long-term clinical course, echocardiographic properties, and predictors of left ventricular failure. J Card Fail 2006;12:726-733. 9. Pignatelli RH, McMahon CJ, Dreyer WJ, et al. Clinical characterization of left ventricular noncompaction in children: a relatively common form of cardiomyopathy. Circulation 2003;108:2672-2678. 10. Stanton C, Bruce C, Connolly H, et al. Isolated left ventricular noncompaction syndrome. Am J Cardiol 2009; 104:1135-1138. 11. Oechslin EN, Attenhofer Jost CH, Rojas JR, et al. Longterm follow-up of 34 adults with isolated left ventricular noncompaction: a distinct cardiomyopathy with poor prognosis. J Am Coll Cardiol 2000;36:493-500. 12. Ichida F, Hamamichi Y, Miyawaki T, et al. Clinical features of isolated noncompaction of the ventricular myocardium: long-term clinical course, hemodynamic properties, and genetic background. J Am Coll Cardiol 1999;34:233-240.

e5 13. Maron BJ, Towbin JA, Thiene G, et al. 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. 14. Agmon Y, Connolly HM, Olson LJ, Khandheria BK, Seward JB. Noncompaction of the ventricular myocardium. J Am Soc Echocardiogr 1999;12:859-863. 15. Petersen SE, Selvanayagam JB, Wiesmann F, et al. Left ventricular non-compaction: insights from cardiovascular magnetic resonance imaging. J Am Coll Cardiol 2005;46:101-105. 16. Ker J, Van Der Merwe C. Isolated left ventricular non-compaction as a cause of thrombo-embolic stroke: a case report and review. Cardiovasc J S Afr 2006;17: 146-147. 17. St€ ollberger C, Wegner C, Finsterer J. CHADS2- and CHA2DS2VASc scores and embolic risk in left ventricular hypertrabeculation/noncompaction. J Stroke Cerebrovasc Dis 2013;22:709-712. 18. Sahin S, Sekban A, Ayalp S, et al. An unusual cause of cardioembolic stroke: isolated left ventricular noncompaction. Neurologist 2008;14:125-127. 19. Baquero GA, Colegrove DJ, Banchs JE. Isolated left ventricular noncompaction causing stroke in a 30-year-old woman: case report and literature review. Tex Heart Inst J 2013;40:331-338. 20. Finsterer J, St€ ollberger C. Juvenile ‘‘cryptogenic’’ stroke from noncompaction in a neuromuscular disease. Cardiology 2014;127:223-226. 21. St€ ollberger C, Finsterer J. New oral anticoagulants for stroke prevention in left ventricular hypertrabeculation/noncompaction? Int J Cardiol 2013;168: 2910-2911.

Noncompaction Cardiomyopathy and Stroke: Case Report and Literature Review.

To describe a rare case of isolated noncompaction cardiomyopathy and stroke and to review the medical literature on noncompaction cardiomyopathy...
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