International Journal of Cardiology 179 (2015) 5–8

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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

Letter to the Editor

Disappearance of left ventricular hypertrabeculation/noncompaction in vacuolar non-neuromuscular cardiomyopathy Claudia Stöllberger a,⁎, Thomas Kolussi b, Michael Hackl c, Stéphane Mahr d, Nikolaus Heinrich d, Martin Grassberger a, Josef Finsterer a a

Krankenanstalt Rudolfstiftung, Juchgasse 25, 1030 Wien, Austria Landeskrankenhaus Wolfsberg, Paul-Hackhofer-Straße 9, 9400 Wolfsberg, Austria Klinikum Klagenfurt, Feschnigstraße 11, 9020 Klagenfurt, Austria d Allgemeines Krankenhaus, Währinger Gürtel 18-20, 1090 Wien, Austria b c

a r t i c l e

i n f o

Article history: Received 7 October 2014 Accepted 19 October 2014 Available online 24 October 2014 Keywords: Heart failure Cardiomyopathy Heart transplantation

Left ventricular hypertrabeculation/noncompaction (LVHT) is a cardiac abnormality of unknown etiology. LVHT may be congenital or develop during lifetime. LVHT may also disappear. A previously published patient with LVHT and renal embolism eventually developed severe heart failure, disappearance of LVHT and underwent heart transplantation [1]. Histologic examination of the explanted heart showed multiple vacuoles in the cardiomyocytes, a finding only once described in LVHT [2]. A previously healthy 20-year old female suffered from sudden pain in the left lumbar region in March 2011. The history was negative for palpitations, dyspnea on exertion, bleeding tendency, or thromboembolism. Since the ECG showed a right bundle branch block, she underwent echocardiography. The left ventricle was dilated and the left ventricular ejection fraction (EF) was 45% (normal N 60%). The apex and lateral wall showed LVHT and within the apex, a thrombus adherent to the left ventricular wall was found (Fig. 1). Cardiac magnetic resonance imaging confirmed these findings. The serum pro-BNP level was 3400 ng/l (normal b 125 ng/l) and troponin I 84 pg/ml (normal b 14 pg/ml). Creatine-kinase and the MB-fraction were normal. A renal infarction, presumably due to cardiogenic embolism, was diagnosed as the cause for the patient's complaints. After initiation of angiotensin-converting-enzyme Abbreviations: EF, ejection fraction; ICD, implantable cardioverter/defibrillator; LVHT, left ventricular hypertrabeculation/noncompaction. ⁎ Corresponding author at: Steingasse 31/18, A-1030 Wien, Austria. E-mail addresses: [email protected] (C. Stöllberger), [email protected] (T. Kolussi), [email protected] (S. Mahr), [email protected] (M. Grassberger), fifi[email protected] (J. Finsterer).

http://dx.doi.org/10.1016/j.ijcard.2014.10.080 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

inhibitors, beta-blockers and oral anticoagulation, left ventricular size decreased, systolic function improved to an EF of 55% and the apical thrombus resolved. Clinical neurologic investigation revealed no abnormal findings. Investigations of the mother, sister and grandmother did not disclose any cardiac symptoms or electrocardiographic or echocardiographic abnormalities. Screening for coagulation disorders (Protein C, Protein S, Factor V Leiden) revealed no abnormalities. Since the apical thrombus disappeared, oral anticoagulation was stopped in July 2011. Because of sustained ventricular tachycardia a one-chamber implantable cardioverter/defibrillator (ICD) was implanted in November 2011. In May 2012 she was hospitalized because of a recurrent renal infarction. An apical thrombus and a decrease of the left ventricular EF to 50% were diagnosed echocardiographically. The serum pro-BNP level had increased to 6370 ng/l. Because of, presumably angiotensin-convertingenzyme inhibitor-induced, cough her pharmacotherapy was changed to candesartan. Oral anticoagulation was restarted. In February 2013 her condition deteriorated rapidly because of atrial fibrillation. The left ventricular systolic function decreased to an EF of 30%. At that time, surprisingly, LVHT was not visible any more at echocardiography. Confirmation

Fig. 1. Transthoracic echocardiographic 4-chamber view in April 2011 showing left ventricular hypertrabeculation/noncompaction of the left ventricular apex and lateral wall.

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Fig. 2. Transesophageal echocardiographic 4-chamber view in December 2014 showing only an echodense structure in the left ventricular apex, most possibly a thrombus.

of that finding by repeated cardiac magnetic resonance imaging was not possible because of the ICD. Despite restoration of sinus rhythm under amiodarone and electrical cardioversion her condition further worsened. In October 2013 she was hospitalized because of pulmonary and systemic congestion. Pro-BNP-levels increased to 8170 ng/l and the left ventricular EF decreased to 15%. Heart transplantation was considered. In November 2013, repeated discharges of the ICD occurred because of ventricular tachycardia and ventricular fibrillation. Despite stabilization of the arrhythmias she developed a cardiogenic shock with multi-organ failure. At that time, even transesophageal echocardiography did not detect LVHT any more (Fig. 2). She needed extracorporeal membrane oxygenation, and heart transplantation was performed in December 2013. The postoperative course was complicated by coagulopathy and multiple

bleeding episodes. After 2 months she was discharged in a rehabilitation center with an immunosuppressive therapy comprising mycophenolate, tacrolimus and prednisolone. At pathoanatomic examination, the explanted heart weighed 422 g. The left ventricle was dilated with flattened trabeculations and moderate diffuse endocardial fibrosis. The lateral wall measured 9 mm, the interventricular septum 17 mm. A thrombus, measuring 15 mm, was found in the left ventricular apex. The coronary arteries were without atherosclerosis. Histologic examination of the left ventricular myocardium (Fig. 3) showed hypertrophy of the cardiomyocytes with slightly enlarged hyperchromatic nuclei. Multiple vacuoles were found in all cardiomyocytes and were accentuated in the subendocardial region, and also present throughout the rest of the myocardium. Subendocardial fibrosis was found with attached coarse-meshed replacement fibrosis. Several areas of scars and compensatory hypertrophy of the cardiomyocytes were found. Additionally, there were areas of fatty degeneration of myocardial cells with empty sarcolemmal tubes. No inflammatory cells were detected. Similar changes were found in the right ventricular myocardium. Hypertrabeculated or noncompacted ventricular myocardium was neither described in the macroscopic nor in the histologic report. Disappearance of LVHT in adults has been reported associated with a decrease in left ventricular size and an improvement of left ventricular systolic function either due to successful pharmacotherapy, cardiac resynchronization therapy or after myocarditis [3–6]. Disappearance of LVHT, like in the presented patient, has also been observed in association with a decrease of systolic function in an adult with Turner mosaic syndrome and coronary heart disease [7]. In another LVHT-patient with mitochondrial myopathy, LVHT was neither visible at follow-up echocardiography nor by pathoanatomic macroscopic inspection, but only at histologic investigation [8]. In children, disappearance of LVHT has been described as an “undulating phenotype” in various cardiomyopathies and in a case with cobalamin C disease [9,10]. In most reported

Fig. 3. Ultrastructure of myocardial tissue showing marked myocyte vacuolization (A, HE, 100×) and accentuated adjacent fibrosis (B, SFOG, 100×). At 400× vacuoles associated with myofibrillar loss are clearly visible (C, SFOG staining). An electron micrograph of cardiac muscle cells also reveals myofibrillar loss with interspersed mitochondria exhibiting sporadic degenerative electron-dense precipitations and partially vacuolated cristae (D).

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Table 1 Reports about vacuolar myocardium in humans. Author

Disease

Mutation

Report

[11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26]

Danon disease Mitochondrial disorder Dilated cardiomyopathy Inclusion body myositis coexisting with hypertrophic CMP Hypertrophic CMP Danon disease Vacuolar glycogen storage disease Takotsubo Cardiomyopathy Cardiomyopathy with prominent autophagic vacuoles Sickle cell anemia Glycogen storage disease Myotonic dystrophy Infantile sialic acid storage disease Fabry disease Chloroquine-induced

c.137GNA in the LAMP-2 gene Homoplasmic mitochondrial tRNA mutations NI Myosin binding protein C3 mutation NI c.179delC at the 3′ end of exon 2 in the LAMP-2 gene NI NI Deletion of 17081C of the SLC22A5 gene NI NI NI NI NI NI NI

Case report N = 3, HTX N = 28, necropsy Case report Case report Case report N = 2 (brother and sister) N = 8, reversible N=2 Case report Endocardial biopsies Case report N=3 Case report N = 2 (mother and son) N=3

NI = not investigated.

cases it remains unclear whether LVHT in fact disappeared or if the trabeculations were still present but not visible any more due to a decrease in left ventricular size leading to smaller spaces between the trabeculations. Since in our patient, LVHT was neither detected at macroscopic inspection of the explanted heart nor at histological examination, it is justified to state that LVHT in fact disappeared, although the pathomechanism of the disappearance remains unknown. In our patient, progression to severe heart failure requiring transplantation suggests that remodeling of the ventricle during progression of heart failure occurred independently of hypertrabeculation. LVHT in this case is quite likely to have been a remodeling effect from a primary myopathy rather than the driving pathologic entity. It is also possible that the left ventricular thrombus pretended LVHT, that LVHT was thus erroneously diagnosed and disappeared because it was never present. The second remarkable observations in the presented patient are the histologic findings of the explanted heart finding showing vacuolization in the cardiomyocytes and subendocardial fibrosis. Vacuoles are a rare but nonspecific finding in end stage nonischemic heart failure due to various cardiomyopathies, and metabolic and neuromuscular disorders as listed in Table 1 [11–26]. Vacuoles have been described only once in LVHT [2,27]. Reversible myocardial vacuolization has also been found in Takotsubo syndrome, a transient left ventricular cardiomyopathy [18]. Neither the patient's history was indicative of one of the disorders listed on the table nor did she ever take chloroquine thus the cause of her myocardial vacuolization remains unknown. Subendocardial fibrosis, as found in our patient, is a frequent unexplained finding in LVHT [28]. It is unclear if subendocardial fibrosis in LVHT is an aging phenomenon, if it develops due to immunologic or inflammatory reactions, if it is the consequence of local blood flow abnormalities or if it is induced by hemodynamic and mechanical factors around the trabeculated myocardium. We conclude from this observation that LVHT may disappear in the course of aggravation of heart failure, finally necessitating heart transplantation. It remains unknown whether excessive vacuolization of the myocardium might have contributed to the development of heart failure. Conflict of interest None. References [1] C. Stöllberger, T. Kolussi, H.W. Umschaden, J. Finsterer, Thromboembolism and ventricular thrombus in non-neuromuscular noncompaction, Int. J. Cardiol. 151 (2011) 124–125.

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