CE: ; JCM-D-14-00372; Total nos of Pages: 3;
JCM-D-14-00372
Research letter
Arrhythmogenic cardiomyopathy with biventricular involvement and noncompaction Cettina Rupertoa, Chiara Mina`a, Francesca Brunc, Rosa Liottab, Stilianos Pyxarasc, Francesco Clemenzaa and Gianfranco Sinagrac J Cardiovasc Med 2015, 16:000–000 a
Heart Failure Unit, bPathology Service, Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (ISMETT), Palermo and cCardiovascular Department, University Hospital of Trieste, Trieste, Italy Correspondence to Cettina Ruperto, Heart Failure Unit, ISMETT, Via Tricomi 5, 90127 Palermo, Italy Tel: +39 334 6222 337; e-mail: [email protected] Received 2 July 2014 Revised 20 October 2014 Accepted 21 October 2014
A 43-year-old woman with a history of palpitations was occasionally diagnosed with moderate left ventricular systolic dysfunction in an echocardiogram performed 7 months after her first pregnancy, in 1994. Her family history was negative for cardiac diseases and she had never undergone cardiac examinations previously. In the following years, she remained asymptomatic on carvedilol. In 2009, irregular heart beat and exertional dyspnoea occurred and frequent premature ventricular beats and two episodes of sustained ventricular tachycardia were recorded. The echocardiogram revealed a biventricular dilatation and severe dysfunction (right ventricular fractional area change 23%; Left ventricular ejection fraction, 31%). The right ventricle (RV) presented diastolic bulging of the apex and infero-lateral wall, while left ventricular apex and the lateral wall had a two-layered myocardial
structure (noncompacted endocardial layer/compacted epicardial layer index was 1.9) (Fig. 1). A diagnosis of Arrhythmogenic right ventricular cardiomyopathy (ARVC) with Left Ventricular Non-compaction (LVNC) was supposed on the basis of the concomitant presence of the ARVC1 and the criteria by Jenni et al.,2 respectively. A cardiac magnetic resonance supported this diagnosis and late gadolinium enhancement suggested the presence of fibrosis in medium and basal anterior and inferolateral wall (Fig. 1). The patient underwent Implantable Cardioverter Defibrillator implantation, and began warfarin and amiodarone in addition to conventional therapy with carvedilol and ramipril. She remained clinically stable until July 2011 when she experienced a worsening of compensation despite optimal medical treatment. A cardiopulmonary exercise test showed a reduction in maximal oxygen consumption to 9.5 ml/kg/min. After diuretic infusion, right heart catheterization confirmed low cardiac output and increased left ventricular filling and right atrial pressures. The patient was placed on our waiting list and, in April 2012, she was transplanted. Posttransplant follow-up was regular. Anatomical examination showed a dilated and thin-walled RV with transmural fibrofatty replacement, adipose infiltration limited to the left ventricular posterior wall and
Fig. 1
(a)
(b)
LA RA LV
LV RV
RV
Hypertrabeculation and deep intertrabecular recesses reaching the epicardium (arrows) observed in left ventricular apex and lateral wall with echocardiography (a) and cardiac magnetic resonance (b). At MRI, moreover, the ratio between the noncompacted and compacted layer was 2.6 in the LV apical infero-lateral wall, while the trabeculated left ventricular mass was approximately 29% of the global left ventricular mass. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
1558-2027 ß 2015 Italian Federation of Cardiology
DOI:10.2459/JCM.0000000000000242
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
CE: ; JCM-D-14-00372; Total nos of Pages: 3;
JCM-D-14-00372
2 Journal of Cardiovascular Medicine 2015, Vol 00 No 00
Fig. 2
(a)
(b)
(c)
(d)
Anatomopathological examination. (a) In the right ventricle, transmural fibrofatty replacement was found principally in the infero-basal region and in the apex, wherein the wall was translucent and extremely thinned (apical wall thickness 1 mm). (b) Toward the left ventricle (LV) apex, and in midventricular lateral wall, hypertrabeculations, and a two-layered myocardial structure with an epicardial compacted and a thick endocardial noncompacted layer, were observed. (c) Focal left ventricular noncompaction: sample taken from left ventricle (LV) wall showing a NC/C ratio of 2 : 1. (d) Left ventricular noncompaction: a hystologic section from the gross sample shown in (c) showed polypoid trabeculations that extend all the way to the epicardial surface.
hypertrabeculation (Fig. 2). Severe degeneration of myocites in the RV and deep intertrabecular recesses in the left ventricle (LV) were found at microscopic examination (Fig. 2). ARVC is a rare primary cardiomyopathy caused by genetic disorders,3,4 with a familial trait in 30–50% of cases.5,6 Several desmosomal mutations7 are thought to be responsible for the progressive loss of ventricular myocytes, with fibrofatty replacement and ventricular electrical instability. ARVC primarily affects the RV, with possible left ventricular involvement,8 and potential evolution to heart failure. LVNC is a genetically heterogeneous disorder and can be9 associated with several mutations in structural proteins that lead to persistent, prominent ventricular trabeculations and deep intertrabecular recesses.10 The European Society of Cardiology (ESC) considers LVNC an ‘unclassified cardiomyopathy’ because it remains unclear whether it is a discrete cardiomyopathy or a simple morphological trait common to many phenotypically distinct cardiomyopathies that share several pathophysiological features.11–13 Whether LVNC can be a morphological trait of right ventricular myocardial diseases, as already described for hypertrophic and dilated cardiomyopathies, needs to be clarified.14
To the best of our knowledge, only a few cases of ARVC associated to LVNC’s features have been15 – 18 reported in the literature, and definitive data are still lacking. We believe that the finding of Non-Compaction (NC) may be part of several cardiac diseases, including ARVC. For this reason, NC should be carefully considered when evaluating right ventricular cardiomyopathies with myocardial hypertrabeculation because of its prognostic role in terms of life-threatening arrhythmias and end-stage heart failure. In this setting, an additional contribution could be given by genetic analysis in order to identify possible mutations common to the two diseases. Moreover, the concurrence of left ventricular dysfunction and LVNC’s characteristic deep intertrabecular recesses intuitively increases the thrombogenic risk and could make an oral anticoagulation treatment inevitable.19,20 In cases such as ours, special attention should be made to assess women who develop heart failure symptoms during or after pregnancy because it may be a latent and subclinical cardiomyopathy, such as ARVC or LVNC.
References 1
Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Eur Heart J 2010; 31:806–814.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
CE: ; JCM-D-14-00372; Total nos of Pages: 3;
JCM-D-14-00372
Research letter. 3
2
3
4
5
6
7 8 9
10
Jenni R, Oechslin E, Schneider J, et al. Echocardiographic and pathoanatomical characteristics of isolated left ventricular noncompaction: a step towards classification as a distinct cardiomyopathy. Heart 2001; 86:666–671. 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. Basso C, Corrado D, Thiene G. Arrhythmogenic right ventricular cardiomyopathy: what’s in a name? From a congenital defect (dysplasia) to a genetically determined cardiomyopathy (dystrophy). Am J Card 2010; 106:275–277. Hamid MS, Norman M, Quraishi A, et al. Prospective evaluation of relatives for familial arrhythmogenic right ventricular cardiomyopathy/dysplasia reveals a need to broaden diagnostic criteria. J Am Coll Cardiol 2002; 40:1445–1450. Nava A, Thiene G, Canciani B, et al. Familial occurrence of right ventricular dysplasia: a study involving nine families. J Am Coll Cardiol 1988; 12:1222–1228. Moric-Janiszewska E, Markiewicz-Łoskot G. Review on the genetics of arrhythmogenic right ventricular dysplasia. Europace 2007; 9:259–266. Pinamonti B, Sinagra G, Salvi A, et al. Left ventricular involvement in right ventricular dysplasia. Am Heart J 1992; 123:711–724. Sen-Chowdhry S, McKenna WJ. Left ventricular noncompaction and cardiomyopathy: cause, contributor, or epiphenomenon? Curr Opin Cardiol 2008; 23:171–175. Jenni R, Oechslin EN, vander Loo B. Isolated ventricular noncompaction of the myocardium in adults. Heart 2007; 93:11–15.
11
12
13
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15
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18
19
20
Elliott P, Andersson B, Arbustini E, et al. Classification of the cardiomyopathies: a position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2008; 29:270–276. Oechslin E, Jenny R. Left ventricular noncompaction revisited: a distinct phenotype with genetic eterogeneity? Eur Heart J 2011; 32:1446–1456. Baldi M, Sgalambro A, Mistri S, et al. Clinical and genetic features of left ventricular noncompaction: a continuum in cardiomyopathies. G Ital Cardiol 2010; 11:377–385. Biagini E, Ragni L, Ferlito M, et al. Different types of cardiomyopathy associated with isolated ventricular noncompaction. Am J Cardiol 2006; 98:821–824. Wozniak O, Konka M, Wlodarska EK. Isolated ventricular noncompaction in a patient initially diagnosed with arrhythmogenic right ventricular cardiomyopathy. Heart 2008; 94:289. Ze-Zhou S. A combination of right ventricular hypertrabeculation/ noncompaction and arrhythmogenic right ventricular cardiomyopathy: a syndrome? Cardiovasc Ultrasound 2008; 6:63. Seiji M, Kiyoyuki E, Koji H, et al. Arrhythmogenic left ventricular cardiomyopathy associated with noncompaction. Ann Thorac Surg 2010; 90:2044–2046. Wlodarska EK, Olgierd W, Marek K, et al. Isolated ventricular noncompaction mimicking arrhythmogenic right ventricular cardiomyopathy: a study of nine patients. Int J Cardiol 2010; 145:107–111. Greutmann M, Mah ML, Silversides CK, et al. Predictors of adverse outcome in adolescents and adults with isolated left ventricular noncompaction. Am J Cardiol 2012; 109:276–281. Wlodarska EK, Wozniak O, Konka M, et al. Thromboembolic complications in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy. Europace 2006; 8:596–600.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
JCM-D-14-00372
Research letter
Arrhythmogenic cardiomyopathy with biventricular involvement and noncompaction Cettina Rupertoa, Chiara Mina`a, Francesca Brunc, Rosa Liottab, Stilianos Pyxarasc, Francesco Clemenzaa and Gianfranco Sinagrac J Cardiovasc Med 2015, 16:000–000 a
Heart Failure Unit, bPathology Service, Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (ISMETT), Palermo and cCardiovascular Department, University Hospital of Trieste, Trieste, Italy Correspondence to Cettina Ruperto, Heart Failure Unit, ISMETT, Via Tricomi 5, 90127 Palermo, Italy Tel: +39 334 6222 337; e-mail: [email protected] Received 2 July 2014 Revised 20 October 2014 Accepted 21 October 2014
A 43-year-old woman with a history of palpitations was occasionally diagnosed with moderate left ventricular systolic dysfunction in an echocardiogram performed 7 months after her first pregnancy, in 1994. Her family history was negative for cardiac diseases and she had never undergone cardiac examinations previously. In the following years, she remained asymptomatic on carvedilol. In 2009, irregular heart beat and exertional dyspnoea occurred and frequent premature ventricular beats and two episodes of sustained ventricular tachycardia were recorded. The echocardiogram revealed a biventricular dilatation and severe dysfunction (right ventricular fractional area change 23%; Left ventricular ejection fraction, 31%). The right ventricle (RV) presented diastolic bulging of the apex and infero-lateral wall, while left ventricular apex and the lateral wall had a two-layered myocardial
structure (noncompacted endocardial layer/compacted epicardial layer index was 1.9) (Fig. 1). A diagnosis of Arrhythmogenic right ventricular cardiomyopathy (ARVC) with Left Ventricular Non-compaction (LVNC) was supposed on the basis of the concomitant presence of the ARVC1 and the criteria by Jenni et al.,2 respectively. A cardiac magnetic resonance supported this diagnosis and late gadolinium enhancement suggested the presence of fibrosis in medium and basal anterior and inferolateral wall (Fig. 1). The patient underwent Implantable Cardioverter Defibrillator implantation, and began warfarin and amiodarone in addition to conventional therapy with carvedilol and ramipril. She remained clinically stable until July 2011 when she experienced a worsening of compensation despite optimal medical treatment. A cardiopulmonary exercise test showed a reduction in maximal oxygen consumption to 9.5 ml/kg/min. After diuretic infusion, right heart catheterization confirmed low cardiac output and increased left ventricular filling and right atrial pressures. The patient was placed on our waiting list and, in April 2012, she was transplanted. Posttransplant follow-up was regular. Anatomical examination showed a dilated and thin-walled RV with transmural fibrofatty replacement, adipose infiltration limited to the left ventricular posterior wall and
Fig. 1
(a)
(b)
LA RA LV
LV RV
RV
Hypertrabeculation and deep intertrabecular recesses reaching the epicardium (arrows) observed in left ventricular apex and lateral wall with echocardiography (a) and cardiac magnetic resonance (b). At MRI, moreover, the ratio between the noncompacted and compacted layer was 2.6 in the LV apical infero-lateral wall, while the trabeculated left ventricular mass was approximately 29% of the global left ventricular mass. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
1558-2027 ß 2015 Italian Federation of Cardiology
DOI:10.2459/JCM.0000000000000242
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
CE: ; JCM-D-14-00372; Total nos of Pages: 3;
JCM-D-14-00372
2 Journal of Cardiovascular Medicine 2015, Vol 00 No 00
Fig. 2
(a)
(b)
(c)
(d)
Anatomopathological examination. (a) In the right ventricle, transmural fibrofatty replacement was found principally in the infero-basal region and in the apex, wherein the wall was translucent and extremely thinned (apical wall thickness 1 mm). (b) Toward the left ventricle (LV) apex, and in midventricular lateral wall, hypertrabeculations, and a two-layered myocardial structure with an epicardial compacted and a thick endocardial noncompacted layer, were observed. (c) Focal left ventricular noncompaction: sample taken from left ventricle (LV) wall showing a NC/C ratio of 2 : 1. (d) Left ventricular noncompaction: a hystologic section from the gross sample shown in (c) showed polypoid trabeculations that extend all the way to the epicardial surface.
hypertrabeculation (Fig. 2). Severe degeneration of myocites in the RV and deep intertrabecular recesses in the left ventricle (LV) were found at microscopic examination (Fig. 2). ARVC is a rare primary cardiomyopathy caused by genetic disorders,3,4 with a familial trait in 30–50% of cases.5,6 Several desmosomal mutations7 are thought to be responsible for the progressive loss of ventricular myocytes, with fibrofatty replacement and ventricular electrical instability. ARVC primarily affects the RV, with possible left ventricular involvement,8 and potential evolution to heart failure. LVNC is a genetically heterogeneous disorder and can be9 associated with several mutations in structural proteins that lead to persistent, prominent ventricular trabeculations and deep intertrabecular recesses.10 The European Society of Cardiology (ESC) considers LVNC an ‘unclassified cardiomyopathy’ because it remains unclear whether it is a discrete cardiomyopathy or a simple morphological trait common to many phenotypically distinct cardiomyopathies that share several pathophysiological features.11–13 Whether LVNC can be a morphological trait of right ventricular myocardial diseases, as already described for hypertrophic and dilated cardiomyopathies, needs to be clarified.14
To the best of our knowledge, only a few cases of ARVC associated to LVNC’s features have been15 – 18 reported in the literature, and definitive data are still lacking. We believe that the finding of Non-Compaction (NC) may be part of several cardiac diseases, including ARVC. For this reason, NC should be carefully considered when evaluating right ventricular cardiomyopathies with myocardial hypertrabeculation because of its prognostic role in terms of life-threatening arrhythmias and end-stage heart failure. In this setting, an additional contribution could be given by genetic analysis in order to identify possible mutations common to the two diseases. Moreover, the concurrence of left ventricular dysfunction and LVNC’s characteristic deep intertrabecular recesses intuitively increases the thrombogenic risk and could make an oral anticoagulation treatment inevitable.19,20 In cases such as ours, special attention should be made to assess women who develop heart failure symptoms during or after pregnancy because it may be a latent and subclinical cardiomyopathy, such as ARVC or LVNC.
References 1
Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Eur Heart J 2010; 31:806–814.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
CE: ; JCM-D-14-00372; Total nos of Pages: 3;
JCM-D-14-00372
Research letter. 3
2
3
4
5
6
7 8 9
10
Jenni R, Oechslin E, Schneider J, et al. Echocardiographic and pathoanatomical characteristics of isolated left ventricular noncompaction: a step towards classification as a distinct cardiomyopathy. Heart 2001; 86:666–671. 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. Basso C, Corrado D, Thiene G. Arrhythmogenic right ventricular cardiomyopathy: what’s in a name? From a congenital defect (dysplasia) to a genetically determined cardiomyopathy (dystrophy). Am J Card 2010; 106:275–277. Hamid MS, Norman M, Quraishi A, et al. Prospective evaluation of relatives for familial arrhythmogenic right ventricular cardiomyopathy/dysplasia reveals a need to broaden diagnostic criteria. J Am Coll Cardiol 2002; 40:1445–1450. Nava A, Thiene G, Canciani B, et al. Familial occurrence of right ventricular dysplasia: a study involving nine families. J Am Coll Cardiol 1988; 12:1222–1228. Moric-Janiszewska E, Markiewicz-Łoskot G. Review on the genetics of arrhythmogenic right ventricular dysplasia. Europace 2007; 9:259–266. Pinamonti B, Sinagra G, Salvi A, et al. Left ventricular involvement in right ventricular dysplasia. Am Heart J 1992; 123:711–724. Sen-Chowdhry S, McKenna WJ. Left ventricular noncompaction and cardiomyopathy: cause, contributor, or epiphenomenon? Curr Opin Cardiol 2008; 23:171–175. Jenni R, Oechslin EN, vander Loo B. Isolated ventricular noncompaction of the myocardium in adults. Heart 2007; 93:11–15.
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Elliott P, Andersson B, Arbustini E, et al. Classification of the cardiomyopathies: a position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2008; 29:270–276. Oechslin E, Jenny R. Left ventricular noncompaction revisited: a distinct phenotype with genetic eterogeneity? Eur Heart J 2011; 32:1446–1456. Baldi M, Sgalambro A, Mistri S, et al. Clinical and genetic features of left ventricular noncompaction: a continuum in cardiomyopathies. G Ital Cardiol 2010; 11:377–385. Biagini E, Ragni L, Ferlito M, et al. Different types of cardiomyopathy associated with isolated ventricular noncompaction. Am J Cardiol 2006; 98:821–824. Wozniak O, Konka M, Wlodarska EK. Isolated ventricular noncompaction in a patient initially diagnosed with arrhythmogenic right ventricular cardiomyopathy. Heart 2008; 94:289. Ze-Zhou S. A combination of right ventricular hypertrabeculation/ noncompaction and arrhythmogenic right ventricular cardiomyopathy: a syndrome? Cardiovasc Ultrasound 2008; 6:63. Seiji M, Kiyoyuki E, Koji H, et al. Arrhythmogenic left ventricular cardiomyopathy associated with noncompaction. Ann Thorac Surg 2010; 90:2044–2046. Wlodarska EK, Olgierd W, Marek K, et al. Isolated ventricular noncompaction mimicking arrhythmogenic right ventricular cardiomyopathy: a study of nine patients. Int J Cardiol 2010; 145:107–111. Greutmann M, Mah ML, Silversides CK, et al. Predictors of adverse outcome in adolescents and adults with isolated left ventricular noncompaction. Am J Cardiol 2012; 109:276–281. Wlodarska EK, Wozniak O, Konka M, et al. Thromboembolic complications in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy. Europace 2006; 8:596–600.
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
