EDITORIAL
European Heart Journal (2016) 37, 1847–1849 doi:10.1093/eurheartj/ehv645
When the money is not in the bank Daniel Jacoby 1* and Antonis Pantazis 2 1 Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA; and 2Heart Hospital, University College London Hospitals Trust, London, UK
Online publish-ahead-of-print 18 December 2015
This editorial refers to ‘Cardiac mesenchymal stromal cells are a source of adipocytes in arrhythmogenic cardiomyopathy’†, by E. Sommariva et al., on page 1835.
There is an apocryphal story about the famous American bank robber ‘Slick’ Willie Sutton. When asked by a reporter, ‘Why do you rob banks?’ he replied, ‘Because that’s where the money is.’ Willie’s wisecrack led to Sutton’s Law, or the principle that when searching for something one is well advised to look for it in the obvious place first. Thus, in developing an understanding of cardiomyopathies it stands to reason that cardiomyocytes should be the focus of disease modelling. Following Sutton’s Law has indeed led investigators to multiple insights, including successful disease modelling using induced pleuripotent stem cells (iPSCs), and development of potential diagnostic tests for arrhythmogenic cardiomyopathy (ACM).1,2 Genetic diagnosis in inherited cardiomyopathies also favours myocyte-specific disease modelling as the protein products of genes with pathogenic mutations identified in families with inherited cardiomyopathy are nearly universally important in myocyte function. Chief among these are proteins responsible for force generation and transmision, cytoskeletal structure, cell–cell adhesion, and transmembrane ion traffic. However, as in all things, context matters. Myocytes function within a complex environment of extracellular matrix, noncontractile cardiac cells, and vascular networks. On top of this, a multitude of immune, paracrine, autocrine, and nervous system mechanisms impact structure and function on a small and large scale. It stands to reason that investigation of myocyte context can and does yield important insights into disease development even when genetic factors suggest a primary role for the myocyte. Notwithstanding recent interest in the role of ion channels in preclinical arrhythmia in ACM,3 fibrofatty infiltration has long been presumed to be the primary substrate for disease expression—as regards both arrhythmic potential and functional deterioration of the ventricular myocardium. Current thinking on the biological pathways from desmosomal gene abnormality to adipogenesis is largely focused on activation of canonical WNT/b-catenin signaling
through nuclear plakoglobin.1 However, the source of adipocytes in the myocardium remains an area of intense curiosity due to its presumed role in the pathogenesis of ACM. In a paper in the current issue of the journal, Elena Sommariva and colleagues have bypassed Sutton’s Law with an important investigation of the role of cardiac mesenchymal stromal cells (C-MSCs) in the pathogenesis of ACM.4 C-MSCs are primitive cells originating from the mesodermal germ layer and are known to give rise to connective tissues, skeletal muscle cells, and cells of the vascular system.5 The exact proportion of myocardium made up by MSCs is unknown, but they are clearly present in important numbers. Compared with cadiomyocytes they are relatively easy to harvest and study, making them good targets for disease modelling. By staining adipocytes for myocyte- and MSC-specific markers, the authors convincingly demonstrate that C-MSCs are an important source of excess apidocytes in cardiac tissue of ACM patients. In order to flesh out this hypothesis, they then demonstrate that C-MSC cells from ACM hearts are more likely to progress down an adipocyte lineage pathway than those from normal subjects. Ultimately, investigating the necessary linkage between desmosome mutation and C-MSC-based adipogenesis, the authors identify expression of desmosomal genes in C-MSCs. These data provide compelling evidence that apidogenesis in ACM is not critically myocyte dependent. This finding may prove helpful for iPSC-based modelling of ACM. In part because ex vivo human cardiomyocytes are inherently challenging to harvest and study, attention has focused on iPSC technology as a strategy for discovery of new biology, and ideally new therapies. Although, as previously noted, iPSC technology has led to profound insights into disease development, modelling with iPSCs continues to be somewhat limited by challenges in recapitulating a mature organ environment. One may suspect that incorporating C-MSCs into iPSC models by means of engineered heart tissue would be more likely to recapitulate the complex interactions that lead to disease development. On a related note, looking at it from the reverse side, can we say that isolated C-MSCs constitute a suitable cellular substrate for mechanistic and therapeutic studies in ACM? It is worth noting
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. † doi:10.1093/eurheartj/ehv579.
* Corresponding author. Departmentof Internal Medicine (Cardiology), Yale School of Medicine, 333 Cedar Street, New Haven, CT 06519, USA. Tel: +1 203 785 7191, Fax: +1 203 785 2917, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].
1848
Editorial
Figure 1 Idealized relationship between phenotype, human tissue disease modeling, and translational clinical impact. ACM, arrhythmogenic cardiomyopathy; ALVC, arrhythmogenic right ventricular cardiomyopathy; ARVC, arrhythmogenic right ventricular cardiomyopathy; C-MSC; cardiac mesenchymal stromal cell; iPS, induced pleuripotent stem; LV, left ventricle; RV, right ventricle.
that intramyocardial fat is not specific to ACM. Theoretically pathological amounts of intramyocardial fat have been observed both in non-ACM myopathies and in normal individuals with benign prognoses.6 Additionally, the link between development of intramyocardial fat, fibrofatty replacement, and ultimately organ dysfunction/ heart failure has yet to be pinned down. With regard to this, current diagnostic criteria for ACM do not include any imaging detection of myocardial fat, and intramyocardial fat without concurrent fibrosis is not considered diagnostically useful on myocardial biopsy.7 Furthermore, studies have shown that arrhythmia may precede structural and histological changes.3 While fat does not appear to be part of the early arrhythmic phenotype in ACM, it may play a significant role when disease has progressed to the myopathic phase. In this sense, C-MSCs are quite likely to best serve as a component of effective modelling for ACM when combined with other factors in a complex environment, similar to iPSCs. Shifting gears to the interaction between genetic mutation and disease expression, what are we to make of the fact that genotypenegative and PKP2 mutation-positive ACM patients are biologically indistinguishable in this study? Have the authors identified a final common pathway to development of all ACM, or have they identified the pathogenic mechanisms of a specific subtype of disease? Replication of these C-MSC findings in other genetically
characterized ACM subtypes (arrhythmogenic left ventricular cardiomyopathy, non-desmosomal-based ACM) would be a useful next step to tease this clinically important question apart. Taking these questions and thoughts into account, is there ultimately hope in translation? The pathobiological insights presented by Sommariva and colleagues broaden our understanding of the pathogenesis of ACM, and identify an additional target for screening of novel therapeutics. They also further inform our knowledge of the potential limitations and benefits of cellular disease modelling. In these ways we may expect that this study’s identification of nonmyocyte pathobiology will add to existing translational models that aim to shed light on diagnosis, prognosis, classification, and treatment of ACM (Figure 1). This hope in translation is an exciting notion that may yet bear clinical fruit, and into which our patients count on our investment. Ultimately, paradigm-shifting disease therapy depends on our continued willingness to investigate all avenues, aiming away from the mark when necessary rather than restricting ourselves to ‘where the money is’.
Funding This work was supported by NIH (I.D. #R21 HL126025-01).
1849
Editorial
Conflict of interest: none declared.
References 1. Garcia-Gras E, Lombardi R, Giocondo MJ, Willerson JT, Schneider MD, Khoury DS, Marian AJ. Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy. J Clin Invest 2006;116:2012 –2021. 2. Asimaki A, Tandri H, Huang H, Halushka MK, Gautam S, Basso C, Hiene G, Tsatsopoulou A, Protonotarios N, McKenna WJ, Calkins H, Saffitz JE. A new diagnostic test for arrhythmogenic right ventricular cardiomyopathy. N Engl J Med 2009;360:1075 –1084. 3. Gomes J, Finlay M, Ahmed AK, Ciaccio EJ, Asimaki A, Saffitz JE, Quarta G, Nobles M, Syrris P, Chaubey S, McKenna WJ, Tinker A, Lambiase PD. Electrophysiological abnormalities precede overt structural changes in arrhythmogenic right ventricular cardiomyopathy due to mutations in desmoplakin—a combined murine and human study. Eur Heart J 2012;33:1942 –1953.
4. Sommariva E, Brambilla S, Carbucicchio C, Gambini E, Meraviglia V, Russo AD, Farina FM, Casella M, Catto V, Pontone G, Chiesa M, Stadiotti I, Cogliati E, Paolin A, Alami NO, Preziuso C, d’Amati G, Colombo GI, Rossini A, Capogrossi MC, Tondo C, Pompilio G. Cardiac mesenchymal stromal cells are a source of adipocytes in arrhythmogenic cardiomyopathy. Eur Heart J 2016;37: 1835 –1846. 5. Salem HK, Thiemermann C. Mesenchymal stromal cells: current understanding and clinical status. Stem Cells 2010;28:585 –596. 6. Christensen AH, Bundgaard H, Schwartz M, Hansen SH, Svendsen JH. Cardiac myotonic dystrophy mimicking arrhythmogenic right ventricular cardiomyopathy in a young sudden cardiac death victim. Circ Arrhythm Electrophysiol 2008;1:317 –320. 7. Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, Calkins H, Corrado D, Cox MG, Daubert JP, Fontaine G, Gear K, Hauer R, Nava A, Picard MH, Protonotarios N, Saffitz JE, Sanborn DM, Steinberg JS, Tandri H, Thiene G, Towbin JA, Tsatsopoulou A, Wichter T, Zareba W. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Eur Heart J 2010;31:806–814.
CARDIOVASCULAR FLASHLIGHT
doi:10.1093/eurheartj/ehv313 Online publish-ahead-of-print 18 July 2015
.............................................................................................................................................................................
Myocardial herniation in constrictive pericarditis mimicking arrhythmogenic right ventricular cardiomyopathy Johannes Budjan1*, Dariusch Haghi2, Thomas Henzler1, and Theano Papavassiliu2 1
Department of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; and First Department of Medicine, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
2
* Corresponding author. Email: [email protected]
A 51-year-old man presented with progressive exertional dyspnoea. After extensive external workup, he was referred to our hospital for further evaluation under the working diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC). Cardiac magnetic resonance imaging and computed tomography revealed thickening of the pericardium (Panels A, B, D, and F, white arrows) with an apical herniation of right ventricular (RV) myocardium (Panels A – D, arrow heads). Unlike apical aneurysms as found in ARVC, the herniated myocardium showed contraction in cardiovascular magnetic resonance imaging cine sequences (Panels A, B, C, and E) and associated trabeculae. Additionally, an atypical septal movement with diastolic bounce (Panel E), atrial enlargement (Panel B), and dilatation of inferior cava vein (not shown) were found. Cardiac catheterization demonstrated elevation and near equalization of left ventricular (LV), pulmonary capillary wedge, RV, and right atrial pressures (Panel G). The RV and LV pressure tracings showed a dip and plateau morphology and enhanced ventricular interdependence. These findings confirmed the diagnosis of constrictive pericarditis. The patient is planned for pericardiectomy. Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].
European Heart Journal (2016) 37, 1847–1849 doi:10.1093/eurheartj/ehv645
When the money is not in the bank Daniel Jacoby 1* and Antonis Pantazis 2 1 Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA; and 2Heart Hospital, University College London Hospitals Trust, London, UK
Online publish-ahead-of-print 18 December 2015
This editorial refers to ‘Cardiac mesenchymal stromal cells are a source of adipocytes in arrhythmogenic cardiomyopathy’†, by E. Sommariva et al., on page 1835.
There is an apocryphal story about the famous American bank robber ‘Slick’ Willie Sutton. When asked by a reporter, ‘Why do you rob banks?’ he replied, ‘Because that’s where the money is.’ Willie’s wisecrack led to Sutton’s Law, or the principle that when searching for something one is well advised to look for it in the obvious place first. Thus, in developing an understanding of cardiomyopathies it stands to reason that cardiomyocytes should be the focus of disease modelling. Following Sutton’s Law has indeed led investigators to multiple insights, including successful disease modelling using induced pleuripotent stem cells (iPSCs), and development of potential diagnostic tests for arrhythmogenic cardiomyopathy (ACM).1,2 Genetic diagnosis in inherited cardiomyopathies also favours myocyte-specific disease modelling as the protein products of genes with pathogenic mutations identified in families with inherited cardiomyopathy are nearly universally important in myocyte function. Chief among these are proteins responsible for force generation and transmision, cytoskeletal structure, cell–cell adhesion, and transmembrane ion traffic. However, as in all things, context matters. Myocytes function within a complex environment of extracellular matrix, noncontractile cardiac cells, and vascular networks. On top of this, a multitude of immune, paracrine, autocrine, and nervous system mechanisms impact structure and function on a small and large scale. It stands to reason that investigation of myocyte context can and does yield important insights into disease development even when genetic factors suggest a primary role for the myocyte. Notwithstanding recent interest in the role of ion channels in preclinical arrhythmia in ACM,3 fibrofatty infiltration has long been presumed to be the primary substrate for disease expression—as regards both arrhythmic potential and functional deterioration of the ventricular myocardium. Current thinking on the biological pathways from desmosomal gene abnormality to adipogenesis is largely focused on activation of canonical WNT/b-catenin signaling
through nuclear plakoglobin.1 However, the source of adipocytes in the myocardium remains an area of intense curiosity due to its presumed role in the pathogenesis of ACM. In a paper in the current issue of the journal, Elena Sommariva and colleagues have bypassed Sutton’s Law with an important investigation of the role of cardiac mesenchymal stromal cells (C-MSCs) in the pathogenesis of ACM.4 C-MSCs are primitive cells originating from the mesodermal germ layer and are known to give rise to connective tissues, skeletal muscle cells, and cells of the vascular system.5 The exact proportion of myocardium made up by MSCs is unknown, but they are clearly present in important numbers. Compared with cadiomyocytes they are relatively easy to harvest and study, making them good targets for disease modelling. By staining adipocytes for myocyte- and MSC-specific markers, the authors convincingly demonstrate that C-MSCs are an important source of excess apidocytes in cardiac tissue of ACM patients. In order to flesh out this hypothesis, they then demonstrate that C-MSC cells from ACM hearts are more likely to progress down an adipocyte lineage pathway than those from normal subjects. Ultimately, investigating the necessary linkage between desmosome mutation and C-MSC-based adipogenesis, the authors identify expression of desmosomal genes in C-MSCs. These data provide compelling evidence that apidogenesis in ACM is not critically myocyte dependent. This finding may prove helpful for iPSC-based modelling of ACM. In part because ex vivo human cardiomyocytes are inherently challenging to harvest and study, attention has focused on iPSC technology as a strategy for discovery of new biology, and ideally new therapies. Although, as previously noted, iPSC technology has led to profound insights into disease development, modelling with iPSCs continues to be somewhat limited by challenges in recapitulating a mature organ environment. One may suspect that incorporating C-MSCs into iPSC models by means of engineered heart tissue would be more likely to recapitulate the complex interactions that lead to disease development. On a related note, looking at it from the reverse side, can we say that isolated C-MSCs constitute a suitable cellular substrate for mechanistic and therapeutic studies in ACM? It is worth noting
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. † doi:10.1093/eurheartj/ehv579.
* Corresponding author. Departmentof Internal Medicine (Cardiology), Yale School of Medicine, 333 Cedar Street, New Haven, CT 06519, USA. Tel: +1 203 785 7191, Fax: +1 203 785 2917, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].
1848
Editorial
Figure 1 Idealized relationship between phenotype, human tissue disease modeling, and translational clinical impact. ACM, arrhythmogenic cardiomyopathy; ALVC, arrhythmogenic right ventricular cardiomyopathy; ARVC, arrhythmogenic right ventricular cardiomyopathy; C-MSC; cardiac mesenchymal stromal cell; iPS, induced pleuripotent stem; LV, left ventricle; RV, right ventricle.
that intramyocardial fat is not specific to ACM. Theoretically pathological amounts of intramyocardial fat have been observed both in non-ACM myopathies and in normal individuals with benign prognoses.6 Additionally, the link between development of intramyocardial fat, fibrofatty replacement, and ultimately organ dysfunction/ heart failure has yet to be pinned down. With regard to this, current diagnostic criteria for ACM do not include any imaging detection of myocardial fat, and intramyocardial fat without concurrent fibrosis is not considered diagnostically useful on myocardial biopsy.7 Furthermore, studies have shown that arrhythmia may precede structural and histological changes.3 While fat does not appear to be part of the early arrhythmic phenotype in ACM, it may play a significant role when disease has progressed to the myopathic phase. In this sense, C-MSCs are quite likely to best serve as a component of effective modelling for ACM when combined with other factors in a complex environment, similar to iPSCs. Shifting gears to the interaction between genetic mutation and disease expression, what are we to make of the fact that genotypenegative and PKP2 mutation-positive ACM patients are biologically indistinguishable in this study? Have the authors identified a final common pathway to development of all ACM, or have they identified the pathogenic mechanisms of a specific subtype of disease? Replication of these C-MSC findings in other genetically
characterized ACM subtypes (arrhythmogenic left ventricular cardiomyopathy, non-desmosomal-based ACM) would be a useful next step to tease this clinically important question apart. Taking these questions and thoughts into account, is there ultimately hope in translation? The pathobiological insights presented by Sommariva and colleagues broaden our understanding of the pathogenesis of ACM, and identify an additional target for screening of novel therapeutics. They also further inform our knowledge of the potential limitations and benefits of cellular disease modelling. In these ways we may expect that this study’s identification of nonmyocyte pathobiology will add to existing translational models that aim to shed light on diagnosis, prognosis, classification, and treatment of ACM (Figure 1). This hope in translation is an exciting notion that may yet bear clinical fruit, and into which our patients count on our investment. Ultimately, paradigm-shifting disease therapy depends on our continued willingness to investigate all avenues, aiming away from the mark when necessary rather than restricting ourselves to ‘where the money is’.
Funding This work was supported by NIH (I.D. #R21 HL126025-01).
1849
Editorial
Conflict of interest: none declared.
References 1. Garcia-Gras E, Lombardi R, Giocondo MJ, Willerson JT, Schneider MD, Khoury DS, Marian AJ. Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy. J Clin Invest 2006;116:2012 –2021. 2. Asimaki A, Tandri H, Huang H, Halushka MK, Gautam S, Basso C, Hiene G, Tsatsopoulou A, Protonotarios N, McKenna WJ, Calkins H, Saffitz JE. A new diagnostic test for arrhythmogenic right ventricular cardiomyopathy. N Engl J Med 2009;360:1075 –1084. 3. Gomes J, Finlay M, Ahmed AK, Ciaccio EJ, Asimaki A, Saffitz JE, Quarta G, Nobles M, Syrris P, Chaubey S, McKenna WJ, Tinker A, Lambiase PD. Electrophysiological abnormalities precede overt structural changes in arrhythmogenic right ventricular cardiomyopathy due to mutations in desmoplakin—a combined murine and human study. Eur Heart J 2012;33:1942 –1953.
4. Sommariva E, Brambilla S, Carbucicchio C, Gambini E, Meraviglia V, Russo AD, Farina FM, Casella M, Catto V, Pontone G, Chiesa M, Stadiotti I, Cogliati E, Paolin A, Alami NO, Preziuso C, d’Amati G, Colombo GI, Rossini A, Capogrossi MC, Tondo C, Pompilio G. Cardiac mesenchymal stromal cells are a source of adipocytes in arrhythmogenic cardiomyopathy. Eur Heart J 2016;37: 1835 –1846. 5. Salem HK, Thiemermann C. Mesenchymal stromal cells: current understanding and clinical status. Stem Cells 2010;28:585 –596. 6. Christensen AH, Bundgaard H, Schwartz M, Hansen SH, Svendsen JH. Cardiac myotonic dystrophy mimicking arrhythmogenic right ventricular cardiomyopathy in a young sudden cardiac death victim. Circ Arrhythm Electrophysiol 2008;1:317 –320. 7. Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, Calkins H, Corrado D, Cox MG, Daubert JP, Fontaine G, Gear K, Hauer R, Nava A, Picard MH, Protonotarios N, Saffitz JE, Sanborn DM, Steinberg JS, Tandri H, Thiene G, Towbin JA, Tsatsopoulou A, Wichter T, Zareba W. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Eur Heart J 2010;31:806–814.
CARDIOVASCULAR FLASHLIGHT
doi:10.1093/eurheartj/ehv313 Online publish-ahead-of-print 18 July 2015
.............................................................................................................................................................................
Myocardial herniation in constrictive pericarditis mimicking arrhythmogenic right ventricular cardiomyopathy Johannes Budjan1*, Dariusch Haghi2, Thomas Henzler1, and Theano Papavassiliu2 1
Department of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; and First Department of Medicine, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
2
* Corresponding author. Email: [email protected]
A 51-year-old man presented with progressive exertional dyspnoea. After extensive external workup, he was referred to our hospital for further evaluation under the working diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC). Cardiac magnetic resonance imaging and computed tomography revealed thickening of the pericardium (Panels A, B, D, and F, white arrows) with an apical herniation of right ventricular (RV) myocardium (Panels A – D, arrow heads). Unlike apical aneurysms as found in ARVC, the herniated myocardium showed contraction in cardiovascular magnetic resonance imaging cine sequences (Panels A, B, C, and E) and associated trabeculae. Additionally, an atypical septal movement with diastolic bounce (Panel E), atrial enlargement (Panel B), and dilatation of inferior cava vein (not shown) were found. Cardiac catheterization demonstrated elevation and near equalization of left ventricular (LV), pulmonary capillary wedge, RV, and right atrial pressures (Panel G). The RV and LV pressure tracings showed a dip and plateau morphology and enhanced ventricular interdependence. These findings confirmed the diagnosis of constrictive pericarditis. The patient is planned for pericardiectomy. Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].
