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12 pages, 8559 KiB

Open AccessArticle

Heterozygous Arrhythmogenic Cardiomyopathy-desmoplakin Mutation Carriers Exhibit a Subclinical Cutaneous Phenotype with Cell Membrane Disruption and Lack of Intercellular Adhesion

by Eva Cabrera-Borrego, Trinidad Montero-Vilchez, Francisco José Bermúdez-Jiménez, Jesús Tercedor-Sánchez, Luis Tercedor-Sánchez, Manuel Sánchez-Díaz, Rosa Macías-Ruiz, María Molina-Jiménez, Francisco Javier Cañizares-García, Eduardo Fernández-Segura, Angel Fernandez-Flores, Salvador Arias-Santiago and Juan Jiménez-Jáimez

J. Clin. Med. 2021, 10(19), 4608; https://doi.org/10.3390/jcm10194608 - 8 Oct 2021

Cited by 4 | Viewed by 1971

Abstract

Genetic variants that result in truncation in desmoplakin (DSP) are a known cause of arrhythmogenic cardiomyopathy (AC). In homozygous carriers, the combined involvement of skin and heart muscle is well defined, however, this is not the case in heterozygous carriers. The [...] Read more.

Genetic variants that result in truncation in desmoplakin (DSP) are a known cause of arrhythmogenic cardiomyopathy (AC). In homozygous carriers, the combined involvement of skin and heart muscle is well defined, however, this is not the case in heterozygous carriers. The aim of this work is to describe cutaneous findings and analyze the molecular and ultrastructural cutaneous changes in this group of patients. Four women and eight men with a mean age of 48 ± 14 years were included. Eight met definitive criteria for AC, one was borderline and three were silent carriers. No relevant macroscopic changes in skin and hair were detected. However, significantly lower skin temperature (29.56 vs. 30.97 °C, p = 0.036) and higher transepidermal water loss (TEWL) (37.62 vs. 23.95 g m 2 h 1, p = 0.028) were observed compared to sex- and age-matched controls. Histopathology of the skin biopsy showed widening of intercellular spaces and acantholysis of keratinocytes in the spinous layer. Immunohistochemistry showed a strongly reduced expression of DSP in all samples. Trichogram showed regular nodules (thickening) compatible with pseudomonilethrix. Therefore, regardless of cardiac involvement, heterozygous patients with truncation-type variants in DSP have lower skin temperature and higher TEWL, constant microscopic skin involvement with specific patterns and pseudomonilethrix in the trichogram. Full article

(This article belongs to the Special Issue Clinical and Research of Genetic Cardiomyopathies)

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14 pages, 2244 KiB

Open AccessArticle

Multiphoton Imaging of Ca²⁺ Instability in Acute Myocardial Slices from a RyR2^R2474S Murine Model of Catecholaminergic Polymorphic Ventricular Tachycardia

by Giulia Borile, Tania Zaglia, Stephan E. Lehnart and Marco Mongillo

J. Clin. Med. 2021, 10(13), 2821; https://doi.org/10.3390/jcm10132821 - 26 Jun 2021

Cited by 2 | Viewed by 2290

Abstract

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a familial stress-induced arrhythmia syndrome, mostly caused by mutations in Ryanodine receptor 2 (RyR2), the sarcoplasmic reticulum (SR) Ca²⁺ release channel in cardiomyocytes. Pathogenetic mutations lead to gain of function in the channel, causing [...] Read more.

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a familial stress-induced arrhythmia syndrome, mostly caused by mutations in Ryanodine receptor 2 (RyR2), the sarcoplasmic reticulum (SR) Ca²⁺ release channel in cardiomyocytes. Pathogenetic mutations lead to gain of function in the channel, causing arrhythmias by promoting diastolic spontaneous Ca²⁺ release (SCR) from the SR and delayed afterdepolarizations. While the study of Ca²⁺ dynamics in single cells from murine CPVT models has increased our understanding of the disease pathogenesis, questions remain on the mechanisms triggering the lethal arrhythmias at tissue level. Here, we combined subcellular analysis of Ca²⁺ signals in isolated cardiomyocytes and in acute thick ventricular slices of RyR2^R2474S knock-in mice, electrically paced at different rates (1–5 Hz), to identify arrhythmogenic Ca²⁺ dynamics, from the sub- to the multicellular perspective. In both models, RyR2^R2474S cardiomyocytes had increased propensity to develop SCR upon adrenergic stimulation, which manifested, in the slices, with Ca²⁺ alternans and synchronous Ca²⁺ release events in neighboring cardiomyocytes. Analysis of Ca²⁺ dynamics in multiple cells in the tissue suggests that SCRs beget SCRs in contiguous cells, overcoming the protective electrotonic myocardial coupling, and potentially generating arrhythmia triggering foci. We suggest that intercellular interactions may underscore arrhythmic propensity in CPVT hearts with ‘leaky’ RyR2. Full article

(This article belongs to the Special Issue Clinical and Research of Genetic Cardiomyopathies)

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17 pages, 5327 KiB

Open AccessArticle

Arrhythmogenic Cardiomyopathy Is a Multicellular Disease Affecting Cardiac and Bone Marrow Mesenchymal Stromal Cells

by Arianna Scalco, Cristina Liboni, Roberta Angioni, Anna Di Bona, Mattia Albiero, Nicole Bertoldi, Gian Paolo Fadini, Gaetano Thiene, Stephen P. Chelko, Cristina Basso, Antonella Viola, Marco Mongillo and Tania Zaglia

J. Clin. Med. 2021, 10(9), 1871; https://doi.org/10.3390/jcm10091871 - 26 Apr 2021

Cited by 13 | Viewed by 3314

Abstract

Arrhythmogenic cardiomyopathy (AC) is a familial cardiac disorder at high risk of arrhythmic sudden death in the young and athletes. AC is hallmarked by myocardial replacement with fibro-fatty tissue, favoring life-threatening cardiac arrhythmias and contractile dysfunction. The AC pathogenesis is unclear, and the [...] Read more.

Arrhythmogenic cardiomyopathy (AC) is a familial cardiac disorder at high risk of arrhythmic sudden death in the young and athletes. AC is hallmarked by myocardial replacement with fibro-fatty tissue, favoring life-threatening cardiac arrhythmias and contractile dysfunction. The AC pathogenesis is unclear, and the disease urgently needs mechanism-driven therapies. Current AC research is mainly focused on ‘desmosome-carrying’ cardiomyocytes, but desmosomal proteins are also expressed by non-myocyte cells, which also harbor AC variants, including mesenchymal stromal cells (MSCs). Consistently, cardiac-MSCs contribute to adipose tissue in human AC hearts. We thus approached AC as a multicellular disorder, hypothesizing that it also affects extra-cardiac bone marrow (BM)-MSCs. Our results show changes in the desmosomal protein profile of both cardiac- and BM- MSCs, from desmoglein-2 (Dsg2)-mutant mice, accompanied with profound alterations in cytoskeletal organization, which are directly caused by AC-linked DSG2 downregulation. In addition, AC BM-MSCs display increased proliferation rate, both in vitro and in vivo, and, by using the principle of the competition homing assay, we demonstrated that mutant circulating BM-MSCs have increased propensity to migrate to the AC heart. Taken altogether, our results indicate that cardiac- and BM- MSCs are additional cell types affected in Dsg2-linked AC, warranting the novel classification of AC as a multicellular and multiorgan disease. Full article

(This article belongs to the Special Issue Clinical and Research of Genetic Cardiomyopathies)

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15 pages, 1290 KiB

Open AccessArticle

Diagnostic Yield of Genetic Testing in Sudden Cardiac Death with Autopsy Findings of Uncertain Significance

by Mercedes Iglesias, Tomas Ripoll-Vera, Consuelo Perez-Luengo, Ana Belen García, Susana Moyano, Juan Carlos Canos, Juan Carlos Borondo, Jorge Alvarez, Damian Heine-Suñer and Bernardino Barcelo

J. Clin. Med. 2021, 10(9), 1806; https://doi.org/10.3390/jcm10091806 - 21 Apr 2021

Cited by 7 | Viewed by 2936

Abstract

Background: Sudden death (SD) in the young usually has an underlying genetic cause. In many cases, autopsy reveals unspecific and inconclusive results, like idiopathic left ventricular hypertrophy (LVH), nonsignificant coronary atherosclerosis (CA), and primary myocardial fibrosis (PMF). Their pathogenicity and their relation to [...] Read more.

Background: Sudden death (SD) in the young usually has an underlying genetic cause. In many cases, autopsy reveals unspecific and inconclusive results, like idiopathic left ventricular hypertrophy (LVH), nonsignificant coronary atherosclerosis (CA), and primary myocardial fibrosis (PMF). Their pathogenicity and their relation to SD cause is unknown. This study aims to evaluate the diagnostic yield of genetic testing in these cases. Methods: SD cases, between 1 and 50 years old, with findings of uncertain significance (idiopathic LVH, nonsignificant CA and PMF) on autopsy were evaluated prospectively, including information about medical and family history and circumstances of death. Genetic testing was performed. Results: In a series of 195 SD cases, we selected 31 cases presenting idiopathic LVH (n = 16, 51.61%), nonsignificant CA (n = 17, 54.84%), and/or PMF (n = 24, 77.42%) in the autopsy. Mean age was 41 ± 7.2 years. Diagnostic yield of genetic test was 67.74%, considering variants of unknown significance (VUS), pathogenic variants (PV) and likely pathogenic variants (LPV); 6.45% including only PV and LPV. Structural genes represented 41,93% (n = 13) of cases, while 38,7% (n = 12) were related to channelopathies. Conclusion: Molecular autopsy in SD cases between 1 and 50 years old, with findings of uncertain significance, has a low diagnostic yield, being VUS the most frequent variant observed. Full article

(This article belongs to the Special Issue Clinical and Research of Genetic Cardiomyopathies)

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16 pages, 3506 KiB

Open AccessArticle

Psychosocial Stress Hastens Disease Progression and Sudden Death in Mice with Arrhythmogenic Cardiomyopathy

by Jacopo Agrimi, Arianna Scalco, Julia Agafonova, Larry Williams III, Nainika Pansari, Gizem Keceli, Seungho Jun, Nadan Wang, Francesca Mastorci, Crystal Tichnell, Brittney Murray, Cynthia A. James, Hugh Calkins, Tania Zaglia, Nazareno Paolocci and Stephen P. Chelko

J. Clin. Med. 2020, 9(12), 3804; https://doi.org/10.3390/jcm9123804 - 24 Nov 2020

Cited by 17 | Viewed by 4258

Abstract

Physiological stressors, such as exercise, can precipitate sudden cardiac death or heart failure progression in patients with arrhythmogenic cardiomyopathy (ACM). Yet, whether and to what extent a highly prevalent and more elusive environmental factor, such as psychosocial stress (PSS), can also increase ACM [...] Read more.

Physiological stressors, such as exercise, can precipitate sudden cardiac death or heart failure progression in patients with arrhythmogenic cardiomyopathy (ACM). Yet, whether and to what extent a highly prevalent and more elusive environmental factor, such as psychosocial stress (PSS), can also increase ACM disease progression is unexplored. Here, we first quantified perceived stress levels in patients with ACM and found these levels correlated with the extent of arrhythmias and cardiac dysfunction. To determine whether the observed correlation is due to causation, we inflicted PSS-via the resident-intruder (RI) paradigm—upon Desmoglein-2 mutant mice, a vigorously used mammalian model of ACM. We found that ACM mice succumbed to abnormally high in-trial, PSS mortality. Conversely, no sudden deaths occurred in wildtype (WT) counterparts. Desmoglein-2 mice that survived RI challenge manifested markedly worse cardiac dysfunction and remodeling, namely apoptosis and fibrosis. Furthermore, WT and ACM mice displayed similar behavior at baseline, but Desmoglein-2 mice exhibited heightened anxiety following RI-induced PSS. This outcome correlated with the worsening of cardiac phenotypes. Our mouse model demonstrates that in ACM-like subjects, PSS is incisive enough to deteriorate cardiac structure and function per se, i.e., in the absence of any pre-existing anxious behavior. Hence, PSS may represent a previously underappreciated risk factor in ACM disease penetrance. Full article

(This article belongs to the Special Issue Clinical and Research of Genetic Cardiomyopathies)

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10 pages, 1043 KiB

Open AccessArticle

Familial Arrhythmogenic Cardiomyopathy: Clinical Determinants of Phenotype Discordance and the Impact of Endurance Sports

by Sarah Costa, Alessio Gasperetti, Argelia Medeiros-Domingo, Deniz Akdis, Corinna Brunckhorst, Ardan M. Saguner and Firat Duru

J. Clin. Med. 2020, 9(11), 3781; https://doi.org/10.3390/jcm9113781 - 23 Nov 2020

Cited by 7 | Viewed by 2399

Abstract

Arrhythmogenic cardiomyopathy (ACM) is primarily a familial disease with autosomal dominant inheritance. Incomplete penetrance and variable expression are common, resulting in diverse clinical manifestations. Although recent studies on genotype–phenotype relationships have improved our understanding of the molecular mechanisms leading to the expression of [...] Read more.

Arrhythmogenic cardiomyopathy (ACM) is primarily a familial disease with autosomal dominant inheritance. Incomplete penetrance and variable expression are common, resulting in diverse clinical manifestations. Although recent studies on genotype–phenotype relationships have improved our understanding of the molecular mechanisms leading to the expression of the full-blown disease, the underlying genetic substrate and the clinical course of asymptomatic or oligo-symptomatic mutation carriers are still poorly understood. We aimed to analyze different phenotypic expression profiles of ACM in the context of the same familial genetic mutation by studying nine adult cases from four different families with four different familial variants (two plakophilin-2 and two desmoglein-2) from the Swiss Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) Registry. The affected individuals with the same genetic variants presented with highly variable phenotypes ranging from no disease or a classical, right-sided disease, to ACM with biventricular presentation. Moreover, some patients developed early-onset, electrically unstable disease whereas others with the same genetic variants presented with late-onset electrically stable disease. Despite differences in age, gender, underlying genotype, and other clinical characteristics, physical exercise has been observed as the common denominator in provoking an arrhythmic phenotype in these families. Full article

(This article belongs to the Special Issue Clinical and Research of Genetic Cardiomyopathies)

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11 pages, 1843 KiB

Open AccessArticle

Association between Left Atrial Deformation and Brain Involvement in Patients with Anderson-Fabry Disease at Diagnosis

by Roberta Esposito, Camilla Russo, Ciro Santoro, Sirio Cocozza, Eleonora Riccio, Regina Sorrentino, Giuseppe Pontillo, Federica Luciano, Massimo Imbriaco, Arturo Brunetti and Antonio Pisani

J. Clin. Med. 2020, 9(9), 2741; https://doi.org/10.3390/jcm9092741 - 25 Aug 2020

Cited by 9 | Viewed by 2389

Abstract

Background: Anderson-Fabry disease (AFD) can induce both central nervous system white matter lesions (WMLs) and cardiac abnormalities including left atrial (LA) dysfunction. We sought to evaluate the possible interrelations of LA structure and function impairment with the presence of WMLs in AFD patients. [...] Read more.

Background: Anderson-Fabry disease (AFD) can induce both central nervous system white matter lesions (WMLs) and cardiac abnormalities including left atrial (LA) dysfunction. We sought to evaluate the possible interrelations of LA structure and function impairment with the presence of WMLs in AFD patients. Methods 22 AFD patients and 22 controls, matched for age and sex, underwent an echo-Doppler exam including quantification of peak atrial longitudinal strain (PALS). AFD patients underwent also a 3-T brain magnetic resonance imaging with a visual quantification of WMLs by Fazekas’ score (FS) on 3D FLAIR images. Results AFD patients had significantly higher left ventricular (LV) mass index (LVMi) and relative wall thickness, and lower PALS compared to controls. Among AFD patients, 9 showed a FS = 0, and 13 a FS > 1. AFD patients with FS ≥ 1 showed lower PALS (29.4 ± 6.7 vs. 37.2 ± 3.9%, p = 0.003) than those with FS = 0, without difference in LA volume index and LVMi. In AFD patients, FS was inversely related to PALS (r = −0.49, p < 0.0001), even after adjusting for LVMi (r = −0.43, p < 0.05). Conclusions In the absence of significant alterations in LA size, AFD patients had lower PALS compared to controls. The inverse association between PALS and presence of WMLs indicates a possible parallel early involvement of heart and brain. Full article

(This article belongs to the Special Issue Clinical and Research of Genetic Cardiomyopathies)

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20 pages, 3081 KiB

Open AccessArticle

Danon Disease-Associated LAMP-2 Deficiency Drives Metabolic Signature Indicative of Mitochondrial Aging and Fibrosis in Cardiac Tissue and hiPSC-Derived Cardiomyocytes

by Giorgia Del Favero, Alois Bonifacio, Teisha J. Rowland, Shanshan Gao, Kunhua Song, Valter Sergo, Eric D. Adler, Luisa Mestroni, Orfeo Sbaizero and Matthew R. G. Taylor

J. Clin. Med. 2020, 9(8), 2457; https://doi.org/10.3390/jcm9082457 - 31 Jul 2020

Cited by 12 | Viewed by 4957

Abstract

Danon disease is a severe X-linked disorder caused by deficiency of the lysosome-associated membrane protein-2 (LAMP-2). Clinical manifestations are phenotypically diverse and consist of hypertrophic and dilated cardiomyopathies, skeletal myopathy, retinopathy, and intellectual dysfunction. Here, we investigated the metabolic landscape of Danon disease [...] Read more.

Danon disease is a severe X-linked disorder caused by deficiency of the lysosome-associated membrane protein-2 (LAMP-2). Clinical manifestations are phenotypically diverse and consist of hypertrophic and dilated cardiomyopathies, skeletal myopathy, retinopathy, and intellectual dysfunction. Here, we investigated the metabolic landscape of Danon disease by applying a multi-omics approach and combined structural and functional readouts provided by Raman and atomic force microscopy. Using these tools, Danon patient-derived cardiac tissue, primary fibroblasts, and human induced pluripotent stem cells differentiated into cardiomyocytes (hiPSC-CMs) were analyzed. Metabolic profiling indicated LAMP-2 deficiency promoted a switch toward glycolysis accompanied by rerouting of tryptophan metabolism. Cardiomyocytes’ energetic balance and NAD+/NADH ratio appeared to be maintained despite mitochondrial aging. In turn, metabolic adaption was accompanied by a senescence-associated signature. Similarly, Danon fibroblasts appeared more stress prone and less biomechanically compliant. Overall, shaping of both morphology and metabolism contributed to the loss of cardiac biomechanical competence that characterizes the clinical progression of Danon disease. Full article

(This article belongs to the Special Issue Clinical and Research of Genetic Cardiomyopathies)

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17 pages, 2643 KiB

Open AccessArticle

Mitochondrial DNA: Hotspot for Potential Gene Modifiers Regulating Hypertrophic Cardiomyopathy

by Parisa K. Kargaran, Jared M. Evans, Sara E. Bodbin, James G. W. Smith, Timothy J. Nelson, Chris Denning and Diogo Mosqueira

J. Clin. Med. 2020, 9(8), 2349; https://doi.org/10.3390/jcm9082349 - 23 Jul 2020

Cited by 9 | Viewed by 4345

Abstract

Hypertrophic cardiomyopathy (HCM) is a prevalent and untreatable cardiovascular disease with a highly complex clinical and genetic causation. HCM patients bearing similar sarcomeric mutations display variable clinical outcomes, implying the involvement of gene modifiers that regulate disease progression. As individuals exhibiting mutations in [...] Read more.

Hypertrophic cardiomyopathy (HCM) is a prevalent and untreatable cardiovascular disease with a highly complex clinical and genetic causation. HCM patients bearing similar sarcomeric mutations display variable clinical outcomes, implying the involvement of gene modifiers that regulate disease progression. As individuals exhibiting mutations in mitochondrial DNA (mtDNA) present cardiac phenotypes, the mitochondrial genome is a promising candidate to harbor gene modifiers of HCM. Herein, we sequenced the mtDNA of isogenic pluripotent stem cell-cardiomyocyte models of HCM focusing on two sarcomeric mutations. This approach was extended to unrelated patient families totaling 52 cell lines. By correlating cellular and clinical phenotypes with mtDNA sequencing, potentially HCM-protective or -aggravator mtDNA variants were identified. These novel mutations were mostly located in the non-coding control region of the mtDNA and did not overlap with those of other mitochondrial diseases. Analysis of unrelated patients highlighted family-specific mtDNA variants, while others were common in particular population haplogroups. Further validation of mtDNA variants as gene modifiers is warranted but limited by the technically challenging methods of editing the mitochondrial genome. Future molecular characterization of these mtDNA variants in the context of HCM may identify novel treatments and facilitate genetic screening in cardiomyopathy patients towards more efficient treatment options. Full article

(This article belongs to the Special Issue Clinical and Research of Genetic Cardiomyopathies)

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11 pages, 1327 KiB

Open AccessArticle

Hereditary ATTR Amyloidosis in Austria: Prevalence and Epidemiological Hot Spots

by Michaela Auer-Grumbach, Rene Rettl, Klemens Ablasser, Hermine Agis, Christian Beetz, Franz Duca, Martin Gattermeier, Franz Glaser, Markus Hacker, Renate Kain, Birgit Kaufmann, Gabor G. Kovacs, Christian Lampl, Neira Ljevakovic, Jutta Nagele, Gerhard Pölzl, Stefan Quasthoff, Bernadette Raimann, Helmut Rauschka, Christian Reiter, Volha Skrahina, Othmar Schuhfried, Raute Sunder-Plassmann, Nicolas D. Verheyen, Julia Wanschitz, Thomas Weber, Reinhard Windhager, Raphael Wurm, Friedrich Zimprich, Wolfgang N. Löscher and Diana Bonderman Show full author list Hide full author list

J. Clin. Med. 2020, 9(7), 2234; https://doi.org/10.3390/jcm9072234 - 14 Jul 2020

Cited by 10 | Viewed by 3624

Abstract

Background: Hereditary transthyretin amyloidosis (hATTR) is an autosomal dominantly inherited disorder caused by an accumulation of amyloid fibrils in tissues due to mutations in the transthyretin (TTR) gene. The prevalence of hATTR is still unclear and likely underestimated in many countries. [...] Read more.

Background: Hereditary transthyretin amyloidosis (hATTR) is an autosomal dominantly inherited disorder caused by an accumulation of amyloid fibrils in tissues due to mutations in the transthyretin (TTR) gene. The prevalence of hATTR is still unclear and likely underestimated in many countries. In order to apply new therapies in a targeted manner, early diagnosis and knowledge of phenotype-genotype correlations are mandatory. This study aimed to assess the prevalence and phenotypic spectrum of hATTR in Austria. Methods: Within the period of 2014–2019, patients with ATTR-associated cardiomyopathy and/or unexplained progressive polyneuropathies were screened for mutations in the TTR gene. Results: We identified 43 cases from 22 families carrying 10 different TTR missense mutations and confirmed two mutational hot spots at c.323A>G (p.His108Arg) and c.337G>C (p.Val113Leu). Two further patients with late onset ATTR carried TTR variants of unknown significance. The majority of patients initially presented with heart failure symptoms that were subsequently accompanied by progressive polyneuropathy in most cases. A total of 55% had a history of carpal tunnel syndrome before the onset of other organ manifestations. Conclusions: Our study underlined the relevance of hATTR in the pathogenesis of amyloid-driven cardiomyopathy and axonal polyneuropathy and indicated considerable genetic heterogeneity of this disease in the Austrian population. The estimated prevalence of hATTR in Austria based on this study is 1:200,000 but a potentially higher number of unknown cases must be taken into account. With respect to new therapeutic approaches, we strongly propose genetic testing of the TTR gene in an extended cohort of patients with unexplained heart failure and progressive polyneuropathy. Full article

(This article belongs to the Special Issue Clinical and Research of Genetic Cardiomyopathies)

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15 pages, 971 KiB

Open AccessArticle

New Insights on Genetic Diagnostics in Cardiomyopathy and Arrhythmia Patients Gained by Stepwise Exome Data Analysis

by Konstantinos Kolokotronis, Natalie Pluta, Eva Klopocki, Erdmute Kunstmann, Daniel Messroghli, Christoph Maack, Shai Tejman-Yarden, Michael Arad, Simone Rost and Brenda Gerull

J. Clin. Med. 2020, 9(7), 2168; https://doi.org/10.3390/jcm9072168 - 9 Jul 2020

Cited by 5 | Viewed by 3555

Abstract

Inherited cardiomyopathies are characterized by clinical and genetic heterogeneity that challenge genetic diagnostics. In this study, we examined the diagnostic benefit of exome data compared to targeted gene panel analyses, and we propose new candidate genes. We performed exome sequencing in a cohort [...] Read more.

Inherited cardiomyopathies are characterized by clinical and genetic heterogeneity that challenge genetic diagnostics. In this study, we examined the diagnostic benefit of exome data compared to targeted gene panel analyses, and we propose new candidate genes. We performed exome sequencing in a cohort of 61 consecutive patients with a diagnosis of cardiomyopathy or primary arrhythmia, and we analyzed the data following a stepwise approach. Overall, in 64% of patients, a variant of interest (VOI) was detected. The detection rate in the main sub-cohort consisting of patients with dilated cardiomyopathy (DCM) was much higher than previously reported (25/36; 69%). The majority of VOIs were found in disease-specific panels, while a further analysis of an extended panel and exome data led to an additional diagnostic yield of 13% and 5%, respectively. Exome data analysis also detected variants in candidate genes whose functional profile suggested a probable pathogenetic role, the strongest candidate being a truncating variant in STK38. In conclusion, although the diagnostic yield of gene panels is acceptable for routine diagnostics, the genetic heterogeneity of cardiomyopathies and the presence of still-unknown causes favor exome sequencing, which enables the detection of interesting phenotype–genotype correlations, as well as the identification of novel candidate genes. Full article

(This article belongs to the Special Issue Clinical and Research of Genetic Cardiomyopathies)

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14 pages, 1920 KiB

Open AccessArticle

Mitochondrial Energetics and Ca²⁺-Activated ATPase in Obstructive Hypertrophic Cardiomyopathy

by Maria Lombardi, Davide Lazzeroni, Annalinda Pisano, Francesca Girolami, Ottavio Alfieri, Giovanni La Canna, Giulia d’Amati, Iacopo Olivotto, Ornella E. Rimoldi, Chiara Foglieni and Paolo G. Camici

J. Clin. Med. 2020, 9(6), 1799; https://doi.org/10.3390/jcm9061799 - 9 Jun 2020

Cited by 7 | Viewed by 3090

Abstract

Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the myocardium associated to mutations in sarcomeric genes, but the link between genotype and phenotype remains poorly understood. Magnetic resonance spectroscopy studies have demonstrated impaired cardiac energetics in patients with HCM, and altered [...] Read more.

Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the myocardium associated to mutations in sarcomeric genes, but the link between genotype and phenotype remains poorly understood. Magnetic resonance spectroscopy studies have demonstrated impaired cardiac energetics in patients with HCM, and altered mitochondria were described in biopsies, but little is known about possible perturbations of mitochondrial function and adenosine triphosphate (ATP) production/consumption. The aim of this study was to investigate possible abnormalities in mitochondrial enzymes generating/scavenging reactive oxygen species, and changes in the Ca²⁺-activated ATPases in myocardial tissue from patients with obstructive HCM undergoing surgical myectomy compared to unused donor hearts (CTRL). Methods and Results: Both the amount and activity of mitochondrial Complex I (nicotinamide adenine dinucleotide -reduced form, NADH, dehydrogenase) were upregulated in HCM vs. CTRL, whilst the activity of Complex V (ATP synthase) was not reduced and ATP levels were significantly higher in HCM vs. CTRL. Antioxidant Mn-activated superoxide dismutase (SOD2) and (m)-aconitase activities were increased in HCM vs. CTRL. The Cu/Zn-activated superoxide dismutase (SOD1) amount and mtDNA copy number were unaltered in HCM. Total Ca²⁺-activated ATPase activity and absolute amount were not different HCM vs. CTRL, but the ratio between ATPase sarcoplasmic/endoplasmic reticulum Ca²⁺ transporting type 2 (ATP2A2) and type 1 (ATP2A1), ATP2A2/ATP2A1, was increased in HCM in favor of the slow isoform (ATP2A2). Conclusion: HCM is characterized by mitochondrial Complex I hyperactivity and preserved Ca²⁺-activated ATPase activity with a partial switch towards slow ATP2A2. This data may give insight into the abnormal cellular energetics observed in HCM cardiomyopathy but other studies would need to be performed to confirm the observations described here. Full article

(This article belongs to the Special Issue Clinical and Research of Genetic Cardiomyopathies)

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18 pages, 2769 KiB

Open AccessArticle

by Hyung Yoon Kim, Jong Eun Park, Sang-Chol Lee, Eun-Seok Jeon, Young Keun On, Sung Mok Kim, Yeon Hyeon Choe, Chang-Seok Ki, Jong-Won Kim and Kye Hun Kim

J. Clin. Med. 2020, 9(6), 1671; https://doi.org/10.3390/jcm9061671 - 1 Jun 2020

Cited by 12 | Viewed by 2979

Abstract

Background: The spectrum of genetic variants and their clinical significance of Hypertrophic cardiomyopathy (HCM) have been poorly studied in Asian patients. The objectives of this study were to assess the spectrum of genetic variants and genotype–phenotype relationships within a Korean HCM population. Methods: [...] Read more.

Background: The spectrum of genetic variants and their clinical significance of Hypertrophic cardiomyopathy (HCM) have been poorly studied in Asian patients. The objectives of this study were to assess the spectrum of genetic variants and genotype–phenotype relationships within a Korean HCM population. Methods: Eighty-nine consecutive unrelated HCM patients were included. All patients underwent genotypic analysis for 23 HCM-associated genes. Clinical parameters including echocardiographic and cardiac magnetic resonance (CMR) parameters were evaluated. A composite of major adverse cardiac and cerebrovascular events was assessed. Results: Genetic variants were detected in 55 of 89 subjects. Pathogenic variants or likely pathogenic variants were identified in 27 of HCM patients in MYBPC3, TNNI3, MYH7, and MYL7. Variants of uncertain significance were identified in 28 patients. There were significant differences in the presence of non-sustained ventricular tachycardia (p = 0.030) and myocardial fibrosis on CMR (p = 0.029) in the detected compared to the not-detected groups. Event-free survival was superior in the not-detected group (p = 0.006). Conclusion: Genetic variants in patients with HCM are relatively common and are associated with adverse clinical events and myocardial fibrosis on CMR. Genotypic analysis may add important information to clinical variables in the assessment of long-term risk for HCM patients. Full article

(This article belongs to the Special Issue Clinical and Research of Genetic Cardiomyopathies)

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10 pages, 423 KiB

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Significance of NT-proBNP and High-Sensitivity Troponin in Friedreich Ataxia

by Lise Legrand, Carole Maupain, Marie-Lorraine Monin, Claire Ewenczyk, Richard Isnard, Rana Alkouri, Alexandra Durr and Francoise Pousset

J. Clin. Med. 2020, 9(6), 1630; https://doi.org/10.3390/jcm9061630 - 28 May 2020

Cited by 8 | Viewed by 2962

Abstract

Background: Friedreich’s ataxia (FA) is a rare autosomal recessive mitochondrial disease resulting of a triplet repeat expansion guanine-adenine-adenine (GAA) in the frataxin (FXN) gene, exhibiting progressive cerebellar ataxia, diabetes and cardiomyopathy. We aimed to determine the relationship between cardiac biomarkers, serum N-terminal pro-brain [...] Read more.

Background: Friedreich’s ataxia (FA) is a rare autosomal recessive mitochondrial disease resulting of a triplet repeat expansion guanine-adenine-adenine (GAA) in the frataxin (FXN) gene, exhibiting progressive cerebellar ataxia, diabetes and cardiomyopathy. We aimed to determine the relationship between cardiac biomarkers, serum N-terminal pro-brain natriuretic peptide (NT-proBNP), and serum cardiac high-sensitivity troponin (hsTnT) concentrations, and the extent of genetic abnormality and cardiac parameters. Methods: Between 2013 and 2015, 85 consecutive genetically confirmed FA adult patients were prospectively evaluated by measuring plasma hsTnT and NT-proBNP concentrations, electrocardiogram, and echocardiography. Results: The 85 FA patients (49% women) with a mean age of 39 ± 12 years, a mean disease onset of 17 ± 11 years had a mean SARA (Scale for the Assessment and Rating of Ataxia) score of 26 ± 10. The median hsTnT concentration was 10 ng/L (3 to 85 ng/L) and 34% had a significant elevated hsTnT ≥ 14 ng/L. Increased septal wall thickness was associated with increased hsTnT plasma levels (p < 0.001). The median NT-proBNP concentration was 31 ng/L (5 to 775 ng/L) and 14% had significant elevated NT-proBNP ≥ 125 ng/L. Markers of increased left ventricular filling pressure (trans mitral E/A and lateral E/E’ ratio) were associated with increased NT-proBNP plasma levels (p = 0.01 and p = 0.01). Length of GAA or the SARA score were not associated with hsTnT or NT-proBNP plasma levels. Conclusion: hsTnT was increased in 1/3 of the adult FA and associated with increased septal wall thickness. Increased NT-proBNP remained a marker of increased left ventricular filling pressure. This could be used to identify patients that should undergo a closer cardiac surveillance. Full article

(This article belongs to the Special Issue Clinical and Research of Genetic Cardiomyopathies)

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Review

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15 pages, 1267 KiB

Open AccessReview

Sex Differences, Genetic and Environmental Influences on Dilated Cardiomyopathy

by Angita Jain, Nadine Norton, Katelyn A. Bruno, Leslie T. Cooper, Jr., Paldeep S. Atwal and DeLisa Fairweather

J. Clin. Med. 2021, 10(11), 2289; https://doi.org/10.3390/jcm10112289 - 25 May 2021

Cited by 28 | Viewed by 4574

Abstract

Dilated cardiomyopathy (DCM) is characterized by dilatation of the left ventricle and impaired systolic function and is the second most common cause of heart failure after coronary heart disease. The etiology of DCM is diverse including genetic pathogenic variants, infection, inflammation, autoimmune diseases, [...] Read more.

Dilated cardiomyopathy (DCM) is characterized by dilatation of the left ventricle and impaired systolic function and is the second most common cause of heart failure after coronary heart disease. The etiology of DCM is diverse including genetic pathogenic variants, infection, inflammation, autoimmune diseases, exposure to chemicals/toxins as well as endocrine and neuromuscular causes. DCM is inherited in 20–50% of cases where more than 30 genes have been implicated in the development of DCM with pathogenic variants in TTN (Titin) most frequently associated with disease. Even though male sex is a risk factor for heart failure, few studies have examined sex differences in the pathogenesis of DCM. We searched the literature for studies examining idiopathic or familial/genetic DCM that reported data by sex in order to determine the sex ratio of disease. We found 31 studies that reported data by sex for non-genetic DCM with an average overall sex ratio of 2.5:1 male to female and 7 studies for familial/genetic DCM with an overall average sex ratio of 1.7:1 male to female. No manuscripts that we found had more females than males in their studies. We describe basic and clinical research findings that may explain the increase in DCM in males over females based on sex differences in basic physiology and the immune and fibrotic response to damage caused by mutations, infections, chemotherapy agents and autoimmune responses. Full article

(This article belongs to the Special Issue Clinical and Research of Genetic Cardiomyopathies)

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17 pages, 3474 KiB

Open AccessReview

Arrhythmogenic Left Ventricular Cardiomyopathy: Genotype-Phenotype Correlations and New Diagnostic Criteria

by Giulia Mattesi, Alberto Cipriani, Barbara Bauce, Ilaria Rigato, Alessandro Zorzi and Domenico Corrado

J. Clin. Med. 2021, 10(10), 2212; https://doi.org/10.3390/jcm10102212 - 20 May 2021

Cited by 26 | Viewed by 4316

Abstract

Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disease characterized by loss of ventricular myocardium and fibrofatty replacement, which predisposes to scar-related ventricular arrhythmias and sudden cardiac death, particularly in the young and athletes. Although in its original description the disease was characterized [...] Read more.

Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disease characterized by loss of ventricular myocardium and fibrofatty replacement, which predisposes to scar-related ventricular arrhythmias and sudden cardiac death, particularly in the young and athletes. Although in its original description the disease was characterized by an exclusive or at least predominant right ventricle (RV) involvement, it has been demonstrated that the fibrofatty scar can also localize in the left ventricle (LV), with the LV lesion that can equalize or even overcome that of the RV. While the right-dominant form is typically associated with mutations in genes encoding for desmosomal proteins, other (non-desmosomal) mutations have been showed to cause the biventricular and left-dominant variants. This has led to a critical evaluation of the 2010 International Task Force criteria, which exclusively addressed the right phenotypic manifestations of ACM. An International Expert consensus document has been recently developed to provide upgraded criteria (“the Padua Criteria”) for the diagnosis of the whole spectrum of ACM phenotypes, particularly left-dominant forms, highlighting the use of cardiac magnetic resonance. This review aims to offer an overview of the current knowledge on the genetic basis, the phenotypic expressions, and the diagnosis of left-sided variants, both biventricular and left-dominant, of ACM. Full article

(This article belongs to the Special Issue Clinical and Research of Genetic Cardiomyopathies)

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17 pages, 3681 KiB

Open AccessReview

Hypertrophic Cardiomyopathy and Primary Restrictive Cardiomyopathy: Similarities, Differences and Phenocopies

by Riccardo Vio, Annalisa Angelini, Cristina Basso, Alberto Cipriani, Alessandro Zorzi, Paola Melacini, Gaetano Thiene, Alessandra Rampazzo, Domenico Corrado and Chiara Calore

J. Clin. Med. 2021, 10(9), 1954; https://doi.org/10.3390/jcm10091954 - 1 May 2021

Cited by 25 | Viewed by 6074

Abstract

Hypertrophic cardiomyopathy (HCM) and primary restrictive cardiomyopathy (RCM) have a similar genetic background as they are both caused mainly by variants in sarcomeric genes. These “sarcomeric cardiomyopathies” also share diastolic dysfunction as the prevalent pathophysiological mechanism. Starting from the observation that patients with [...] Read more.

Hypertrophic cardiomyopathy (HCM) and primary restrictive cardiomyopathy (RCM) have a similar genetic background as they are both caused mainly by variants in sarcomeric genes. These “sarcomeric cardiomyopathies” also share diastolic dysfunction as the prevalent pathophysiological mechanism. Starting from the observation that patients with HCM and primary RCM may coexist in the same family, a characteristic pathophysiological profile of HCM with restrictive physiology has been recently described and supports the hypothesis that familiar forms of primary RCM may represent a part of the phenotypic spectrum of HCM rather than a different genetic cardiomyopathy. To further complicate this scenario some infiltrative (amyloidosis) and storage diseases (Fabry disease and glycogen storage diseases) may show either a hypertrophic or restrictive phenotype according to left ventricular wall thickness and filling pattern. Establishing a correct etiological diagnosis among HCM, primary RCM, and hypertrophic or restrictive phenocopies is of paramount importance for cascade family screening and therapy. Full article

(This article belongs to the Special Issue Clinical and Research of Genetic Cardiomyopathies)

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18 pages, 723 KiB

Open AccessReview

Left Ventricular Noncompaction—A Systematic Review of Risk Factors in the Pediatric Population

by Katarzyna Łuczak-Woźniak and Bożena Werner

J. Clin. Med. 2021, 10(6), 1232; https://doi.org/10.3390/jcm10061232 - 16 Mar 2021

Cited by 14 | Viewed by 2663

Abstract

Left ventricular noncompaction (LVNC) is a heterogeneous, often hereditary group of diseases, which may have diverse clinical manifestations. This article reviews the risk factors for unfavorable outcomes of LVNC in children, as well as discuss the diagnostic methods and the differences between pediatric [...] Read more.

Left ventricular noncompaction (LVNC) is a heterogeneous, often hereditary group of diseases, which may have diverse clinical manifestations. This article reviews the risk factors for unfavorable outcomes of LVNC in children, as well as discuss the diagnostic methods and the differences between pediatric and adult LVNC. Through a systematic review of the literature, a total of 1983 articles were outlined; 23 of them met the inclusion criteria. In echocardiography the following have been associated with adverse outcomes in children: Left ventricular ejection fraction, end-diastolic dimension, left ventricular posterior wall compaction, and decreased strains. T-wave abnormalities and increased spatial peak QRS-T angle in ECG, as well as arrhythmia, were observed in children at greater risk. Cardiac magnetic resonance is a valuable tool to identify those with systolic dysfunction and late gadolinium enhancement. Genetic testing appears to help identify children at risk, because mutations in particular genes have been associated with worse outcomes. ECG and imaging tests, such as echocardiography and magnetic resonance, help outline risk factors for unfavorable outcomes of LVNC in children and in identifying outpatients who require more attention. Refining the current diagnostic criteria is crucial to avoid inadequate restrain from physical activity. Full article

(This article belongs to the Special Issue Clinical and Research of Genetic Cardiomyopathies)

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26 pages, 515 KiB

Open AccessReview

Genetic Cardiomyopathies: The Lesson Learned from hiPSCs

by Ilaria My and Elisa Di Pasquale

J. Clin. Med. 2021, 10(5), 1149; https://doi.org/10.3390/jcm10051149 - 9 Mar 2021

Cited by 7 | Viewed by 3586

Abstract

Genetic cardiomyopathies represent a wide spectrum of inherited diseases and constitute an important cause of morbidity and mortality among young people, which can manifest with heart failure, arrhythmias, and/or sudden cardiac death. Multiple underlying genetic variants and molecular pathways have been discovered in [...] Read more.

Genetic cardiomyopathies represent a wide spectrum of inherited diseases and constitute an important cause of morbidity and mortality among young people, which can manifest with heart failure, arrhythmias, and/or sudden cardiac death. Multiple underlying genetic variants and molecular pathways have been discovered in recent years; however, assessing the pathogenicity of new variants often needs in-depth characterization in order to ascertain a causal role in the disease. The application of human induced pluripotent stem cells has greatly helped to advance our knowledge in this field and enabled to obtain numerous in vitro patient-specific cellular models useful to study the underlying molecular mechanisms and test new therapeutic strategies. A milestone in the research of genetically determined heart disease was the introduction of genomic technologies that provided unparalleled opportunities to explore the genetic architecture of cardiomyopathies, thanks to the generation of isogenic pairs. The aim of this review is to provide an overview of the main research that helped elucidate the pathophysiology of the most common genetic cardiomyopathies: hypertrophic, dilated, arrhythmogenic, and left ventricular noncompaction cardiomyopathies. A special focus is provided on the application of gene-editing techniques in understanding key disease characteristics and on the therapeutic approaches that have been tested. Full article

(This article belongs to the Special Issue Clinical and Research of Genetic Cardiomyopathies)

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15 pages, 1404 KiB

Open AccessReview

Diagnosis and Risk Prediction of Dilated Cardiomyopathy in the Era of Big Data and Genomics

by Arjan Sammani, Annette F. Baas, Folkert W. Asselbergs and Anneline S. J. M. te Riele

J. Clin. Med. 2021, 10(5), 921; https://doi.org/10.3390/jcm10050921 - 26 Feb 2021

Cited by 20 | Viewed by 4546

Abstract

Dilated cardiomyopathy (DCM) is a leading cause of heart failure and life-threatening ventricular arrhythmias (LTVA). Work-up and risk stratification of DCM is clinically challenging, as there is great heterogeneity in phenotype and genotype. Throughout the last decade, improved genetic testing of patients has [...] Read more.

Dilated cardiomyopathy (DCM) is a leading cause of heart failure and life-threatening ventricular arrhythmias (LTVA). Work-up and risk stratification of DCM is clinically challenging, as there is great heterogeneity in phenotype and genotype. Throughout the last decade, improved genetic testing of patients has identified genotype–phenotype associations and enhanced evaluation of at-risk relatives leading to better patient prognosis. The field is now ripe to explore opportunities to improve personalised risk assessments. Multivariable risk models presented as “risk calculators” can incorporate a multitude of clinical variables and predict outcome (such as heart failure hospitalisations or LTVA). In addition, genetic risk scores derived from genome/exome-wide association studies can estimate an individual’s lifetime genetic risk of developing DCM. The use of clinically granular investigations, such as late gadolinium enhancement on cardiac magnetic resonance imaging, is warranted in order to increase predictive performance. To this end, constructing big data infrastructures improves accessibility of data by using electronic health records, existing research databases, and disease registries. By applying methods such as machine and deep learning, we can model complex interactions, identify new phenotype clusters, and perform prognostic modelling. This review aims to provide an overview of the evolution of DCM definitions as well as its clinical work-up and considerations in the era of genomics. In addition, we present exciting examples in the field of big data infrastructures, personalised prognostic assessment, and artificial intelligence. Full article

(This article belongs to the Special Issue Clinical and Research of Genetic Cardiomyopathies)

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21 pages, 297 KiB

Open AccessReview

The Multifaced Perspectives of Genetic Testing in Pediatric Cardiomyopathies and Channelopathies

by Nicoleta-Monica Popa-Fotea, Cosmin Cojocaru, Alexandru Scafa-Udriste, Miruna Mihaela Micheu and Maria Dorobantu

J. Clin. Med. 2020, 9(7), 2111; https://doi.org/10.3390/jcm9072111 - 4 Jul 2020

Cited by 1 | Viewed by 2815

Abstract

Pediatric inherited cardiomyopathies (CMPs) and channelopathies (CNPs) remain important causes of death in this population, therefore, there is a need for prompt diagnosis and tailored treatment. Conventional evaluation fails to establish the diagnosis of pediatric CMPs and CNPs in a significant proportion, prompting [...] Read more.

Pediatric inherited cardiomyopathies (CMPs) and channelopathies (CNPs) remain important causes of death in this population, therefore, there is a need for prompt diagnosis and tailored treatment. Conventional evaluation fails to establish the diagnosis of pediatric CMPs and CNPs in a significant proportion, prompting further, more complex testing to make a diagnosis that could influence the implementation of lifesaving strategies. Genetic testing in CMPs and CNPs may help unveil the underlying cause, but needs to be carried out with caution given the lack of uniform recommendations in guidelines about the precise time to start the genetic evaluation or the type of targeted testing or whole-genome sequencing. A very diverse etiology and the scarce number of randomized studies of pediatric CMPs and CNPs make genetic testing of these maladies far more particular than their adult counterpart. The genetic diagnosis is even more puzzling if the psychological impact point of view is taken into account. This review aims to put together different perspectives, state-of-the art recommendations—synthetizing the major indications from European and American guidelines—and psychosocial outlooks to construct a comprehensive genetic assessment of pediatric CMPs and CNPs. Full article

(This article belongs to the Special Issue Clinical and Research of Genetic Cardiomyopathies)

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