Primary Myocardial Fibrosis as an Alternative Phenotype Pathway of Inherited Cardiac Structural Disorders

Junttila, M. Juhani; Holmström, Lauri; Pylkäs, Katri; Mantere, Tuomo; Kaikkonen, Kari; Porvari, Katja; Kortelainen, Marja-Leena; Pakanen, Lasse; Kerkelä, Risto; Myerburg, Robert J.; Huikuri, Heikki V.

doi:10.1161/circulationaha.117.032175

Cited by 45 publications

(51 citation statements)

References 51 publications

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“…[n=2], HCM [n=4], and DCM [n=4]). 13 In line with our findings, no variants were identified in genes associated to primary electrical disorders.…”

Section: Discussionsupporting

confidence: 88%

“…In one patient who died at the age of 26 with ACM one likely pathogenic variant and one rare VUS were identified in DSP ( Table 2, Supplementary Table 3 case P1). One case with non-specific findings (idiopathic fibrosis) hosted the likely pathogenic TTN variant suggesting that this may be an early presentation of DCM as suggested by recent data from Finland 13 . No pathogenic or likely pathogenic variants were identified in genes associated with primarily electrical disorders.…”

Section: Resultsmentioning

confidence: 80%

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The yield of postmortem genetic testing in sudden death cases with structural findings at autopsy

et al. 2019

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“…[n=2], HCM [n=4], and DCM [n=4]). 13 In line with our findings, no variants were identified in genes associated to primary electrical disorders.…”

Section: Discussionsupporting

confidence: 88%

Section: Resultsmentioning

confidence: 80%

The yield of postmortem genetic testing in sudden death cases with structural findings at autopsy

et al. 2019

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“…Isolated LV fibrosis without any RV or LV functional or volumetric abnormality is not uncommon in AC and can be the only manifestation of the disease before SCD. 21,22 In our population, among the relatives with a DSP variant identified during familial screening, 13 did not have an AMC history or cardiomyopathy phenotype, but five (38%) were found to have LV sub-epicardial LGE on CMR, suggesting isolated LV fibrosis. Similarly, in the family with DSG2 mutation, two on the three asymptomatic relatives carrying the mutation had isolated LV LGE on CMR.…”

Section: Acute Myocarditis As a Diagnostic Criterion For Desmoplakin-mentioning

confidence: 84%

Familial screening in case of acute myocarditis reveals inherited arrhythmogenic left ventricular cardiomyopathies

et al. 2020

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Aims Several data suggest that acute myocarditis could be related to genetic variants involved in familial cardiomyopathies, particularly arrhythmogenic cardiomyopathy, but the management of patients with acute myocarditis and their families regarding their risk for having an associated inherited cardiomyopathy is unclear. Methods and results Families with at least one individual with a documented episode of acute myocarditis and at least one individual with a cardiomyopathy or a history of sudden death were included in the study. Comprehensive pedigree, including genetic testing, and history of these families were analysed. Six families were included. Genetic analysis revealed a variant in desmosomal proteins genes in all the probands [five in desmoplakin (DSP) gene and one in desmoglein 2 gene]. In the five families identified with a DSP variant, genetic testing was triggered by the association of an acute myocarditis with a single case of apparently isolated dilated cardiomyopathy or sudden death. Familial screening identified 28 DSP variant carriers; 39% had an arrhythmogenic left ventricular (LV) cardiomyopathy phenotype. Familial histories of sudden death were frequent, and a remarkable phenotype of isolated LV late gadolinium enhancement on contrast-enhanced cardiac magnetic resonance without any other structural abnormality was found in 38% of asymptomatic mutation carriers. None of the DSP variant carriers had imaging characteristics of right ventricle involvement meeting current Task Force criteria for arrhythmogenic right ventricular cardiomyopathy. Conclusions Comprehensive familial screening including genetic testing in case of acute myocarditis associated with a family history of cardiomyopathy or sudden death revealed unknown or misdiagnosed arrhythmogenic variant carriers with left-dominant phenotypes that frequently evade arrhythmogenic right ventricular cardiomyopathy Task Force criteria. In view of our results, acute myocarditis should be considered as an additional criterion for arrhythmogenic cardiomyopathy, and genetic testing should be advised in patients who experience acute myocarditis and have a family history of cardiomyopathy or sudden death.

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“…In postmortem autopsies of young patients dying from sudden cardiac death, primary cardiac fibrosis (defined as myocardial fibrosis in the absence of identifiable causes, or known cardiomyocyte pathology) is commonly found 238 . However, in many of these cases, genetic analysis identified cardiomyocyte-specific gene mutations 239 , suggesting that fibrosis may not be triggered through primary activation of interstitial cells, but may reflect activation through cardiomyocyte-derived fibrogenic signals. In a recent study, subjects with a frameshift mutation of SEPRINE1, the gene encoding PAI-1, exhibited primary cardiac fibrosis, attributed to the release of cardiomyocyte-derived TGF-β 240 .…”

Section: The Ecm In Genetic Cardiomyopathiesmentioning

confidence: 99%

The Extracellular Matrix in Ischemic and Nonischemic Heart Failure

Frangogiannis

2019

Circulation Research

352

287

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The ECM (extracellular matrix) network plays a crucial role in cardiac homeostasis, not only by providing structural support, but also by facilitating force transmission, and by transducing key signals to cardiomyocytes, vascular cells, and interstitial cells. Changes in the profile and biochemistry of the ECM may be critically implicated in the pathogenesis of both heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. The patterns of molecular and biochemical ECM alterations in failing hearts are dependent on the type of underlying injury. Pressure overload triggers early activation of a matrix-synthetic program in cardiac fibroblasts, inducing myofibroblast conversion, and stimulating synthesis of both structural and matricellular ECM proteins. Expansion of the cardiac ECM may increase myocardial stiffness promoting diastolic dysfunction. Cardiomyocytes, vascular cells and immune cells, activated through mechanosensitive pathways or neurohumoral mediators may play a critical role in fibroblast activation through secretion of cytokines and growth factors. Sustained pressure overload leads to dilative remodeling and systolic dysfunction that may be mediated by changes in the interstitial protease/antiprotease balance. On the other hand, ischemic injury causes dynamic changes in the cardiac ECM that contribute to regulation of inflammation and repair and may mediate adverse cardiac remodeling. In other pathophysiologic conditions, such as volume overload, diabetes mellitus, and obesity, the cell biological effectors mediating ECM remodeling are poorly understood and the molecular links between the primary insult and the changes in the matrix environment are unknown. This review article discusses the role of ECM macromolecules in heart failure, focusing on both structural ECM proteins (such as fibrillar and nonfibrillar collagens), and specialized injury-associated matrix macromolecules (such as fibronectin and matricellular proteins). Understanding the role of the ECM in heart failure may identify therapeutic targets to reduce geometric remodeling, to attenuate cardiomyocyte dysfunction, and even to promote myocardial regeneration.

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Primary Myocardial Fibrosis as an Alternative Phenotype Pathway of Inherited Cardiac Structural Disorders

Cited by 45 publications

References 51 publications

The yield of postmortem genetic testing in sudden death cases with structural findings at autopsy

The yield of postmortem genetic testing in sudden death cases with structural findings at autopsy

Familial screening in case of acute myocarditis reveals inherited arrhythmogenic left ventricular cardiomyopathies

The Extracellular Matrix in Ischemic and Nonischemic Heart Failure

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