Sudden death related cardiomyopathies – Arrhythmogenic right ventricular cardiomyopathy, arrhythmogenic cardiomyopathy, and exercise-induced cardiomyopathy

Goff, Zackary D.; Calkins, Hugh

doi:10.1016/j.pcad.2019.04.002

Cited by 21 publications

(22 citation statements)

References 84 publications

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“…As endurance training decreases cardiac function and provokes ventricular arrhythmias [17,18], PKP2-Hz mice were subjected to one-month voluntary running on a treadmill. PKP2-Hz mice exposed to exercise training did not show increased levels of fibrosis (Figure 3A, Figure S3), signs of hypertrophy (Figure 3B,C, Table S1), affected cardiac contractility (Figure 3F), or changes in electrocardiogram (ECG) parameters (Table S2), compared to controls.…”

Section: Resultsmentioning

confidence: 99%

“…Additional to PKP2 variants, several additional factors (secondary hits) have been proposed to contribute to ACM development. Participation in endurance exercise is a key risk factor for developing ACM, its progression toward heart failure, and for the occurrence of arrhythmias and sudden death [17,18,19]. In that regard, patients with ACM are often recommended to avoid endurance training [20].…”

Section: Introductionmentioning

confidence: 99%

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Plakophilin-2 Haploinsufficiency Causes Calcium Handling Deficits and Modulates the Cardiac Response Towards Stress

Opbergen

Noorman

Pfenniger

et al. 2019

IJMS

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Human variants in plakophilin-2 (PKP2) associate with most cases of familial arrhythmogenic cardiomyopathy (ACM). Recent studies show that PKP2 not only maintains intercellular coupling, but also regulates transcription of genes involved in Ca2+ cycling and cardiac rhythm. ACM penetrance is low and it remains uncertain, which genetic and environmental modifiers are crucial for developing the cardiomyopathy. In this study, heterozygous PKP2 knock-out mice (PKP2-Hz) were used to investigate the influence of exercise, pressure overload, and inflammation on a PKP2-related disease progression. In PKP2-Hz mice, protein levels of Ca2+-handling proteins were reduced compared to wildtype (WT). PKP2-Hz hearts exposed to voluntary exercise training showed right ventricular lateral connexin43 expression, right ventricular conduction slowing, and a higher susceptibility towards arrhythmias. Pressure overload increased levels of fibrosis in PKP2-Hz hearts, without affecting the susceptibility towards arrhythmias. Experimental autoimmune myocarditis caused more severe subepicardial fibrosis, cell death, and inflammatory infiltrates in PKP2-Hz hearts than in WT. To conclude, PKP2 haploinsufficiency in the murine heart modulates the cardiac response to environmental modifiers via different mechanisms. Exercise upon PKP2 deficiency induces a pro-arrhythmic cardiac remodeling, likely based on impaired Ca2+ cycling and electrical conduction, versus structural remodeling. Pathophysiological stimuli mainly exaggerate the fibrotic and inflammatory response.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Plakophilin-2 Haploinsufficiency Causes Calcium Handling Deficits and Modulates the Cardiac Response Towards Stress

Opbergen

Noorman

Pfenniger

et al. 2019

IJMS

View full text Add to dashboard Cite

show abstract

“…Arrhythmogenic right ventricular cardiomyopathy is a rare cardiovascular disease belonging to a subset of cardiomyopathies known as “arrhythmogenic cardiomyopathies” that each carry a propensity for arrhythmia 4 . First described by Fontaine and colleagues, arrhythmogenic right ventricular cardiomyopathy is now understood as a genetically determined myocardial dystrophy propagated by an autosomal dominant pattern of inheritance, incomplete penetrance, and variable expressivity 5 . In afflicted patients, pathogenic mutations lead to fibrofatty replacement of cardiac myocytes 6 .…”

Section: Discussionmentioning

confidence: 99%

Emergency department extracorporeal membrane oxygenation as a rescue therapy for ventricular tachycardia electrical storm: a case report

et al. 2020

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Arrhythmogenic right ventricular cardiomyopathy is a cause of sudden cardiac death in often otherwise healthy young adults. Cardiac arrest following an unstable tachydysrhythmia may be the primary presenting symptom. Venous arterial extracorporeal life support via extracorporeal membrane oxygenation (VA ECMO) has been used as a rescue strategy in emergency departments (EDs) for patients with cardiac arrest unresponsive to conventional cardiopulmonary resuscitation. We present a case of a previously healthy 18‐year‐old male who presented to our emergency department with ECG features of arrhythmogenic right ventricular cardiomyopathy and subsequent pulseless polymorphic ventricular tachycardia refractory cardiac arrest, treated with ED‐initiated VA ECMO.

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“…Presently there is no causal therapy and the main goals of treatment are to control symptoms, delay the progression toward heart failure, and to prevent SCD with implantable cardioverter defibrillators (ICDs) [ 1 , 3 , 4 ]. However, ICD implant is associated with significant device-related complications and the selection of candidates for ICD is still unsatisfactory [ 13 , 14 , 15 , 16 ]. Therefore, a better understanding of the underpinning mechanisms of early cardiac arrhythmias in ACM could facilitate diagnosis, risk stratification and treatment of ACM patients.…”

Section: Introductionmentioning

confidence: 99%

Established and Emerging Mechanisms in the Pathogenesis of Arrhythmogenic Cardiomyopathy: A Multifaceted Disease

Gao

Puthenvedu

Lombardi

et al. 2020

IJMS

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Arrhythmogenic cardiomyopathy (ACM) is a heritable myocardial disease that manifests with cardiac arrhythmias, syncope, sudden cardiac death, and heart failure in the advanced stages. The pathological hallmark of ACM is a gradual replacement of the myocardium by fibroadiposis, which typically starts from the epicardium. Molecular genetic studies have identified causal mutations predominantly in genes encoding for desmosomal proteins; however, non-desmosomal causal mutations have also been described, including genes coding for nuclear proteins, cytoskeleton componentsand proteins involved in excitation-contraction coupling. Despite the poor prognosis, currently available treatments can only partially control symptoms and to date there is no effective therapy for ACM. Inhibition of the canonical Wnt/β-catenin pathway and activation of the Hippo and the TGF-β pathways have been implicated in the pathogenesis of ACM. Yet, our understanding of the molecular mechanisms involved in the development of the disease and the cell source of fibroadiposis remains incomplete. Elucidation of the pathogenesis of the disease could facilitate targeted approaches for treatment. In this manuscript we will provide a comprehensive review of the proposed molecular and cellular mechanisms of the pathogenesis of ACM, including the emerging evidence on abnormal calcium homeostasis and inflammatory/autoimmune response. Moreover, we will propose novel hypothesis about the role of epicardial cells and paracrine factors in the development of the phenotype. Finally, we will discuss potential innovative therapeutic approaches based on the growing knowledge in the field.

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Sudden death related cardiomyopathies – Arrhythmogenic right ventricular cardiomyopathy, arrhythmogenic cardiomyopathy, and exercise-induced cardiomyopathy

Cited by 21 publications

References 84 publications

Plakophilin-2 Haploinsufficiency Causes Calcium Handling Deficits and Modulates the Cardiac Response Towards Stress

Plakophilin-2 Haploinsufficiency Causes Calcium Handling Deficits and Modulates the Cardiac Response Towards Stress

Emergency department extracorporeal membrane oxygenation as a rescue therapy for ventricular tachycardia electrical storm: a case report

Established and Emerging Mechanisms in the Pathogenesis of Arrhythmogenic Cardiomyopathy: A Multifaceted Disease

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