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Review
. 2022 Aug 4;4(11):959-969.
doi: 10.1016/j.cjco.2022.07.012. eCollection 2022 Nov.

Arrhythmic Sudden Cardiac Death in Heart Failure With Preserved Ejection Fraction: Mechanisms, Genetics, and Future Directions

Sina Safabakhsh  1 , Abdullah Al-Shaheen  2 , Elizabeth Swiggum  1 , Lisa Mielniczuk  3 , Maxime Tremblay-Gravel  4 , Zachary Laksman  1
Affiliations
Review

Arrhythmic Sudden Cardiac Death in Heart Failure With Preserved Ejection Fraction: Mechanisms, Genetics, and Future Directions

Sina Safabakhsh et al. CJC Open. .

Abstract
in English, French

Heart failure with preserved ejection fraction (HFpEF) is an increasingly recognized disorder. Many clinical trials have failed to demonstrate benefit in patients with HFpEF but have recognized alarming rates of sudden cardiac death (SCD). Genetic testing has become standard in the workup of patients with otherwise unexplained cardiac arrest, but the genetic architecture of HFpEF, and the overlap of a genetic predisposition to HFpEF and arrhythmias, is poorly understood. An understanding of the genetics of HFpEF and related SCD has the potential to redefine and generate novel diagnostic, prognostic, and therapeutic tools. In this review, we examine recent pathophysiological and clinical advancements in our understanding of HFpEF, which reinforce the heterogeneity of the condition. We also discuss data describing SCD events in patients with HFpEF and review the current literature on genetic underpinnings of HFpEF. Mechanisms of arrhythmogenesis which may lead to SCD in this population are also explored. Lastly, we outline several areas of promise for experimentation and clinical trials that have the potential to further advance our understanding of and contribute to improved clinical care of this patient population.

L’insuffisance cardiaque à fraction d’éjection préservée (ICFEP) est une anomalie de plus en plus reconnue. De nombreux essais cliniques n’ont pas permis de démontrer les avantages chez les patients atteints d’ICFEP, mais ont permis de reconnaître les taux alarmants de mort subite d’origine cardiaque (MSC). Le dépistage génétique est désormais un examen qui fait partie du bilan de santé des patients qui subissent un arrêt cardiaque inexpliqué autrement, mais l’architecture génétique de l’ICFEP et le chevauchement entre la prédisposition génétique à l’ICFEP et la prédisposition aux arythmies demeurent mal compris. La compréhension de la génétique de l’ICFEP et de la MSC associée a le potentiel de redéfinir et de générer de nouveaux outils de diagnostic, de pronostic et de traitement. Dans la présente revue, nous nous sommes penchés sur les récentes avancées physiopathologiques et cliniques dans notre compréhension de l’ICFEP, qui renforcent l’hétérogénéité de cette maladie. Nous nous sommes aussi intéressés aux données qui décrivent les événements de MSC chez les patients atteints d’ICFEP et passons en revue la littérature actuelle sur les fondements génétiques de l’ICFEP. Les mécanismes de l’arythmogenèse qui peuvent mener à la MSC au sein de cette population sont aussi abordés. Enfin, nous présentons plusieurs domaines d’expérimentation prometteurs et les essais cliniques qui ont le potentiel de faire progresser notre compréhension et de contribuer à l’amélioration des soins cliniques au sein de cette population de patients.

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Figures

Figure 1
Figure 1
Pathophysiological mechanisms contributing to the onset and progression of heart failure with preserved ejection fraction. HFpEF, heart failure with preserved ejection fraction; RAAS, renin-angiotensin-aldosterone system; ROS, reactive oxygen species. Reproduced from Sweeney et al. under Creative Commons Attribution 4.0 International (CC BY 4.0) license.
Figure 2
Figure 2
Common genetic variants found in genome-wide association studies of heart failure. Most studies to date have failed to differentiate patients by ejection fraction and so phenotype-specific data on heart failure with preserved ejection fraction and heart failure with reduced ejection fraction are scarce. Reproduced from Lumbers et al.under Creative Commons Attribution 4.0 International (CC BY 4.0) license.
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