Gene therapies for arrhythmias in heart failure

Akar, Fadi G.; Hajjar, Roger J.

doi:10.1007/s00424-014-1485-3

Cited by 7 publications

(7 citation statements)

References 68 publications

(94 reference statements)

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“…Of note, in addition to potential effects on myocardial excitability and conduction properties, this modification might also provoke triggered activity and promote vulnerability to ventricular arrhythmias (Akar & Hajjar, 2014;, as observed in Ucp2 −/− mice. Of note, in addition to potential effects on myocardial excitability and conduction properties, this modification might also provoke triggered activity and promote vulnerability to ventricular arrhythmias (Akar & Hajjar, 2014;, as observed in Ucp2 −/− mice.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, as alterations of the slope factor of the action potential upstroke depend on sodium channel availability, these data could also hint at increased activity of the late sodium current. Of note, in addition to potential effects on myocardial excitability and conduction properties, this modification might also provoke triggered activity and promote vulnerability to ventricular arrhythmias (Akar & Hajjar, 2014;, as observed in Ucp2 −/− mice. However, in the present study we also measured a more hyperpolarized resting membrane potential in Ucp2 −/− cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

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Through modulation of cardiac Ca²⁺ handling, UCP2 affects cardiac electrophysiology and influences the susceptibility for Ca²⁺‐mediated arrhythmias

Larbig

Reda

Paar

et al. 2017

Experimental Physiology

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What is the central question of this study? Knockdown of UCP2 reduces mitochondrial Ca uptake. This suggests that Ucp2 knockout mice need to have additional effects on cytosolic Ca handling to prevent Ca overload. However, the specific mechanisms and their impact on cardiac electrophysiology remain speculative. What is the main finding and its importance? In Ucp2 knockout mice, decreased mitochondrial Ca uptake is compensated for by functional inhibition of L-type Ca channels and resultant shortening of action potential duration. UCP2-dependent modulations have a major impact on cardiac electrophysiology, resulting in alterations of ECG characteristics and a higher susceptibility to Ca -mediated ventricular arrhythmias. Uncoupling protein 2 (mitochondrial, proton carrier) (UCP2) belongs to a superfamily of mitochondrial ion transporters. Owing to its beneficial influence on production of reactive oxygen species, it is suggested to reduce cardiac ischaemia-reperfusion injury. Recent studies have uncovered its ability to regulate mitochondrial Ca uptake and therefore to influence cardiac cytosolic Ca handling, indicating compensatory pathways to avoid toxic Ca overload in Ucp2 knockout (Ucp2 ) mice. However, the specific mechanisms and their impact on cardiac electrophysiology remain speculative. Molecular analyses, whole-cell patch clamp in cardiomyocytes and ECG studies were performed in Ucp2 and wild-type (WT) control mice. Furthermore, to explore the impact on cardiac arrhythmogenicity, ECG monitoring was performed in basal conditions and during Ca -mediated stress using Bay K 8644. Although cardiac ryanodine receptor 2, NCX1, L-type Ca channel (LTCC) and SERCA2a expression were not altered, Ucp2 mice revealed major variations in cardiac electrophysiology. The LTCC current and APD were decreased in Ucp2 mice, indicating compensatory mechanisms. Furthermore, in Ucp2 mice, an increased slope factor of action potential upstrokes and more hyperpolarized resting membrane potential were measured, suggesting variations in cardiac excitability. In agreement with alterations of cellular physiology in Ucp2 mice, reductions in PR and QRS as well as shortening of the QTc interval were noted in ECG recordings. Importantly, an increased incidence of cellular after-depolarizations and more pronounced susceptibility to Ca -mediated arrhythmias were observed. Furthermore, although expression of UCP3 was not different, levels of PRMT1 were significantly higher in Ucp2 mice. Our observations indicate compensatory mechanisms by which Ucp2 mice prevent toxic cytosolic Ca overload. UCP2-dependent modulations have a major impact on cardiac electrophysiology and influence susceptibility to Ca -mediated ventricular arrhythmias.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Through modulation of cardiac Ca²⁺ handling, UCP2 affects cardiac electrophysiology and influences the susceptibility for Ca²⁺‐mediated arrhythmias

Larbig

Reda

Paar

et al. 2017

Experimental Physiology

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“…Malignant ventricular tachyarrhythmias are caused by either (1) enhanced automaticity, (2) triggered activity or (3) reentry. The first two conditions refer to cellular phenomena, whereas the latter is a matter of the cardiac electrophysiological network [57,58,59].…”

Section: Pathophysiology Of Calcium Mediated Ventricular Arrhythmiamentioning

confidence: 99%

Pathophysiology of Calcium Mediated Ventricular Arrhythmias and Novel Therapeutic Options with Focus on Gene Therapy

Paar

Jirak

Larbig

et al. 2019

IJMS

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Cardiac arrhythmias constitute a major health problem with a huge impact on mortality rates and health care costs. Despite ongoing research efforts, the understanding of the molecular mechanisms and processes responsible for arrhythmogenesis remains incomplete. Given the crucial role of Ca2+-handling in action potential generation and cardiac contraction, Ca2+ channels and Ca2+ handling proteins represent promising targets for suppression of ventricular arrhythmias. Accordingly, we report the different roles of Ca2+-handling in the development of congenital as well as acquired ventricular arrhythmia syndromes. We highlight the therapeutic potential of gene therapy as a novel and innovative approach for future arrhythmia therapy. Furthermore, we discuss various promising cellular and mitochondrial targets for therapeutic gene transfer currently under investigation.

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“…This has allowed investigators to use targeted gene-based approaches to correct abnormal excitability in the atria, ventricles, and the cardiac conduction system. In this article, we provide an update on some of the most promising gene therapy approaches that have emerged in recent years for the treatment of tachy- and brady-arrhythmias in HF [6]. Details including the target gene, choice of vector, delivery technique, target tissue, and species are shown in Tables 1–3.…”

Section: Introductionmentioning

confidence: 99%

Gene therapy to restore electrophysiological function in heart failure

Motloch¹,

Akar²

2015

Expert Opinion on Biological Therapy

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Introduction Heart failure (HF) is a major public health epidemic and a leading cause of morbidity and mortality in the industrialized world. Existing treatments for patients with HF are often associated with pro-arrhythmic activity and risk of sudden cardiac death (SCD). Therefore, development of novel, effective, and safe therapeutic options for HF patients is a critical area of unmet need. Areas Covered In this article, we review recent advances in the emerging field of cardiac gene therapy for the treatment of tachy- and brady- arrhythmias in HF. We provide an overview of gene-based approaches that modulate myocardial conduction, repolarization, calcium cycling, and adrenergic signaling to restore heart rate and rhythm. Expert Opinion We highlight major advantages of gene therapy for arrhythmias, including the ability to selectively target specific cell populations and to limit the therapeutic effect to the region that requires modification. We illustrate how advances in our fundamental understanding of the molecular origins of arrhythmogenic disorders are allowing investigators to use targeted gene-based approaches to successfully correct abnormal excitability in the atria, ventricles, and conduction system. Translation of various gene therapy approaches to humans may revolutionize our ability to combat lethal arrhythmias in HF patients.

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Gene therapies for arrhythmias in heart failure

Cited by 7 publications

References 68 publications

Through modulation of cardiac Ca²⁺ handling, UCP2 affects cardiac electrophysiology and influences the susceptibility for Ca²⁺‐mediated arrhythmias

Through modulation of cardiac Ca²⁺ handling, UCP2 affects cardiac electrophysiology and influences the susceptibility for Ca²⁺‐mediated arrhythmias

Pathophysiology of Calcium Mediated Ventricular Arrhythmias and Novel Therapeutic Options with Focus on Gene Therapy

Gene therapy to restore electrophysiological function in heart failure

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Gene therapies for arrhythmias in heart failure

Cited by 7 publications

References 68 publications

Through modulation of cardiac Ca2+ handling, UCP2 affects cardiac electrophysiology and influences the susceptibility for Ca2+‐mediated arrhythmias

Through modulation of cardiac Ca2+ handling, UCP2 affects cardiac electrophysiology and influences the susceptibility for Ca2+‐mediated arrhythmias

Pathophysiology of Calcium Mediated Ventricular Arrhythmias and Novel Therapeutic Options with Focus on Gene Therapy

Gene therapy to restore electrophysiological function in heart failure

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Through modulation of cardiac Ca²⁺ handling, UCP2 affects cardiac electrophysiology and influences the susceptibility for Ca²⁺‐mediated arrhythmias

Through modulation of cardiac Ca²⁺ handling, UCP2 affects cardiac electrophysiology and influences the susceptibility for Ca²⁺‐mediated arrhythmias