Reversal of Cardiac Dysfunction After Long-Term Expression of SERCA2a by Gene Transfer in a Pre-Clinical Model of Heart Failure

Kawase, Yoshiaki; Ly, Hung Q.; Prunier, Fabrice; Lebeche, Djamel; Shi, Yanfen; Jin, Hongwei; Hadri, Lahouaria; Yoneyama, Ryuichi; Hoshino, Kozo; Takewa, Yoshiaki; Satoh, Susumu; Peluso, Richard W.; Zsebo, Krisztina M.; Gwathmey, Judith K.; Tardif, Jean‐Claude; Tanguay, Jean‐François; Hajjar, Roger J.

doi:10.1016/j.jacc.2007.12.014

Cited by 298 publications

(221 citation statements)

References 34 publications

Supporting

Mentioning

213

Contrasting

Unclassified

Order By: Relevance

“…Recent reports found that ANP expression is a more sensitive marker of volume overload than pressure overload [36]. In addition, long-term overexpression of SERCA2a in this animal model can preserve systolic function and potentially prevent diastolic dysfunction and LV remodeling [134].…”

Section: Volume-overload-induced Hfmentioning

confidence: 95%

Rodent models of heart failure: an updated review

et al. 2012

View full text Add to dashboard Cite

Heart failure (HF) is one of the major health and economic burdens worldwide, and its prevalence is continuously increasing. The study of HF requires reliable animal models to study the chronic changes and pharmacologic interventions in myocardial structure and function and to follow its progression toward HF. Indeed, during the past 40 years, basic and translational scientists have used small animal models to understand the pathophysiology of HF and find more efficient ways of preventing and managing patients suffering from congestive HF (CHF). Each species and each animal model has advantages and disadvantages, and the choice of one model over another should take them into account for a good experimental design. The aim of this review is to describe and highlight the advantages and drawbacks of some commonly used HF rodents models, including both non-genetically and genetically engineered models, with a specific subchapter concerning diastolic HF models.

show abstract

Section: Volume-overload-induced Hfmentioning

confidence: 95%

Rodent models of heart failure: an updated review

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Following proof‐of‐principal studies in rodents, preclinical investigation using adeno‐associated virus serotype 1 (AAV1)‐mediated SERCA2a gene transfer provided clear benefits in nonischemic HF secondary to either volume overloading in pigs3 or tachycardia pacing in sheep 4, 5. The utility of this therapy for reversing pre‐established cardiac dysfunction when delivered at an advanced stage of ischemic HF caused by chronic MI is unknown, as most studies focused on prevention rather than reversal of cardiac dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Primary Effect of SERCA2a Gene Transfer on Conduction Reserve in Chronic Myocardial Infarction

Motloch

Cacheux

Ishikawa

et al. 2018

JAHA

Self Cite

View full text Add to dashboard Cite

Background SERCA2a gene transfer (GT) improves mechano‐electrical function in animal models of nonischemic heart failure Whether SERCA2a GT reverses pre‐established remodeling at an advanced stage of ischemic heart failure is unclear. We sought to uncover the electrophysiological effects of adeno‐associated virus serotype 1.SERCA2a GT following myocardial infarction (MI).Methods and ResultsPigs developed mechanical dysfunction 1 month after anterior MI, at which point they received intracoronary adeno‐associated virus serotype 1.SERCA2a (MI+SERCA2a) or saline (MI) and were maintained for 2 months. Age‐matched naive pigs served as controls (Control). In vivo ECG‐and‐hemodynamic properties were assessed before and after dobutamine stress. The electrophysiological substrate was measured using optical action potential (AP) mapping in controls, MI, and MI+SERCA2a preparations. In vivo ECG measurements revealed comparable QT durations between groups. In contrast, prolonged QRS duration and increased frequency of R′ waves were present in MI but not MI+SERCA2a pigs relative to controls. SERCA2a GT reduced in in vivo arrhythmias in response to dobutamine. Ex vivo preparations from MI but not MI+SERCA2a or control pigs were prone to pacing‐induced ventricular tachycardia and fibrillation. Underlying these arrhythmias was pronounced conduction velocity slowing in MI versus MI+SERCA2a at elevated rates leading to ventricular tachycardia and fibrillation. Reduced susceptibility to ventricular tachycardia and fibrillation in MI+SERCA2a pigs was not related to hemodynamic function, contractile reserve, fibrosis, or the expression of Cx43 and Nav1.5. Rather, SERCA2a GT decreased phosphoactive CAMKII‐delta levels by >50%, leading to improved excitability at fast rates.Conclusions SERCA2a GT increases conduction velocity reserve, likely by preventing CAMKII overactivation. Our findings suggest a primary effect of SERCA2a GT on myocardial excitability, independent of altered mechanical function.

show abstract

“…Using a volume overload heart failure pig model, adeno-associated virus-mediated gene delivery of SERCA2a showed improvements in cardiac contractility and left ventricular remodeling for the first time in the large animals. 5 This beneficial effect was further confirmed in sheep 7,25 and dog 23 models of pacing-induced heart failure, chronic ischemia pig 79 and sheep model of myocardial infarction with mitral valve regurgitation model. 6 Consistent beneficial effects of SERCA2a gene transfer in different etiology of heart failure models support its significance in a failing heart.…”

Section: Calcium Cycling Proteinsmentioning

confidence: 78%

“…However, a pig model of mitral valve regurgitation is the only model so far used in large animal gene therapy evaluations. 5,9 In these studies, the chordae of mitral valve were percutaneously cut by biopsy catheter and resulted in left ventricular hypertrophy and dilatation, with the development of significant heart failure. A major limitation of this model is the relatively high mortality ranging from 35 to 50%, 5,34 reflecting the severity of the heart failure.…”

Section: Volume Overload Modelmentioning

confidence: 99%

“…Indeed, the efficacy of virus-mediated sarcoplasmic reticulum calcium ion (Ca 2+ ) ATPase (SERCA2a) gene transfer, which led to the initiation of the aforementioned clinical trial, was supported by a large amount of preclinical data with remarkable effect in large animals. [3][4][5][6][7][8][9] In this review, we discuss the current status of cardiac gene therapy focusing on large animal studies, with emphasis on animal models, targeted genes, vector types and delivery methods.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation