New insights into SERCA2a gene therapy in heart failure: pay attention to the negative effects of B-type natriuretic peptides

Abstract

Sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a) is a target of interest in gene therapy for heart failure with reduced ejection fraction (HFrEF). However, the results of an important clinical study, the Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) trial, were controversial. Promising results were observed in the CUPID 1 trial, but the results of the CUPID 2 trial were negative. The factors that caused the controversial results remain unclear. Importantly, enrolled patients were required to have a higher plasma level of B-type natriuretic peptide (BNP) in the CUPID 2 trial. Moreover, BNP was shown to inhibit SERCA2a expression. Therefore, it is possible that high BNP levels interact with treatment effects of SERCA2a gene transfer and accordingly lead to negative results of CUPID 2 trial. From this point of view, effects of SERCA2a gene therapy should be explored in heart failure with preserved ejection fraction, which is characterised by lower BNP levels compared with HFrEF. In this review, we summarise the current knowledge of SERCA2a gene therapy for heart failure, analyse potential interaction between BNP levels and therapeutic effects of SERCA2a gene transfer and provide directions for future research to solve the identified problems.

In vitro model of ischemic heart failure using human induced pluripotent stem cell–derived cardiomyocytes

“…In fact, SERCA2a gene therapy was shown in vitro to improve the contractile function of human cardiomyocytes isolated from patients afflicted with heart failure and is being tested as a new therapy for heart failure patients. (11)(12)(13) Thus, an in vitro model of human ischemic heart failure should present with reduced contraction, reduced calcium flux amplitudes, reduced SERCA2a protein expression, prolonged calcium transient duration, prolonged action potential duration and reduced PLN phosphorylation. Additionally, the functional phenotype should be rescued using established SERCA2a gene therapy approaches known to improve cardiomyocyte contractile function.…”

“…SERCA2a gene overexpression in the heart rapidly hastens the removal of cytosolic calcium during diastole, thus alleviating diastolic dysfunction. In fact, SERCA2a gene therapy was shown in vitro to improve the contractile function of human CMs isolated from patients afflicted with heart failure and is being tested as a new therapy for patients with heart failure ( 11 – 13 ). Thus, an in vitro model of human ischemic heart failure should present with reduced contraction, reduced calcium flux amplitudes, reduced SERCA2a protein expression, prolonged calcium transient duration (CaTD), prolonged action potential duration (APD), and reduced PLN phosphorylation.…”

Alteration of myocardial structure and function in RAF1-associated Noonan syndrome: Insights from cardiac disease modeling based on patient-derived iPSCs

“…Previous studies have shown that the RAS-MAPK pathway regulates SERCA2A, PLN, and LTCC expression that is downregulated during hypertrophy and heart failure [6,27,28]. Consistently, an increase in BNP, which is known as a HCM biomarker, leads to a decrease in SERCA2A expression [70].…”

Manganese-enhanced MRI of the myocardium

“…Its fundamental role in excitation–contraction coupling makes calcium handling central to pathophysiological and adaptive mechanisms of defective contractile function and impaired relaxation in cardiomyopathy. Several studies have demonstrated reduced sarcoendoplasmic reticulum calcium storage and release, with decreased SERCA2a and upregulated sodium–calcium exchanger activity 15. Altered expression and activity of voltage-gated L-type calcium channels in heart failure and hypertrophy observed in several studies are incompletely understood,16 although highlight the centrality of calcium handling to cardiomyocyte dysfunction.…”