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New insights into SERCA2a gene therapy in heart failure: pay attention to the negative effects of B-type natriuretic peptides
  1. Yuting Zhai1,
  2. Yuanyuan Luo2,
  3. Pei Wu1,
  4. Dongye Li1
  1. 1 Institute of Cardiovascular Disease Research, Xuzhou Medical University, Xuzhou, Jiangsu, China
  2. 2 Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
  1. Correspondence to Professor Dongye Li, Institute of Cardiovascular Disease Research, Xuzhou Medical University, Xuzhou, Jiangsu 221002, China; dongyeli{at}


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.

  • heart failure
  • SERCA2a
  • B-type natriuretic peptide
  • gene therapy

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  • YZ and YL contributed equally.

  • Contributors YZ and YL contributed equally to this paper. YZ and YL conceived the review, collected literature and wrote the first draft of the manuscript. YZ and PW analysed the relevant literature and created the figures. DL conceived the review and critically revised the manuscript.

  • Funding This work was supported by the National Natural Science Foundation of China (81570326) and the Science and Technology Plan Projects of Xuzhou City (KC16SH099).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.