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The SGLT2i Dapagliflozin Reduces RV Mass Independent of Changes in RV Pressure Induced by Pulmonary Artery Banding

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Abstract

Background

Sodium glucose linked transporter 2 (SGLT2) inhibition not only reduces morbidity and mortality in patients with diagnosed heart failure but also prevents the development of heart failure hospitalization in those at risk. While studies to date have focused on the role of SGLT2 inhibition in left ventricular failure, whether this drug class is efficacious in the treatment and prevention of right heart failure has not been explored.

Hypothesis

We hypothesized that SGLT2 inhibition would reduce the structural, functional, and molecular responses to pressure overload of the right ventricle.

Methods

Thirteen-week-old Fischer F344 rats underwent pulmonary artery banding (PAB) or sham surgery prior to being randomized to receive either the SGLT2 inhibitor: dapagliflozin (0.5 mg/kg/day) or vehicle by oral gavage. After 6 weeks of treatment, animals underwent transthoracic echocardiography and invasive hemodynamic studies. Animals were then terminated, and their hearts harvested for structural and molecular analyses.

Results

PAB induced features consistent with a compensatory response to increased right ventricular (RV) afterload with elevated mass, end systolic pressure, collagen content, and alteration in calcium handling protein expression (all p < 0.05 when compared to sham + vehicle). Dapagliflozin reduced RV mass, including both wet and dry weight as well as normalizing the protein expression of SERCA 2A, phospho-AMPK and LC3I/II ratio expression (all p < 0.05).

Significance

Dapagliflozin reduces the structural, functional, and molecular manifestations of right ventricular pressure overload. Whether amelioration of these early changes in the RV may ultimately lead to a reduction in RV failure remains to be determined.

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Data Availability

All data generated or analysed during this study are included in this published article.

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Acknowledgements

We would like to thank the imaging facility core at SMH hospital.

Funding

Studies were supported by research grants from the St. Michael's Hospital Foundation and Astra Zeneca. Dr. Gilbert is the Canada Research Chair in Diabetes Complication’s, and this research was made possible, in part, by the Canada Research Chair’s Program. A.A. is supported by a Diabetes Investigator Award from Diabetes Canada and holds the Keenan Chair in Medicine at St. Michael’s Hospital and University of Toronto. V.G.Y. was supported by a Post-doctoral Fellowship from Diabetes Canada and is supported by a D H. Gales Family Charitable Foundation Post-doctoral Fellowship from the Banting and Best Diabetes Centre. Dr Kim A Connelly holds the Keenan chair for Research Leadership, at the Keenan Research centre for Biomedical Science, Toronto.

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Authors and Affiliations

  1. Keenan Research Center for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, 30 bond St, Toronto, ON, M5B1W8, Canada

    Kim A. Connelly, Ellen Wu, Aylin Visram, Sri Nagarjun Batchu, Veera Ganesh Yerra, Kerri Thai, Linda Nghiem, Yanling Zhang, Golam Kabir, J. F. Desjardins, Andrew Advani & Richard E. Gilbert

  2. Division of Cardiology, Labatt Family Heart Center Toronto, Toronto, ON, Canada

    Mark K. Friedberg

  3. Physiology and Experimental Medicine, Hospital for Sick Children and University of Toronto, Toronto, ON, Canada

    Mark K. Friedberg

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  1. Kim A. Connelly
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Contributions

KAC and REG designed study and wrote manuscript. EW, AV, SNB, VGY, KT, LN, YZ, GK, and JFD performed all experimental work and generated results. MFK and AA critically reviewed manuscript and made suggestions to results and discussion. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Kim A. Connelly or Richard E. Gilbert.

Ethics declarations

Ethics Approval and Consent to Participate

The study design and protocol were reviewed and approved by the St. Michael’s Hospital Animal care committee.

Consent for Publication

Not applicable.

Competing Interests

KAC has received research grants to his institution from Astra Zeneca and Boehringer Ingelheim, received support for travel to scientific meeting from Boehringer Ingelheim and honoraria for speaking engagements and ad hoc participation in advisory boards from Astra Zeneca, Boehringer Ingelheim, and Janssen. REG has received research grants to his institution from Astra Zeneca and Boehringer Ingelheim, received support for travel to scientific meeting from Astra Zeneca and honoraria for speaking engagements and ad hoc participation in advisory boards from Astra Zeneca, Boehringer Ingelheim, and Janssen. A.A. has received research support through his institution from AstraZeneca and Boehringer Ingelheim and KC, REG, and AA are listed as inventors on a patent application by Boehringer Ingelheim on the use of DPP-4 inhibitors in heart failure. All other authors declare no competing interests.

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Connelly, K.A., Wu, E., Visram, A. et al. The SGLT2i Dapagliflozin Reduces RV Mass Independent of Changes in RV Pressure Induced by Pulmonary Artery Banding. Cardiovasc Drugs Ther 38, 57–68 (2024). https://doi.org/10.1007/s10557-022-07377-1

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