bims-hafaim 2023-09-03 papers

Issue of 2023–09–03
five papers selected by
Kyle McCommis, Saint Louis University

J Cardiovasc Pharmacol. 2023 Aug 25.

Dapagliflozin Attenuates HFpEF Remodeling and Dysfunction by Elevating β-Hydroxybutyrate-activated Citrate Synthase.

Xinxin Zhang, Ning Wang, Peng Fu, Yanliang An, Fangfang Sun, Chengdong Wang, Xiao Han, Yunlong Zhang, Xiaohong Yu, Ying Liu.

ABSTRACT: Heart failure with preserved ejection fraction (HFpEF) is highly prevalent, accounting for 50% of all heart failure patients, and is associated with significant mortality. Sodium-glucose cotransporter subtype inhibitor (SGLT2i) is recommended as AHA and ESC guidelines for the treatment of HFpEF, but the mechanism of SGLT2i to prevent and treat cardiac remodeling and dysfunction is currently unknown, hindering the understanding of the pathophysiology of HFpEF and the development of novel therapeutics. HFpEF model was induced by a high-fat diet (HFD - 60% calories from lard) + N[w]-nitro-l-arginine methyl ester (L-NAME - 0.5 g/L) (2 Hit) in male Sprague-Dawley rats can effectively recapture the myriad phenotype of HFpEF. This study's results showed that administration of dapagliflozin (DAPA, SGLT2 inhibitor) significantly limited the 2-Hit-induced cardiomyocyte hypertrophy, apoptosis, inflammation, oxidative stress, and fibrosis. It also improved cardiac diastolic and systolic dysfunction in a late-stage progression of HFpEF. Mechanistically, DAPA influences energy metabolism associated with fatty acid intake and mitochondrial dysfunction in HFpEF by increasing β-hydroxybutyric acid (β-OHB) levels, directing activation of citrate synthase (CS), reducing acetyl coenzyme A (acetyl-CoA) pools, modulating ATP production, and increasing expression of mitochondrial oxidative phosphorylation system complexes I-V. Additionally, following clinical DAPA therapy, the blood levels of β-OHB and CS increased and the levels of acetyl-CoA in the blood of HFpEF patients fell. SGLT2i plays a beneficial role in the prevention and treatment of cardiac remodeling and dysfunction in HFpEF model by attenuating cardiometabolic dysregulation.

DOI: https://doi.org/10.1097/FJC.0000000000001474

Eur J Heart Fail. 2023 Aug 26.

Heart failure, chronic obstructive pulmonary disease and efficacy and safety of dapagliflozin in heart failure with mildly reduced or preserved ejection fraction: Insights from DELIVER.

Jawad H Butt, Henri Lu, Toru Kondo, Erasmus Bachus, Rudolf A de Boer, Silvio E Inzucchi, Pardeep S Jhund, Mikhail N Kosiborod, Carolyn S P Lam, Felipe A Martinez, Muthiah Vaduganathan, Scott D Solomon, John J V McMurray.

AIM: Chronic obstructive pulmonary disease (COPD) is common in heart failure with a mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) and is associated with worse outcomes. In a pre-specified analysis of DELIVER, we investigated the relationship between COPD status and outcomes, and the efficacy and safety of dapagliflozin, compared with placebo, according to COPD status.
METHODS AND RESULTS: Patients with severe pulmonary disease (including COPD) were excluded from the trial. The primary outcome was a composite of cardiovascular death or worsening heart failure. Of the 6261 patients with data on baseline COPD status, 694 (11.1%) had a known history of this condition. The risk of the primary endpoint was higher in patients with mild-to-moderate COPD compared with those without COPD (adjusted hazard ratio [HR] 1.28, 95% confidence interval [CI] 1.08-1.51). The benefit of dapagliflozin on the primary outcome was consistent irrespective of COPD status (no COPD: HR 0.82 [95% CI 0.72-0.93]; COPD: HR 0.82 [95% CI 0.62-1.10]; pinteraction = 0.98). Consistent effects were observed for heart failure, cardiovascular, and all-cause hospitalization, and deaths, and composites of these. Dapagliflozin, as compared with placebo, improved the Kansas City Cardiomyopathy Questionnaire scores from baseline to 8 months to a similar extent in patients with and without mild-to-moderate COPD (pinteraction ≥ 0.63). Adverse events and treatment discontinuation were not more frequent with dapagliflozin than with placebo irrespective of COPD status.
CONCLUSIONS: Mild-to-moderate COPD is common in patients with HFmrEF/HFpEF and is associated with worse outcomes. The beneficial effects of dapagliflozin compared with placebo on clinical events and symptoms were consistent, regardless of COPD status.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03619213.

Keywords: Chronic obstructive pulmonary disease; Clinical trial; Dapagliflozin; Heart failure; Outcomes

DOI: https://doi.org/10.1002/ejhf.3000

JCI Insight. 2023 Aug 24. pii: e166713. [Epub ahead of print]

Cardiac gene therapy rescues diabetic cardiomyopathy and lowers blood glucose.

Jing Li, Bradley Richmond, Ahmad A Cluntun, Ryan Bia, Maureen A Walsh, Kikuyo Shaw, J David Symons, Sarah Franklin, Jared Rutter, Katsuhiko Funai, Robin M Shaw, TingTing Hong.

Diabetic cardiomyopathy, an increasingly global epidemic and a major cause of heart failure with preserved ejection fraction (HFpEF), is associated with hyperglycemia, insulin resistance, and intra-cardiomyocyte calcium mishandling. Here we identify that, in db/db mice with type 2 diabetes induced HFpEF, abnormal remodeling of cardiomyocyte transverse-tubule microdomains occurs with downregulation of the membrane scaffolding protein cardiac bridging integrator 1 (cBIN1). Transduction of cBIN1 by AAV9 gene therapy can restore transverse-tubule microdomains to normalize intracellular distribution of calcium handling proteins and, surprisingly, glucose transporter 4 (GLUT4). Cardiac proteomics revealed that AAV9-cBIN1 normalizes components of calcium handling and GLUT4 translocation machineries. Functional studies further identified that AAV9-cBIN1 normalizes insulin-dependent glucose uptake in diabetic cardiomyocytes. Phenotypically, AAV9-cBIN1 rescues cardiac lusitropy, improves exercise intolerance, and ameliorates hyperglycemia in diabetic mice. Restoration of transverse-tubule microdomains can improve cardiac function in the setting of diabetic cardiomyopathy, and also improve systemic glycemic control.

Keywords: Cardiology; Cell Biology; Gene therapy; Glucose metabolism; Heart failure

DOI: https://doi.org/10.1172/jci.insight.166713

Glob Heart. 2023 ;18(1): 45

Effect of Dapagliflozin in Patients with Heart Failure: A Systematic Review and Meta-Analysis.

Ahmed E Ali, Muhammad Sabry Mazroua, Mariam ElSaban, Nadia Najam, Aditi S Kothari, Taha Mansoor, Tanya Amal, Joanna Lee, Rahul Kashyap.

Background: Heart failure (HF) is a major cause of recurrent hospitalization and death worldwide. Sodium-glucose cotransporter-2 inhibitors including dapagliflozin are anti-diabetic drugs with promising cardiovascular (CV) effects. We performed systematic review and meta-analysis of randomized controlled trials investigating the effects of dapagliflozin in heart failure patients.
Methods: We searched PubMed, Scopus and ScienceDirect databases. A total of 1,567 studies from January 2017 to September 10, 2022, were screened. After applying exclusion criteria, 22 studies were retrieved for full-text screening, and nine of them were eligible for this meta-analysis. Effect estimates for dichotomous variables were expressed as risk ratio (RR) and 95% CI. The primary outcomes were the incidence of all-cause mortality, hospitalization due to HF, and CV death. This review was registered on PROSPERO with ID CRD42022347793.
Results: A total of 14,032 patients were included. The overall risk ratio of all-cause mortality favored the dapagliflozin group over the placebo/standard therapy group (RR = 0.89, 95% CI: 0.82-0.97, P = 0.006) and the pooled studies were not heterogenous (I2 = 0%). Additionally, dapagliflozin significantly reduced the hospitalization due to heart failure (RR = 0.76, 95% CI: 0.70-0.84, P > 0.00001, I2 = 0%), cardiovascular death (RR = 0.87, 95% CI: 0.78-0.97, P = 0.01, I2 = 0%) and their composite outcomes.
Conclusion: Dapagliflozin reduces the risk of all-cause mortality, heart failure hospitalizations and cardiovascular death in a wide range of heart failure patients.

Keywords: Dapagliflozin; Diabetes Mellitus; Forxiga; Heart failure; SGLT2-inhibitors

DOI: https://doi.org/10.5334/gh.1258

J Cardiovasc Transl Res. 2023 Aug 31.

Myocardial Metabolic Reprogramming in HFpEF.

Zihui Zhang, Mingchu Sun, Wenhua Jiang, Lu Yu, Chan Zhang, Heng Ma.

Heart failure (HF) caused by structural or functional cardiac abnormalities is a significant cause of morbidity and mortality worldwide. While HF with reduced ejection fraction (HErEF) is well understood, more than half of patients have HF with preserved ejection fraction (HFpEF). Currently, the treatment for HFpEF primarily focuses on symptom alleviation, lacking specific drugs. The stressed heart undergoes metabolic switches in substrate preference, which is a compensatory process involved in cardiac pathological remodeling. Although metabolic reprogramming in HF has gained attention in recent years, its role in HFpEF still requires further elucidation. In this review, we present a summary of cardiac mitochondrial dysfunction and cardiac metabolic reprogramming in HFpEF. Additionally, we emphasize potential therapeutic approaches that target metabolic reprogramming for the treatment of HFpEF.

Keywords: Heart failure with preserved ejection fraction; Heart failure with reduced ejection fraction; Metabolic reprogramming; Mitochondrial dysfunction

DOI: https://doi.org/10.1007/s12265-023-10433-2