bims-hafaim 2023-03-19 papers

Issue of 2023–03–19
six papers selected by
Kyle McCommis, Saint Louis University

J Clin Invest. 2023 Mar 16. pii: e162309. [Epub ahead of print]

RIP140 deficiency enhances cardiac fuel metabolism and protects mice from heart failure.

Tsunehisa Yamamoto, Santosh K Maurya, Elizabeth Pruzinsky, Kirill Batmanov, Yang Xiao, Sarah M Sulon, Tomoya Sakamoto, Yang Wang, Ling Lai, Kendra S McDaid, Swapnil V Shewale, Teresa C Leone, Timothy R Koves, Deborah M Muoio, Pieterjan Dierickx, Mitchell A Lazar, E Douglas Lewandowski, Daniel P Kelly.

During development of heart failure, capacity for cardiomyocyte fatty acid oxidation (FAO) and ATP production is progressively diminished contributing to pathologic cardiac hypertrophy and contractile dysfunction. Receptor interacting protein 140 (RIP140; Nrip1) has been shown to function as a transcriptional co-repressor of oxidative metabolism. We found that mice with striated muscle deficiency of RIP140 (strNrip1-/-) exhibit increased expression of a broad array of genes involved in mitochondrial energy metabolism and contractile function in heart and skeletal muscle. strNrip1-/- mice were resistant to the development of pressure overload-induced cardiac hypertrophy, and cardiomyocyte-specific RIP140 deficient (csNrip1-/-) mice were defended against development of heart failure caused by pressure overload combined with myocardial infarction. Genomic enhancers activated by RIP140 deficiency in cardiomyocytes were enriched in binding motifs for transcriptional regulators of mitochondrial function (estrogen-related receptor) and cardiac contractile proteins (myocyte enhancer factor 2). Consistent with a role in the control of cardiac fatty acid oxidation, loss of RIP140 in heart resulted in augmented triacylglyceride turnover and FA utilization. We conclude that RIP140 functions as a suppressor of a transcriptional regulatory network that controls cardiac fuel metabolism and contractile function, representing a potential therapeutic target for heart failure.

Keywords: Cardiology; Heart failure; Mitochondria; Transcription

DOI: https://doi.org/10.1172/JCI162309

Commun Biol. 2023 Mar 17. 6(1): 278

The SGLT2 inhibitor empagliflozin improves cardiac energy status via mitochondrial ATP production in diabetic mice.

Jungmi Choi, Naoki Matoba, Daiki Setoyama, Daiki Watanabe, Yuichiro Ohnishi, Ryuto Yasui, Yuichirou Kitai, Aki Oomachi, Yutaro Kotobuki, Yoichi Nishiya, Michael Paul Pieper, Hiromi Imamura, Motoko Yanagita, Masamichi Yamamoto.

Empagliflozin, a sodium-glucose co-transporter 2 inhibitor developed, has been shown to reduce cardiovascular events in patients with type 2 diabetes and established cardiovascular disease. Several studies have suggested that empagliflozin improves the cardiac energy state which is a partial cause of its potency. However, the detailed mechanism remains unclear. To address this issue, we used a mouse model that enabled direct measurement of cytosolic and mitochondrial ATP levels. Empagliflozin treatment significantly increased cytosolic and mitochondrial ATP levels in the hearts of db/db mice. Empagliflozin also enhanced cardiac robustness by maintaining intracellular ATP levels and the recovery capacity in the infarcted area during ischemic-reperfusion. Our findings suggest that empagliflozin enters cardiac mitochondria and directly causes these effects by increasing mitochondrial ATP via inhibition of NHE1 and Nav1.5 or their common downstream sites. These cardioprotective effects may be involved in the beneficial effects on heart failure seen in clinical trials.

DOI: https://doi.org/10.1038/s42003-023-04663-y

J Transl Med. 2023 Mar 16. 21(1): 199

Increased circulating uric acid aggravates heart failure via impaired fatty acid metabolism.

Bowen Lou, Haoyu Wu, Hannes Ott, Katrin Bennewitz, Chen Wang, Gernot Poschet, Hui Liu, Zuyi Yuan, Jens Kroll, Jianqing She.

BACKGROUND: Increased circulating uric acid (UA) concentration may disrupt cardiac function in heart failure patients, but the specific mechanism remains unclear. Here, we postulate that hyperuremia induces sterol regulatory element binding protein 1 (SREBP1), which in turn activate hepatic fatty acid biosynthesis response, leading to cardiac dysfunction.
METHODS AND RESULTS: Increased circulating uric acid was observed in heart failure patients and inversely correlated to cardiac function. Besides, uric acid correlated to circulating lipids profile based on metabolomics in heart failure patients. Using cultured human hepatoellular carcinomas (HepG2) and Tg(myl7:egfp) zebrafish, we demonstrated that UA regulated fatty acid synthase (FASN) via SREBP1 signaling pathway, leading to FFA accumulation and impaired energy metabolism, which could be rescued via SREBP1 knockdown. In ISO treated zebrafish, UA aggravated heart failure via increased cardiovascular cavity size, decreased heart beats, pericardial edema and long-stretched heart deformation.
CONCLUSIONS: Our findings suggest that UA-SREBP1-FASN signaling exacerbates cardiac dysfunction during FFA accumulation. Identification of this mechanism may help in treatment and prevention of heart failure.

Keywords: Fatty acid; Heart failure; Sterol regulatory element binding proteins 1; Uric acid

DOI: https://doi.org/10.1186/s12967-023-04050-5

Indian Heart J. 2023 Mar 11. pii: S0019-4832(23)00043-3. [Epub ahead of print]

SGLT2 inhibitors and Cardiovascular Outcomes in Heart Failure with Mildly Reduced and Preserved Ejection Fraction: A Systematic Review and Meta-Analysis.

Mainak Banerjee, Rimesh Pal, Kirthana Nair, Satinath Mukhopadhyay.

AIM: To provide a pooled effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on cardiovascular outcomes in patients with heart failure with preserved ejection fraction (HFpEF: ≥50%) or/and mildly reduced EF (HFmrEF: 41-49%) regardless of baseline diabetes.
METHODS: We systemically searched PubMed/MEDLINE, Embase, Web of Science databases and clinical trial registries using appropriate keywords till August 28, 2022, to identify randomized controlled trials (RCTs) or post-hoc analysis of RCTs, reporting cardiovascular death (CVD) and/or urgent visits/hospitalization for heart failure(HHF) in patients with HFmrEF/HFpEF receiving SGLTi vs. placebo. Hazard ratios (HR) with 95% confidence intervals (CI) for outcomes were pooled together using generic inverse variance method with fixed-effects model.
RESULTS: We identified six RCTs, pooling data retrieved from 15769 patients with HFmrEF/HFpEF. Pooled analysis showed that compared to placebo, SGLT2i use was significantly associated with improved CVD/HHF outcomes in HFmrEF/HFpEF (pooled HR 0.80, 95% CI: 0.74, 0.86, p<0.001, I2=0%). When separately analyzed, benefits of SGLT2i remained significant across HFpEF (N=8891, HR 0.79, 95% CI: 0.71, 0.87, p<0.001, I2=0%) and HFmrEF (N=4555, HR 0.77, 95% CI: 0.67, 0.89, p<0.001, I2=40%). Consistent benefits were observed also in HFmrEF/HFpEF subgroup without baseline diabetes (N=6507, HR 0.80, 95% CI: 0.70, 0.91, p<0.001, I2=0%). Sensitivity analysis including the DELIVER and EMPEROR-Preserved trials found a trend towards significant beneficial effects on CV deaths with no heterogeneity (HR 0.90, 95% CI: 0.79, 1.02, p=0.08, I2=0%).
CONCLUSIONS: This meta-analysis established the place of SGLT2i as a foundational therapy among patients with HF with preserved and mildly reduced EF regardless of diabetes.

Keywords: Dapagliflozin; Empagliflozin; Heart failure; SGLT2 inhibitors; Sotagliflozin; T2DM

DOI: https://doi.org/10.1016/j.ihj.2023.03.003

Cureus. 2023 Feb;15(2): e34687

Effects of Sodium-Glucose Cotransporter Inhibitor Use in Type 2 Diabetes Mellitus Patients With Heart Failure.

Silpa Choday, Niriksha Ravi, Anusha Parisapogu, Blessing T Ojinna, Mingma L Sherpa.

The advances in the development of sodium-glucose cotransporter 2 inhibitors (SGLT2i) have expanded the variety of favorable approaches to treating diabetes mellitus. It is possible to have an improvement in insulin resistance and natriuresis by inhibiting the reabsorption of sodium and glucose at the proximal tubules in the kidney, and a decrease in cardiovascular mortality in patients with diabetes mellitus (DM). In addition, SGLT2i provides renoprotection by reducing intraglomerular higher blood pressure. The usage of SGLT2i also provides hemodynamic and metabolic benefits. SGLT2i demonstrates large cardiovascular benefits in patients both with and without diabetes, as well as in existing heart failure patients. These SGLT2i have direct and indirect effects on the kidney, likely contributing to stated cardiovascular benefits. Here we review the literature on the direct effects of SGLT2 inhibitors in diabetic patients with heart failure (HF). We assume that the benefit in cardiac cells modulated by SGLT2i is due to the inhibition of sodium transporters affecting intracellular sodium homeostasis. In conclusion, the sodium transporters in cardiac cells provide, at least partly, an example of the clinical benefits of SGLT2i observed in HF patients.

Keywords: cardiac insufficiency; diabetes mellitus; gliflozins; heart failure; high blood glucose; insulin resistance; reduced ejection fraction; sglt2 inhibitors

DOI: https://doi.org/10.7759/cureus.34687