bims-hafaim 2021-12-19 papers

Issue of 2021–12–19
five papers selected by
Kyle McCommis, Saint Louis University

Cardiovasc Diabetol. 2021 Dec 16. 20(1): 236

SGLT-2 inhibitors and cardiorenal outcomes in patients with or without type 2 diabetes: a meta-analysis of 11 CVOTs.

Dario Giugliano, Miriam Longo, Lorenzo Scappaticcio, Giuseppe Bellastella, Maria Ida Maiorino, Katherine Esposito.

BACKGROUND: It has been suggested that sodium-glucose cotransporter 2 (SGLT-2) inhibitors reduce the cardiorenal risk in patients with type 2 diabetes (T2D). The purpose of this study is to provide an update of all large cardiovascular outcome trials (CVOTs) with SGLT-2 inhibitors to assess their cardiorenal efficacy in patients with and without T2D.
METHODS: An electronic search up to 30 September 2021 was conducted in PubMed, EMBASE, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov. to determine eligible trials. We included CVOTs comparing any SGLT-2 inhibitor with placebo, reporting desired cardiovascular or renal outcomes and with a follow-up duration of at least 6 months.
RESULTS: Eleven CVOTs, with data from five SGLT-2 inhibitors (empagliflozin, canagliflozin, dapagliflozin, ertugliflozin and sotagliflozin) and 77,541 participants, were included. In the overall analysis, the risk of the composite CV mortality or hospitalization for heart failure (HF) was reduced by 23% (HR = 0.77, 95% CI 0.73-0.82, P < 0.001) compared with placebo, with not significant heterogeneity (I2 = 26%, P = 0.20), and irrespective of the presence of T2D (P for interaction = 0.81) and age (> 65 vs ≤ 65 years, P for interaction = 0.78). The risk of CV mortality, total mortality and hospitalization for HF was significantly reduced by 16%, 13%, and 32%, respectively; similarly, the risk of the composite renal outcome was reduced by 35% (HR = 0.65, 95% CI 0.56-0.75), with moderate heterogeneity (I2 = 32%). In the analysis of 6 CVOTs reporting the data, the risk of major cardiovascular events (MACE) was reduced by 12%, with low heterogeneity (I2 = 21.2%, P = 0.19) and irrespective of the presence of established CV disease at baseline (P for interaction = 0.46).
CONCLUSIONS: Therapy with SGLT-2 inhibitors in patients with cardiometabolic and renal diseases results in a sustained to moderate reduction of the composite CV death or hospitalization for HF, robust reduction of HF and renal outcomes, moderate reduction of CV mortality, total mortality and MACE.

Keywords: Cardiorenal outcomes; Cardiovascular outcome trials; SGLT-2 inhibitors; Type 2 diabetes

DOI: https://doi.org/10.1186/s12933-021-01430-3

Am J Physiol Heart Circ Physiol. 2021 Dec 17.

An assessment of thermoneutral housing conditions on murine cardiometabolic function.

Xian Chen, Eliza Bollinger, Teresa Cunio, Federico Damilano, John C Stansfield, Cynthia A Pinkus, Steven Kreuser, Dinesh K Hirenallur-Shanthappa, Rachel J Roth Flach.

Mouse models are used to model human diseases and perform pharmacological efficacy testing to advance therapies to humans; most of these studies are conducted in room temperature conditions. At room temperature (22°C), mice are cold stressed and must utilize brown adipose tissue (BAT) to maintain body temperature. This cold stress increases catecholamine tone to maintain adipocyte lipid release via lipolysis, which will fuel adaptive thermogenesis. Maintaining rodents at thermoneutral temperatures (28°C) ameliorates the need for adaptive thermogenesis, thus reducing catecholamine tone and BAT activity. Cardiovascular tone is also determined by catecholamine levels in rodents, as beta adrenergic stimuli are primary drivers of not only lipolytic, but also ionotropic and chronotropic responses. As mice have increased catecholamine tone at room temperature, we investigated how thermoneutral housing conditions would impact cardiometabolic function. Here, we show a rapid and reversible effect of thermoneutrality on both heart rate and blood pressure in chow fed animals, which was blunted in animals fed high fat diet. Animals subjected to transverse aortic constriction displayed compensated hypertrophy at room temperature, while animals displayed less hypertrophy and trends towards worse systolic function at thermoneutrality. Despite these dramatic changes in blood pressure and heart rate at thermoneutral housing conditions, enalapril effectively improved cardiac hypertrophy and gene expression alterations. There were surprisingly few differences in cardiac parameters in high fat fed animals at thermoneutrality. Overall, these data suggest that thermoneutral housing may alter some aspects of cardiac remodeling in preclinical mouse models of heart failure.

Keywords: Cardiometabolism; Heart failure; Thermoneutrality

DOI: https://doi.org/10.1152/ajpheart.00461.2021

Front Pharmacol. 2021 ;12 771940

Enhancing Fatty Acids Oxidation via L-Carnitine Attenuates Obesity-Related Atrial Fibrillation and Structural Remodeling by Activating AMPK Signaling and Alleviating Cardiac Lipotoxicity.

Yudi Zhang, Yuping Fu, Tiannan Jiang, Binghua Liu, Hongke Sun, Ying Zhang, Boyuan Fan, Xiaoli Li, Xinghua Qin, Qiangsun Zheng.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical setting. Its pathogenesis was associated with metabolic disorder, especially defective fatty acids oxidation (FAO). However, whether promoting FAO could prevent AF occurrence and development remains elusive. In this study, we established a mouse model of obesity-related AF through high-fat diet (HFD) feeding, and used l-carnitine (LCA, 150 mg/kg⋅BW/d), an endogenous cofactor of carnitine palmitoyl-transferase-1B (CPT1B; the rate-limiting enzyme of FAO) to investigate whether FAO promotion can attenuate the AF susceptibility in obesity. All mice underwent electrophysiological assessment for atrial vulnerability, and echocardiography, histology and molecular evaluation for AF substrates and underlying mechanisms, which were further validated by pharmacological experiments in vitro. HFD-induced obese mice increased AF vulnerability and exhibited apparent atrial structural remodeling, including left atrial dilation, cardiomyocyte hypertrophy, connexin-43 remodeling and fibrosis. Pathologically, HFD apparently leads to defective cardiac FAO and subsequent lipotoxicity, thereby evoking a set of pathological reactions including oxidative stress, DNA damage, inflammation, and insulin resistance. Enhancing FAO via LCA attenuated lipotoxicity and lipotoxicity-induced pathological changes in the atria of obese mice, resulting in restored structural remodeling and ameliorated AF susceptibility. Mechanistically, LCA activated AMPK/PGC1α signaling both in vivo and in vitro, and pharmacological inhibition of AMPK via Compound C attenuated LCA-induced cardio-protection in palmitate-treated primary atrial cardiomyocytes. Taken together, our results demonstrated that FAO promotion via LCA attenuated obesity-mediated AF and structural remodeling by activating AMPK signaling and alleviating atrial lipotoxicity. Thus, enhancing FAO may be a potential therapeutic target for AF.

Keywords: AMPK (5′-AMP activated kinase); atrial fibrillation; fatty acids oxidation; l-carnitine; lipotoxicity; obesity

DOI: https://doi.org/10.3389/fphar.2021.771940

Cell Signal. 2021 Dec 10. pii: S0898-6568(21)00302-8. [Epub ahead of print] 110213

Protein phosphatase 2A in the healthy and failing heart: New insights and therapeutic opportunities.

Nicola M Sergienko, Daniel G Donner, Lea M D Delbridge, Julie R McMullen, Kate L Weeks.

Protein phosphatases have emerged as critical regulators of phosphoprotein homeostasis in settings of health and disease. Protein phosphatase 2A (PP2A) encompasses a large subfamily of enzymes that remove phosphate groups from serine/threonine residues within phosphoproteins. The heterogeneity in PP2A structure, which arises from the grouping of different catalytic, scaffolding and regulatory subunit isoforms, creates distinct populations of catalytically active enzymes (i.e. holoenzymes) that localise to different parts of the cell. This structural complexity, combined with other regulatory mechanisms, such as interaction of PP2A heterotrimers with accessory proteins and post-translational modification of the catalytic and/or regulatory subunits, enables PP2A holoenzymes to target phosphoprotein substrates in a highly specific manner. In this review, we summarise the roles of PP2A in cardiac physiology and disease. PP2A modulates numerous processes that are vital for heart function including calcium handling, contractility, β-adrenergic signalling, metabolism and transcription. Dysregulation of PP2A has been observed in human cardiac disease settings, including heart failure and atrial fibrillation. Efforts are underway, particularly in the cancer field, to develop therapeutics targeting PP2A activity. The development of small molecule activators of PP2A (SMAPs) and other compounds that selectively target specific PP2A holoenzymes (e.g. PP2A/B56α and PP2A/B56ε) will improve understanding of the function of different PP2A species in the heart, and may lead to the development of therapeutics for normalising aberrant protein phosphorylation in settings of cardiac remodelling and dysfunction.

Keywords: Heart failure; Kinases; PP2A; Protein phosphatase 2A; Therapies

DOI: https://doi.org/10.1016/j.cellsig.2021.110213

Curr Opin Lipidol. 2021 Dec 13.

Very long-chain saturated fatty acids and diabetes and cardiovascular disease.

Rozenn N Lemaitre, Irena B King.

PURPOSE OF REVIEW: In contrast to other saturated fatty acids, very long-chain saturated fatty acids (VLSFAs) have received limited attention The purpose of this review is to summarize the associations of VLSFAs, including arachidic acid, behenic acid, and lignoceric acid, with cardiovascular disease outcomes and type 2 diabetes; to discuss the findings implications; and to call for future studies of the VLSFAs.
RECENT FINDINGS: Increased levels of circulating VLSFAs have been found associated with lower risks of incident heart failure, atrial fibrillation, coronary heart disease, mortality, sudden cardiac arrest, type 2 diabetes, and with better aging. The VLSFA associations are paralleled by associations of plasma ceramide and sphingomyelin species carrying a VLSFA with lower risks of heart failure, atrial fibrillation, and mortality, suggesting VLSFAs affect the biological activity of ceramides and sphingomyelins thereby impacting health. For diabetes, there is no such parallel and the associations of VLSFAs with diabetes may be confounded or mediated by triglyceride and circulating palmitic acid, possible biomarkers of de novo lipogenesis.
SUMMARY: In many ways, the epidemiology has preceded our knowledge of VLSFAs biology. We hope this review will spur interest from the research community in further studying these potentially beneficial fatty acids.

DOI: https://doi.org/10.1097/MOL.0000000000000806