bims-hafaim 2024-05-19 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2024‒05‒19
seven papers selected by
Kyle McCommis, Saint Louis University

In the heart and beyond: Mitochondrial dysfunction in heart failure with preserved ejection fraction (HFpEF).
Sodium-glucose co-transporter 2 Inhibitors Act Independently of SGLT2 to Confer Benefit for Heart Failure with Reduced Ejection Fraction in Mice.
Effect of dapagliflozin in patients with diabetes and heart failure with mildly reduced or preserved ejection fraction according to background glucose-lowering therapy: A pre-specified analysis of the DELIVER trial.
Energy Metabolism: From Physiological Changes to Targets in Sepsis-induced Cardiomyopathy.
Sodium-glucose exchanger 2 inhibitor canagliflozin promotes mitochondrial metabolism and alleviates salt-induced cardiac hypertrophy via preserving SIRT3 expression.
MICU3 Regulates Mitochondrial Calcium and Cardiac Hypertrophy.
Comparison of the stage-dependent mitochondrial changes in response to pressure overload between the diseased right and left ventricle in the rat.

Curr Opin Pharmacol. 2024 May 16. pii: S1471-4892(24)00031-6. [Epub ahead of print]76 102461

In the heart and beyond: Mitochondrial dysfunction in heart failure with preserved ejection fraction (HFpEF).

Nisha Bhattarai, Iain Scott.

Heart failure with preserved ejection fraction (HFpEF) is a major cardiovascular disorder with increasing prevalence and a limited range of targeted treatment options. While HFpEF can be derived from several different etiologies, much of the current growth in the disease is being driven by metabolic dysfunction (e.g. obesity, diabetes, hypertension). Deleterious changes in mitochondrial energy metabolism are a common feature of HFpEF, and may help to drive the progression of the disease. In this brief article we aim to review various aspects of cardiac mitochondrial dysfunction in HFpEF, discuss the emerging topic of HFpEF-driven mitochondrial dysfunction in tissues beyond the heart, and examine whether supporting mitochondrial function may be a therapeutic approach to arrest or reverse disease development.

DOI: https://doi.org/10.1016/j.coph.2024.102461
bioRxiv. 2024 May 02. pii: 2024.04.29.591665. [Epub ahead of print]

Sodium-glucose co-transporter 2 Inhibitors Act Independently of SGLT2 to Confer Benefit for Heart Failure with Reduced Ejection Fraction in Mice.

Justin H Berger, Timothy R Matsuura, Caitlyn E Bowman, Renee Taing, Jiten Patel, Ling Lai, Teresa C Leone, Jeffrey D Reagan, Saptarsi M Haldar, Zoltan Arany, Daniel P Kelly.

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are novel, potent heart failure medications with an unknown mechanism of action. We sought to determine if the beneficial actions of SGLT2i in heart failure were on- or off-target, and related to metabolic reprogramming, including increased lipolysis and ketogenesis. The phenotype of mice treated with empagliflozin and genetically engineered mice constitutively lacking SGLT2 mirrored metabolic changes seen in human clinical trials (including reduced blood glucose, increased ketogenesis, and profound glucosuria). In a mouse heart failure model, SGLT2i treatment, but not generalized SGLT2 knockout, resulted in improved systolic function and reduced pathologic cardiac remodeling. SGLT2i treatment of the SGLT2 knockout mice sustained the cardiac benefits, demonstrating an off-target role for these drugs. This benefit is independent of metabolic changes, including ketosis. The mechanism of action and target of SGLT2i in HF remain elusive.

DOI: https://doi.org/10.1101/2024.04.29.591665
Eur J Heart Fail. 2024 May 15.

Effect of dapagliflozin in patients with diabetes and heart failure with mildly reduced or preserved ejection fraction according to background glucose-lowering therapy: A pre-specified analysis of the DELIVER trial.

Mats Christian Højbjerg Lassen, John W Ostrominski, Silvio E Inzucchi, Brian L Claggett, Ian Kulac, Pardeep Jhund, Rudolf A de Boer, Adrian F Hernandez, Mikhail N Kosiborod, Carolyn S P Lam, Felipe A Martinez, Sanjiv J Shah, Akshay S Desai, Magnus Petersson, Anna Maria Langkilde, Kieran F Docherty, John J V McMurray, Scott D Solomon, Muthiah Vaduganathan.

  AIMS: Type 2 diabetes (T2D) and heart failure (HF) frequently coexist, but whether clinical outcomes and treatment effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) vary in relation to background glucose-lowering therapy (GLT) in this population is uncertain.METHODS AND RESULTS: DELIVER randomized patients with HF and left ventricular ejection fraction (LVEF) >40% to dapagliflozin or placebo. The primary outcome was a composite of worsening HF (HF hospitalization or urgent HF visit) or cardiovascular death. In this pre-specified analysis of participants with T2D, treatment effects were assessed by number and class of background GLT(s). Of 3150 participants with T2D at baseline, 22.9% were on no GLT, 36.5% were treated with 1 GLT, and 40.6% with ≥2 GLTs. During follow-up (median: 2.3 years), treatment benefits of dapagliflozin (vs. placebo) on the primary outcome were consistent irrespective of the number of background GLTs (0 GLTs: hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.50-1.00; 1 GLT: HR 1.04, 95% CI 0.80-1.34; ≥2 GLTs: HR 0.71, 95% CI 0.56-0.90; pinteraction = 0.59). Similar findings were observed among participants with (HR 0.73, 95% CI 0.59-0.92) and without background metformin use (HR 0.89, 95% CI 0.72-1.11; pinteraction = 0.22) and in participants with (HR 0.89, 95% CI 0.69-1.16) and without background insulin use (HR 0.78, 95% CI 0.65-0.95; pinteraction = 0.45). Dapagliflozin was well-tolerated irrespective of the number of background GLTs.
CONCLUSIONS: Dapagliflozin safely and consistently improved clinical outcomes among individuals with T2D and HF with LVEF >40% irrespective of the number and class of background GLTs, and the benefits were not influenced by concomitant metformin or insulin use. These data bolster contemporary guidelines supporting first-line SGLT2i among individuals with T2D and HF, irrespective of background GLT.

Keywords:  Dapagliflozin; Diabetes; Heart failure; Medical therapy

DOI:  https://doi.org/10.1002/ejhf.3269
Hellenic J Cardiol. 2024 May 09. pii: S1109-9666(24)00114-3. [Epub ahead of print]

Energy Metabolism: From Physiological Changes to Targets in Sepsis-induced Cardiomyopathy.

Dan Ni, Xiaofang Lin, Chuanhuang Deng, Ludong Yuan, Jing Li, Yuxuan Liu, Pengfei Liang, Bimei Jiang.

  Sepsis is a systemic inflammatory response syndrome caused by a variety of dysregulated responses to host infection with life-threatening multi-organ dysfunction. Among the injuries or dysfunctions involved in the course of sepsis, cardiac injury and dysfunction often occur and are associated with the pathogenesis of hemodynamic disturbances, also defined as sepsis-induced cardiomyopathy (SIC). The process of myocardial metabolism is tightly regulated and adapts to various cardiac output demands. The heart is a metabolically flexible organ capable of utilizing all classes of energy substrates, including carbohydrates, lipids, amino acids, and ketone bodies to produce ATP. The demand of cardiac cells for energy metabolism changes substantially in septic cardiomyopathy with distinct etiological causes and different times. This review describes changes in cardiomyocyte energy metabolism under normal physiological conditions and some features of myocardial energy metabolism in septic cardiomyopathy, and briefly outlines the role of the mitochondria as a center of energy metabolism in the septic myocardium, revealing that changes in energy metabolism can serve as a potential future therapy for infectious cardiomyopathy.

Keywords:  Mitochondria; Myocardial metabolism; Sepsis-induced cardiomyopathy

DOI:  https://doi.org/10.1016/j.hjc.2024.05.010
J Adv Res. 2024 May 12. pii: S2090-1232(24)00173-5. [Epub ahead of print]

Sodium-glucose exchanger 2 inhibitor canagliflozin promotes mitochondrial metabolism and alleviates salt-induced cardiac hypertrophy via preserving SIRT3 expression.

Yu Zhao, Zongshi Lu, Hexuan Zhang, Lijuan Wang, Fang Sun, Qiang Li, Tingbing Cao, Bowen Wang, Huan Ma, Mei You, Qing Zhou, Xiao Wei, Li Li, Yingying Liao, Zhencheng Yan, Daoyan Liu, Peng Gao, Zhiming Zhu.

  INTRODUCTION: Excess salt intake is not only an independent risk factor for heart failure, but also one of the most important dietary factors associated with cardiovascular disease worldwide. Metabolic reprogramming in cardiomyocytes is an early event provoking cardiac hypertrophy that leads to subsequent cardiovascular events upon high salt loading. Although SGLT2 inhibitors, such as canagliflozin, displayed impressive cardiovascular health benefits, whether SGLT2 inhibitors protect against cardiac hypertrophy-related metabolic reprogramming upon salt loading remain elusive.OBJECTIVES: To investigate whether canagliflozin can improve salt-induced cardiac hypertrophy and the underlying mechanisms.
METHODS: Dahl salt-sensitive rats developed cardiac hypertrophy by feeding them an 8% high-salt diet, and some rats were treated with canagliflozin. Cardiac function and structure as well as mitochondrial function were examined. Cardiac proteomics, targeted metabolomics and SIRT3 cardiac-specific knockout mice were used to uncover the underlying mechanisms.
RESULTS: In Dahl salt-sensitive rats, canagliflozin showed a potent therapeutic effect on salt-induced cardiac hypertrophy, accompanied by lowered glucose uptake, reduced accumulation of glycolytic end-products and improved cardiac mitochondrial function, which was associated with the recovery of cardiac expression of SIRT3, a key mitochondrial metabolic regulator. Cardiac-specific knockout of SIRT3 not only exacerbated salt-induced cardiac hypertrophy but also abolished the therapeutic effect of canagliflozin. Mechanistically, high salt intake repressed cardiac SIRT3 expression through a calcium-dependent epigenetic modifications, which could be blocked by canagliflozin by inhibiting SGLT1-mediated calcium uptake. SIRT3 improved myocardial metabolic reprogramming by deacetylating MPC1 in cardiomyocytes exposed to pro-hypertrophic stimuli. Similar to canagliflozin, the SIRT3 activator honokiol also exerted therapeutic effects on cardiac hypertrophy.
CONCLUSION: Cardiac mitochondrial dysfunction caused by SIRT3 repression is a critical promotional determinant of metabolic pattern switching underlying salt-induced cardiac hypertrophy. Improving SIRT3-mediated mitochondrial function by SGLT2 inhibitors-mediated calcium handling would represent a therapeutic strategy against salt-related cardiovascular events.

Keywords:  Cardiac hypertrophy; High salt intake; Metabolic reprogramming; SIRT3; Sodium-glucose exchanger 2 inhibitors

DOI:  https://doi.org/10.1016/j.jare.2024.04.030
Circ Res. 2024 May 15.

MICU3 Regulates Mitochondrial Calcium and Cardiac Hypertrophy.

Barbara Roman, Yusuf Mastoor, Junhui Sun, Hector Chapoy Villanueva, Gabriela Hinojosa, Danielle Springer, Julia C Liu, Elizabeth Murphy.

  BACKGROUND: Calcium (Ca2+) uptake by mitochondria occurs via the mitochondrial Ca2+ uniporter. Mitochondrial Ca2+ uniporter exists as a complex, regulated by 3 MICU (mitochondrial Ca2+ uptake) proteins localized in the intermembrane space: MICU1, MICU2, and MICU3. Although MICU3 is present in the heart, its role is largely unknown.METHODS: We used CRISPR-Cas9 to generate a mouse with global deletion of MICU3 and an adeno-associated virus (AAV9) to overexpress MICU3 in wild-type mice. We examined the role of MICU3 in regulating mitochondrial calcium ([Ca2+]m) in ex vivo hearts using an optical method following adrenergic stimulation in perfused hearts loaded with a Ca2+-sensitive fluorophore. Additionally, we studied how deletion and overexpression of MICU3, respectively, impact cardiac function in vivo by echocardiography and the molecular composition of the mitochondrial Ca2+ uniporter complex via Western blot, immunoprecipitation, and Blue native-PAGE analysis. Finally, we measured MICU3 expression in failing human hearts.
RESULTS: Knock out MICU3 hearts and cardiomyocytes exhibited a significantly smaller increase in [Ca2+]m than wild-type hearts following acute isoproterenol infusion. In contrast, overexpression of MICU3 hearts exhibited an enhanced increase in [Ca2+]m compared with control hearts. Echocardiography analysis showed no significant difference in cardiac function in knock out MICU3 mice relative to wild-type mice at baseline. However, overexpression of MICU3 animals exhibited significantly reduced ejection fraction and fractional shortening compared with control mice. We observed a significant increase in the ratio of heart weight to tibia length in overexpression of MICU3 hearts compared with controls, consistent with hypertrophy. We also found a significant decrease in MICU3 protein and expression in failing human hearts.
CONCLUSIONS: Our results indicate that increased and decreased expression of MICU3 enhances and reduces, respectively, the uptake of [Ca2+]m in the heart. We conclude that MICU3 plays an important role in regulating [Ca2+]m physiologically, and overexpression of MICU3 is sufficient to induce cardiac hypertrophy, making MICU3 a possible therapeutic target.

Keywords:  calcium; cardiomegaly; echocardiography; mitochondria; myocytes, cardiac

DOI:  https://doi.org/10.1161/CIRCRESAHA.123.324026
Basic Res Cardiol. 2024 May 17.

Comparison of the stage-dependent mitochondrial changes in response to pressure overload between the diseased right and left ventricle in the rat.

Ling Li, Bernd Niemann, Fabienne Knapp, Sebastian Werner, Christian Mühlfeld, Jan Philipp Schneider, Liane M Jurida, Nicole Molenda, M Lienhard Schmitz, Xiaoke Yin, Manuel Mayr, Rainer Schulz, Michael Kracht, Susanne Rohrbach.

  The right ventricle (RV) differs developmentally, anatomically and functionally from the left ventricle (LV). Therefore, characteristics of LV adaptation to chronic pressure overload cannot easily be extrapolated to the RV. Mitochondrial abnormalities are considered a crucial contributor in heart failure (HF), but have never been compared directly between RV and LV tissues and cardiomyocytes. To identify ventricle-specific mitochondrial molecular and functional signatures, we established rat models with two slowly developing disease stages (compensated and decompensated) in response to pulmonary artery banding (PAB) or ascending aortic banding (AOB). Genome-wide transcriptomic and proteomic analyses were used to identify differentially expressed mitochondrial genes and proteins and were accompanied by a detailed characterization of mitochondrial function and morphology. Two clearly distinguishable disease stages, which culminated in a comparable systolic impairment of the respective ventricle, were observed. Mitochondrial respiration was similarly impaired at the decompensated stage, while respiratory chain activity or mitochondrial biogenesis were more severely deteriorated in the failing LV. Bioinformatics analyses of the RNA-seq. and proteomic data sets identified specifically deregulated mitochondrial components and pathways. Although the top regulated mitochondrial genes and proteins differed between the RV and LV, the overall changes in tissue and cardiomyocyte gene expression were highly similar. In conclusion, mitochondrial dysfuntion contributes to disease progression in right and left heart failure. Ventricle-specific differences in mitochondrial gene and protein expression are mostly related to the extent of observed changes, suggesting that despite developmental, anatomical and functional differences mitochondrial adaptations to chronic pressure overload are comparable in both ventricles.

Keywords:  Heart failure; Hypertrophy; LV; Mitochondria; RV

DOI:  https://doi.org/10.1007/s00395-024-01051-3