bims-hafaim 2024-06-23 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2024‒06‒23
eight papers selected by
Kyle McCommis, Saint Louis University

Loss of mitochondrial pyruvate transport initiates cardiac glycogen accumulation and heart failure.
Effects of Diet-induced Metabolic Syndrome on Cardiac Function and Angiogenesis in Response to Sodium-glucose Cotransporter-2 Inhibitor Canagliflozin.
Cardiac Metabolism.
Extrarenal benefits of SGLT2 inhibitors in the treatment of cardiomyopathy.
Two-hit mouse model of heart failure with preserved ejection fraction combining diet-induced obesity and renin-mediated hypertension.
A Mitochondrial Basis for Heart Failure Progression.
The Impact of the Withdrawal of SGLT2 Inhibitors on Clinical Outcomes in Patients with Heart Failure.
Mechanisms of heart failure and chronic kidney disease protection by SGLT2 inhibitors in nondiabetic conditions.

bioRxiv. 2024 Jun 09. pii: 2024.06.06.597841. [Epub ahead of print]

Loss of mitochondrial pyruvate transport initiates cardiac glycogen accumulation and heart failure.

Rachel C Weiss, Kelly D Pyles, Kevin Cho, Michelle Brennan, Jonathan S Fisher, Gary J Patti, Kyle S McCommis.

Background: Heart failure involves metabolic alterations including increased glycolysis despite unchanged or decreased glucose oxidation. The mitochondrial pyruvate carrier (MPC) regulates pyruvate entry into the mitochondrial matrix, and cardiac deletion of the MPC in mice causes heart failure. How MPC deletion results in heart failure is unknown.Methods: We performed targeted metabolomics and isotope tracing in wildtype (fl/fl) and cardiac-specific Mpc2-/- (CS-Mpc2-/-) hearts after in vivo injection of U- 13 C-glucose. Cardiac glycogen was assessed biochemically and by transmission electron microscopy. Cardiac uptake of 2-deoxyglucose was measured and western blotting performed to analyze insulin signaling and enzymatic regulators of glycogen synthesis and degradation. Isotope tracing and glycogen analysis was also performed in hearts from mice fed either low-fat diet or a ketogenic diet previously shown to reverse the CS-Mpc2-/- heart failure. Cardiac glycogen was also assessed in mice infused with angiotensin-II that were fed low-fat or ketogenic diet.
Results: Failing CS-Mpc2-/- hearts contained normal levels of ATP and phosphocreatine, yet these hearts displayed increased enrichment from U- 13 C-glucose and increased glycolytic metabolite pool sizes. 13 C enrichment and pool size was also increased for the glycogen intermediate UDP-glucose, as well as increased enrichment of the glycogen pool. Glycogen levels were increased ∼6-fold in the failing CS-Mpc2-/- hearts, and glycogen granules were easily detected by electron microscopy. This increased glycogen synthesis occurred despite enhanced inhibitory phosphorylation of glycogen synthase and reduced expression of glycogenin-1. In young, non-failing CS-Mpc2-/- hearts, increased glycolytic 13 C enrichment occurred, but glycogen levels remained low and unchanged compared to fl/fl hearts. Feeding a ketogenic diet to CS-Mpc2-/- mice reversed the heart failure and normalized the cardiac glycogen and glycolytic metabolite accumulation. Cardiac glycogen levels were also elevated in mice infused with angiotensin-II, and both the cardiac hypertrophy and glycogen levels were improved by ketogenic diet.
Conclusions: Our results indicate that loss of MPC in the heart causes glycogen accumulation and heart failure, while a ketogenic diet can reverse both the glycogen accumulation and heart failure. We conclude that maintaining mitochondrial pyruvate import and metabolism is critical for the heart, unless cardiac pyruvate metabolism is reduced by consumption of a ketogenic diet.

DOI: https://doi.org/10.1101/2024.06.06.597841
J Thorac Cardiovasc Surg. 2024 Jun 13. pii: S0022-5223(24)00524-5. [Epub ahead of print]

Effects of Diet-induced Metabolic Syndrome on Cardiac Function and Angiogenesis in Response to Sodium-glucose Cotransporter-2 Inhibitor Canagliflozin.

Dwight D Harris, Mark Broadwin, Sharif A Sabe, Chris Stone, Meghamsh Kanuparthy, Ju-Woo Nho, Krishna Bellam, Debolina Banerjee, M Ruhul Abid, Frank W Sellke.

  INTRODUCTION: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are antidiabetic medications that have been shown to decrease cardiovascular events and heart failure-related mortality in clinical studies. We attempt to examine the complex interplay between metabolic syndrome (MS) and the SGLT-2 inhibitor canagliflozin (CAN) in a clinically relevant model of chronic myocardial ischemia (CMI).METHODS: Twenty-one Yorkshire swine were fed a high-fat diet starting at six weeks of age to induce MS. At 11 weeks, all underwent placement of an ameroid constrictor around the left circumflex coronary artery to induce CMI. After two weeks, swine received either control (CON, n=11) or CAN 300 mg PO daily (n=10) for 5 weeks, whereupon all underwent terminal harvest.
RESULTS: There was a significant increase in cardiac output and heart rate with a decrease in pulse pressure in the CAN group compared to CON (all p<0.05). The CAN group had a significant increase in capillary density (p=0.02). Interestingly, there was no change in myocardial perfusion or arteriolar density. CAN induced a significant increase in markers of angiogenesis, including p-eNOS, eNOS, VEGFR1, HSP70, and ERK (all p<0.05), plausibly resulting in capillary angiogenesis.
CONCLUSIONS: CAN treatment leads to a significant increase in capillary density and augmented cardiac function in a swine model of CMI in the setting of MS. This work further elucidates the mechanism of SGLT-2 inhibitors in patients with cardiac disease; however, more studies are needed to determine if this increase in capillary density plays a role in the improvements seen in clinical studies.

Keywords:  Ameroid Constrictor; Angiogenesis; Canagliflozin; Chronic Myocardial Ischemia; Metabolic Syndrome; Sodium-glucose Cotransporter-2 Inhibitor

DOI:  https://doi.org/10.1016/j.jtcvs.2024.06.004
Adv Exp Med Biol. 2024 ;1441 365-396

Cardiac Metabolism.

Silvia Martin-Puig, Ivan Menendez-Montes.

  The heart is composed of a heterogeneous mixture of cellular components perfectly intermingled and able to integrate common environmental signals to ensure proper cardiac function and performance. Metabolism defines a cell context-dependent signature that plays a critical role in survival, proliferation, or differentiation, being a recognized master piece of organ biology, modulating homeostasis, disease progression, and adaptation to tissue damage. The heart is a highly demanding organ, and adult cardiomyocytes require large amount of energy to fulfill adequate contractility. However, functioning under oxidative mitochondrial metabolism is accompanied with a concomitant elevation of harmful reactive oxygen species that indeed contributes to the progression of several cardiovascular pathologies and hampers the regenerative capacity of the mammalian heart. Cardiac metabolism is dynamic along embryonic development and substantially changes as cardiomyocytes mature and differentiate within the first days after birth. During early stages of cardiogenesis, anaerobic glycolysis is the main energetic program, while a progressive switch toward oxidative phosphorylation is a hallmark of myocardium differentiation. In response to cardiac injury, different signaling pathways participate in a metabolic rewiring to reactivate embryonic bioenergetic programs or the utilization of alternative substrates, reflecting the flexibility of heart metabolism and its central role in organ adaptation to external factors. Despite the well-established metabolic pattern of fetal, neonatal, and adult cardiomyocytes, our knowledge about the bioenergetics of other cardiac populations like endothelial cells, cardiac fibroblasts, or immune cells is limited. Considering the close intercellular communication and the influence of nonautonomous cues during heart development and after cardiac damage, it will be fundamental to better understand the metabolic programs in different cardiac cells in order to develop novel interventional opportunities based on metabolic rewiring to prevent heart failure and improve the limited regenerative capacity of the mammalian heart.

Keywords:  Cardiac development; Cardiac metabolism; Cardiac regeneration; Fatty acid oxidation; Glycolysis; Hypoxia; Oxidative stress; Pentose phosphate pathway

DOI:  https://doi.org/10.1007/978-3-031-44087-8_19
Physiology (Bethesda). 2024 Jun 18.

Extrarenal benefits of SGLT2 inhibitors in the treatment of cardiomyopathy.

Veera Ganesh Yerra, Kim A Connelly.

  Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as pivotal medications for heart failure, demonstrating remarkable cardiovascular benefits extending beyond their glucose-lowering effects. The unexpected cardiovascular advantages have intrigued and prompted the scientific community to delve into the mechanistic underpinnings of these novel actions. Pre-clinical studies have generated many mechanistic theories, ranging from their renal and extra-renal effects to potential direct actions on cardiac muscle cells, to elucidate the mechanisms linking these drugs to clinical cardiovascular outcomes. Despite the strengths and limitations of each theory, many await validation in human studies. Furthermore, whether SGLT2 inhibitors confer therapeutic benefits in specific subsets of cardiomyopathies akin to their efficacy in other heart failure populations remains unclear. By examining the shared pathological features between heart failure resulting from vascular diseases and other causes of cardiomyopathy, certain specific molecular actions of SGLT2 inhibitors (particularly those targeting cardiomyocytes) would support the concept that these medications will yield therapeutic benefits across a broad range of cardiomyopathies. This article aims to discuss important mechanisms of SGLT2 inhibitors and their implications in hypertrophic and dilated cardiomyopathies. Furthermore, we offer insights into future research directions for SGLT2 inhibitor studies, which hold the potential to further elucidate the proposed biological mechanisms in greater detail.

Keywords:  Dilated cardiomyopathy; Heart failure; Hypertrophic cardiomyopathy; Sodium glucose co-transporter 2

DOI:  https://doi.org/10.1152/physiol.00008.2024
bioRxiv. 2024 Jun 09. pii: 2024.06.06.597821. [Epub ahead of print]

Two-hit mouse model of heart failure with preserved ejection fraction combining diet-induced obesity and renin-mediated hypertension.

Justin H Berger, Yuji Shi, Timothy R Matsuura, Kirill Batmanov, Xian Chen, Kelly Tam, Mackenzie Marshall, Richard Kue, Jiten Patel, Renee Taing, Russell Callaway, Joanna Griffin, Attila Kovacs, Dinesh Hirenallur Shanthappa, Russell Miller, Bei B Zhang, Rachel J Roth Flach, Daniel P Kelly.

Heart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis is poorly understood. The ability to assess genetic and pharmacologic interventions is hampered by the lack of robust preclinical mouse models of HFpEF. We have developed a novel "2-hit" model, which combines obesity and insulin resistance with chronic pressure overload to recapitulate clinical features of HFpEF. C57BL6/NJ mice fed a high fat diet for >10 weeks were administered an AAV8-driven vector resulting in constitutive overexpression of mouse Renin1d . Control mice, HFD only, Renin only and HFD-Renin (aka "HFpEF") littermates underwent a battery of cardiac and extracardiac phenotyping. HFD-Renin mice demonstrated obesity and insulin resistance, a 2-3-fold increase in circulating renin levels that resulted in 30-40% increase in left ventricular hypertrophy, preserved systolic function, and diastolic dysfunction indicated by altered E/e', IVRT, and strain measurements; increased left atrial mass; elevated natriuretic peptides; and exercise intolerance. Transcriptomic and metabolomic profiling of HFD-Renin myocardium demonstrated upregulation of pro-fibrotic pathways and downregulation of metabolic pathways, in particular branched chain amino acid catabolism, similar to findings in human HFpEF. Treatment of these mice with the sodium-glucose cotransporter 2 inhibitor empagliflozin, an effective but incompletely understood HFpEF therapy, improved exercise tolerance, left heart enlargement, and insulin homeostasis. The HFD-Renin mouse model recapitulates key features of human HFpEF and will enable studies dissecting the contribution of individual pathogenic drivers to this complex syndrome. Addition of HFD-Renin mice to the preclinical HFpEF model platform allows for orthogonal studies to increase validity in assessment of interventions.NEW & NOTEWORTHY: Heart failure with preserved ejection fraction (HFpEF) is a complex disease to study due to limited preclinical models. We rigorously characterize a new two-hit HFpEF mouse model, which allows for dissecting individual contributions and synergy of major pathogenic drivers, hypertension and diet-induced obesity. The results are consistent and reproducible in two independent laboratories. This high-fidelity pre-clinical model increases the available, orthogonal models needed to improve our understanding of the causes and assessment treatments for HFpEF.

DOI: https://doi.org/10.1101/2024.06.06.597821
Cardiovasc Drugs Ther. 2024 Jun 15.

A Mitochondrial Basis for Heart Failure Progression.

William D Watson, Per M Arvidsson, Jack J J Miller, Andrew J Lewis, Oliver J Rider.

  In health, the human heart is able to match ATP supply and demand perfectly. It requires 6 kg of ATP per day to satisfy demands of external work (mechanical force generation) and internal work (ion movements and basal metabolism). The heart is able to link supply with demand via direct responses to ADP and AMP concentrations but calcium concentrations within myocytes play a key role, signalling both inotropy, chronotropy and matched increases in ATP production. Calcium/calmodulin-dependent protein kinase (CaMKII) is a key adapter to increased workload, facilitating a greater and more rapid calcium concentration change. In the failing heart, this is dysfunctional and ATP supply is impaired. This review aims to examine the mechanisms and pathologies that link increased energy demand to this disrupted situation. We examine the roles of calcium loading, oxidative stress, mitochondrial structural abnormalities and damage-associated molecular patterns.

Keywords:  ATP; Calcium; Heart failure; Mitochondria; Redox

DOI:  https://doi.org/10.1007/s10557-024-07582-0
J Clin Med. 2024 May 29. pii: 3196. [Epub ahead of print]13(11):

The Impact of the Withdrawal of SGLT2 Inhibitors on Clinical Outcomes in Patients with Heart Failure.

Masaki Nakagaito, Teruhiko Imamura, Ryuichi Ushijima, Makiko Nakamura, Koichiro Kinugawa.

  Background: The clinical impact of the withdrawal of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on all-cause readmission in patients with heart failure remains unknown. Methods: We enrolled a total of 212 consecutive patients who were hospitalized for heart failure and received SGLT2i during their index hospitalization between February 2016 and July 2022. Of these patients, 51 terminated SGLT2i during or after their index hospitalization. We evaluated the prognostic impact of the withdrawal of SGLT2i on the primary outcome, which was defined as the all-cause readmission rate/times. Results: Over a median of 23.2 months, all-cause readmission occurred in 38 out of 51 patients (74.5%) withdrawn from SGLT2i and 93 out of 161 patients (57.8%) with continuation of SGLT2i (p = 0.099). The incidence of all-cause readmissions per year was 0.97 [0-1.50] in patients withdrawn from SGLT2i and 0.50 [0-1.03] in patients with continuation of SGLT2i (p = 0.030). There was no significant difference in total medical costs (62,906 [502-187,246] versus 29,236 [7920-180,305] JPY per month, p = 0.866) between both patient groups. Conclusions: Termination of SGLT2i may be associated with incremental all-cause readmission and no benefit in reducing total medical costs.

Keywords:  SGLT2 inhibitor; heart failure; hospitalization; medical cost

DOI:  https://doi.org/10.3390/jcm13113196
Am J Physiol Cell Physiol. 2024 Jun 17.

Mechanisms of heart failure and chronic kidney disease protection by SGLT2 inhibitors in nondiabetic conditions.

Adriana C C Girardi, Juliano Z Polidoro, Paulo C Castro, Andrea Pio de Abreu, Irene L Noronha, Luciano F Drager.

  Sodium-glucose cotransporter 2 inhibitors (SGLT2i), initially developed for type 2 diabetes (T2D) treatment, have demonstrated significant cardiovascular and renal benefits in heart failure (HF) and chronic kidney disease (CKD), irrespective of T2D. This review provides an analysis of the multifaceted mechanisms underlying the cardiorenal benefits of SGLT2i in HF and CKD outside of the T2D context. Eight major aspects of the protective effects of SGLT2i beyond glycemic control are explored: (i) the impact on renal hemodynamics and tubuloglomerular feedback; (ii) the natriuretic effects via proximal tubule Na+/H+ exchanger NHE3 inhibition; (iii) the modulation of neurohumoral pathways with evidence of attenuated sympathetic activity; (iv) the impact on erythropoiesis, not only in the context of local hypoxia, but also systemic inflammation and iron regulation; (v) the uricosuria and mitigation of the hyperuricemic environment in cardiorenal syndromes; (vi) the multiorgan metabolic reprogramming including the potential induction of a fasting-like state, improvement in glucose and insulin tolerance and stimulation of lipolysis and ketogenesis; (vii) the vascular endothelial growth factor A (VEGF-A) upregulation and angiogenesis, and (viii) the direct cardiac effects. The intricate interplay between renal, neurohumoral, metabolic, and cardiac effects underscore the complexity of SGLT2i actions and provides valuable insights into their therapeutic implications for HF and CKD. Furthermore, this review sets the stage for future research to evaluate the individual contributions of these mechanisms in diverse clinical settings.

Keywords:  SGLT2; chronic kidney disease; gliflozins; heart failure; proximal tubule

DOI:  https://doi.org/10.1152/ajpcell.00143.2024