bims-hafaim 2022-06-12 papers

Issue of 2022–06–12
five papers selected by
Kyle McCommis, Saint Louis University

Front Cardiovasc Med. 2022 ;9 879209

Changes in the Left Ventricular Eicosanoid Profile in Human Dilated Cardiomyopathy.

Deanna K Sosnowski, K Lockhart Jamieson, Ahmed M Darwesh, Hao Zhang, Hedieh Keshavarz-Bahaghighat, Robert Valencia, Anissa Viveiros, Matthew L Edin, Darryl C Zeldin, Gavin Y Oudit, John M Seubert.

Objective: Metabolites derived from N-3 and N-6 polyunsaturated fatty acids (PUFAs) have both beneficial and detrimental effects on the heart. However, contribution of these lipid mediators to dilated cardiomyopathy (DCM)-associated mitochondrial dysfunction remains unknown. This study aimed to characterize DCM-specific alterations in the PUFA metabolome in conjunction with cardiac mitochondrial quality in human explanted heart tissues.
Methods: Left ventricular tissues obtained from non-failing control (NFC) or DCM explanted hearts, were assessed for N-3 and N-6 PUFA metabolite levels using LC-MS/MS. mRNA and protein expression of CYP2J2, CYP2C8 and epoxide hydrolase enzymes involved in N-3 and N-6 PUFA metabolism were quantified. Cardiac mitochondrial quality was assessed by transmission electron microscopy, measurement of respiratory chain complex activities and oxygen consumption (respiratory control ratio, RCR) during ADP-stimulated ATP production.
Results: Formation of cardioprotective CYP-derived lipid mediators, epoxy fatty acids (EpFAs), and their corresponding diols were enhanced in DCM hearts. These findings were corroborated by increased expression of CYP2J2 and CYP2C8 enzymes, as well as microsomal and soluble epoxide hydrolase enzymes, suggesting enhanced metabolic flux and EpFA substrate turnover. DCM hearts demonstrated marked damage to mitochondrial ultrastructure and attenuated mitochondrial function. Incubation of fresh DCM cardiac fibers with the protective EpFA, 19,20-EDP, significantly improved mitochondrial function.
Conclusions: The current study demonstrates that increased expressions of CYP-epoxygenase enzymes and epoxide hydrolases in the DCM heart correspond with enhanced PUFA-derived EpFA turnover. This is accompanied by severe mitochondrial functional impairment which can be rescued by the administration of exogenous EpFAs.

Keywords: CYP450; dilated cardiomyopathy (DCM); eicosanoids; mitochondria; soluble epoxide hydrolase (sEH)

DOI: https://doi.org/10.3389/fcvm.2022.879209

Circ Res. 2022 Jun 10. 130(12): 1965-1993

Animal Models of Dysregulated Cardiac Metabolism.

Heiko Bugger, Nikole J Byrne, E Dale Abel.

As a muscular pump that contracts incessantly throughout life, the heart must constantly generate cellular energy to support contractile function and fuel ionic pumps to maintain electrical homeostasis. Thus, mitochondrial metabolism of multiple metabolic substrates such as fatty acids, glucose, ketones, and lactate is essential to ensuring an uninterrupted supply of ATP. Multiple metabolic pathways converge to maintain myocardial energy homeostasis. The regulation of these cardiac metabolic pathways has been intensely studied for many decades. Rapid adaptation of these pathways is essential for mediating the myocardial adaptation to stress, and dysregulation of these pathways contributes to myocardial pathophysiology as occurs in heart failure and in metabolic disorders such as diabetes. The regulation of these pathways reflects the complex interactions of cell-specific regulatory pathways, neurohumoral signals, and changes in substrate availability in the circulation. Significant advances have been made in the ability to study metabolic regulation in the heart, and animal models have played a central role in contributing to this knowledge. This review will summarize metabolic pathways in the heart and describe their contribution to maintaining myocardial contractile function in health and disease. The review will summarize lessons learned from animal models with altered systemic metabolism and those in which specific metabolic regulatory pathways have been genetically altered within the heart. The relationship between intrinsic and extrinsic regulators of cardiac metabolism and the pathophysiology of heart failure and how these have been informed by animal models will be discussed.

Keywords: diabetes; glucose; heart failure; mitochondria; models, animal

DOI: https://doi.org/10.1161/CIRCRESAHA.122.320334

Front Cardiovasc Med. 2022 ;9 882089

The Efficacy and Safety of the Combined Therapy of Sodium-Glucose Co-Transporter-2 Inhibitors and Angiotensin Receptor-Neprilysin Inhibitor in Patients With Heart Failure With Reduced Ejection Fraction: A Meta-Analysis of the EMPEROR-Reduced and DAPA-HF Sub-Analysis.

Yanxia Lin, Huanrui Zhang, Shijie Zhao, Ling Chen, Jinyang Li, Xiaoou Wang, Wen Tian.

Background: Both sodium-glucose co-transporter-2 (SGLT-2) inhibitors and angiotensin receptor-neprilysin inhibitor (ARNI) were recommended to treat heart failure with reduced ejection fraction (HFrEF). However, no trial was conducted to assess the efficacy and safety of the combined therapy of SGLT-2 inhibitors and ARNI in patients with HFrEF.
Methods: We performed a meta-analysis of the prespecified subgroups from DAPA-HF and EMPEROR-Reduced trials. The primary endpoint was the composite risk of cardiovascular death or hospitalization for heart failure. The risk of cardiovascular death, all-cause death, a composite of serious adverse renal outcomes, and volume depletion were also estimated.
Results: The risk of the composite of cardiovascular death or hospitalization for heart failure was reduced in combined therapy of SGLT-2 inhibitors and ARNI, compared with ARNI monotherapy (RR.68, 95% CI.53 to.85, P = 0.001). When compared with SGLT-2 inhibitors monotherapy, the events of cardiovascular death (RR.64, 95% CI.46 to 0.87, P = 0.005) and all-cause death (RR.72, 95% CI.55 to.94, P = 0.01) were significantly less in combined therapy, accompanied by elevated incidence of volume depletion (RR 1.55, 95% CI 1.22 to 1.96, P = 0.0003).
Conclusion: Combined therapy has additional benefits over monotherapy in patients with HFrEF, however, it is accompanied by a possibly higher risk of volume depletion.

Keywords: angiotensin receptor-neprilysin inhibitor; combined therapy; heart failure; meta-analysis; sodium-glucose co-transporter-2 inhibitors

DOI: https://doi.org/10.3389/fcvm.2022.882089

Curr Res Physiol. 2022 ;5 232-239

Empagliflozin restores cardiac metabolic flexibility in diet-induced obese C57BL6/J mice.

Bingxian Xie, Wesley Ramirez, Amanda M Mills, Brydie R Huckestein, Moira Anderson, Martha M Pangburn, Eric Y Lang, Steven J Mullet, Byron W Chuan, Lanping Guo, Ian Sipula, Christopher P O'Donnell, Stacy G Wendell, Iain Scott, Michael J Jurczak.

Sodium-glucose co-transporter type 2 (SGLT2) inhibitor therapy to treat type 2 diabetes unexpectedly reduced all-cause mortality and hospitalization due to heart failure in several large-scale clinical trials, and has since been shown to produce similar cardiovascular disease-protective effects in patients without diabetes. How SGLT2 inhibitor therapy improves cardiovascular disease outcomes remains incompletely understood. Metabolic flexibility refers to the ability of a cell or organ to adjust its use of metabolic substrates, such as glucose or fatty acids, in response to physiological or pathophysiological conditions, and is a feature of a healthy heart that may be lost during diabetic cardiomyopathy and in the failing heart. We therefore undertook studies to determine the effects of SGLT2 inhibitor therapy on cardiac metabolic flexibility in vivo in obese, insulin resistant mice using a [U13C]-glucose infusion during fasting and hyperinsulinemic euglycemic clamp. Relative rates of cardiac glucose versus fatty acid use during fasting were unaffected by EMPA, whereas insulin-stimulated rates of glucose use were significantly increased by EMPA, alongside significant improvements in cardiac insulin signaling. These metabolic effects of EMPA were associated with reduced cardiac hypertrophy and protection from ischemia. These observations suggest that the cardiovascular disease-protective effects of SGLT2 inhibitors may in part be explained by beneficial effects on cardiac metabolic substrate selection.

DOI: https://doi.org/10.1016/j.crphys.2022.05.003

Int J Mol Sci. 2022 May 25. pii: 5943. [Epub ahead of print]23(11):

The Transcription Factor EB (TFEB) Sensitizes the Heart to Chronic Pressure Overload.

Sebastian Wundersitz, Cristina Pablo Tortola, Sibylle Schmidt, Ramon Oliveira Vidal, Melanie Kny, Alexander Hahn, Lukas Zanders, Hugo A Katus, Sascha Sauer, Christian Butter, Friedrich C Luft, Oliver J Müller, Jens Fielitz.

The transcription factor EB (TFEB) promotes protein degradation by the autophagy and lysosomal pathway (ALP) and overexpression of TFEB was suggested for the treatment of ALP-related diseases that often affect the heart. However, TFEB-mediated ALP induction may perturb cardiac stress response. We used adeno-associated viral vectors type 9 (AAV9) to overexpress TFEB (AAV9-Tfeb) or Luciferase-control (AAV9-Luc) in cardiomyocytes of 12-week-old male mice. Mice were subjected to transverse aortic constriction (TAC, 27G; AAV9-Luc: n = 9; AAV9-Tfeb: n = 14) or sham (AAV9-Luc: n = 9; AAV9-Tfeb: n = 9) surgery for 28 days. Heart morphology, echocardiography, gene expression, and protein levels were monitored. AAV9-Tfeb had no effect on cardiac structure and function in sham animals. TAC resulted in compensated left ventricular hypertrophy in AAV9-Luc mice. AAV9-Tfeb TAC mice showed a reduced LV ejection fraction and increased left ventricular diameters. Morphological, histological, and real-time PCR analyses showed increased heart weights, exaggerated fibrosis, and higher expression of stress markers and remodeling genes in AAV9-Tfeb TAC compared to AAV9-Luc TAC. RNA-sequencing, real-time PCR and Western Blot revealed a stronger ALP activation in the hearts of AAV9-Tfeb TAC mice. Cardiomyocyte-specific TFEB-overexpression promoted ALP gene expression during TAC, which was associated with heart failure. Treatment of ALP-related diseases by overexpression of TFEB warrants careful consideration.

Keywords: heart failure; left ventricular hypertrophy; transcription factor EB

DOI: https://doi.org/10.3390/ijms23115943