bims-hafaim 2022-02-06 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2022–02–06
nine papers selected by
Kyle McCommis, Saint Louis University

Effect of Dapagliflozin, Compared With Placebo, According to Baseline Risk in DAPA-HF.
Mitochondrial Creatine Kinase Attenuates Pathologic Remodeling in Heart Failure.
SGLT2 Inhibitors and Ketone Metabolism in Heart Failure.
Sodium-glucose cotransporter 2 inhibitors in heart failure with reduced or preserved ejection fraction: a meta-analysis.
Panax notoginseng Saponin Protects Against Diabetic Cardiomyopathy Through Lipid Metabolism Modulation.
Strategies for Imaging Metabolic Remodeling of the Heart in Obesity and Heart Failure.
Mitochondria in Pathological Cardiac Hypertrophy Research and Therapy.
Protective Effect of Trimetazidine on Potassium Ion Homeostasis in Myocardial Tissue in Mice with Heart Failure.
Empagliflozin Alleviates Left Ventricle Hypertrophy in High-Fat-Fed Mice by Modulating Renin Angiotensin Pathway.

JACC Heart Fail. 2022 Feb;pii: S2213-1779(21)00440-6. [Epub ahead of print]10(2): 104-118

Effect of Dapagliflozin, Compared With Placebo, According to Baseline Risk in DAPA-HF.

DAPA-HF Investigators and Committees

   OBJECTIVES: The authors sought to examine the effect of dapagliflozin across the spectrum of risk in patients enrolled in DAPA-HF.
BACKGROUND: In the DAPA-HF (Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure) trial, the sodium-glucose cotransporter 2 inhibitor dapagliflozin decreased the risk of worsening HF events and cardiovascular death in patients with HF and reduced ejection fraction.
METHODS: The MAGGIC (Meta-analysis Global Group in Chronic Heart Failure) and the PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) PREDICT-HF (Risk of Events and Death in the Contemporary Treatment of Heart Failure) risk models were used to categorize patients according to risk score quintiles. The authors analyzed rates of the primary composite outcome of a worsening HF event or cardiovascular death, its components, and all-cause mortality according to risk quintile and whether risk modified the effect of dapagliflozin.
RESULTS: The MAGGIC score was available for 4,740 of 4,744 patients in DAPA-HF (median score 22 [IQR: 18-25]). A1-point increase was associated with an 8.2% (95% CI: 6.9%-9.4%) higher relative risk of the primary endpoint (P < 0.001). The benefit of dapagliflozin over placebo for the primary endpoint was similar across the spectrum of MAGGIC risk score (interaction P = 0.71). Applying the overall relative risk reduction (26%) with dapagliflozin added to standard therapy resulted in 7 fewer patients in the highest MAGGIC risk quintile experiencing a primary outcome, compared with 2 in the lowest quintile, per 100 person-years of treatment. The findings with PREDICT-HF were similar, although this model led to better risk discrimination.
CONCLUSIONS: The benefits of dapagliflozin were consistent across the broad spectrum of baseline risk in DAPA-HF.

Keywords:  MAGGIC; PREDICT-HF; heart failure; prognostic model; risk score; sodium-glucose cotransporter 2 inhibitor; survival

DOI:  https://doi.org/10.1016/j.jchf.2021.09.002
Circ Res. 2022 Feb 03. CIRCRESAHA121319648

Mitochondrial Creatine Kinase Attenuates Pathologic Remodeling in Heart Failure.

Gizem Keceli, Ashish Gupta, Joevin Sourdon, Refaat Gabr, Michael Schär, Swati Dey, Carlo G Tocchetti, Annina Stuber, Jacopo Agrimi, Yi Zhang, Michelle Leppo, Charles Steenbergen, Shenghan Lai, Lisa R Yanek, Brian O'Rourke, Gary Gerstenblith, Paul A Bottomley, Yibin Wang, Nazareno Paolocci, Robert G Weiss.

   BACKGROUND: Abnormalities in cardiac energy metabolism occur in heart failure (HF) and contribute to contractile dysfunction, but their role, if any, in HF-related pathologic remodeling is much less established. CK (creatine kinase), the primary muscle energy reserve reaction which rapidly provides ATP at the myofibrils and regenerates mitochondrial ADP, is down-regulated in experimental and human HF. To test the hypotheses that pathologic remodeling in human HF is related to impaired cardiac CK energy metabolism and that rescuing CK attenuates maladaptive hypertrophy in experimental HF.
METHODS: First, in 27 HF patients and 14 healthy subjects, we measured cardiac energetics and left ventricular remodeling using noninvasive magnetic resonance 31P spectroscopy and magnetic resonance imaging, respectively. Second, we tested the impact of metabolic rescue with cardiac-specific overexpression of either Ckmyofib (myofibrillar CK) or Ckmito (mitochondrial CK) on HF-related maladaptive hypertrophy in mice.
RESULTS: In people, pathologic left ventricular hypertrophy and dilatation correlate closely with reduced myocardial ATP levels and rates of ATP synthesis through CK. In mice, transverse aortic constriction-induced left ventricular hypertrophy and dilatation are attenuated by overexpression of CKmito, but not by overexpression of CKmyofib. CKmito overexpression also attenuates hypertrophy after chronic isoproterenol stimulation. CKmito lowers mitochondrial reactive oxygen species, tissue reactive oxygen species levels, and upregulates antioxidants and their promoters. When the CK capacity of CKmito-overexpressing mice is limited by creatine substrate depletion, the protection against pathologic remodeling is lost, suggesting the ADP regenerating capacity of the CKmito reaction rather than CK protein per se is critical in limiting adverse HF remodeling.
CONCLUSIONS: In the failing human heart, pathologic hypertrophy and adverse remodeling are closely related to deficits in ATP levels and in the CK energy reserve reaction. CKmito, sitting at the intersection of cardiac energetics and redox balance, plays a crucial role in attenuating pathologic remodeling in HF.
REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00181259.

Keywords:  antioxidants; creatine; dilatation; heart failure; myofibrils

DOI:  https://doi.org/10.1161/CIRCRESAHA.121.319648
J Lipid Atheroscler. 2022 Jan;11(1): 1-19

SGLT2 Inhibitors and Ketone Metabolism in Heart Failure.

Huitzilihuitl Saucedo-Orozco, Suzanne N Voorrips, Salva R Yurista, Rudolf A de Boer, B Daan Westenbrink.

  Sodium-glucose cotransporter-2 (SGLT2) inhibitors have emerged as powerful drugs that can be used to treat heart failure (HF) patients, both with preserved and reduced ejection fraction and in the presence or absence of type 2 diabetes. While the mechanisms underlying the salutary effects of SGLT2 inhibitors have not been fully elucidated, there is clear evidence for a beneficial metabolic effect of these drugs. In this review, we discuss the effects of SGLT2 inhibitors on cardiac energy provision secondary to ketone bodies, pathological ventricular remodeling, and inflammation in patients with HF. While the specific contribution of ketone bodies to the pleiotropic cardiovascular benefits of SGLT2 inhibitors requires further clarification, ketone bodies themselves may also be used as a therapy for HF.

Keywords:  Heart failure; Inflammation; Ketone bodies; Sodium-glucose transporter 2 inhibitors; Ventricular remodeling

DOI:  https://doi.org/10.12997/jla.2022.11.1.1
ESC Heart Fail. 2022 Feb 02.

Sodium-glucose cotransporter 2 inhibitors in heart failure with reduced or preserved ejection fraction: a meta-analysis.

Arjun K Pandey, Nitish K Dhingra, Makoto Hibino, Vijay Gupta, Subodh Verma.

   AIMS: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to be an effective therapy in improving heart failure outcomes. We conducted a meta-analysis of randomized controlled trials to evaluate the efficacy of SGLT2 inhibitors in heart failure patients with either a reduced or preserved ejection fraction.
METHODS AND RESULTS: We searched MEDLINE and EMBASE for large (≥1000 patients) randomized controlled trials evaluating the effects of SGLT2 inhibitors compared with placebo in the setting of heart failure until September 2021. Our primary outcome was the composite of heart failure hospitalization and cardiovascular death, and secondary outcomes included all-cause mortality and total heart failure hospitalizations. We pooled hazard ratios and risk ratios and evaluated risk of bias with the Cochrane Collaboration tool. Four randomized controlled trials (DAPA HF, EMPEROR-Preserved, EMPEROR-Reduced, and SOLOIST-WHF) were included (n = 15 684); two of which evaluated patients with a reduced LVEF, one of which evaluated patients with a preserved LVEF, and one of which included both. Treatment with SGLT2 inhibitors resulted in a significant reduction in the composite of CV death and heart failure hospitalization (HR: 0.76, 95% CI: 0.70, 0.82, I2 : 0%, P < 0.00001). This was consistent in sub-groups of patients with LVEF ≤40% (n = 9199, HR: 0.74, 95% CI: 0.68, 0.81, I2 : 0%) and LVEF >40% (n = 6482, HR: 0.78, 95% CI: 0.68, 0.89, I2 : 0%, P-for-interaction: 0.57), as well as in sub-groups of patients with and without diabetes mellitus at baseline (P-for-interaction: 0.81). SGLT2 inhibitors were associated with a significant reduction in cardiovascular death (HR: 0.87, 95% CI: 0.79, 0.97, I2 : 0%, P < 0.00001) and total heart failure hospitalization (RR: 0.71, 95% CI: 0.67, 0.76, I2 : 0%, P < 0.00001); although a potential trend towards reduced all-cause mortality was noted with SGLT2 inhibitors, no statistically significant difference was observed (HR: 0.91, 95% CI: 0.83, 1.00, I2 : 14%, P = 0.05).
CONCLUSIONS: Sodium-glucose cotransporter 2 inhibitors reduce cardiovascular death and heart failure hospitalization among patients with heart failure, regardless of LVEF status.

Keywords:  Diabetes; HFpEF; HFrEF; SGLT2i

DOI:  https://doi.org/10.1002/ehf2.13805
J Am Heart Assoc. 2022 Feb 03. e023540

Panax notoginseng Saponin Protects Against Diabetic Cardiomyopathy Through Lipid Metabolism Modulation.

Chenyang Zhang, Bin Zhang, Xuelian Zhang, Min Wang, Xiaobo Sun, Guibo Sun.

  Background People with diabetes are more likely to develop cardiovascular diseases. Lipotoxicity plays a key role in the development of diabetic cardiomyopathy. Panax notoginseng saponin (PNS) has been used to treat diabetes and obesity. However, the role of PNS in diabetic cardiomyopathy remains unclear. Methods and Results Diabetic db/db mice received high-dose (200 mg/kg per day) or medium-dose (100 mg/kg per day) PNS by gavage for 12 weeks until week 36. Lipid accumulation and cardiac function in diabetic mice were detected and possible mechanisms involved were explored. PNS significantly improved body weight, body fat content, serum lipids, adipocytokines, and antioxidative function in db/db mice. Lipid accumulation in adipose tissue, liver, and heart were also alleviated by PNS treatment. Cardiac function and mitochondrial structure were also improved by PNS. H9c2 cells were treated with palmitate acid, and PNS pretreatment reduced lipid accumulation, mitochondrial reactive oxygen species, as well as improved mitochondrial membrane potential and mitochondrial oxygen consumption rate. Levels of proteins and expression of genes related to glucose and lipid metabolism, antioxidative function, and mitochondrial dynamics were also improved by PNS administration. Conclusions PNS attenuated heart dysfunction in diabetic mice by reducing lipotoxicity as well as modulating oxidative stress and improving mitochondrial function.

Keywords:  PNS; diabetic cardiomyopathy; lipid metabolism; mitochondria; oxidative stress

DOI:  https://doi.org/10.1161/JAHA.121.023540
Curr Cardiol Rep. 2022 Feb 02.

Strategies for Imaging Metabolic Remodeling of the Heart in Obesity and Heart Failure.

Amier Haidar, Heinrich Taegtmeyer.

   PURPOSE OF REVIEW: Define early myocardial metabolic changes among patients with obesity and heart failure, and to describe noninvasive methods and their applications for imaging cardiac metabolic remodeling.
RECENT FINDINGS: Metabolic remodeling precedes, triggers, and sustains functional and structural remodeling in the stressed heart. Alterations in cardiac metabolism can be assessed by using a variety of molecular probes. The glucose tracer analog, 18F-FDG, and the labeled tracer 11C-palmitate are still the most commonly used tracers to assess glucose and fatty acid metabolism, respectively. The development of new tracer analogs and imaging agents, including those targeting the peroxisome proliferator-activated receptor (PPAR), provides new opportunities for imaging metabolic activities at a molecular level. While the use of cardiac magnetic resonance spectroscopy in the clinical setting is limited to the assessment of intramyocardial and epicardial fat, new technical improvements are likely to increase its usage in the setting of heart failure. Noninvasive imaging methods are an effective tool for the serial assessment of alterations in cardiac metabolism, either during disease progression, or in response to treatment.

Keywords:  Heart failure; Metabolic imaging; Myocardial metabolism; Obesity

DOI:  https://doi.org/10.1007/s11886-022-01650-3
Front Cardiovasc Med. 2021 ;8 822969

Mitochondria in Pathological Cardiac Hypertrophy Research and Therapy.

Dan Yang, Han-Qing Liu, Fang-Yuan Liu, Zhen Guo, Peng An, Ming-Yu Wang, Zheng Yang, Di Fan, Qi-Zhu Tang.

  Cardiac hypertrophy, a stereotypic cardiac response to increased workload, ultimately progresses to severe contractile dysfunction and uncompensated heart failure without appropriate intervention. Sustained cardiac overload inevitably results in high energy consumption, thus breaking the balance between mitochondrial energy supply and cardiac energy demand. In recent years, accumulating evidence has indicated that mitochondrial dysfunction is implicated in pathological cardiac hypertrophy. The significant alterations in mitochondrial energetics and mitochondrial proteome composition, as well as the altered expression of transcripts that have an impact on mitochondrial structure and function, may contribute to the initiation and progression of cardiac hypertrophy. This article presents a summary review of the morphological and functional changes of mitochondria during the hypertrophic response, followed by an overview of the latest research progress on the significant modulatory roles of mitochondria in cardiac hypertrophy. Our article is also to summarize the strategies of mitochondria-targeting as therapeutic targets to treat cardiac hypertrophy.

Keywords:  cardiac hypertrophy; mitochondria; mitophagy; regulatory mechanisms; therapeutic strategies

DOI:  https://doi.org/10.3389/fcvm.2021.822969
Biomed Res Int. 2022 ;2022 2387860

Protective Effect of Trimetazidine on Potassium Ion Homeostasis in Myocardial Tissue in Mice with Heart Failure.

Kaijing Yang, Yitao Xue, Miao Yu, Huachen Jiao, Yan Li, Xijin Wei, Wenwen Liu, Yang Sun, Nannan Chen, Linlin Song, Ting Yu, Kaiming Chen, Dadong Guo.

The occurrence of heart failure (HF) is closely correlated with the disturbance of mitochondrial energy metabolism, and trimetazidine (TMZ) has been regarded as an effective agent in treating HF. Intracellular potassium ion (K+) homeostasis, which is modulated by K+ channels and transporters, is crucial for maintaining normal myocardial function and can be disrupted by HF. This study is aimed at exploring the protective effect of TMZ on K+ homeostasis within myocardial tissue in mice with HF. We observed the pathological changes of myocardial tissue under microscopes and further measured the content of adenosine triphosphate (ATP), the activity of Na+-K+ ATPase, and the expression of ATP1α1 at the mRNA and protein levels. Moreover, we also analyzed the changes in K+ flux across the myocardial tissue in mice. As a result, we found that there was a large amount of myocardial fiber lysis and fracture in HF myocardial tissue. Meanwhile, the potassium flux of mice with HF was reduced, and the expression of ATP1α1, the activity of Na+-K+ ATPase, and the supply and delivery of ATP were also decreased. In contrast, TMZ can effectively treat HF by restoring K+ homeostasis in the local microenvironment of myocardial tissues.

DOI: https://doi.org/10.1155/2022/2387860
J Renin Angiotensin Aldosterone Syst. 2022 ;2022 8861911

Empagliflozin Alleviates Left Ventricle Hypertrophy in High-Fat-Fed Mice by Modulating Renin Angiotensin Pathway.

Juliana Cordovil Cotrin, Gabriel Santos Martins de Souza, Tamiris Ingrid Petito-da-Silva, Luiz Eduardo Macedo Cardoso, Vanessa Souza-Mello, Sandra Barbosa-da-Silva.

Aims. The cardiobenefits of empagliflozin are multidimensional, and some mechanisms are still unclear. The aim of the present study was to evaluate the effect of treatment with empagliflozin on biometric parameters and gene expression in the local cardiac RAS, oxidative stress, and endoplasmic reticulum pathways in a mouse model. Main Methods. Forty male C57BL/6 mice were fed with control (C) or high-fat (HF) diets for 10 weeks. After that, the groups were redistributed according to the treatment with empagliflozin-CE or HFE. The empagliflozin was administered via food for 5 weeks (10 mg/kg/day). We performed biochemical analyses, blood pressure monitoring, oral glucose tolerance test, left ventricle (LV) stereology, RT-qPCR for genes related to classical and counterregulatory local RAS, oxidative stress, and endoplasmic reticulum stress. Key Findings. In comparison to HF, HFE decreased body mass and improved glucose intolerance and insulin resistance. The cardiac parameters were enhanced after treatment as expressed by decrease in plasma cholesterol, plasma uric acid, and systolic blood pressure. In addition, LV analysis showed that empagliflozin reduces cardiomyocyte area and LV thickness. The local RAS had less activity of the classical pathway and positive effects on the counterregulatory pathway. Empagliflozin treatment also decreased oxidative stress and endoplasmic reticulum stress-related genes. Significance. Our results suggests that empagliflozin modulates the local RAS pathway towards alleviation of oxidative stress and ER stress in the LV, which may be a route to its effects on improved cardiac remodeling.

DOI: https://doi.org/10.1155/2022/8861911