bims-hafaim 2023-04-23 papers

Issue of 2023‒04‒23
six papers selected by
Kyle McCommis
Saint Louis University

JACC Heart Fail. 2023 Mar 17. pii: S2213-1779(23)00091-4. [Epub ahead of print]

The Lure of Cardiac Metabolism in the Diagnosis, Prevention, and Treatment of Heart Failure.

Daniele Rodolico, Gabriele G Schiattarella, Heinrich Taegtmeyer.

Energy substrate metabolism and contractile function are tightly coupled in the heart. Within this framework, heart failure may be viewed as a state of impaired energy transfer. The metabolic changes in the failing heart are linked to functional and structural changes. A worthwhile goal is to measure metabolic flux and its regulation quantitatively, and to do this in a manner that leads to targeted interventions. For several good reasons, this goal has been elusive until now. The development of new analytical and imaging techniques offers the potential of exploring the landscape of metabolic changes across the different stages of heart failure. In this Review Topic of the Month, we focus on concepts and brevity to provide a strategic overview of cardiac metabolism in the diagnosis, prevention, and treatment of nonischemic heart failure.

Keywords: cardiac remodeling; flux-based analysis; imaging; metabolic unloading

DOI: https://doi.org/10.1016/j.jchf.2023.02.007

Circulation. 2023 Apr 18.

Assessment of Cardiac Energy Metabolism, Function, and Physiology in Patients With Heart Failure Taking Empagliflozin: The Randomized, Controlled EMPA-VISION Trial.

BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have emerged as a paramount treatment for patients with heart failure (HF), irrespective of underlying reduced or preserved ejection fraction. However, a definite cardiac mechanism of action remains elusive. Derangements in myocardial energy metabolism are detectable in all HF phenotypes, and it was proposed that SGLT2i may improve energy production. The authors aimed to investigate whether treatment with empagliflozin leads to changes in myocardial energetics, serum metabolomics, and cardiorespiratory fitness.METHODS: EMPA-VISION is a prospective, randomized, double-blind, placebo-controlled, mechanistic trial that enrolled 72 symptomatic patients with chronic HF with reduced ejection fraction (HFrEF; n=36; left ventricular ejection fraction ≤40%; New York Heart Association class ≥II; NT-proBNP [N-terminal pro-B-type natriuretic peptide] ≥125 pg/mL) and HF with preserved ejection fraction (HFpEF; n=36; left ventricular ejection fraction ≥50%; New York Heart Association class ≥II; NT-proBNP ≥125 pg/mL). Patients were stratified into respective cohorts (HFrEF versus HFpEF) and randomly assigned to empagliflozin (10 mg; n=35: 17 HFrEF and 18 HFpEF) or placebo (n=37: 19 HFrEF and 18 HFpEF) once daily for 12 weeks. The primary end point was a change in the cardiac phosphocreatine:ATP ratio (PCr:ATP) from baseline to week 12, determined by phosphorus magnetic resonance spectroscopy at rest and during peak dobutamine stress (65% of age-maximum heart rate). Mass spectrometry on a targeted set of 19 metabolites was performed at baseline and after treatment. Other exploratory end points were investigated.
RESULTS: Empagliflozin treatment did not change cardiac energetics (ie, PCr:ATP) at rest in HFrEF (adjusted mean treatment difference [empagliflozin - placebo], -0.25 [95% CI, -0.58 to 0.09]; P=0.14) or HFpEF (adjusted mean treatment difference, -0.16 [95% CI, -0.60 to 0.29]; P=0.47]. Likewise, there were no changes in PCr:ATP during dobutamine stress in HFrEF (adjusted mean treatment difference, -0.13 [95% CI, -0.35 to 0.09]; P=0.23) or HFpEF (adjusted mean treatment difference, -0.22 [95% CI, -0.66 to 0.23]; P=0.32). No changes in serum metabolomics or levels of circulating ketone bodies were observed.
CONCLUSIONS: In patients with either HFrEF or HFpEF, treatment with 10 mg of empagliflozin once daily for 12 weeks did not improve cardiac energetics or change circulating serum metabolites associated with energy metabolism when compared with placebo. Based on our results, it is unlikely that enhancing cardiac energy metabolism mediates the beneficial effects of SGLT2i in HF.
REGISTRATION: URL: https://www.
CLINICALTRIALS: gov; Unique identifier: NCT03332212.

Keywords: empagliflozin; heart failure; magnetic resonance spectroscopy; sodium-glucose transporter proteins

DOI: https://doi.org/10.1161/CIRCULATIONAHA.122.062021

Biomed Pharmacother. 2023 Apr 13. pii: S0753-3322(23)00479-1. [Epub ahead of print]162 114691

Doxorubicin downregulates autophagy to promote apoptosis-induced dilated cardiomyopathy via regulating the AMPK/mTOR pathway.

Sheng Zhang, Xueping Wei, Haijin Zhang, Youping Wu, Junsong Jing, Rongrong Huang, Ting Zhou, Jingjin Hu, Yueguo Wu, Yuanyuan Li, Zhenqiang You.

The broad-spectrum antineoplastic drug doxorubicin (DOX) has one of the most serious chronic side effects on the heart, dilated cardiomyopathy, but the precise molecular mechanisms underlying disease progression subsequent to long latency periods remain puzzling. Here, we established a model of DOX-induced dilated cardiomyopathy. In a cardiac cytology exploration, we found that differentially expressed genes in the KEGG signaling pathway enrichment provided a novel complex network of mTOR bridging autophagy and oxidative stress. Validation results showed that DOX caused intracellular reactive oxygen species accumulation in cardiomyocytes, disrupted mitochondria, led to imbalanced intracellular energy metabolism, and triggered cardiomyocyte apoptosis. Apoptosis showed a negative correlation with DOX-regulated cardiomyocyte autophagy. To evaluate whether the inhibition of mTOR could upregulate autophagy to protect cardiomyocytes, we used rapamycin to restore autophagy depressed by DOX. Rapamycin increased cardiomyocyte survival by easing the autophagic flux blocked by DOX. In addition, rapamycin reduced oxidative stress, prevented mitochondrial damage, and restored energy metabolic homeostasis in DOX-treated cardiomyocytes. In vivo, we used metformin (Met) which is an AMPK activator to protect cardiac tissue to alleviate DOX-induced dilated cardiomyopathy. In this study, Met significantly attenuated the oxidative stress response of myocardial tissue caused by DOX and activated cardiomyocyte autophagy to maintain cardiomyocyte energy metabolism and reduce cardiomyocyte apoptosis by downregulating mTOR activity. Overall, our study revealed the role of autophagy and apoptosis in DOX-induced dilated cardiomyopathy and demonstrated the potential role of regulation of the AMPK/mTOR axis in the treatment of DOX-induced dilated cardiomyopathy.

Keywords: AMPK; Apoptosis; Autophagy; Dilated cardiomyopathy; Doxorubicin; MTOR

DOI: https://doi.org/10.1016/j.biopha.2023.114691

Eur J Intern Med. 2023 Apr 14. pii: S0953-6205(23)00115-2. [Epub ahead of print]

The effect of sodium-glucose cotransporter-2 inhibitors on cardiac structure remodeling and function: A meta-analysis of randomized controlled trials.

Gang Fan, Dian-Long Guo.

BACKGROUND: It has been proven that sodium-glucose co-transporter 2 inhibitors (SGLT2is) improve the prognosis of patients with heart failure, independent of the presence of diabetes mellitus. Whether SGLT2 inhibitors affect cardiac structural remodeling and cardiac function is still uncertain.METHODS: We included published randomized controlled trials (RCTs) to compare the effect of SGLT2is and control therapy in patients with or without heart failure. The meta-analysis was performed using Review Manager 5.3 software.
RESULTS: A total of 15 RCTs with a total of 1343 patients were selected for this meta-analysis, 663 of whom were on SGLT2is treatment and 680 of whom were in the control group. SGLT2is significantly improved heart rate (HR) [MD: -2.74, 95% CI (-4.71, -0.77), P = 0.006], left atrium volume index (LAVi) [MD: -1.99, 95% CI (-3.23,-0.75), P = 0.002], E/e' [MD: -1.47, 95% CI (-1.83,-1.10), P<0.00001], left ventricular mass index (LVMi) [MD: -2.38, 95% CI (-4.35, -0.40), P = 0.02], left ventricular end-systolic volume (LVESV) [MD: -6.50, 95% CI (-11.15,-1.84), P = 0.006], and left ventricular ejection fraction (LVEF) [MD: 1.78, 95% CI (0.56,3.01), P = 0.004] in the total population. Subgroup analysis indicated that compared with other SGLT2is, empagliflozin significantly decreased LVEDV, LVESV,LVMi, LAVi, E/e', and increased LVEF (P<0.05). In addition, the cardiac anti-remodeling effects of SGLT2 are particularly significant in patients with heart failure.
CONCLUSION: Our study showed that SGLT2is, particularly empagliflozin, significantly reverse cardiac remodeling in patients with heart failure. Empagliflozin may be a potentially promising agent to reverse cardiac remodeling in clinical practice.

Keywords: Cardiac remodeling; Empagliflozin; Heart failure; Meta-analysis; SGLT2i

DOI: https://doi.org/10.1016/j.ejim.2023.04.002

Circulation. 2023 Apr 17.

Jmjd4 Facilitates Pkm2 Degradation in Cardiomyocytes and Is Protective Against Dilated Cardiomyopathy.

Yansong Tang, Mengying Feng, Yang Su, Teng Ma, Hongjie Zhang, Hongchun Wu, Xiaoyu Wang, Shuyue Shi, Ying Zhang, Yawei Xu, Shijun Hu, Ke Wei, Dachun Xu.

BACKGROUND: A large portion of idiopathic and familial dilated cardiomyopathy (DCM) cases have no obvious causal genetic variant. Although altered response to metabolic stress has been implicated, the molecular mechanisms underlying the pathogenesis of DCM remain elusive. The JMJD family proteins, initially identified as histone deacetylases, have been shown to be involved in many cardiovascular diseases. Despite their increasingly diverse functions, whether JMJD family members play a role in DCM remains unclear.METHODS: We examined Jmjd4 expression in patients with DCM, and conditionally deleted and overexpressed Jmjd4 in cardiomyocytes in vivo to investigate its role in DCM. RNA sequencing, metabolites profiling, and mass spectrometry were used to dissect the molecular mechanism of Jmjd4-regulating cardiac metabolism and hypertrophy.
RESULTS: We found that expression of Jmjd4 is significantly decreased in hearts of patients with DCM. Induced cardiomyocyte-specific deletion of Jmjd4 led to spontaneous DCM with severely impaired mitochondrial respiration. Pkm2, the less active pyruvate kinase compared with Pkm1, which is normally absent in healthy adult cardiomyocytes but elevated in cardiomyopathy, was found to be drastically accumulated in hearts with Jmjd4 deleted. Jmjd4 was found mechanistically to interact with Hsp70 to mediate degradation of Pkm2 through chaperone-mediated autophagy, which is dependent on hydroxylation of K66 of Pkm2 by Jmjd4. By enhancing the enzymatic activity of the abundant but less active Pkm2, TEPP-46, a Pkm2 agonist, showed a significant therapeutic effect on DCM induced by Jmjd4 deficiency, and heart failure induced by pressure overload, as well.
CONCLUSION: Our results identified a novel role of Jmjd4 in maintaining metabolic homeostasis in adult cardiomyocytes by degrading Pkm2 and suggest that Jmjd4 and Pkm2 may be therapeutically targeted to treat DCM, and other cardiac diseases with metabolic dysfunction, as well.

Keywords: HSP70 heat-shock proteins; JMJD4 protein, human; Pkm protein, mouse; cardiomyopathy, dilated; chaperone-mediated autophagy; hydroxylation

DOI: https://doi.org/10.1161/CIRCULATIONAHA.123.064121

J Physiol. 2023 Apr 17.

Ketone body oxidation: Glycogen-sparing yet glucose-dependent?

Heather L Petrick, Philippe J M Pinckaers, Henver S Brunetta.

Keywords: beta-hydroxybutyrate; glucose; glycogen; heart; ketone bodies; muscle

DOI: https://doi.org/10.1113/JP284561