bims-hafaim 2023-02-26 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2023–02–26
eleven papers selected by
Kyle McCommis, Saint Louis University

The KLF7/PFKL/ACADL axis modulates cardiac metabolic remodelling during cardiac hypertrophy in male mice.
Is it time for class I recommendation for sodium-glucose cotransporter-2 inhibitors in heart failure with mildly reduced or preserved ejection fraction?: An updated systematic review and meta-analysis.
Contribution of skeletal muscle-specific microRNA-133b to insulin resistance in heart failure.
Downregulation of extramitochondrial BCKDH and its uncoupling from AMP deaminase in type 2 diabetic OLETF rat hearts.
The Impact of SGLT2 Inhibitor Dapagliflozin on Adropin Serum Levels in Men and Women with Type 2 Diabetes Mellitus and Chronic Heart Failure.
Iron chelation alleviates multiple pathophysiological pathways in a rat model of cardiac pressure overload.
SGLT2 inhibitors for prevention of primary and secondary cardiovascular outcomes: A meta-analysis of randomized controlled trials.
Mapping the metabolic reprogramming induced by sodium-glucose cotransporter 2 inhibition.
Sodium-Glucose Cotransporter 2 Inhibitors Among Heart Failure With Mildly Reduced and Preserved Ejection Fraction.
A Sweet Solution for Heart Failure With Preserved Ejection Fraction: The Role of Sodium-Glucose Cotransporter-2 Inhibitors.
Cardiac Involvement in Mitochondrial Disorders.

Nat Commun. 2023 Feb 21. 14(1): 959

The KLF7/PFKL/ACADL axis modulates cardiac metabolic remodelling during cardiac hypertrophy in male mice.

Cao Wang, Shupei Qiao, Yufang Zhao, Hui Tian, Wei Yan, Xiaolu Hou, Ruiqi Wang, Bosong Zhang, Chaofan Yang, Fuxing Zhu, Yanwen Jiao, Jiaming Jin, Yue Chen, Weiming Tian.

The main hallmark of myocardial substrate metabolism in cardiac hypertrophy or heart failure is a shift from fatty acid oxidation to greater reliance on glycolysis. However, the close correlation between glycolysis and fatty acid oxidation and underlying mechanism by which causes cardiac pathological remodelling remain unclear. We confirm that KLF7 simultaneously targets the rate-limiting enzyme of glycolysis, phosphofructokinase-1, liver, and long-chain acyl-CoA dehydrogenase, a key enzyme for fatty acid oxidation. Cardiac-specific knockout and overexpression KLF7 induce adult concentric hypertrophy and infant eccentric hypertrophy by regulating glycolysis and fatty acid oxidation fluxes in male mice, respectively. Furthermore, cardiac-specific knockdown phosphofructokinase-1, liver or overexpression long-chain acyl-CoA dehydrogenase partially rescues the cardiac hypertrophy in adult male KLF7 deficient mice. Here we show that the KLF7/PFKL/ACADL axis is a critical regulatory mechanism and may provide insight into viable therapeutic concepts aimed at the modulation of cardiac metabolic balance in hypertrophied and failing heart.

DOI: https://doi.org/10.1038/s41467-023-36712-9
Front Cardiovasc Med. 2023 ;10 1046194

Is it time for class I recommendation for sodium-glucose cotransporter-2 inhibitors in heart failure with mildly reduced or preserved ejection fraction?: An updated systematic review and meta-analysis.

Sukrit Treewaree, Narathorn Kulthamrongsri, Weerapat Owattanapanich, Rungroj Krittayaphong.

   Background: In heart failure with reduced ejection fraction (HFrEF), sodium-glucose cotransporter-2 (SGLT2) inhibitors were demonstrated to lower cardiovascular mortality (CV death) and hospitalization for heart failure (HHF); however, the advantages of SGLT2 inhibitors in heart failure with mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF) are less clear. SGLT2 inhibitors were reported to enhance quality of life (QoL) in HFmrEF or HFpEF patients; however, the findings among studies are inconsistent.
Objective: To conduct an updated systematic review and meta-analysis of recent data to assess the effect of SGLT2 inhibitors on cardiovascular outcomes and QoL in patients with HFmrEF or HFpEF.
Method: Three databases were searched for studies that evaluated SGLT2 inhibitors and their effect on cardiovascular outcomes, including CV death, HHF, all-cause death, and the composite outcome of CV death, HHF, and urgent visit for heart failure (HF), and patient QoL (Kansas City Cardiomyopathy Questionnaire [KCCQ] score compared to baseline, and increase in KCCQ score ≥ 5 points) that were published during January 2000-August 2022. The meta-analysis was performed using the inverse variance method and random-effects model. INPLASY registration: INPLASY202290023.
Results: Sixteen studies (9 recent RCTs) were included, and a total of 16,710 HFmrEF or HFpEF patients were enrolled. SGLT2 inhibitors significantly reduced composite cardiovascular outcome (CV death/HHF/urgent visit for HF; pooled hazard ratio [HR]: 0.80, 95% confidence interval [95%CI]: 0.74-0.86) and HHF alone (HR: 0.74, 95%CI: 0.67-0.82), but there was no significant reduction in CV death alone (HR: 0.93, 95%CI: 0.82-1.05). Benefit of SGLT2 inhibitors for decreasing CV death/HHF was observed across all subgroups, including left ventricular ejection fraction (LVEF) range, diabetes status, New York Heart Association functional class, and baseline renal function. For total HHF, SGLT2 inhibitors conferred benefit in both LVEF 50-60% (HR: 0.64, 95%CI: 0.54-0.76), and LVEF >60% (HR: 0.84, 95%CI: 0.71-0.98). Significant change was observed in the KCCQ-clinical summary score compared to baseline (mean difference: 1.33, 95%CI: 1.31-1.35), and meaningful improvement in QoL was shown across all 3 types of increase in KCCQ score ≥ 5 points.
Conclusion: This study demonstrates the benefits of SGLT2 inhibitors for improving cardiovascular outcomes and QoL in HFmrEF or HFpEF patients.

Keywords:  heart failure with mildly reduced ejection fraction; heart failure with preserved ejection fraction; meta-analysis; sodium-glucose cotransporter-2 inhibitors; systematic review

DOI:  https://doi.org/10.3389/fcvm.2023.1046194
Am J Physiol Heart Circ Physiol. 2023 Feb 24.

Contribution of skeletal muscle-specific microRNA-133b to insulin resistance in heart failure.

Fernanda Carrizo Velasquez, Barbara Román, Erick O Hernández-Ochoa, Michelle K Leppo, Sharon K Truong, Charles Steenbergen, Martin F Schneider, Robert G Weiss, Samarjit Das.

  Insulin resistance (IR) is one of the hallmarks of heart failure (HF). Abnormalities in skeletal muscle (SM) metabolism have been identified in HF. However, the underlying mechanisms of IR development in SM in HF is poorly understood. Herein, we hypothesize that HF upregulates miR-133b in SM, and in turn alters glucose metabolism and the propensity towards IR. Mitochondria isolated from SM of mice with HF induced by transverse aortic constriction (TAC) showed lower respiration, and downregulation of muscle-specific components of the TCA cycle, AMP deaminase 1 (AMPD1) and fumarate, compared to those from control animals. RNA-Seq and subsequent qPCR validation confirmed an upregulation of SM-specific miRNA, miR-133b, in TAC vs sham animals. miR-133b overexpression alone resulted in significantly lower mitochondrial respiration, cellular glucose uptake, and glycolysis along with lower ATP production and cellular energy reserve compared to the scramble in C2C12 cells. miR-133b binds to the 3'-UTR of KLF15, the transcription factor for the insulin sensitive glucose transporter, GLUT4. Overexpression of miR-133b lowers GLUT4, and lowers pAkt in presence of insulin in C2C12 cells. Finally, lowering miR-133b in primary skeletal myocytes isolated from TAC mice using antagomir-133b reversed the changes in KLF15, GLUT4 and AMPD1 compared to the scramble transfected myocytes. Taken together these data demonstrate a role for SM miR-133b in altered glucose metabolism in HF and suggest the therapeutic potential in HF to improve glucose uptake and glycolysis by restoring GLUT4 abundance. The data uncover a novel mechanism for IR and ultimately SM metabolic abnormalities in HF.

Keywords:  Heart Failure; Mitochondria; Skeletal Muscle; miR-133b; microRNA

DOI:  https://doi.org/10.1152/ajpheart.00250.2022
Physiol Rep. 2023 Feb;11(4): e15608

Downregulation of extramitochondrial BCKDH and its uncoupling from AMP deaminase in type 2 diabetic OLETF rat hearts.

Toshifumi Ogawa, Hidemichi Kouzu, Arata Osanami, Yuki Tatekoshi, Tatsuya Sato, Atsushi Kuno, Yugo Fujita, Shoya Ino, Masaki Shimizu, Yuki Toda, Wataru Ohwada, Toshiyuki Yano, Masaya Tanno, Takayuki Miki, Tetsuji Miura.

  Systemic branched-chain amino acid (BCAA) metabolism is dysregulated in cardiometabolic diseases. We previously demonstrated that upregulated AMP deaminase 3 (AMPD3) impairs cardiac energetics in a rat model of obese type 2 diabetes, Otsuka Long-Evans-Tokushima fatty (OLETF). Here, we hypothesized that the cardiac BCAA levels and the activity of branched-chain α-keto acid dehydrogenase (BCKDH), a rate-limiting enzyme in BCAA metabolism, are altered by type 2 diabetes (T2DM), and that upregulated AMPD3 expression is involved in the alteration. Performing proteomic analysis combined with immunoblotting, we discovered that BCKDH localizes not only to mitochondria but also to the endoplasmic reticulum (ER), where it interacts with AMPD3. Knocking down AMPD3 in neonatal rat cardiomyocytes (NRCMs) increased BCKDH activity, suggesting that AMPD3 negatively regulates BCKDH. Compared with control rats (Long-Evans Tokushima Otsuka [LETO] rats), OLETF rats exhibited 49% higher cardiac BCAA levels and 49% lower BCKDH activity. In the cardiac ER of the OLETF rats, BCKDH-E1α subunit expression was downregulated, while AMPD3 expression was upregulated, resulting in an 80% lower AMPD3-E1α interaction compared to LETO rats. Knocking down E1α expression in NRCMs upregulated AMPD3 expression and recapitulated the imbalanced AMPD3-BCKDH expressions observed in OLETF rat hearts. E1α knockdown in NRCMs inhibited glucose oxidation in response to insulin, palmitate oxidation, and lipid droplet biogenesis under oleate loading. Collectively, these data revealed previously unrecognized extramitochondrial localization of BCKDH in the heart and its reciprocal regulation with AMPD3 and imbalanced AMPD3-BCKDH interactions in OLETF. Downregulation of BCKDH in cardiomyocytes induced profound metabolic changes that are observed in OLETF hearts, providing insight into mechanisms contributing to the development of diabetic cardiomyopathy.

Keywords:  AMP deaminase; branched-chain amino acids; branched-chain α-keto acid dehydrogenase; diabetic cardiomyopathy

DOI:  https://doi.org/10.14814/phy2.15608
Biomedicines. 2023 Feb 04. pii: 457. [Epub ahead of print]11(2):

The Impact of SGLT2 Inhibitor Dapagliflozin on Adropin Serum Levels in Men and Women with Type 2 Diabetes Mellitus and Chronic Heart Failure.

Alexander A Berezin, Zeljko Obradovic, Ivan M Fushtey, Tetiana A Berezina, Evgen V Novikov, Lukas Schmidbauer, Michael Lichtenauer, Alexander E Berezin.

   BACKGROUND: adropin plays a protective role in cardiac remodeling through supporting energy metabolism and water homeostasis and suppressing inflammation. Low circulating levels of adropin were positively associated with the risk of cardiovascular diseases and type 2 diabetes mellitus (T2DM). We hypothesized that sodium-glucose linked transporter 2 (SGLT2) inhibitor dapagliflosin might represent cardiac protective effects in T2DM patients with known chronic HF through the modulation of adropin levels.
METHODS: we prospectively enrolled 417 patients with T2DM and HF from an entire cohort of 612 T2DM patients. All eligible patients were treated with the recommended guided HF therapy according to their HF phenotypes, including SGLT2 inhibitor dapagliflozin 10 mg, daily, orally. Anthropometry, clinical data, echocardiography/Doppler examinations, and measurements of biomarkers were performed at the baseline and over a 6-month interval of SGLT2 inhibitor administration.
RESULTS: in the entire group, dapagliflozin led to an increase in adropin levels by up to 26.6% over 6 months. In the female subgroup, the relative growth (Δ%) of adropin concentrations was sufficiently higher (Δ% = 35.6%) than that in the male subgroup (Δ% = 22.7%). A multivariate linear regression analysis of the entire group showed that the relative changes (Δ) in the left ventricular (LV) ejection fraction (LVEF), left atrial volume index (LAVI), and E/e' were significantly associated with increased adropin levels. In the female subgroup, but not in the male subgroup, ΔLVEF (p = 0.046), ΔLAVI (p = 0.001), and ΔE/e' (p = 0.001) were independent predictive values for adropin changes.
CONCLUSION: the levels of adropin seem to be a predictor for the favorable modification of hemodynamic performances during SGLT2 inhibition, independent ofN-terminal brain natriuretic pro-peptide levels.

Keywords:  adropin; dapagliflosin; heart failure; hemodynamics; natriuretic peptide; type 2 diabetes mellitus

DOI:  https://doi.org/10.3390/biomedicines11020457
Free Radic Biol Med. 2023 Feb 21. pii: S0891-5849(23)00091-6. [Epub ahead of print]

Iron chelation alleviates multiple pathophysiological pathways in a rat model of cardiac pressure overload.

Mihai Lupu, Camelia Alexandra Coada, Diana-Valentina Tudor, Ioana Baldea, Adrian Florea, Vlad-Alexandru Toma, Ana Lupsor, Remus Moldovan, Nicoleta Decea, Gabriela Adriana Filip.

  Iron dysmetabolism affects a great proportion of heart failure patients, while chronic hypertension is one of the most common risk factors for heart failure and death in industrialized countries. Serum data from reduced ejection fraction heart failure patients show a relative or absolute iron deficiency, whereas cellular myocardial analyses field equivocal data. An observed increase in organellar iron deposits was incriminated to cause reactive oxygen species formation, lipid peroxidation, and cell death. Therefore, we studied the effects of iron chelation on a rat model of cardiac hypertrophy. Suprarenal abdominal aortic constriction was achieved surgically, with a period of nine weeks to accommodate the development of chronic pressure overload. Next, deferiprone (100 mg/kg/day), a lipid permeable iron chelator, was administered for two weeks. Pressure overload resulted in increased inflammation, fibrotic remodeling, lipid peroxidation, left ventricular hypertrophy and mitochondrial iron derangements. Deferiprone reduced cardiac inflammation, lipid peroxidation, mitochondrial iron levels, and hypertrophy, without affecting circulating iron levels or ejection fraction. In conclusion, metallic molecules may pose ambivalent effects within the cardiovascular system, with beneficial effects of iron redistribution, chiefly in the mitochondria.

Keywords:  Chelation; Chronic heart failure; Hypertension; Iron metabolism; Lipid peroxidation

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.02.018
Heart Lung. 2023 Feb 16. pii: S0147-9563(23)00036-5. [Epub ahead of print]59 109-116

SGLT2 inhibitors for prevention of primary and secondary cardiovascular outcomes: A meta-analysis of randomized controlled trials.

Guijun He, Guosu Yang, Xiaoyu Huang, Duan Luo, Chao Tang, Zhen Zhang.

   BACKGROUND: Many clinical studies have shown that sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce cardiovascular risks, such as heart failure, myocardial infarction and cardiovascular death.
OBJECTIVE: To investigate the use of SGLT2i for the prevention of primary and secondary cardiovascular outcomes.
METHODS: Pubmed, Embase and Cochrane libraries databases were searched and meta-analysis was performed using Revman 5.4.
RESULTS: Eleven studies with a total of 34,058 cases were analyzed. SGLT2i significantly reduced major adverse cardiovascular events (MACE) in patients with prior myocardial infarction (MI) (OR 0.83, 95% CI 0.73-0.94, p = 0.004), no prior MI (OR 0. 82, 95% CI 0.74-0.90, p<0.0001), prior coronary atherosclerotic disease (CAD) (OR 0.82, 95% CI 0.73-0.93, p = 0.001) and no prior CAD (OR 0.82, 95% CI 0.76-0.91, p = 0.0002) compared with placebo. In addition, SGLT2i significantly reduced hospitalization due to heart failure (HF) in patients with prior MI (OR 0.69, 95% CI 0.55-0.87, p = 0.001), no prior MI (OR 0.63, 95% CI 0.55-0. 72, p<0.00001), prior CAD (OR 0.65, 95% CI 0.53-0.79, p<0.0001) and no prior CAD (OR 0.65, 95% CI 0.56-0.75, p<0.00001) compared with placebo. SGLT2i reduced cardiovascular mortality and all-cause mortality events. MI (OR 0.79, 95% CI 0.70-0.88, p<0.0001), renal damage (OR 0.73, 95% CI 0.58-0.91, p = 0.004), all-cause hospitalization (OR 0.89, 95% CI 0.83-0.96, p = 0.002), systolic and diastolic blood pressure were all significantly reduced in patients receiving SGLT2i.
CONCLUSION: SGLT2i was effective in prevention of primary and secondary cardiovascular outcomes.

Keywords:  Cardiovascular death; Cardiovascular events; Meta-analysis; Myocardial infarction; SGLT2i

DOI:  https://doi.org/10.1016/j.hrtlng.2023.02.009
JCI Insight. 2023 Feb 21. pii: e164296. [Epub ahead of print]

Mapping the metabolic reprogramming induced by sodium-glucose cotransporter 2 inhibition.

Aviram Kogot-Levin, Yael Riahi, Ifat Abramovich, Ofri Mosenzon, Bella Agranovich, Liat Kadosh, Rachel Ben-Haroush Schyr, Doron Kleiman, Liad Hinden, Erol Cerasi, Danny Ben-Zvi, Ernesto Bernal-Mizrachi, Joseph Tam, Eyal Gottlieb, Gil Leibowitz.

  Diabetes is associated with increased risk for kidney and liver diseases, congestive heart failure, and mortality. Urinary glucose excretion using sodium-glucose cotransporter 2 (SGLT2) inhibitors prevents these adverse outcomes. We performed in vivo metabolic labeling with 13C-glucose in normoglycemic and diabetic mice treated with or without the SGLT2 inhibitor dapagliflozin, followed by simultaneous metabolomics and metabolic flux analyses in different organs and the plasma. We found that in diabetes, glycolysis and glucose oxidation are impaired in the kidney, liver, and heart. Treatment with dapagliflozin failed to rescue glycolysis and further inhibited pyruvate kinase activity in the liver. SGLT2 inhibition increased glucose oxidation in all organs; in the kidney, this effect was associated with modulation of the redox state, which may protect against oxidative stress. In addition, diabetes was associated with altered methionine cycle metabolism, evident by decreased betaine and methionine levels, whereas treatment with SGLT2i increased hepatic betaine along with decreased homocysteine levels. mTORC1 activity was inhibited by SGLT2i along with stimulation of AMPK in both normoglycemic and diabetic animals, possibly explaining the protective effects against kidney, liver, and heart diseases. Collectively, our findings suggest that SGLT2i induces metabolic reprogramming orchestrated by AMPK-mTORC1 signaling with common and distinct effects in various tissues with implications for diabetes and aging.

Keywords:  Diabetes; Glucose metabolism; Metabolism; Signal transduction; Therapeutics

DOI:  https://doi.org/10.1172/jci.insight.164296
Ann Pharmacother. 2023 Feb 17. 10600280231154021

Sodium-Glucose Cotransporter 2 Inhibitors Among Heart Failure With Mildly Reduced and Preserved Ejection Fraction.

Judy W M Cheng, Vincent Colucci, James S Kalus, Sarah A Spinler.

   OBJECTIVE: Results from large placebo-controlled randomized trials in patients with heart failure with mid-range ejection fraction (HFmrEF) and HF with preserved EF (HFpEF) have become available recently. This article discusses results of these clinical trials.
DATA SOURCES: Peer-reviewed articles were identified from MEDLINE (1966 to December 31, 2022) using search terms dapagliflozin, empagliflozin, SGLT-2Is, HFmrEF, and HFpEF.
STUDY SELECTION AND DATA EXTRACTION: Eight completed, pertinent clinical trials were included.
DATA SYNTHESIS: EMPEROR-Preserved, and DELIVER demonstrated that empagliflozin and dapagliflozin reduce CV death and heart failure hospitalization (HHF) in patients with HFmrEF and HFpEF, with/without diabetes when added to a standard heart failure (HF) regimen. The benefit is primarily due to reduction in HHF. Additional data from post hoc analyses of trials of dapagliflozin, ertugliflozin, and sotagliflozin suggest that these benefits may be a class effect. Benefits appear greatest in patients with left ventricular ejection fraction 41% up to about 65%.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: While many pharmacologic treatments have been proven to reduce mortality and improve cardiovascular (CV) outcomes in people with HFmrEF and HF with reduced EF (HFrEF), there are few therapy which improve CV outcome in people with HFpEF. SGLT-2I become one of the first class of pharmacologic agent that can be used to reduce HHF and CV mortality.
CONCLUSION: Studies showed that empagliflozin and dapagliflozin reduce the combined risk of CV death or HHF in patients with HFmrEF and HFpEF when added to a standard HF regimen. Given that benefit has now been demonstrated across the spectrum of HF, SGLT-2Is should be considered one of the standard HF pharmacotherapy.

Keywords:  heart failure with mildly reduced ejection fraction; heart failure with preserved ejection fraction; sodium-glucose co-transporter 2 inhibitors

DOI:  https://doi.org/10.1177/10600280231154021
Circ Heart Fail. 2023 Feb;16(2): e010283

A Sweet Solution for Heart Failure With Preserved Ejection Fraction: The Role of Sodium-Glucose Cotransporter-2 Inhibitors.

Ruben A Salazar, Steven C Stroud, Ersilia M DeFilippis.

DOI: https://doi.org/10.1161/CIRCHEARTFAILURE.122.010283
Curr Heart Fail Rep. 2023 Feb 18.

Cardiac Involvement in Mitochondrial Disorders.

Tudor-Alexandru Popoiu, Jan Dudek, Christoph Maack, Edoardo Bertero.

   PURPOSE OF REVIEW: We review pathophysiology and clinical features of mitochondrial disorders manifesting with cardiomyopathy.
RECENT FINDINGS: Mechanistic studies have shed light into the underpinnings of mitochondrial disorders, providing novel insights into mitochondrial physiology and identifying new therapeutic targets. Mitochondrial disorders are a group of rare genetic diseases that are caused by mutations in mitochondrial DNA (mtDNA) or in nuclear genes that are essential to mitochondrial function. The clinical picture is extremely heterogeneous, the onset can occur at any age, and virtually, any organ or tissue can be involved. Since the heart relies primarily on mitochondrial oxidative metabolism to fuel contraction and relaxation, cardiac involvement is common in mitochondrial disorders and often represents a major determinant of their prognosis.

Keywords:  Cardiolipin; Cardiomyopathy; Electron transport chain; Mitochondrial DNA; Mitochondrial disease

DOI:  https://doi.org/10.1007/s11897-023-00592-3