bims-hafaim 2025-03-23 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2025–03–23
seven papers selected by
Kyle McCommis, Saint Louis University

Heart ketone metabolism under acute ketone supplementation in ZDF rats, a type 2 diabetes heart failure model.
Ketone body metabolism and cardiometabolic implications for cognitive health.
SIRT6 mitigates doxorubicin-induced cardiomyopathy via amelioration of mitochondrial dysfunction: A mechanistic study implicating the activation of the Nrf-2/FUNDC1 signaling axis.
Mitochondrial quality control in cardiomyocytes: safeguarding the heart against disease and ageing.
Safety and efficacy of SGLT2 inhibitors in heart failure patients with ischemic and non-ischemic etiologies: a systematic review and meta-analyses.
Interleukin-6 in Heart Failure With Reduced Ejection Fraction and the Effect of Dapagliflozin: An Exploratory Analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure Trial.
Timing and Adherence Matter for Sodium-Glucose Cotransporter-2 Inhibitors in Heart Failure.

EJNMMI Res. 2025 Mar 14. 15(1): 23

Heart ketone metabolism under acute ketone supplementation in ZDF rats, a type 2 diabetes heart failure model.

Etienne Croteau, Gabriel Richard, Patrick Prud'Homme, Etienne Rousseau, Stephen C Cunnane, Véronique Dumulon-Perreault, Otman Sarrhini, Serge Phoenix, Sébastien Tremblay, Brigitte Guérin, Roger Lecomte.

   BACKGROUND: In non-insulin-dependent, type 2, diabetes mellitus (T2D), glucose metabolism is compromised, and the heart loses its metabolic flexibility. The Zucker Diabetic Fatty rat (ZDF) model, which replicates the pathophysiology of T2D in patients, shows that as T2D progresses so does heart failure. Heart ketone metabolism seems to play a role in mitigating the heart failure process. This study assesses ketone metabolism in a ZDF heart failure model using cardiac PET imaging.
METHODS: Six lean ZDF rats (CTRL) and six diabetic obese ZDF rats (T2D) were evaluated for coronary flow reserve (CFR) using [13N]ammonia ([13N]NH3) cardiac PET. In addition, rats were evaluated with [11C]acetoacetate ([11C]AcAc) PET during rest and stress conditions to assess ketone metabolism, both at baseline and under an acute exogenous ketone ester oral supplementation. Blood chemistry, cardiac function and hemodynamic parameters were also evaluated under these conditions.
RESULTS: CFR was impaired in the T2D model (CTRL: 1.8 ± 0.5; T2D: 1.4 ± 0.2, p < 0.05) suggesting the development of heart failure in the T2D model. Blood ketones increased more than 2-fold after supplementation. The [11C]AcAc heart ketone uptake values with and without ketone supplementation were similar for the CTRL group, and these values were higher than for T2D rats. For the T2D group, the uptake decreased by 20% at rest under ketone supplementation vs. no supplementation (p < 0.05) and remained unchanged under stress with and without supplementation. Because of this decrease at rest, the stress/rest ratio after supplementation increases to the level observed in CTRL. [11C]AcAc heart ketone metabolism showed a slight decrease under stress for the CTRL group, but not for the T2D. Under ketone supplementation, the metabolism stress/rest ratio increased only in T2D (1.25 ± 0.29, p = 0.03 compared to baseline).
CONCLUSION: In a rat model of T2D and CFR impairment, we were able to measure changes in ketone metabolism using [11C]AcAc PET at rest and under stress with and without acute ketone supplementation. Our findings suggest that the heart ketone metabolism of T2D rats is impaired during the heart failure process. Ketone supplementation may have the potential to restore this cardiac reserve.

Keywords:  Acetoacetate; Beta-hydroxybutyrate; Heart failure; Ketone bodies; Myocardial blood flow; Positron emission tomography; Type II diabetes

DOI:  https://doi.org/10.1186/s13550-025-01215-9
NPJ Metab Health Dis. 2024 ;pii: 29. [Epub ahead of print]2

Ketone body metabolism and cardiometabolic implications for cognitive health.

Kyle Fulghum, Sebastian F Salathe, Xin Davis, John P Thyfault, Patrycja Puchalska, Peter A Crawford.

Cardiometabolic complications of obesity present a growing public health concern and are associated with poor outcomes, mediated in part by an increased risk for cardiovascular disease, metabolic dysfunction-associated fatty liver disease, and systemic insulin resistance. Recent studies support that both insulin resistance and obesity are also associated with aberrant brain metabolism and cognitive impairment similar to what is observed in neurodegenerative diseases. Central to these pathological outcomes are adverse changes in tissue glucose and ketone body metabolism, suggesting that regulation of substrate utilization could be a mechanistic link between the cardiometabolic outcomes of obesity and the progression of cognitive decline. Here, we review ketone body metabolism in physiological and pathological conditions with an emphasis on the therapeutic potential of ketone bodies in treating cardiometabolic diseases and neurodegenerative diseases that lead to cognitive decline. We highlight recent findings in the associations among cardiometabolic disease, ketone body metabolism, and cognitive health while providing a theoretical framework by which ketone bodies may promote positive health outcomes and preserve cognitive function.

DOI: https://doi.org/10.1038/s44324-024-00029-y
Int J Med Sci. 2025 ;22(7): 1640-1657

SIRT6 mitigates doxorubicin-induced cardiomyopathy via amelioration of mitochondrial dysfunction: A mechanistic study implicating the activation of the Nrf-2/FUNDC1 signaling axis.

Qi Wang, Hongshuo Shi, Haowen Zhuang, Guangtong Dong, Kuo Gao, Leilei Liu, Hao Zhou, Yifeng Nie, Junyan Wang, Li Liu.

  Doxorubicin-induced myocardial injury, characterized by myocardial hypertrophy and heart failure (HF), represents a primary contributor to end-stage cardiovascular mortality associated with anthracycline drugs. Prior research has elucidated that SIRT6-mediated oxidative processes and mitochondrial metabolic reprogramming are pivotal in sustaining energy metabolism during mitochondrial damage in cardiomyocytes. In the aftermath of doxorubicin-induced myocardial injury, myocardial hypertrophy and fibrosis exacerbate the impairment of cardiac ejection function, resulting in elevated myocardial oxygen consumption. This condition is accompanied by disrupted ATP production, diminished mitochondrial biogenesis, and inadequate synthesis of new mitochondrial DNA, collectively triggering necroptosis and apoptosis pathways. Our preliminary experimental results have confirmed that SIRT6, associated with traditional medicine, exerts cardioprotective effects. Nevertheless, the interaction between SIRT6 and Nrf-2-mediated mitochondrial biogenesis in the context of doxorubicin-induced HF and myocardial hypertrophy remains inadequately understood. The generation of mitochondria is a key mechanism that is involved in DNA repair and cell cycle management.

Keywords:  Nrf-2; SIRT6; doxorubicin cardiomyopathy; mitochondrial biogenesis; necroptosis

DOI:  https://doi.org/10.7150/ijms.101520
Nat Rev Cardiol. 2025 Mar 20.

Mitochondrial quality control in cardiomyocytes: safeguarding the heart against disease and ageing.

Rishith Ravindran, Åsa B Gustafsson.

Mitochondria are multifunctional organelles that are important for many different cellular processes, including energy production and biosynthesis of fatty acids, haem and iron-sulfur clusters. Mitochondrial dysfunction leads to a disruption in these processes, the generation of excessive reactive oxygen species, and the activation of inflammatory and cell death pathways. The consequences of mitochondrial dysfunction are particularly harmful in energy-demanding organs such as the heart. Loss of terminally differentiated cardiomyocytes leads to cardiac remodelling and a reduced ability to sustain contraction. Therefore, cardiomyocytes rely on multilayered mitochondrial quality control mechanisms to maintain a healthy population of mitochondria. Mitochondrial chaperones protect against protein misfolding and aggregation, and resident proteases eliminate damaged proteins through proteolysis. Irreparably damaged mitochondria can also be degraded through mitochondrial autophagy (mitophagy) or ejected from cells inside vesicles. The accumulation of dysfunctional mitochondria in cardiomyocytes is a hallmark of ageing and cardiovascular disease. This accumulation is driven by impaired mitochondrial quality control mechanisms and contributes to the development of heart failure. Therefore, there is a strong interest in developing therapies that directly target mitochondrial quality control in cardiomyocytes. In this Review, we discuss the current knowledge of the mechanisms involved in regulating mitochondrial quality in cardiomyocytes, how these pathways are altered with age and in disease, and the therapeutic potential of targeting mitochondrial quality control pathways in cardiovascular disease.

DOI: https://doi.org/10.1038/s41569-025-01142-1
Egypt Heart J. 2025 Mar 19. 77(1): 32

Safety and efficacy of SGLT2 inhibitors in heart failure patients with ischemic and non-ischemic etiologies: a systematic review and meta-analyses.

Hasan Fareed Siddiqui, Adam Bilal Khan, Muhammad Moiz Nasir, Taleen Hashmi, Aisha Fareed Siddiqui, Hanzla Asim, Bushra Iqtidar Siddiqui.

   BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) show promise as a therapy for heart failure (HF); however, the safety and efficacy of SGLT2i in different HF etiologies are uncertain, thus arising the need for a meta-analyses.
MAIN TEXT: PubMed and Scopus were queried until May 2023 for studies comparing SGLT2i with placebo in HF patients with ischemic and non-ischemic etiologies. Meta-analyses were performed using risk ratio and hazard ratio. A fixed effect model was used. Outcomes assessed were hospitalization due to HF (HHF), cardiovascular death (CVD), CVD/HHF, all-cause mortality, volume depletion, fracture, and discontinuation of drug due to adverse effects. Four RCTs were included (15,676 patients). Analysis revealed no significant differences in CVD/HHF between ischemic [HR: 0.77 (0.70-0.86) P < 0.00001] and non-ischemic patients [HR: 0.72 (0.65-0.80) P < 0.00001] using SGLT2i (P = 0.35). Significant reductions were seen in HHF in both ischemic [RR 0.74 (0.65-0.84) P < 0.00001] and non-ischemic [RR 0.68 (0.59-0.78) P < 0.00001] patients (P = 0.39), with the effect more notable in the non-ischemic cohort. However, CVD significantly decreased in non-ischemic patients [RR 0.78 (0.63-0.95) P = 0.01], whereas no significant reduction was noted in ischemic patients [RR 0.94 (0.80-1.10) P = 0.43] (P-interaction = 0.15). All-cause mortality was significantly reduced in non-ischemic patients [RR 0.80 (0.67-0.96) P = 0.02] but not in ischemic patients [RR 0.96 (0.83-1.10) P = 0.52]. No significant safety events were observed in the SGLT2i cohort including volume depletion [RR 1.08 (0.94-1.25) P = 0.26], fracture [RR 1.02 (0.77-1.36) P = 0.88], or discontinuation of drug due to adverse effects [RR 0.97 (0.86-1.10) P = 0.65].
CONCLUSION: Similar CVD/HHF outcomes for ischemic and non-ischemic patients with SGLT2i. Significant HHF reductions in both groups. Non-ischemic patients showed greater improvements in CVD and all-cause mortality. However, no subgroup difference between ischemic and non-ischemic cause of heart failure was noted in our analysis.

Keywords:  All-cause mortality; Cardiovascular death; Heart failure; Hospitalization due to heart failure; Meta-analyses; Sodium-glucose cotransporter 2 inhibitors

DOI:  https://doi.org/10.1186/s43044-025-00623-5
JACC Heart Fail. 2025 Feb 26. pii: S2213-1779(25)00090-3. [Epub ahead of print]

Interleukin-6 in Heart Failure With Reduced Ejection Fraction and the Effect of Dapagliflozin: An Exploratory Analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure Trial.

Kieran F Docherty, Kirsty McDowell, Paul Welsh, Mark C Petrie, Inder Anand, David D Berg, Rudolf A de Boer, Lars Køber, Mikhail N Kosiborod, Felipe A Martinez, Eileen O'Meara, David A Morrow, Piotr Ponikowski, Marc S Sabatine, Naveed Sattar, Morten Schou, Ann Hammarstedt, Mikaela Sjöstrand, Anna Maria Langkilde, Pardeep S Jhund, Scott D Solomon, John J V McMurray.

   BACKGROUND: Inflammation may play an important pathophysiological role in the development and progression of heart failure (HF). Interleukin (IL)-6 is a circulating cytokine and is the main regulator of the release of C-reactive protein (CRP).
OBJECTIVES: The authors examined the association between IL-6 and high-sensitivity (hs)-CRP and outcomes in patients with HFrEF in the DAPA-HF trial and their relationship with the effect of dapagliflozin.
METHODS: Inclusion criteria included: 1) NYHA functional class II-IV; 2) left ventricular ejection fraction ≤40%; 3) elevated N-terminal pro-B-type natriuretic peptide; and 4) estimated glomerular filtration rate ≥30 mL/min/1.73 m2. The primary outcome was a composite of a worsening HF event or cardiovascular death. IL-6 and hs-CRP were measured at baseline and 12 months (Roche Diagnostics). The associations between IL-6 and hs-CRP and outcomes were adjusted for known prognostic variables, including NT-proBNP.
RESULTS: Among 2,940 patients, median IL-6 and hs-CRP at baseline were 6.01 pg/mL (Q1-Q3: 4.18-9.28 pg/mL) and 2.05 mg/L (Q1-Q3: 0.83-4.9 mg/L), respectively. Baseline IL-6 tertiles (T) were: T1 ≤4.72 pg/mL; T2 4.73-7.89 pg/mL; and T3 ≥7.90 pg/mL. The adjusted risks of the primary outcome relative to T1 were as follows: T2 = HR 1.34 (95% CI: 1.04-1.73) and T3 = HR 1.80 (95% CI: 1.41-2.31). A rise in IL-6 between baseline and 12 months was associated with worse outcomes. The beneficial effect of dapagliflozin on the primary outcome was consistent regardless of IL-6 concentration (continuous interaction P = 0.57), with similar results for hs-CRP. Dapagliflozin did not reduce IL-6 or hs-CRP at 12 months.
CONCLUSIONS: In DAPA-HF, elevated IL-6 and hs-CRP levels were each associated with the risk of worsening HF or cardiovascular death. Dapagliflozin reduced the risk of adverse outcomes regardless of baseline IL-6 or hs-CRP. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124).

Keywords:  SGLT2i; heart failure; inflammation; interleukin-6

DOI:  https://doi.org/10.1016/j.jchf.2024.12.012
J Am Heart Assoc. 2025 Mar 21. e037035

Timing and Adherence Matter for Sodium-Glucose Cotransporter-2 Inhibitors in Heart Failure.

Mehmet Birhan Yilmaz, Ahmet Celik, Anil Sahin, Tugce Colluoglu, Dilek Ural, Arzu Kanik, Naim Ata, Mustafa Mahir Ulgu, Şuayip Birinci.

   BACKGROUND: It is imperative to maintain the use of sodium-glucose cotransporter-2 inhibitors (SGLT-2is) in patients with diabetes both after the index diagnosis of heart failure (HF) and even prior to the index diagnosis of HF. We aimed to investigate whether timing of SGLT-2 is before the index diagnosis of HF, and second, adherence to SGLT-2is in the form of the proportion of days covered metric matter in patients with HF and diabetes.
METHODS AND RESULTS: All-cause death up to 7 years were evaluated in HF with diabetes from the subgroup analysis of TRends-HF (TRends in Heart Failure in Türkiye). Patients with HF and diabetes, who were prescribed an SGLT-2i either before or after the index diagnosis of HF were identified, categorized according to duration of exposure before the index HF diagnosis and according to proportion of days covered after the index diagnosis of HF, and compared with nonusers. There were 1 229 833 patients with HF and diabetes in the cohort. A total of 247 987 were on an SGLT-2i and had available timing data, and 14.06% had SGLT-2i on board before the index HF diagnosis. Median duration of SGLT-2i exposure before the index HF diagnosis was 417 days. Prognosis was the best among patients with diabetes who were prescribed an SGLT-2i before the index diagnosis of HF with an exposure more than median duration. Of note, among patients who were prescribed an SGLT-2i after the index HF diagnosis; there was a numerically graded increase in all-cause mortality rate such that a >10% decrease in SGLT-2i proportion of days covered was associated with a 59% increase in all-cause death (hazard ratio, 1.21-2.09).
CONCLUSIONS: Regardless of time or adherence, SGLT-2is offer a remarkable all-cause death benefit to patients with HF and diabetes. SGLT-2is' all-cause death benefit for patients with HF and diabetes was greatest when it was prescribed before the HF index diagnosis. Poor adherence to SGLT-2is was associated with worsening survival in patients with HF and diabetes following the diagnosis of index HF.

Keywords:  SGLT‐2 inhibitors; adherence; diabetes; heart failure; timing

DOI:  https://doi.org/10.1161/JAHA.124.037035