bims-hafaim 2023-08-27 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2023–08–27
eight papers selected by
Kyle McCommis, Saint Louis University

Efficacy of Dapagliflozin According to Geographic Location of Patients With Heart Failure.
Comparative Metabolomics in Single Ventricle Patients after Fontan Palliation: A Strong Case for a Targeted Metabolic Therapy.
SIRT6 mediated histone H3K9ac deacetylation involves myocardial remodelling through regulating myocardial energy metabolism in TAC mice.
Increased acylcarnitines in infant heart failure indicate fatty acid oxidation inhibition: towards therapeutic options?
Association between Dapagliflozin, Cardiac Biomarkers and Cardiac Remodeling in Patients with Diabetes Mellitus and Heart Failure.
Elevated Plasma Levels of Ketone Bodies Are Associated With All-Cause Mortality and Incidence of Heart Failure in Older Adults: The CHS.
Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors in Heart Failure: An Umbrella Review.
Inhibition of pyruvate dehydrogenase kinase 4 attenuates myocardial and mitochondrial injury in sepsis-induced cardiomyopathy.

J Am Coll Cardiol. 2023 Aug 02. pii: S0735-1097(23)05964-8. [Epub ahead of print]

Efficacy of Dapagliflozin According to Geographic Location of Patients With Heart Failure.

Toru Kondo, Xiaowen Wang, Mingming Yang, Pardeep S Jhund, Brian L Claggett, Muthiah Vaduganathan, Adrian F Hernandez, Carolyn S P Lam, Silvio E Inzucchi, Felipe A Martinez, Rudolf A de Boer, Mikhail N Kosiborod, Akshay S Desai, Lars Køber, Piotr Ponikowski, Marc S Sabatine, Anna Maria Langkilde, Magnus Petersson, Natalia Zaozerska, Erasmus Bachus, Scott D Solomon, John J V McMurray.

   BACKGROUND: Because clinical characteristics and prognosis vary by geographic region in patients with heart failure (HF), the response to treatment may also vary. A previous report suggested that the efficacy of sodium-glucose cotransporter-2 inhibitor efficacy in heart failure with reduced ejection fraction (HFrEF) may be modified by region.
OBJECTIVES: The goal of this study was to examine the efficacy and safety of dapagliflozin in patients with HF according to geographic region.
METHODS: We conducted a patient-level pooled analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trials, which evaluated the effects of dapagliflozin in HFrEF and heart failure with mildly reduced ejection fraction (HFmrEF)/heart failure with preserved ejection fraction (HFpEF), respectively. The primary outcome was the composite of worsening HF or cardiovascular death.
RESULTS: Among 11,007 patients, 5,159 (46.9%) were enrolled in Europe, 1,528 (13.9%) in North America, 1,998 (18.2%) in South America, and 2,322 (21.1%) in Asia. The rate of the primary outcome (per 100 person-years) was higher in North America (13.9 [95% CI: 12.5-15.4]) than in other regions: Europe 10.8 (95% CI: 10.1-11.5), South America 10.0 (95% CI: 9.0-11.1), and Asia 10.5 (95% CI: 9.5-11.5). The benefit of dapagliflozin on the primary outcome was not modified by region: dapagliflozin vs placebo HR: Europe, 0.85 (95% CI: 0.75-0.96); North America, 0.75 (95% CI: 0.61-0.93); South America, 0.72 (95% CI: 0.58-0.89); and Asia, 0.74 (95% CI: 0.61-0.91) (P interaction = 0.40). This was the same when evaluated separately for HFrEF (P interaction = 0.39) and HFmrEF/HFpEF (P interaction = 0.84). Patients in North America discontinued randomized treatment more frequently than did those elsewhere (placebo discontinuation: 21.8% in North America vs 6.4% in South America), but discontinuation rates did not differ between placebo and dapagliflozin by region.
CONCLUSIONS: The efficacy and safety of dapagliflozin were consistent across global regions despite geographic differences in patient characteristics, background treatment, and event rates.

Keywords:  clinical trial; geographic region; heart failure; sodium-glucose cotransporter-2 inhibitors

DOI:  https://doi.org/10.1016/j.jacc.2023.05.056
Metabolites. 2023 Aug 09. pii: 932. [Epub ahead of print]13(8):

Comparative Metabolomics in Single Ventricle Patients after Fontan Palliation: A Strong Case for a Targeted Metabolic Therapy.

David Renaud, Sabine Scholl-Bürgi, Daniela Karall, Miriam Michel.

  Most studies on single ventricle (SV) circulation take a physiological or anatomical approach. Although there is a tight coupling between cardiac contractility and metabolism, the metabolic perspective on this patient population is very recent. Early findings point to major metabolic disturbances, with both impaired glucose and fatty acid oxidation in the cardiomyocytes. Additionally, Fontan patients have systemic metabolic derangements such as abnormal glucose metabolism and hypocholesterolemia. Our literature review compares the metabolism of patients with a SV circulation after Fontan palliation with that of patients with a healthy biventricular (BV) heart, or different subtypes of a failing BV heart, by Pubmed review of the literature on cardiac metabolism, Fontan failure, heart failure (HF), ketosis, metabolism published in English from 1939 to 2023. Early evidence demonstrates that SV circulation is not only a hemodynamic burden requiring staged palliation, but also a metabolic issue with alterations similar to what is known for HF in a BV circulation. Alterations of fatty acid and glucose oxidation were found, resulting in metabolic instability and impaired energy production. As reported for patients with BV HF, stimulating ketone oxidation may be an effective treatment strategy for HF in these patients. Few but promising clinical trials have been conducted thus far to evaluate therapeutic ketosis with HF using a variety of instruments, including ketogenic diet, ketone esters, and sodium-glucose co-transporter-2 (SGLT2) inhibitors. An initial trial on a small cohort demonstrated favorable outcomes for Fontan patients treated with SGLT2 inhibitors. Therapeutic ketosis is worth considering in the treatment of Fontan patients, as ketones positively affect not only the myocardial energy metabolism, but also the global Fontan physiopathology. Induced ketosis seems promising as a concerted therapeutic strategy.

Keywords:  Fontan; biventricular; heart failure; ketogenic therapy; ketones; metabolism; nutrition; single ventricle

DOI:  https://doi.org/10.3390/metabo13080932
J Cell Mol Med. 2023 Aug 21.

SIRT6 mediated histone H3K9ac deacetylation involves myocardial remodelling through regulating myocardial energy metabolism in TAC mice.

Shuqi Wu, Jiaojiao Zhang, Chang Peng, Yixiang Ma, Xiaochun Tian.

  Pathological myocardial remodelling is the initial factor of chronic heart failure (CHF) and is induced by multiple factors. We previously demonstrated that histone acetylation is involved in CHF in transverse aortic constriction (TAC) mice, a model for pressure overload-induced heart failure. In this study, we investigated whether the histone deacetylase Sirtuin 6 (SIRT6), which mediates deacetylation of histone 3 acetylated at lysine 9 (H3K9ac), is involved pathological myocardial remodelling by regulating myocardial energy metabolism and explored the underlying mechanisms. We generated a TAC mouse model by partial thoracic aortic banding. TAC mice were injected with the SIRT6 agonist MDL-800 at a dose of 65 mg/kg for 8 weeks. At 4, 8 and 12 weeks after TAC, the level of H3K9ac increased gradually, while the expression of SIRT6 and vascular endothelial growth factor A (VEGFA) decreased gradually. MDL-800 reversed the effects of SIRT6 on H3K9ac in TAC mice and promoted the expression of VEGFA in the hearts of TAC mice. MDL-800 also attenuated mitochondria damage and improved mitochondrial respiratory function through upregulating SIRT6 in the hearts of TAC mice. These results revealed a novel mechanism in which SIRT6-mediated H3K9ac level is involved pathological myocardial remodelling in TAC mice through regulating myocardial energy metabolism. These findings may assist in the development of novel methods for preventing and treating pathological myocardial remodelling.

Keywords:  SIRT6; energy metabolism; histone deacetylation; mechanism; myocardial remodelling

DOI:  https://doi.org/10.1111/jcmm.17915
ESC Heart Fail. 2023 Aug 23.

Increased acylcarnitines in infant heart failure indicate fatty acid oxidation inhibition: towards therapeutic options?

Jean Issa, Pierre Lodewyckx, Hélène Blasco, Isabelle Benz-de-Bretagne, François Labarthe, Bruno Lefort.

   AIMS: Heart failure in adults is characterized by reduction of long-chain fatty acid oxidation in favour of carbohydrate metabolism. This adaptive phenomenon becomes maladaptive because energy conversion decreases and lipid toxic derivatives known to impair cardiac function are accumulating. No data are available concerning metabolic modification in heart failure in children.
METHODS AND RESULTS: In order to evaluate the fatty acid oxidation in children suffering from heart failure, acylcarnitine profiles on dried blood spots were obtained from children under 16 years old with dilated cardiomyopathy and clinical heart failure (DCM-HF) and control children. Nine children were included in the DCM-HF group and eight in the control group. Acylcarnitine profiles revealed a significant 3.1-fold increase of total acylcarnitines (sum of C3 to C18 acylcarnitine species) in DCM-HF children compared with controls. This result persisted considering the sum of long-chain acylcarnitines (sum of C14 to C18 species), medium-chain acylcarnitines (sum of C8 to C12 species), and short-chain acylcarnitines (sum of C3 to C6 species), respectively, 2.0-, 2.6-, and 1.9-fold increase compared with the control group. A significant linear correlation was found between left ventricular dilatation or ejection fraction and acylcarnitines accumulation. Finally, acylcarnitine ratio C16OH/C16 and C18OH/C18 enhanced in the DCM-HF group, suggesting a diminution of the long-chain hydroxyl acyl-CoA dehydrogenase activity.
CONCLUSIONS: Our results suggest down-regulation of fatty acid oxidation in children with heart failure. Such lipidomic alteration could worsen heart function and may suggest considering a metabolic treatment of heart failure in children.

Keywords:  Acylcarnitines; Children; Dilated cardiomyopathy; Fatty acid beta-oxidation; Heart failure

DOI:  https://doi.org/10.1002/ehf2.14449
Life (Basel). 2023 Aug 20. pii: 1778. [Epub ahead of print]13(8):

Association between Dapagliflozin, Cardiac Biomarkers and Cardiac Remodeling in Patients with Diabetes Mellitus and Heart Failure.

Andrew Xanthopoulos, Nikolaos Katsiadas, Spyridon Skoularigkis, Dimitrios E Magouliotis, Niki Skopeliti, Sotirios Patsilinakos, Alexandros Briasoulis, Filippos Triposkiadis, John Skoularigis.

  Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are a relatively new class of antidiabetic drugs that have shown favorable effects in heart failure (HF) patients, irrespective of the left ventricular ejection fraction (LVEF). Recent studies have demonstrated the beneficial effects of empagliflozin on cardiac function and structure; however, less is known about dapagliflozin. The purpose of the current work was to investigate the association between the use of dapagliflozin and cardiac biomarkers as well as the cardiac structure in a cohort of patients with HF and diabetes mellitus (DM). The present work was an observational study that included 118 patients (dapagliflozin group n = 60; control group n = 58) with HF and DM. The inclusion criteria included: age > 18 years, a history of DM and HF, regardless of LVEF, and hospitalization for HF exacerbation within the previous 6 months. The exclusion criteria were previous treatment with SGLT2i or glucagon-like peptide-1 receptor agonists, a GFR< 30 and life expectancy < 1 year. The evaluation of patients (at baseline, 6 and 12 months) included a clinical assessment, laboratory blood tests and echocardiography. The Mann-Whitney test was used for the comparison of continuous variables between the two groups, while Friedman's analysis of variance for repeated measures was used for the comparison of continuous variables. Troponin (p < 0.001) and brain natriuretic peptide (BNP) (p < 0.001) decreased significantly throughout the follow-up period in the dapagliflozin group, but not in the control group (p > 0.05 for both). The LV end-diastolic volume index (p < 0.001 for both groups) and LV end-systolic volume index (p < 0.001 for both groups) decreased significantly in the dapagliflozin and the control group, respectively. The LVEF increased significantly (p < 0.001) only in the dapagliflozin group, whereas the global longitudinal strain (GLS) improved in the dapagliflozin group (p < 0.001) and was impaired in the control group (p = 0.021). The left atrial volume index decreased in the dapagliflozin group (p < 0.001) but remained unchanged in the control group (p = 0.114). Lastly, the left ventricular mass index increased significantly both in the dapagliflozin (p = 0.003) and control group (p = 0.001). Dapagliflozin, an SGLT2i, was associated with a reduction in cardiac biomarkers and with reverse cardiac remodeling in patients with HF and DM.

Keywords:  dapagliflozin; diabetes mellitus; heart failure; remodeling; sodium glucose cotransporter-2 inhibitors

DOI:  https://doi.org/10.3390/life13081778
J Am Heart Assoc. 2023 Aug 23. e029960

Elevated Plasma Levels of Ketone Bodies Are Associated With All-Cause Mortality and Incidence of Heart Failure in Older Adults: The CHS.

Sebastian Niezen, Margery A Connelly, Calvin Hirsch, Jorge R Kizer, Maria E Benitez, Scott Minchenberg, Maria Camila Perez-Matos, Zhenghui Gordon Jiang, Kenneth J Mukamal.

  Background Chronic disease, such as heart failure, influences cellular metabolism and shapes circulating metabolites. The relationships between key energy metabolites and chronic diseases in aging are not well understood. This study aims to determine the relationship between main components of energy metabolism with all-cause mortality and incident heart failure. Methods and Results We analyzed the association between plasma metabolite levels with all-cause mortality and incident heart failure among US older adults in the CHS (Cardiovascular Health Study). We followed 1758 participants without heart failure at baseline with hazard ratios (HRs) of analyte levels and metabolic profiles characterized by high levels of ketone bodies for all-cause mortality and incident heart failure. Multivariable Cox analyses revealed a dose-response relationship of 50% increase in all-cause mortality between lowest and highest quintiles of ketone body concentrations (HR, 1.5 [95% CI, 1.0-1.9]; P=0.007). Ketone body levels remained associated with incident heart failure after adjusting for cardiovascular disease confounders (HR, 1.2 [95% CI, 1.0-1.3]; P=0.02). Using K-means cluster analysis, we identified a cluster with higher levels of ketone bodies, citrate, interleukin-6, and B-type natriuretic peptide but lower levels of pyruvate, body mass index, and estimated glomerular filtration rate. The cluster with elevated ketone body levels was associated with higher all-cause mortality (HR, 1.7 [95% CI, 1.1-2.7]; P=0.01). Conclusions Higher concentrations of ketone bodies predict incident heart failure and all-cause mortality in an older US population, independent of metabolic and cardiovascular confounders. This association suggests a potentially important relationship between ketone body metabolism and aging.

Keywords:  aging; heart failure; ketone bodies; metabolism; mortality

DOI:  https://doi.org/10.1161/JAHA.123.029960
Cureus. 2023 Jul;15(7): e42113

Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors in Heart Failure: An Umbrella Review.

Raj Roy, Saketh Vinjamuri, Rishabh Baskara Salian, Nosheen Hafeez, Dakshin Meenashi Sundaram, Tirath Patel, Thulasi Ram Gudi, Advait M Vasavada.

  Heart failure remains a leading cause of hospitalization and death, and presents a significant challenge for healthcare providers despite the advancements in its management. This umbrella review aimed to pool the results of meta-analyses on the use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors in the treatment of heart failure patients. A literature search was done on five databases: PubMed, Cochrane Library, Scopus, Global Index Medicus, and Science Direct for articles with full texts available online. Meta-analyses of five or more randomized controlled trials (RCTs) were included; the assessment of multiple systematic reviews (AMSTAR) was used to assess the quality of included studies. A systematic search identified 10 relevant meta-analyses of RCTs, with primary analyses including outcome data from 171,556 heart failure patients. A pooled review showed that SGLT-2 inhibitors significantly reduced the risk of heart failure hospitalization, cardiovascular death, mortality, serious adverse events, and improved quality of life. SGLT-2 inhibitors are likely safe and effective in managing patients with heart failure especially considering the acute outcomes.

Keywords:  cardiology research; heart failure hospitalization; heart failure prognosis; sglt2 inhibitors and heart failure; sodium-glucose cotransporter-2 (sglt-2) inhibitors

DOI:  https://doi.org/10.7759/cureus.42113
J Infect Dis. 2023 Aug 25. pii: jiad365. [Epub ahead of print]

Inhibition of pyruvate dehydrogenase kinase 4 attenuates myocardial and mitochondrial injury in sepsis-induced cardiomyopathy.

Tangtian Chen, Liang Ye, Jing Zhu, Bin Tan, Qin Yi, Yanting Sun, Qiumin Xie, Han Xiang, Rui Wang, Jie Tian, Hao Xu.

   BACKGROUND: Sepsis-induced cardiomyopathy (SIC) is a cardiac dysfunction caused by sepsis, with mitochondrial dysfunction being a critical contributor. Pyruvate dehydrogenase kinase 4 (PDK4) is a kinase of pyruvate dehydrogenase (PDH) with multifaceted actions in mitochondrial metabolism. However, its role in SIC remains unknown.
METHODS: Serum PDK4 levels were measured and analyzed in 27 SIC children, 30 septic children, and 29 healthy children. In addition, the effects of PDK4 knockdown or inhibition on the function and structure of the myocardium and mitochondria of mice exhibiting SIC were assessed.
RESULTS: The findings from the analysis of children with SIC revealed that PDK4 was significantly elevated and correlated with disease severity and organ injury. SIC nonsurvivors displayed higher serum PDK4 levels than survivors. Furthermore, mice with SIC benefited from PDK4 knockdown or inhibition, showing improved myocardial contractile function, reduced myocardial injury, and decreased mitochondrial structural injury and dysfunction. In addition, inhibition of PDK4 decreased the inhibitory phosphorylation of pyruvate dehydrogenase complex E1 subunit alpha (PDHE1α), improved abnormal pyruvate metabolism and mitochondrial dysfunction.
CONCLUSIONS: PDK4 is a potential biomarker for the diagnosis and prognosis of SIC. In experimental SIC, PDK4 promotes mitochondrial dysfunction with increased phosphorylation of PDHE1α and abnormal pyruvate metabolism.

Keywords:  Mitochondrial dysfunction; PDHE1α; PDK4; Pyruvate metabolism; Sepsis-induced cardiomyopathy

DOI:  https://doi.org/10.1093/infdis/jiad365