bims-hafaim 2023-08-13 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2023‒08‒13
eight papers selected by
Kyle McCommis
Saint Louis University

[Potential implications of ketone body metabolism changes and ketogenic therapy in the treatment of heart failure].
Driving force of deteriorated cellular environment in heart failure: Metabolic remodeling.
The Impact of SGLT2 Inhibitors on Cardiovascular Outcomes in Patients With Heart Failure With Preserved Ejection Fraction.
The role of mitochondria in myocardial damage caused by energy metabolism disorders: From mechanisms to therapeutics.
Polymorphic variants at NDUFC2, encoding a mitochondrial complex I subunit, associate with cardiac hypertrophy in human hypertension.
Short-term outcomes after sodium-glucose cotransporter-2 inhibitor initiation in a cohort of heart failure patients.
Mitochondrial metabolites predict adverse cardiovascular events in individuals with diabetes.
Empagliflozin improves cardiac function in rats with chronic heart failure.

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2023 Jul;35(7): 769-772

[Potential implications of ketone body metabolism changes and ketogenic therapy in the treatment of heart failure].

Qiong Wang, Siyu Yan, Shuyu Kuang, Mengmeng Zhou, Chunling Jiang.

Heart failure (HF) has become a major challenge in the treatment of global cardiovascular diseases. Great progress has been made in the drug treatment of HF, however, rehospitalization rate and mortality of patients with HF are still high. Hence, there is an urgent need to explore new treatment strategy and new underlying pathogenic mechanisms. In recent years, some researchers have suggested that regulation of ketone body metabolism may become a potentially promising therapeutic approach for HF. Some studies showed that the oxidative utilization of fatty acids and glucose was decreased in the failing heart, accompanied by the increase of ketone body oxidative metabolism. The enhancement of ketone body metabolism in HF is a compensatory change during HF. The failing heart preferentially uses ketone body oxidation to provide energy, which helps to improve the body's cardiac function. This review will discuss the potential significance of ketone body metabolism in the treatment of HF from three aspects: normal myocardial ketone body metabolism, the change of ketone body metabolism in HF, the effect of ketogenic therapy on HF and its treatment.

DOI: https://doi.org/10.3760/cma.j.cn121430-20221008-00891
Clinics (Sao Paulo). 2023 Aug 07. pii: S1807-5932(23)00099-6. [Epub ahead of print]78 100263

Driving force of deteriorated cellular environment in heart failure: Metabolic remodeling.

Lu Fan, Chenchen Meng, Xiaoming Wang, Yunjiao Wang, Yanyang Li, Shichao Lv, Junping Zhang.

  Heart Failure (HF) has been one of the leading causes of death worldwide. Though its latent mechanism and therapeutic manipulation are updated and developed ceaselessly, there remain great gaps in the cognition of heart failure. High morbidity and readmission rates among HF patients are waiting to be addressed. Recent studies have found that myocardial energy metabolism was closely related to heart failure, in which substrate utilization, as well as intermediate metabolism disorders, insulin resistance, oxidative stress, and mitochondrial dysfunction, might underlie systolic dysfunction and progression of HF. This article centers on the changes and counteraction of cardiac energy metabolism in the failing heart. Therefore, targeting impaired energy provision is of great potential in the treatment of HF. And shifting the objective from traditional neurohormones to improving the cellular environment is expected to further optimize the management of HF.

Keywords:  Deteriorated cellular environment; Heart failure; Metabolic remodeling; Pharmacological agents; Physiological metabolism; Stem cells

DOI:  https://doi.org/10.1016/j.clinsp.2023.100263
Ann Pharmacother. 2023 Aug 05. 10600280231189508

The Impact of SGLT2 Inhibitors on Cardiovascular Outcomes in Patients With Heart Failure With Preserved Ejection Fraction.

Jessica A Starr, Nathan A Pinner.

  OBJECTIVE: To evaluate the role of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with heart failure with preserved ejection fraction (HFpEF).DATA SOURCES: A literature search of PubMed, the Cochrane Library, and Google Scholar databases (January 2015 to June 20, 2023) was performed with keywords: sodium-glucose co-transporter 2 inhibitors OR SGLT2 inhibitors OR bexagliflozin OR canagliflozin OR dapagliflozin OR empagliflozin OR ertugliflozin OR sotagliflozin AND heart failure OR heart failure with preserved ejection fraction, and terms related to CV outcomes including cardiovascular death, hospitalization, hospitalization for heart failure, mortality, death, and major adverse cardiovascular event (MACE).
STUDY SELECTION AND DATA EXTRACTION: The reference list from retrieved articles as well as relevant review articles was considered. Pivotal randomized controlled trials and meta-analyses with a primary or secondary end point of CV death or heart failure hospitalization were included. Studies conducted solely in a diabetic patient population were excluded.
DATA SYNTHESIS: Dapagliflozin and empagliflozin, in a broad population of heart failure patients including, HFrEF, HFmrEF, HFpEF, and without diabetes, have shown consistent improvement in the combined outcome of CV death and hospitalization for heart failure (HR 0.80, 95% CI 0.73-0.87) and in the reduction of heart failure hospitalizations (HR 0.74, 95% CI 0.67-0.83). In patients with HFpEF, cardiovascular mortality was not demonstrated (HR 0.88, 95% CI 0.77-1.00). Rates of adverse events were low.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Patients with HFpEF and NYHA class II-III with frequent symptoms or hospitalizations for heart failure derive the most benefit from SGLT2 inhibitors with an overall goal of a reduction in heart failure hospitalizations.
CONCLUSIONS: The treatment of HFpEF has made progress, but there is still work to be done. Now, SGLT2 inhibitor therapy can be used to further help with symptom control and reduce overall hospitalizations for heart failure.

Keywords:  SGLT2 inhibitors; cardiovascular outcomes; dapagliflozin; diabetes; empagliflozin; heart failure; heart failure with preserved ejection fraction

DOI:  https://doi.org/10.1177/10600280231189508
Free Radic Biol Med. 2023 Aug 09. pii: S0891-5849(23)00581-6. [Epub ahead of print]

The role of mitochondria in myocardial damage caused by energy metabolism disorders: From mechanisms to therapeutics.

Ao-Lin Li, Lu Lian, Xin-Nong Chen, Wen-Hui Cai, Xin-Biao Fan, Ya-Jie Fan, Ting-Ting Li, Ying-Yu Xie, Jun-Ping Zhang.

  Myocardial damage is the most serious pathological consequence of cardiovascular diseases and an important reason for their high mortality. In recent years, because of the high prevalence of systemic energy metabolism disorders (e.g., obesity, diabetes mellitus, and metabolic syndrome), complications of myocardial damage caused by these disorders have attracted widespread attention. Energy metabolism disorders are independent of traditional injury-related risk factors, such as ischemia, hypoxia, trauma, and infection. An imbalance of myocardial metabolic flexibility and myocardial energy depletion are usually the initial changes of myocardial injury caused by energy metabolism disorders, and abnormal morphology and functional destruction of the mitochondria are their important features. Specifically, mitochondria are the centers of energy metabolism, and recent evidence has shown that decreased mitochondrial function, caused by an imbalance in mitochondrial quality control, may play a key role in myocardial injury caused by energy metabolism disorders. Under chronic energy stress, mitochondria undergo pathological fission, while mitophagy, mitochondrial fusion, and biogenesis are inhibited, and mitochondrial protein balance and transfer are disturbed, resulting in the accumulation of nonfunctional and damaged mitochondria. Consequently, damaged mitochondria lead to myocardial energy depletion and the accumulation of large amounts of reactive oxygen species, further aggravating the imbalance in mitochondrial quality control and forming a vicious cycle. In addition, impaired mitochondria coordinate calcium homeostasis imbalance, and epigenetic alterations participate in the pathogenesis of myocardial damage. These pathological changes induce rapid progression of myocardial damage, eventually leading to heart failure or sudden cardiac death. To intervene more specifically in the myocardial damage caused by metabolic disorders, we need to understand the specific role of mitochondria in this context in detail. Accordingly, promising therapeutic strategies have been proposed. We also summarize the existing therapeutic strategies to provide a reference for clinical treatment and developing new therapies.

Keywords:  Calcium homeostasis; Energy metabolism; Epigenetics; Mitochondria; Mitochondrial quality control; Myocardial damage; Oxidative stress; Therapy

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.08.009
Mol Med. 2023 Aug 09. 29(1): 107

Polymorphic variants at NDUFC2, encoding a mitochondrial complex I subunit, associate with cardiac hypertrophy in human hypertension.

Giovanna Gallo, Maurizio Forte, Maria Cotugno, Simona Marchitti, Rosita Stanzione, Giuliano Tocci, Franca Bianchi, Silvia Palmerio, Mariarosaria Scioli, Giacomo Frati, Sebastiano Sciarretta, Emanuele Barbato, Massimo Volpe, Speranza Rubattu.

  BACKGROUND: A dysfunction of NADH dehydrogenase, the mitochondrial Complex I (CI), associated with the development of left ventricular hypertrophy (LVH) in previous experimental studies. A deficiency of Ndufc2 (subunit of CI) impairs CI activity causing severe mitochondrial dysfunction. The T allele at NDUFC2/rs11237379 variant associates with reduced gene expression and impaired mitochondrial function. The present study tested the association of both NDUFC2/rs11237379 and NDUFC2/rs641836 variants with LVH in hypertensive patients. In vitro studies explored the impact of reduced Ndufc2 expression in isolated cardiomyocytes.METHODS: Two-hundred-forty-six subjects (147 male, 59.7%), with a mean age of 59 ± 15 years, were included for the genetic association analysis. Ndufc2 silencing was performed in both H9c2 and rat primary cardiomyocytes to explore the hypertrophy development and the underlying signaling pathway.
RESULTS: The TT genotype at NDUFC2/rs11237379 associated with significantly reduced gene expression. Multivariate analysis revealed that patients carrying this genotype showed significant differences for septal thickness (p = 0.07), posterior wall thickness (p = 0.008), RWT (p = 0.021), LV mass/BSA (p = 0.03), compared to subjects carrying either CC or CT genotypes. Patients carrying the A allele at NDUFC2/rs641836 showed significant differences for septal thickness (p = 0.017), posterior wall thickness (p = 0.011), LV mass (p = 0.003), LV mass/BSA (p = 0.002) and LV mass/height2.7(p = 0.010) after adjustment for covariates. In-vitro, the Ndufc2 deficiency-dependent mitochondrial dysfunction caused cardiomyocyte hypertrophy, pointing to SIRT3-AMPK-AKT-MnSOD as a major underlying signaling pathway.
CONCLUSIONS: We demonstrated for the first time a significant association of NDUFC2 variants with LVH in human hypertension and highlight a key role of Ndufc2 deficiency-dependent CI mitochondrial dysfunction on increased susceptibility to cardiac hypertrophy development.

Keywords:  Cardiac hypertrophy; Hypertension; Mitochondrial complex I; Mitochondrial dysfunction; NDUFC2; SIRT3

DOI:  https://doi.org/10.1186/s10020-023-00701-x
ESC Heart Fail. 2023 Aug 07.

Short-term outcomes after sodium-glucose cotransporter-2 inhibitor initiation in a cohort of heart failure patients.

Bryan O Pérez Martínez, Sarah K Adie, Vincent D Marshall, Matthew C Konerman.

  AIMS: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) decrease mortality and risk of hospitalization in patients with heart failure with reduced ejection fraction (HFrEF). SGLT2i have a natriuretic effect shortly after initiation, followed by a lasting osmotic diuretic effect. We sought to evaluate rates of acute kidney injury (AKI) and therapy discontinuation with SGLT2i initiation in a real-world cohort of HFrEF patients.METHODS AND RESULTS: We abstracted data on 200 patients with HFrEF initiated on a SGLT2i in the outpatient setting at the University of Michigan (between 1 July 2016 and 2 July 2022). Our co-primary endpoints were rate of AKI and discontinuation of SGLT2i. A total of 200 patients were included. The majority of patients were male (64%) with a mean left ventricular ejection fraction (LVEF) of 27%. One hundred and four (52%) patients had diabetes mellitus. Most patients exhibited New York Heart Association class II (51.5%) or III (33.5%) symptoms. The majority of patients (54%) were taking an angiotensin-receptor neprilysin inhibitor. The mean daily furosemide equivalent diuretic dose was 93.3 mg. AKI occurred in 22 patients and 18 patients discontinued their SGLT2i. Yeast infection (n = 6), hypotension (n = 5), and AKI (n = 4) were the most common reasons for discontinuation. Using receiver operating characteristic curve analysis, the strongest models for AKI were A1C [area underneath its curve (AUC) = 75.8, empirical confidence interval (ECI) 66.5-83.5]; baseline serum creatinine (SCr) (AUC = 72.0, ECI 65.7-78.7); LVEF (AUC = 67.6, ECI 58.4-75.8); and furosemide equivalent diuretic dose (AUC = 66.0, ECI 57.5-74.6). Similarly, the strongest positive models for SGLT2i discontinuation were A1C (AUC = 81.1, ECI 74.8-87.2); baseline SCr (AUC = 67.4, ECI 58.7-75.5); LVEF (AUC = 68.7, ECI 58.9-76.5); and furosemide equivalent diuretic dose (AUC = 67.2, ECI 58.2-76.0).
CONCLUSIONS: A1C was the strongest model of AKI, and SGLT2i discontinuation in HFrEF patients started on SGLT2i. Glucosuria may be related to this effect. Patients with higher baseline SCr on higher doses of loop diuretics may be at greater risk of these outcomes. Future prospective studies will be needed to further evaluate these findings and other models of AKI and SGLT2i discontinuation to guide clinical use of SGLT2 inhibitors.

Keywords:  Acute kidney injury; Cardiovascular disease; Diabetes; Heart failure; SGLT2i

DOI:  https://doi.org/10.1002/ehf2.14489
JCI Insight. 2023 Aug 08. pii: e168563. [Epub ahead of print]

Mitochondrial metabolites predict adverse cardiovascular events in individuals with diabetes.

Jessica A Regan, Robert J Mentz, Maggie Nguyen, Jennifer B Green, Lauren K Truby, Olga Ilkayeva, Christopher Newgard, John B Buse, Harald Sourij, C David Sjöström, Naveed Sattar, Robert W McGarrah, Yinggan Zheng, Darren K McGuire, Eberhard Standl, Paul Armstrong, Eric Peterson, Adrian Hernandez, Rury R Holman, Svati H Shah.

  Metabolic mechanisms underlying the heterogeneity of major adverse cardiovascular events (MACE) risk in individuals with type 2 diabetes mellitus (T2D) remain unclear. We hypothesized that circulating metabolites reflecting mitochondrial dysfunction predict incident MACE in T2D. Targeted mass-spectrometry profiling of 60 metabolites was performed on baseline plasma from TECOS (discovery) and EXSCEL (validation) trial biomarker substudy cohorts. A principal components analysis metabolite factor comprised of medium-chain acylcarnitines was associated with MACE in TECOS and validated in EXSCEL, with higher levels associated with higher MACE risk. Meta-analysis showed that long-chain acylcarnitines and dicarboxylacylcarnitines were also associated with MACE. Metabolites remained associated with MACE in multivariate models and favorably changed with exenatide therapy. A third cohort (CATHGEN) with T2D assessed whether these metabolites improved discriminative capability multivariate for MACE; nine metabolites (medium- and long-chain acylcarnitines and one dicarboxylacylcarnitine) were associated with time-to-MACE in CATHGEN. Addition of these metabolites to clinical models minimally improved the discriminative capability for MACE but did significantly down reclassify risk. Thus, metabolites reporting on dysregulated mitochondrial fatty acid oxidation are higher in individuals with T2D who experience subsequent MACE. These biomarkers may improve CV risk prediction models, be therapy responsive, and highlight emerging risk mechanisms.

Keywords:  Cardiology; Cardiovascular disease; Diabetes; Metabolism; Mitochondria

DOI:  https://doi.org/10.1172/jci.insight.168563
Naunyn Schmiedebergs Arch Pharmacol. 2023 Aug 11.

Empagliflozin improves cardiac function in rats with chronic heart failure.

Zhenzhen Wang, Qian Liu, Xiaofang Wang, Pengpeng Wang, Zhuwen Wang, Fenglei Zhang.

  The objective of this study is to examine the effect of empagliflozin on cardiac function in rats with chronic heart failure and the possible mechanism. Forty 6-week-old male SD rats were randomly divided into the control group, empagliflozin treatment group, and sham-operated group. SD rats in the control group and empagliflozin treatment group were subjected to ligation of the anterior descending coronary artery to induce an acute myocardial infarction model. SD rats in the sham-operated group were only subjected to threading of the anterior descending branch of the coronary artery without ligation. On the second day after surgery, the control group and sham operation group were given physiological saline by gavage, while the empagliflozin treatment group was given empagliflozin (30 mg/kg/day) by gavage. Sixteen weeks later, cardiac function, intracellular reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP), serum brain natriuretic peptide, hypersensitive C-reactive protein (hs-CRP), iNOS expression levels, and myocardial morphological changes were observed. Compared with that in the control group, heart function in the empagliflozin-treated group was significantly improved, MMP was increased, intracellular ROS levels were decreased, and NT-proBNP and hs-CRP were significantly reduced, and HE staining showed that the cell oedema was less than that in the control group, tissue arrangement was more orderly, and iNOS expression was inhibited. Empagliflozin can improve cardiac function in rats with chronic heart failure, and the mechanism may involve inhibiting inflammation, reducing myocardial oxidative stress, and improving myocardial fibrosis.

Keywords:  Chronic heart failure; Empagliflozin; Hypersensitive C-reactive protein; Membrane potential; Reactive oxygen species

DOI:  https://doi.org/10.1007/s00210-023-02655-7