bims-hafaim 2024-03-31 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2024‒03‒31
nine papers selected by
Kyle McCommis, Saint Louis University

Loss of Cardiac PFKFB2 Drives Metabolic, Functional, and Electrophysiological Remodeling in the Heart.
Fasting Plasma Ketone Bodies Are Associated with NT-proBNP: A Potential Mechanism to Provide Fuel for the Failing Heart.
Cardiovascular Effects of Oral Ketone Ester Treatment in Patients With Heart Failure With Reduced Ejection Fraction: A Randomized, Controlled, Double-Blind Trial.
Mitochondrial energy metabolism in diabetic cardiomyopathy: Physiological adaption, pathogenesis, and therapeutic targets.
HINT2 protects against pressure overload-induced cardiac remodelling through mitochondrial pathways.
Proteomic Profiling of SGLT-2 Inhibitor Canagliflozin in a Swine Model of Chronic Myocardial Ischemia.
Reduced mitochondrial pyruvate carrier expression in hearts with heart failure and reduced ejection fraction patients: ischemic vs. non-ischemic origin.
Alterations in Mitochondrial Oxidative Phosphorylation System: Relationship of Complex V and Cardiac Dysfunction in Human Heart Failure.
Contemporary pharmacological treatment and management of heart failure.

J Am Heart Assoc. 2024 Mar 27. e033676

Loss of Cardiac PFKFB2 Drives Metabolic, Functional, and Electrophysiological Remodeling in the Heart.

Kylene M Harold, Satoshi Matsuzaki, Atul Pranay, Brooke L Loveland, Albert Batushansky, Maria F Mendez Garcia, Craig Eyster, Stavros Stavrakis, Ying Ann Chiao, Michael Kinter, Kenneth M Humphries.

  BACKGROUND: Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) is a critical glycolytic regulator responsible for upregulation of glycolysis in response to insulin and adrenergic signaling. PFKFB2, the cardiac isoform of PFK-2, is degraded in the heart in the absence of insulin signaling, contributing to diabetes-induced cardiac metabolic inflexibility. However, previous studies have not examined how the loss of PFKFB2 affects global cardiac metabolism and function.METHODS AND RESULTS: To address this, we have generated a mouse model with a cardiomyocyte-specific knockout of PFKFB2 (cKO). Using 9-month-old cKO and control mice, we characterized the impacts of PFKFB2 on cardiac metabolism, function, and electrophysiology. cKO mice have a shortened life span of 9 months. Metabolically, cKO mice are characterized by increased glycolytic enzyme abundance and pyruvate dehydrogenase activity, as well as decreased mitochondrial abundance and beta oxidation, suggesting a shift toward glucose metabolism. This was supported by a decrease in the ratio of palmitoyl carnitine to pyruvate-dependent mitochondrial respiration in cKO relative to control animals. Metabolomic, proteomic, and Western blot data support the activation of ancillary glucose metabolism, including pentose phosphate and hexosamine biosynthesis pathways. Physiologically, cKO animals exhibited impaired systolic function and left ventricular dilation, represented by reduced fractional shortening and increased left ventricular internal diameter, respectively. This was accompanied by electrophysiological alterations including increased QT interval and other metrics of delayed ventricular conduction.
CONCLUSIONS: Loss of PFKFB2 results in metabolic remodeling marked by cardiac ancillary pathway activation. This could delineate an underpinning of pathologic changes to mechanical and electrical function in the heart.

Keywords:  echocardiography; electrocardiography; glucose; glycolysis; metabolism

DOI:  https://doi.org/10.1161/JAHA.123.033676
J Clin Med. 2024 Mar 07. pii: 1541. [Epub ahead of print]13(6):

Fasting Plasma Ketone Bodies Are Associated with NT-proBNP: A Potential Mechanism to Provide Fuel for the Failing Heart.

Constantin L Palm, Irina Shalaurova, Margery A Connelly, Stephan J L Bakker, Berend Daan Westenbrink, Robin P F Dullaart.

  Background: Heart failure (HF) features a shift in metabolism towards enhanced utilization of ketone bodies. While elevations in plasma natriuretic peptides represent a biochemical hallmark of HF, natriuretic peptides may promote lipolysis, thereby contributing to fatty acid availability for ketogenesis. Methods: We cross-sectionally tested to what extent fasting plasma total ketone bodies (measured using nuclear magnetic resonance spectroscopy) are associated with N-terminal pro-BNP (NT-proBNP; electrochemiluminescent sandwich immunoassay) in individuals with and without HF. Results: Among 6217 participants from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, 203 were identified with HF. NT-proBNP was four-fold and total ketone bodies were 25% higher in HF participants (each p < 0.001). In both participants with and without HF, total ketone body levels correlated with NT-proBNP (r = 0.116 and 0.185, respectively; p < 0.001). In multivariable linear regression analysis adjusted for relevant covariates, total ketone bodies remained associated with NT-proBNP in the whole cohort (std β = 0.08, p < 0.001), without a difference in participants with and without HF (p interaction: 0.52). Conclusion: This general population-based study reveals an independent association of fasting total body ketone bodies with plasma NT-proBNP. Our findings suggest that a metabolic defense mechanism could be operative, providing the myocardium with ketone bodies to meet its energy demands.

Keywords:  N-terminal pro-B-type natriuretic peptide; cardiology; epidemiology; heart failure; ketone bodies

DOI:  https://doi.org/10.3390/jcm13061541
Circulation. 2024 Mar 27.

Cardiovascular Effects of Oral Ketone Ester Treatment in Patients With Heart Failure With Reduced Ejection Fraction: A Randomized, Controlled, Double-Blind Trial.

Kristoffer Berg-Hansen, Nigopan Gopalasingam, Kristian Hylleberg Christensen, Bertil Ladefoged, Mads Jønsson Andersen, Steen Hvitfeldt Poulsen, Barry A Borlaug, Roni Nielsen, Niels Møller, Henrik Wiggers.

  BACKGROUND: Heart failure triggers a shift in myocardial metabolic substrate utilization, favoring the ketone body 3-hydroxybutyrate as energy source. We hypothesized that 14-day treatment with ketone ester (KE) would improve resting and exercise hemodynamics and exercise capacity in patients with heart failure with reduced ejection fraction.METHODS: In a randomized, double-blind cross-over study, nondiabetic patients with heart failure with reduced ejection fraction received 14-day KE and 14-day isocaloric non-KE comparator regimens of 4 daily doses separated by a 14-day washout period. After each treatment period, participants underwent right-sided heart catheterization, echocardiography, and blood sampling at plasma trough levels and after dosing. Participants underwent an exercise hemodynamic assessment after a second dosing. The primary end point was resting cardiac output (CO). Secondary end points included resting and exercise pulmonary capillary wedge pressure and peak exercise CO and metabolic equivalents.
RESULTS: We included 24 patients with heart failure with reduced ejection fraction (17 men; 65±9 years of age; all White). Resting CO at trough levels was higher after KE compared with isocaloric comparator (5.2±1.1 L/min versus 5.0±1.1 L/min; difference, 0.3 L/min [95% CI, 0.1-0.5), and pulmonary capillary wedge pressure was lower (8±3 mm Hg versus 11±3 mm Hg; difference, -2 mm Hg [95% CI, -4 to -1]). These changes were amplified after KE dosing. Across all exercise intensities, KE treatment was associated with lower mean exercise pulmonary capillary wedge pressure (-3 mm Hg [95% CI, -5 to -1] ) and higher mean CO (0.5 L/min [95% CI, 0.1-0.8]), significantly different at low to moderate steady-state exercise but not at peak. Metabolic equivalents remained similar between treatments. In exploratory analyses, KE treatment was associated with 18% lower NT-proBNP (N-terminal pro-B-type natriuretic peptide; difference, -98 ng/L [95% CI, -185 to -23]), higher left ventricular ejection fraction (37±5 versus 34±5%; P=0.01), and lower left atrial and ventricular volumes.
CONCLUSIONS: KE treatment for 14 days was associated with higher CO at rest and lower filling pressures, cardiac volumes, and NT-proBNP levels compared with isocaloric comparator. These changes persisted during exercise and were achieved on top of optimal medical therapy. Sustained modulation of circulating ketone bodies is a potential treatment principle in patients with heart failure with reduced ejection fraction.
REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05161650.

Keywords:  cardiac output; esters; exercise; heart failure; hemodynamics; hydroxybutyrate dehydrogenase; metabolism

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.067971
Chin Med J (Engl). 2024 Mar 25.

Mitochondrial energy metabolism in diabetic cardiomyopathy: Physiological adaption, pathogenesis, and therapeutic targets.

Wanlin Ye, Kun Han, Maodi Xie, Sheyu Li, Guo Chen, Yanyan Wang, Tao Li.

ABSTRACT: Diabetic cardiomyopathy is defined as abnormal structure and function of the heart in the setting of diabetes, which could eventually develop heart failure and leads to the death of the patients. Although blood glucose control and medications to heart failure show beneficial effects on this disease, there is currently no specific treatment for diabetic cardiomyopathy. Over the past few decades, the pathophysiology of diabetic cardiomyopathy has been extensively studied, and an increasing number of studies pinpoint that impaired mitochondrial energy metabolism is a key mediator as well as a therapeutic target. In this review, we summarize the latest research in the field of diabetic cardiomyopathy, focusing on mitochondrial damage and adaptation, altered energy substrates, and potential therapeutic targets. A better understanding of the mitochondrial energy metabolism in diabetic cardiomyopathy may help to gain more mechanistic insights and generate more precise mitochondria-oriented therapies to treat this disease.

DOI: https://doi.org/10.1097/CM9.0000000000003075
J Cell Mol Med. 2024 Apr;28(8): e18276

HINT2 protects against pressure overload-induced cardiac remodelling through mitochondrial pathways.

Nan Zhang, Zi-Ying Zhou, Yan-Yan Meng, Hai-Han Liao, Shan-Qi Mou, Zheng Lin, Han Yan, Si Chen, Qi-Zhu Tang.

  Histidine triad nucleotide-binding protein 2 (HINT2) is an enzyme found in mitochondria that functions as a nucleotide hydrolase and transferase. Prior studies have demonstrated that HINT2 plays a crucial role in ischemic heart disease, but its importance in cardiac remodelling remains unknown. Therefore, the current study intends to determine the role of HINT2 in cardiac remodelling. HINT2 expression levels were found to be lower in failing hearts and hypertrophy cardiomyocytes. The mice that overexpressed HINT2 exhibited reduced myocyte hypertrophy and cardiac dysfunction in response to stress. In contrast, the deficiency of HINT2 in the heart of mice resulted in a worsening hypertrophic phenotype. Further analysis indicated that upregulated genes were predominantly associated with the oxidative phosphorylation and mitochondrial complex I pathways in HINT2-overexpressed mice after aortic banding (AB) treatment. This suggests that HINT2 increases the expression of NADH dehydrogenase (ubiquinone) flavoprotein (NDUF) genes. In cellular studies, rotenone was used to disrupt mitochondrial complex I, and the protective effect of HINT2 overexpression was nullified. Lastly, we predicted that thyroid hormone receptor beta might regulate HINT2 transcriptional activity. To conclusion, the current study showcased that HINT2 alleviates pressure overload-induced cardiac remodelling by influencing the activity and assembly of mitochondrial complex I. Thus, targeting HINT2 could be a novel therapeutic strategy for reducing cardiac remodelling.

Keywords:  HINT2; NDUFs; cardiac remodelling; hypertrophy; mitochondrial complex I

DOI:  https://doi.org/10.1111/jcmm.18276
Biomedicines. 2024 Mar 06. pii: 588. [Epub ahead of print]12(3):

Proteomic Profiling of SGLT-2 Inhibitor Canagliflozin in a Swine Model of Chronic Myocardial Ischemia.

Dwight D Harris, Sharif A Sabe, Mark Broadwin, Christopher Stone, Cynthia Xu, Jiayu Hu, Meghamsh Kanuparthy, M Ruhul Abid, Frank W Sellke.

  BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are known to be cardioprotective independent of glucose control, but the mechanisms of these benefits are unclear. We previously demonstrated improved cardiac function and decreased fibrosis in a swine model of chronic myocardial ischemia. The goal of this study is to use high-sensitivity proteomic analyses to characterize specific molecular pathways affected by SGLT-2 inhibitor canagliflozin (CAN) therapy in a swine model of chronic myocardial ischemia.METHODS: Chronic myocardial ischemia was induced in sixteen Yorkshire swine via the placement of an ameroid constrictor to the left circumflex coronary artery. After two weeks of recovery, swine received either 300 mg of CAN daily (n = 8) or a control (n = 8). After five weeks of therapy, the group of swine were euthanized, and left ventricular tissue was harvested and sent for proteomic analysis.
RESULTS: Total proteomic analysis identified a total of 3256 proteins between the CAN and control groups. Three hundred and five proteins were statistically different. This included 55 proteins that were downregulated (p < 0.05, fold change <0.5) and 250 that were upregulated (p < 0.05, fold change >2) with CAN treatment. Pathway analysis demonstrated the upregulation of several proteins involved in metabolism and redox activity in the CAN-treated group. The CAN group also exhibited a downregulation of proteins involved in motor activity and cytoskeletal structure.
CONCLUSIONS: In our swine model of chronic myocardial ischemia, CAN therapy alters several proteins involved in critical molecular pathways, including redox regulation and metabolism. These findings provide additional mechanistic insights into the cardioprotective effects of canagliflozin.

Keywords:  canagliflozin; cardiac index; chronic myocardial ischemia; metabolism; proteomic; redox; sodium–glucose cotransporter-2 inhibitors; swine

DOI:  https://doi.org/10.3390/biomedicines12030588
Front Cardiovasc Med. 2024 ;11 1349417

Reduced mitochondrial pyruvate carrier expression in hearts with heart failure and reduced ejection fraction patients: ischemic vs. non-ischemic origin.

Paula Lopez-Vazquez, Mariana Fernandez-Caggiano, Eduardo Barge-Caballero, Gonzalo Barge-Caballero, David Couto-Mallon, Zulaika Grille-Cancela, Paula Blanco-Canosa, Maria J Paniagua-Martin, Daniel Enriquez-Vazquez, Jose M Vazquez-Rodriguez, Nieves Domenech, Maria G Crespo-Leiro.

  Introduction and objectives: Mitochondrial pyruvate carrier (MPC) mediates the entry of pyruvate into mitochondria, determining whether pyruvate is incorporated into the Krebs cycle or metabolized in the cytosol. In heart failure (HF), a large amount of pyruvate is metabolized to lactate in the cytosol rather than being oxidized inside the mitochondria. Thus, MPC activity or expression might play a key role in the fate of pyruvate during HF. The purpose of this work was to study the levels of the two subunits of this carrier, named MPC1 and MPC2, in human hearts with HF of different etiologies.Methods: Protein and mRNA expression analyses were conducted in cardiac tissues from three donor groups: patients with HF with reduced ejection fraction (HFrEF) with ischemic cardiomyopathy (ICM) or idiopathic dilated cardiomyopathy (IDC), and donors without cardiac pathology (Control). MPC2 plasma levels were determined by ELISA.
Results: Significant reductions in the levels of MPC1, MPC2, and Sirtuin 3 (SIRT3) were observed in ICM patients compared with the levels in the Control group. However, no statistically significant differences were revealed in the analysis of MPC1 and MPC2 gene expression among the groups. Interestingly, Pyruvate dehydrogenase complex (PDH) subunits expression were increased in the ICM patients. In the case of IDC patients, a significant decrease in MPC1 was observed only when compared with the Control group. Notably, plasma MPC2 levels were found to be elevated in both disease groups compared with that in the Control group.
Conclusion: Decreases in MPC1 and/or MPC2 levels were detected in the cardiac tissues of HFrEF patients, with ischemic or idiopatic origen, indicating a potential reduction in mitochondrial pyruvate uptake in the heart, which could be linked to unfavorable clinical features.

Keywords:  heart failure; idiopathic dilated cardiomyopathy; ischemic heart; mitochondria; mitochondrial pyruvate carrier

DOI:  https://doi.org/10.3389/fcvm.2024.1349417
Antioxidants (Basel). 2024 Feb 26. pii: 285. [Epub ahead of print]13(3):

Alterations in Mitochondrial Oxidative Phosphorylation System: Relationship of Complex V and Cardiac Dysfunction in Human Heart Failure.

Isaac Giménez-Escamilla, Carlota Benedicto, Lorena Pérez-Carrillo, Marta Delgado-Arija, Irene González-Torrent, Roger Vilchez, Luis Martínez-Dolz, Manuel Portolés, Estefanía Tarazón, Esther Roselló-Lletí.

  Heart failure (HF) is a disease related to bioenergetic mitochondrial abnormalities. However, the whole status of molecules involved in the oxidative phosphorylation system (OXPHOS) is unknown. Therefore, we analyzed the OXPHOS transcriptome of human cardiac tissue by RNA-seq analyses (mRNA n = 36; ncRNA n = 30) in HF patients (ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM)) and control subjects. We detected 28 altered genes in these patients, highlighting greater deregulation in ICM. Specifically, we found a general overexpression of complex V (ATP synthase) elements, among them, ATP5I (ICM, FC = 2.04; p < 0.01), ATP5MJ (ICM, FC = 1.33, p < 0.05), and ATP5IF1 (ICM, FC = 1.81; p < 0.001), which presented a significant correlation with established echocardiographic parameters of cardiac remodeling and ventricular function as follows: left ventricular end-systolic (p < 0.01) and end-diastolic (p < 0.01) diameters, and ejection fraction (p < 0.05). We also detected an increase in ATP5IF1 protein levels (ICM, FC = 1.75; p < 0.01) and alterations in the microRNA expression levels of miR-208b-3p (ICM, FC = -1.44, p < 0.001), miR-483-3p (ICM, FC = 1.37, p < 0.01), regulators of ATP5I. Therefore, we observed the deregulation of the OXPHOS transcriptome in ICM patients, highlighting the overexpression of complex V and its relationship with cardiac remodeling and function.

Keywords:  OXPHOS; cardiac remodeling; complex V; heart failure; ischemic and dilated cardiomyopathy; mitochondria

DOI:  https://doi.org/10.3390/antiox13030285
Nat Rev Cardiol. 2024 Mar 26.

Contemporary pharmacological treatment and management of heart failure.

Biykem Bozkurt.

The prevention and treatment strategies for heart failure (HF) have evolved in the past two decades. The stages of HF have been redefined, with recognition of the pre-HF state, which encompasses asymptomatic patients who have developed either structural or functional cardiac abnormalities or have elevated plasma levels of natriuretic peptides or cardiac troponin. The first-line treatment of patients with HF with reduced ejection fraction includes foundational therapies with angiotensin receptor-neprilysin inhibitors, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, β-blockers, mineralocorticoid receptor antagonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors and diuretics. The first-line treatment of patients with HF with mildly reduced ejection fraction or with HF with preserved ejection fraction includes SGLT2 inhibitors and diuretics. The timely initiation of these disease-modifying therapies and the optimization of treatment are crucial in all patients with HF. Reassessment after initiation of these therapies is recommended to evaluate patient symptoms, health status and left ventricular function, and timely referral to a HF specialist is necessary if a patient has persistent advanced HF symptoms or worsening HF. Lifestyle modification and treatment of comorbidities such as diabetes mellitus, ischaemic heart disease and atrial fibrillation are crucial through each stage of HF. This Review provides an overview of the management strategies for HF according to disease stages that are derived from the recommendations in the latest US and European HF guidelines.

DOI: https://doi.org/10.1038/s41569-024-00997-0