bims-hafaim 2023-07-02 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2023–07–02
eight papers selected by
Kyle McCommis, Saint Louis University

Nicotinamide Riboside Improves Cardiac Function and Prolongs Survival After Disruption of the Cardiomyocyte Clock.
Therapeutic effects on the development of heart failure with preserved ejection fraction by the sodium-glucose cotransporter 2 inhibitor dapagliflozin in type 2 diabetes.
Left ventricular mass predicts cardiac reverse remodelling in patients treated with empagliflozin.
COX5A Alleviates Doxorubicin-Induced Cardiotoxicity by Suppressing Oxidative Stress, Mitochondrial Dysfunction and Cardiomyocyte Apoptosis.
Heart-type fatty acid binding protein is related to severity and established cardiac biomarkers of heart failure.
Insulin resistance is associated with subclinical myocardial dysfunction and reduced functional capacity in heart failure with preserved ejection fraction.
Pathophysiological basis of the cardiological benefits of SGLT-2 inhibitors: a narrative review.
Sodium-Glucose Co-Transporter 2 Inhibitors in Heart Failure-Current Evidence in Special Populations.

Front Mol Med. 2022 ;pii: 887733. [Epub ahead of print]2

Nicotinamide Riboside Improves Cardiac Function and Prolongs Survival After Disruption of the Cardiomyocyte Clock.

Pieterjan Dierickx, Bryce J Carpenter, Isaac Celwyn, Daniel P Kelly, Joseph A Baur, Mitchell A Lazar.

  The REV-ERB nuclear receptors are key components of the circadian clock. Loss of REV-ERBs in the mouse heart causes dilated cardiomyopathy and premature lethality. This is associated with a marked reduction in NAD+ production, but whether this plays a role in the pathophysiology of this heart failure model is not known. Here, we show that supplementation with the NAD+ precursor NR as a dietary supplement improves heart function and extends the lifespan of female mice lacking cardiac REV-ERBs. Thus, boosting NAD+ levels can improve cardiac function in a setting of heart failure caused by disruption of circadian clock factors, providing new insights into the links between the circadian clock, energy metabolism, and cardiac function.

Keywords:  NAD+; cardiac metabolism; circadian clock; heart failure; nuclear hormone receptors

DOI:  https://doi.org/10.3389/fmmed.2022.887733
Diabetol Metab Syndr. 2023 Jun 29. 15(1): 141

Therapeutic effects on the development of heart failure with preserved ejection fraction by the sodium-glucose cotransporter 2 inhibitor dapagliflozin in type 2 diabetes.

Bin Feng, Peiran Yu, Hao Yu, Buyun Qian, Yuan Li, Kangyun Sun, Bimin Shi, Nannan Zhang, Guidong Xu.

   BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a common disease with high morbidity and lacks effective treatment. We investigated the protective effects of the long-term application of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin on diabetes-associated HFpEF in a rat model. Serum proteomics and metabolomics analysis were also conducted in type 2 diabetic patients with HFpEF treated with dapagliflozin.
METHODS: Male Zucker diabetic fatty (ZDF) rats were used as a model of diabetic cardiomyopathy. From weeks 16 to 28, animals were given a vehicle or dapagliflozin (1 mg/kg) once daily. Primary blood biochemistry indices, echocardiography, histopathology, and cardiac hemodynamics were determined during the study period. The key markers of myocardial fibrosis, nitro-oxidative stress, inflammation, apoptosis, autophagy, and AMPK/mTOR signaling were examined. Additionally, healthy controls and individuals with type 2 diabetes were enrolled and 16 serum samples from 4 groups were randomly selected. Serum proteome and metabolome changes after dapagliflozin treatment were analyzed in diabetic individuals with HFpEF.
RESULTS: Dapagliflozin effectively prevented the development of HFpEF in rats with diabetes by mitigating nitro-oxidative stress, pro-inflammatory cytokines, myocardial hypertrophy, and fibrosis, reducing apoptosis, and restoring autophagy through AMPK activating and mTOR pathway repressing. Proteomics and metabolomics revealed that cholesterol and high-density lipoprotein particle metabolism, nicotinate and nicotinamide metabolism, arginine biosynthesis, and cAMP and peroxisome proliferator-activated receptor (PPAR) signaling are the major disturbed pathways in HFpEF patients treated with dapagliflozin.
CONCLUSION: Long-term treatment with dapagliflozin significantly prevented the development of HFpEF in diabetic rats. Dapagliflozin could be a promising therapeutic strategy in managing HFpEF individuals with type 2 diabetes.

Keywords:  AMPK/mTOR; Dapagliflozin; Diabetic cardiomyopathy; Heart failure with preserved ejection fraction; Multi-omic analysis

DOI:  https://doi.org/10.1186/s13098-023-01116-8
Cardiovasc Diabetol. 2023 Jun 28. 22(1): 152

Left ventricular mass predicts cardiac reverse remodelling in patients treated with empagliflozin.

Pankaj Puar, Makoto Hibino, C David Mazer, Andrew T Yan, Arjun K Pandey, Adrian Quan, Hwee Teoh, David A Hess, Raj Verma, Kim A Connelly, Subodh Verma.

   BACKGROUND: The cardiovascular (CV) benefits of sodium-glucose transport protein 2 inhibitors have been attributed, in part, to cardiac reverse remodelling. The EMPA-HEART CardioLink-6 study reported that sodium-glucose cotransporter-2 inhibition for 6 months with empagliflozin was associated with a significant reduction in left ventricular mass indexed to body surface area (LVMi). In this sub-analysis, we evaluated whether baseline LVMi may influence how empagliflozin affects cardiac reverse remodelling.
METHODS: A total of 97 patients with type 2 diabetes and coronary artery disease were randomized to empagliflozin (10 mg/d) or matching placebo for 6 months. The study cohort was divided into those whose baseline LVMi was ≤ 60 g/m2 and those who had a baseline LVMi > 60 g/m2. Subgroup comparisons were conducted using a linear regression model adjusted for baseline values (ANCOVA) that included an interaction term between LVMi subgroup and treatment.
RESULTS: Baseline LVMi was 53.3 g/m2 (49.2-57.2) and 69.7 g/m2 (64.2-76.1) for those with baseline ≤ 60 g/m2 (n = 54) and LVMi > 60 g/m2 (n = 43) respectively. The adjusted difference of LVMi regression between those randomized to empagliflozin and placebo were - 0.46 g/m2 (95% CI: -3.44, 2.52, p = 0.76) in the baseline LVMi ≤ 60 g/m2 subgroup and - 7.26 g/m2 (95% CI: -11.40, -3.12, p = 0.0011) in the baseline LVMi > 60 g/m2 subgroup (p-for-interaction = 0.007). No significant associations were found between baseline LVMi and 6-month change in LV end systolic volume-indexed (p-for-interaction = 0.086), LV end diastolic volume-indexed (p-for-interaction = 0.34), or LV ejection fraction (p-for-interaction = 0.15).
CONCLUSIONS: Patients with higher LVMi at baseline experienced greater LVM regression with empagliflozin.

Keywords:  Cardiac reverse remodelling; Diabetes; Heart failure; Left ventricle; SGLT2 inhibition

DOI:  https://doi.org/10.1186/s12933-023-01849-w
Int J Mol Sci. 2023 Jun 20. pii: 10400. [Epub ahead of print]24(12):

COX5A Alleviates Doxorubicin-Induced Cardiotoxicity by Suppressing Oxidative Stress, Mitochondrial Dysfunction and Cardiomyocyte Apoptosis.

Peipei Zhang, Hao Lu, Yuan Wu, Danbo Lu, Chenguang Li, Xiangdong Yang, Zhangwei Chen, Juying Qian, Junbo Ge.

  Doxorubicin (DOX) as a chemotherapeutic agent can cause mitochondrial dysfunction and heart failure. COX5A has been described as an important regulator of mitochondrial energy metabolism. We investigate the roles of COX5A in DOX-induced cardiomyopathy and explore the underlying mechanisms. C57BL/6J mice and H9c2 cardiomyoblasts were treated with DOX, and the COX5A expression was assessed. An adeno-associated virus serum type 9 (AAV9) and lenti-virus system were used to upregulate COX5A expression. Echocardiographic parameters, morphological and histological analyses, transmission electron microscope and immunofluorescence assays were used to assess cardiac and mitochondrial function. In a human study, we found that cardiac COX5A expression was dramatically decreased in patients with end-stage dilated cardiomyopathy (DCM) compared to the control group. COX5A was significantly downregulated following DOX stimulation in the heart of mice and H9c2 cells. Reduced cardiac function, decreased myocardium glucose uptake, mitochondrial morphology disturbance, reduced activity of mitochondrial cytochrome c oxidase (COX) and lowered ATP content were detected after DOX stimulation in mice, which could be significantly improved by overexpression of COX5A. Overexpression of COX5A effectively protected against DOX-induced oxidative stress, mitochondrial dysfunction and cardiomyocyte apoptosis in vivo and in vitro. Mechanistically, the phosphorylation of Akt (Thr308) and Akt (Ser473) were also decreased following DOX treatment, which could be reserved by the upregulation of COX5A. Furthermore, PI3K inhibitors abrogated the protection effects of COX5A against DOX-induced cardiotoxicity in H9c2 cells. Thus, we identified that PI3K/Akt signaling was responsible for the COX5A-mediated protective role in DOX-induced cardiomyopathy. These results demonstrated the protective effect of COX5A in mitochondrial dysfunction, oxidative stress, and cardiomyocyte apoptosis, providing a potential therapeutic target in DOX-induced cardiomyopathy.

Keywords:  COX5A; apoptosis; doxorubicin; mitochondrial dysfunction; oxidative stress

DOI:  https://doi.org/10.3390/ijms241210400
Adv Lab Med. 2021 Nov;2(4): 541-549

Heart-type fatty acid binding protein is related to severity and established cardiac biomarkers of heart failure.

Damien Gruson, Christina Adamantidou, Sylvie A Ahn, Michel F Rousseau.

   Objectives: To determine concentrations of heart-type fatty acid-binding protein (HFABP) in patients with heart failure with reduced ejection fraction (HFrEF) and its potential value for prognostic assessment.
Methods: Circulating levels of HFABP were measured with an automated chemiluminescent immunoassay in 25 healthy volunteers and 60 HFrEF patients.
Results: Concentrations of HFABP were significantly increased in heart failure patients in comparison to healthy volunteers. HFABP levels were significantly correlated to New York Heart Association classes and to established biomarkers of cardiac dysfunction and remodeling (amino-terminal pro-B-type natriuretic peptide [NT-proBNP], fibroblast growth factor 23, and galectin-3). HFABP concentrations were also predictive of cardiovascular (CV) death and combination with NT-proBNP might be synergistic for risk assessment.
Conclusions: HFABP levels are increased in HFrEF patients, related to adverse CV outcomes, and might assist physicians for patient's management.

Keywords:  NT-proBNP; biomarker; heart failure; heart failure with reduced ejection fraction (HFrEF); outcome; risk

DOI:  https://doi.org/10.1515/almed-2021-0035
J Cardiol. 2023 Jun 24. pii: S0914-5087(23)00153-3. [Epub ahead of print]

Insulin resistance is associated with subclinical myocardial dysfunction and reduced functional capacity in heart failure with preserved ejection fraction.

Brent Gudenkauf, Gabriel Shaya, Monica Mukherjee, Erin D Michos, Jose Madrazo, Lena Mathews, Sanjiv J Shah, Kavita Sharma, Allison G Hays.

   BACKGROUND: Obesity and insulin resistance are prevalent in heart failure with preserved ejection fraction (HFpEF) and are associated with adverse cardiovascular outcomes. Measuring insulin resistance is difficult outside of research settings, and its correlation to parameters of myocardial dysfunction and functional status is unknown.
METHODS: A total of 92 HFpEF patients with New York Heart Association class II to IV symptoms underwent clinical assessment, 2D echocardiography, and 6-minute walk (6MW) test. Insulin resistance was defined by estimated glucose disposal rate (eGDR) using the formula: eGDR = 19.02 - [0.22 x body mass index (BMI), kg/m2] - (3.26 x hypertension, presence) - (0.61 x glycated hemoglobin, %). Lower eGDR indicates increased insulin resistance (unfavorable). Myocardial structure and function were assessed by left ventricular (LV) mass, average E/e' ratio, right ventricular systolic pressure, left atrial volume, LV ejection fraction, LV longitudinal strain (LVLS), and tricuspid annular plane systolic excursion. Associations between eGDR and adverse myocardial function were evaluated in unadjusted and multivariable-adjusted analyses using analysis of variance testing and multivariable linear regression.
RESULTS: Mean age (SD) was 65 (11) years, 64% were women, and 95% had hypertension. Mean (SD) BMI was 39 (9.6) kg/m2, glycated hemoglobin 6.7 (1.6) %, and eGDR 3.3 (2.6) mg x kg-1min-1. Increased insulin resistance was associated with worse LVLS in a graded fashion [mean (SD) -13.8% (4.9%), -14.4% (5.8%), -17.5% (4.4%) for first, second, and third eGDR tertiles, respectively, p = 0.047]. This association persisted after multivariable adjustment, p = 0.040. There was also a significant association between worse insulin resistance and decreased 6MW distance on univariate analysis, but not on multivariable adjusted analysis.
CONCLUSION: Our findings may inform treatment strategies focused on the use of tools to estimate insulin resistance and selection of insulin sensitizing drugs which may improve cardiac function and exercise capacity.

Keywords:  Echocardiography; Heart failure; Heart failure with preserved ejection fraction; Insulin resistance

DOI:  https://doi.org/10.1016/j.jjcc.2023.06.008
Cardiovasc Diabetol. 2023 Jun 30. 22(1): 164

Pathophysiological basis of the cardiological benefits of SGLT-2 inhibitors: a narrative review.

Cristina Panico, Benedetta Bonora, Antonella Camera, Nino Cristiano Chilelli, Giuliana Da Prato, Giuseppe Favacchio, Valeria Grancini, Veronica Resi, Maurizio Rondinelli, Emanuela Zarra, Basilio Pintaudi.

  In recent years, GLP-1 receptor agonists (GLP-1RA), and SGLT-2 inhibitors (SGLT-2i) have become available, which have become valuable additions to therapy for type 2 diabetes as they are associated with low risk for hypoglycemia and cardiovascular benefits. Indeed, SGLT-2i have emerged as a promising class of agents to treat heart failure (HF). By inhibiting SGLT-2, these agents lead to excretion of glucose in urine with subsequent lowering of plasma glucose, although it is becoming clear that the observed benefits in HF cannot be explained by glucose-lowering alone. In fact, multiple mechanisms have been proposed to explain the cardiovascular and renal benefits of SGLT-2i, including hemodynamic, anti-inflammatory, anti-fibrotic, antioxidant, and metabolic effects. Herein, we review the available evidence on the pathophysiology of the cardiological benefits of SGLT-2i. In diabetic heart disease, in both clinical and animal models, the effect of SGLT-2i have been shown to improve diastolic function, which is even more evident in HF with preserved ejection fraction. The probable pathogenic mechanisms likely involve damage from free radicals, apoptosis, and inflammation, and therefore fibrosis, many of which have been shown to be improved by SGLT-2i. While the effects on systolic function in models of diabetic heart disease and HF with preserved ejection fraction is limited and contrasting, it is a key element in patients with HF and reduced ejection fraction both with and without diabetes. The significant improvement in systolic function appears to lead to subsequent structural remodeling of the heart with a reduction in left ventricle volume and a consequent reduction in pulmonary pressure. While the effects on cardiac metabolism and inflammation appear to be consolidated, greater efforts are still warranted to further define the entity to which these mechanisms contribute to the cardiovascular benefits of SGLT-2i.

Keywords:  Cardiovascular; Heart failure; Mechanism of action; Pathophysiology; SGLT2 inhibitors; Type 2 diabetes

DOI:  https://doi.org/10.1186/s12933-023-01855-y
Life (Basel). 2023 May 25. pii: 1256. [Epub ahead of print]13(6):

Sodium-Glucose Co-Transporter 2 Inhibitors in Heart Failure-Current Evidence in Special Populations.

Gassan Moady, Tuvia Ben Gal, Shaul Atar.

  Sodium-glucose co-transporter 2 (SGLT2) inhibitors, originally used for diabetes mellitus, are gaining more popularity for other indications, owing to their positive cardiovascular and renal effects. SGLT2 inhibitors reduce heart failure (HF) hospitalization and improve cardiovascular outcomes in patients with type 2 diabetes. Later, SGLT2 inhibitors were evaluated in patients with HF with reduced ejection fraction (HFREF) and had beneficial effects independent of the presence of diabetes. Recently, reductions in cardiovascular outcomes were also observed in patients with HF with preserved ejection fraction (HFPEF). SGLT2 inhibitors also reduced renal outcomes in patients with chronic kidney disease. Overall, these drugs have an excellent safety profile with a negligible risk of genitourinary tract infections and ketoacidosis. In this review, we discuss the current data on SGLT2 inhibitors in special populations, including patients with acute myocardial infarction, acute HF, right ventricular (RV) failure, left ventricular assist device (LVAD), and type 1 diabetes. We also discuss the potential mechanisms behind the cardiovascular benefits of these medications.

Keywords:  cardiovascular outcomes; diabetes; heart failure; sodium-glucose co-transporter

DOI:  https://doi.org/10.3390/life13061256