bims-hafaim 2021-11-14 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2021–11–14
eight papers selected by
Kyle McCommis, Saint Louis University

Dapagliflozin and atrial fibrillation in heart failure with reduced ejection fraction: Insights from DAPA-HF.
Increased fatty acid oxidation enzyme activity in the hearts of mice fed a high fat diet does not correlate with improved cardiac contractile function.
Patients With Type 2 Diabetes Mellitus and Heart Failure Benefit More From Sodium-Glucose Cotransporter 2 Inhibitor: A Systematic Review and Meta-Analysis.
Cardiac-specific VEGFB overexpression reduces lipoprotein lipase activity and improves insulin action in rat heart.
Effect of empagliflozin on ketone bodies in patients with stable chronic heart failure.
In-Hospital Initiation of Sodium-Glucose Cotransporter-2 Inhibitors for Heart Failure With Reduced Ejection Fraction.
Long-Chain and Very Long-Chain Ceramides Mediate Doxorubicin-Induced Toxicity and Fibrosis.
Interplay Between Gut Microbiota and Amino Acid Metabolism in Heart Failure.

Eur J Heart Fail. 2021 Nov 11.

Dapagliflozin and atrial fibrillation in heart failure with reduced ejection fraction: Insights from DAPA-HF.

Jawad H Butt, Kieran F Docherty, Pardeep S Jhund, Rudolf A De Boer, Michael Böhm, Akshay S Desai, Jonathan G Howlett, Silvio E Inzucchi, Mikhail N Kosiborod, Felipe A Martinez, Jose C Nicolau, Mark C Petrie, Piotr Ponikowski, Olof Bengtsson, Anna Maria Langkilde, Morten Schou, Mikaela Sjöstrand, Scott D Solomon, Marc S Sabatine, John Jv McMurray, Lars Køber.

   AIMS: Among patients with heart failure and reduced ejection fraction (HFrEF), those with atrial fibrillation (AF) may respond differently to certain treatments than patients without AF. We investigated the efficacy and safety of dapagliflozin in patients with HFrEF with and without AF in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF). We also examined the effect of dapagliflozin on new-onset AF.
METHODS AND RESULTS: The primary outcome was the composite of an episode of worsening HF (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death. Of the 4744 patients randomized, 1910 (40.3%) had "any AF" (history of AF or AF on enrolment electrocardiogram). Compared with placebo, dapagliflozin reduced the risk of worsening HF or cardiovascular death to a similar extent in patients with and without any AF (HR 0.75 [95% CI, 0.62-0.92]) and 0.74 [95% CI, 0.62-0.88]), respectively; P for interaction = 0.88). Consistent benefits were observed for the components of the primary outcome, all-cause mortality, and improvement of Kansas City Cardiomyopathy Questionnaire total symptom score. Among patients without AF at baseline, dapagliflozin did not significantly reduce the risk of new-onset AF compared with placebo (HR 0.86 [95% CI, 0.60-1.22]). However, patients with new-onset AF had a 5 to 6-fold higher risk of adverse outcomes when compared to those without incident AF.
CONCLUSIONS: Dapagliflozin, compared with placebo, reduced the risk of worsening HF events, cardiovascular death, and all-cause death, and improved symptoms, in patients with and without AF. Dapagliflozin did not reduce the risk of new-onset AF. This article is protected by copyright. All rights reserved.

Keywords:  Heart failure; atrial fibrillation; dapagliflozin; randomised trial

DOI:  https://doi.org/10.1002/ejhf.2381
Curr Res Physiol. 2020 Dec;3 44-49

Increased fatty acid oxidation enzyme activity in the hearts of mice fed a high fat diet does not correlate with improved cardiac contractile function.

Dharendra Thapa, Janet R Manning, Bellina A S Mushala, Michael W Stoner, Manling Zhang, Iain Scott.

  Changes in the acetylation status of mitochondrial proteins have been linked to the development of metabolic dysfunction in a number of tissues. Increased lysine acetylation has been reported in the hearts of obese mice, and is associated with changes in fuel metabolism, redox status, and mitochondrial oxidative phosphorylation. In this study, we examined whether diet-induced changes in the acetylation of mitochondrial acyl-CoA dehydrogenases affected fatty acid oxidation enzyme activity and contractile function in the obese mouse heart. Exposure to a long-term high fat diet in wildtype mice led to the hyperacetylation of short- and long-chain acyl-CoA dehydrogenases SCAD and LCAD, which correlated with their increased enzymatic activity in vitro. Cardiomyocyte-specific deletion of the mitochondrial acetyltransferase-related protein GCN5L1 prevented both the hyperacetylation and increased activity of these enzymes under the same conditions of dietary excess. Despite the potential for increased cardiac fatty acid oxidation activity, wildtype mice did not display any increase in cardiac contractility following exposure to a high fat diet. We conclude that the potential energetic benefits of elevated fatty acid oxidation activity are not sufficient to counter the various deleterious effects of a high fat diet on cardiac function.

Keywords:  Cardiac contractility; Fatty acid oxidation; GCN5L1; Lysine acetylation; Mitochondria

DOI:  https://doi.org/10.1016/j.crphys.2020.11.001
Front Endocrinol (Lausanne). 2021 ;12 664533

Patients With Type 2 Diabetes Mellitus and Heart Failure Benefit More From Sodium-Glucose Cotransporter 2 Inhibitor: A Systematic Review and Meta-Analysis.

Chengcong Chen, Hong Peng, Mingzhu Li, Xiyan Lu, Miao Huang, Yongmei Zeng, Guoqing Dong.

   Background: Patients with type 2 diabetes mellitus (T2DM) and heart failure (HF) are at higher risk of mortality and hospitalization for heart failure (HHF). A recent study showed that sodium-glucose cotransporter 2 (SGLT-2) inhibitors may be a promising choice.
Methods: We searched the PubMed, Embase, and Cochrane databases of clinical trials for randomized controlled trials investigating the long-term effects of SGLT-2 inhibitors in patients with T2DM and HF compared with placebo. The primary outcome was cardiovascular death or HHF, and the secondary outcomes included cardiovascular death (CV death), HHF, and all-cause mortality. We also conducted an exploratory analysis and tried to identify the population, which will benefit more from the treatment.
Results: After the study selection, a total of 5 trials, including 4 subgroup analyses, met the eligibility criteria. The results suggested that the use of SGLT-2 inhibitors was associated with a reduction in the incidence of CV death or HHF (HR, 0.69[95%CI, 0.63-0.77], P<0.00001), CV death (HR, 0.80[95%CI, 0.69-0.92], P = 0.001), HHF (HR, 0.67[95%CI, 0.60-0.76], P < 0.00001), and all-cause mortality (HR, 0.74[95%CI, 0.64-0.86], P < 0.0001). Moreover, patients with T2DM and HF may benefit more from the treatment than those with T2DM/HF.
Conclusion: The long-term use of SGLT-2 inhibitors can help reduce the risk of mortality and HHF in patients with T2DM and HF.
Systematic Review Registration: PROSPERO [https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021233156], identifier [CRD42021233156].

Keywords:  heart failure; hospitalization for heart failure; risk of mortality; sodium-glucose cotransporter 2 inhibitor; type 2 diabetes mellitus

DOI:  https://doi.org/10.3389/fendo.2021.664533
Am J Physiol Endocrinol Metab. 2021 Nov 08.

Cardiac-specific VEGFB overexpression reduces lipoprotein lipase activity and improves insulin action in rat heart.

Rui Shang, Nathaniel Lal, ChaeSyng Lee, Yajie Zhai, Karanjit Puri, Oscar Seira, Robert C Boushel, Ibrahim Sultan, Markus Räsänen, Kari Alitalo, Bahira Hussein, Brian Rodrigues.

  Cardiac muscle utilizes multiple sources of energy including glucose and fatty acid (FA). The heart cannot synthesize FA and relies on obtaining it from other sources, with lipoprotein lipase (LPL) breakdown of lipoproteins suggested to be a key source of FA for cardiac use. Recent work has indicated that cardiac vascular endothelial growth factor B (VEGFB) overexpression expands the coronary vasculature and facilitates metabolic reprogramming that favours glucose utilization. We wanted to explore whether this influence of VEGFB on cardiac metabolism involves regulation of LPL activity with consequent effects on lipotoxicity and insulin signalling. The transcriptomes of rats with and without cardiomyocyte-specific overexpression of human VEGFB were compared by using RNA-sequencing. Isolated perfused hearts or cardiomyocytes incubated with heparin were used to enable measurement of LPL activity. Untargeted metabolomic analysis was performed for quantification of cardiac lipid metabolites. Cardiac insulin sensitivity was evaluated using fast-acting insulin. Isolated heart and cardiomyocytes were used to determine transgene-encoded VEGFB isoform secretion patterns and mitochondrial oxidative capacity using high-resolution respirometry and extracellular flux analysis. In vitro, primary transgenic cardiomyocytes incubated overnight and thus exposed to abundantly secreted VEGFB isoforms in the absence of any in vivo confounding regulators of cardiac metabolism demonstrated higher basal oxygen consumption. In the whole heart, VEGFB overexpression induced an angiogenic response that was accompanied by limited cardiac LPL activity through multiple mechanisms. This was associated with a lowered accumulation of lipid intermediates, diacylglycerols and lysophosphatidylcholine, that are known to influence insulin action. In response to exogenous insulin, transgenic hearts demonstrated increased insulin sensitivity. In conclusion, the interrogation of VEGFB function on cardiac metabolism uncovered an intriguing and previously unappreciated effect to lower LPL activity and prevent lipid metabolite accumulation to improve insulin action. VEGFB could be a potential cardioprotective therapy to treat metabolic disorders, for example diabetes.

Keywords:  angiogenesis; cardiomyocyte; lipid metabolites; metabolism; substrate utilization

DOI:  https://doi.org/10.1152/ajpendo.00219.2021
Cardiovasc Diabetol. 2021 11 09. 20(1): 219

Effect of empagliflozin on ketone bodies in patients with stable chronic heart failure.

R Pietschner, J Kolwelter, A Bosch, K Striepe, S Jung, D Kannenkeril, C Ott, M Schiffer, S Achenbach, R E Schmieder.

BACKGROUND: Recent studies indicated that sodium glucose cotransporter (SGLT)2 inhibition increases levels of ketone bodies in the blood in patients with type 1 and 2 diabetes. Other studies suggested that in patients with chronic heart failure (CHF), increased myocardial oxygen demand can be provided by ketone bodies as a fuel substrate. Experimental studies reported that ketone bodies, specifically beta-hydroxybutyrate (β-OHB) may increase blood pressure (BP) by impairing endothelium-dependant relaxation, thereby leading to increased vascular stiffness. In our study we assessed whether the SGLT 2 inhibition with empagliflozin increases ketone bodies in patients with stable CHF and whether such an increase impairs BP and vascular function.
METHODS: In a prospective, double blind, placebo controlled, parallel-group single centre study 75 patients with CHF (left ventricular ejection fraction 39.0 ± 8.2%) were randomised (2:1) to the SGLT-2 inhibitor empagliflozin 10 mg orally once daily or to placebo, 72 patients completed the study. After a run-in phase we evaluated at baseline BP by 24 h ambulatory blood pressure (ABP) monitoring, vascular stiffness parameters by the SphygmoCor system (AtCor Medical, Sydney, NSW, Australia) and fasting metabolic parameters, including β-OHB by an enzymatic assay (Beckman Coulter DxC 700 AU). The same measurements were repeated 12 weeks after treatment. In 19 of the 72 patients serum levels of β-OHB were beneath the lower border of our assay (< 0.05 mmol/l) therefore being excluded from the subsequent analysis.
RESULTS: In patients with stable CHF, treatment with empagliflozin (n = 36) was followed by an increase of β-OHB by 33.39% (p = 0.017), reduction in 24 h systolic (p = 0.038) and diastolic (p = 0.085) ABP, weight loss (p = 0.003) and decrease of central systolic BP (p = 0.008) and central pulse pressure (p = 0.008). The increase in β-OHB was related to an attenuated decrease of empagliflozin-induced 24 h systolic (r = 0.321, p = 0.069) and diastolic (r = 0.516, p = 0.002) ABP and less reduction of central systolic BP (r = 0.470, p = 0.009) and central pulse pressure (r = 0.391, p = 0.033). No significant changes were seen in any of these parameters after 12 weeks of treatment in the placebo group (n = 17).
CONCLUSION: In patients with stable CHF ketone bodies as assessed by β-OHB increased after treatment with empagliflozin. This increase led to an attenuation of the beneficial effects of empagliflozin on BP and vascular parameters. Trial registration The study was registered at http://www.clinicaltrials.gov (NCT03128528).

DOI: https://doi.org/10.1186/s12933-021-01410-7
J Am Coll Cardiol. 2021 Nov 16. pii: S0735-1097(21)06274-4. [Epub ahead of print]78(20): 2004-2012

In-Hospital Initiation of Sodium-Glucose Cotransporter-2 Inhibitors for Heart Failure With Reduced Ejection Fraction.

Vishal N Rao, Evan Murray, Javed Butler, Lauren B Cooper, Zachary L Cox, Mona Fiuzat, Jennifer B Green, JoAnn Lindenfeld, Darren K McGuire, Michael E Nassif, Cara O'Brien, Neha Pagidipati, Kavita Sharma, Muthiah Vaduganathan, Orly Vardeny, Gregg C Fonarow, Robert J Mentz, Stephen J Greene.

  Sodium-glucose cotransporter-2 inhibitor therapy is well suited for initiation during the heart failure hospitalization, owing to clinical benefits that accrue rapidly within days to weeks, a strong safety and tolerability profile, minimal to no effects on blood pressure, and no excess risk of adverse kidney events. There is no evidence to suggest that deferring initiation to the outpatient setting accomplishes anything beneficial. Instead, there is compelling evidence that deferring in-hospital initiation exposes patients to excess risk of early postdischarge clinical worsening and death. Lessons from other heart failure with reduced ejection fraction therapies highlight that deferring initiation of guideline-recommended medications to the U.S. outpatient setting carries a >75% chance they will not be initiated within the next year. Recognizing that 1 in 4 patients hospitalized for worsening heart failure die or are readmitted within 30 days, clinicians should embrace the in-hospital period as an optimal time to initiate sodium-glucose cotransporter-2 inhibitor therapy and treat this population with the urgency it deserves.

Keywords:  guideline-directed medical therapy; heart failure; in-hospital prescribing; medical therapy; sodium-glucose cotransporter-2 inhibitors

DOI:  https://doi.org/10.1016/j.jacc.2021.08.064
Int J Mol Sci. 2021 Nov 01. pii: 11852. [Epub ahead of print]22(21):

Long-Chain and Very Long-Chain Ceramides Mediate Doxorubicin-Induced Toxicity and Fibrosis.

Tom Kretzschmar, Mohamed M Bekhite, Jasmine M F Wu, Daniela Haase, Martin Förster, Tina Müller, Sandor Nietzsche, Martin Westermann, Marcus Franz, Markus H Gräler, P Christian Schulze.

  Doxorubicin (Dox) is a chemotherapeutic agent with cardiotoxicity associated with profibrotic effects. Dox increases ceramide levels with pro-inflammatory effects, cell death, and fibrosis. The purpose of our study was to identify the underlying ceramide signaling pathways. We aimed to characterize the downstream effects on cell survival, metabolism, and fibrosis. Human fibroblasts (hFSF) were treated with 0.7 µM of Dox or transgenically overexpressed ceramide synthase 2 (FLAG-CerS2). Furthermore, cells were pre-treated with MitoTempo (MT) (2 h, 20 µM) or Fumonisin B1 (FuB) (4 h, 100 µM). Protein expression was measured by Western blot or immunofluorescence (IF). Ceramide levels were determined with mass spectroscopy (MS). Visualizations were conducted using laser scanning microscopy (LSM) or electron microscopy. Mitochondrial activity was measured using seahorse analysis. Dox and CerS2 overexpression increased CerS2 protein expression. Coherently, ceramides were elevated with the highest peak for C24:0. Ceramide- induced mitochondrial ROS production was reduced with MT or FuB preincubation. Mitochondrial homeostasis was reduced and accompanied by reduced ATP production. Our data show that the increase in pro-inflammatory ceramides is an essential contributor to Dox side-effects. The accumulation of ceramides resulted in a lipotoxic shift and subsequently mitochondrial structural and functional damage, which was partially reversible following inhibition of ceramide synthesis.

Keywords:  ceramides; fibrosis; mitochondrial function; reactive oxygen species; respiratory chain

DOI:  https://doi.org/10.3390/ijms222111852
Front Cardiovasc Med. 2021 ;8 752241

Interplay Between Gut Microbiota and Amino Acid Metabolism in Heart Failure.

Gulinigaer Tuerhongjiang, Manyun Guo, Xiangrui Qiao, Bowen Lou, Chen Wang, Haoyu Wu, Yue Wu, Zuyi Yuan, Jianqing She.

  Heart failure (HF) is a complex clinical syndrome of which the incidence is on the rise worldwide. Cardiometabolic disorders are associated with the deterioration of cardiac function and progression of HF. Recently, there has been renewed interest in gut microbiota (GM) and its metabolites in the cardiovascular disease. HF-caused hypoperfusion could increase intestinal permeability, and a "leaky" bowel leads to bacterial translocation and make its metabolites more easily enter the circulation. Considerable evidence shows that the composition of microbiota and amino acids (AAs) has been altered in HF patients, and AAs could serve as a diagnostic and prognostic biomarker in HF. The findings indicate that the gut-amino acid-HF axis may play a key role in the progression of HF. In this paper, we focus on the interrelationship between the AA metabolism and GM alterations during the development of heart failure. We also discuss the potential prognostic and therapeutic value of the gut-amino acid-HF axis in the cortex of HF.

Keywords:  amino acids; cardiometabolic disorders; gut microbiota; heart failure; metabolism

DOI:  https://doi.org/10.3389/fcvm.2021.752241