bims-hafaim 2023-01-08 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2023–01–08
twelve papers selected by
Kyle McCommis, Saint Louis University

Enhanced protein acetylation initiates fatty acid-mediated inhibition of cardiac glucose transport.
Blood Pressure and Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: DELIVER.
Mechanisms of SGLT2 Inhibitors in Heart Failure and Their Clinical Value.
ALDH2 attenuates ischemia and reperfusion injury through regulation of mitochondrial fusion and fission by PI3K/AKT/mTOR pathway in diabetic cardiomyopathy.
Pleiotropic effect of sodium-glucose cotransporter 2 inhibitors on blood pressure.
A high-sucrose diet exacerbates the left ventricular phenotype in a high fat-fed streptozotocin rat model of diabetic cardiomyopathy.
Effects of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on substrate metabolism in prediabetic insulin resistant individuals: A randomized, double-blind crossover trial.
Acetate suppresses myocardial contraction via the short-chain fatty acid receptor GPR43.
WNT/β-catenin pathway is a key regulator of cardiac function and energetic metabolism.
Clinical efficacy of SGLT2 inhibitors with different SGLT1/SGLT2 selectivity in cardiovascular outcomes among patients with and without heart failure: A systematic review and meta-analysis of randomized trials.
Cardiovascular and renal effects of SGLT2 inhibitor initiation in acute heart failure: a meta-analysis of randomized controlled trials.
Biomarker signature and pathophysiological pathways in chronic heart failure patients with metabolic syndrome.

Am J Physiol Heart Circ Physiol. 2023 Jan 06.

Enhanced protein acetylation initiates fatty acid-mediated inhibition of cardiac glucose transport.

Marine De Loof, Edith Renguet, Audrey Ginion, Caroline Bouzin, Sandrine Horman, Christophe Beauloye, Luc Bertrand, Laurent Bultot.

  Fatty acids (FAs) rapidly and efficiently reduce cardiac glucose uptake in the Randle cycle or glucose-FA cycle. This fine-tuned physiological regulation is critical to allow optimal substrate allocation during fasted and fed states. However, the mechanisms involved in the direct FA-mediated control of glucose transport have not been totally elucidated yet. We previously reported that leucine and ketone bodies, other cardiac substrates, impair glucose uptake by increasing global protein acetylation from acetyl-CoA. As FAs generate acetyl-CoA as well, we postulated that protein acetylation is enhanced by FAs and participates to their inhibitory action on cardiac glucose uptake. Here, we demonstrated that both palmitate and oleate promoted a rapid increase in protein acetylation in primary cultured adult rat cardiomyocytes, which correlated with an inhibition of insulin-stimulated glucose uptake. This glucose absorption deficit was caused by an impairment in the translocation of vesicles containing the glucose transporter GLUT4 to the plasma membrane, although insulin signaling remained unaffected. Interestingly, pharmacological inhibition of lysine acetyltransferases (KATs) prevented this increase in protein acetylation and glucose uptake inhibition induced by FAs. Similarly, FA-mediated inhibition of insulin-stimulated glucose uptake could be prevented by KAT inhibitors in perfused hearts. To summarize, enhanced protein acetylation can be considered as an early event in the FA-induced inhibition of glucose transport in the heart, explaining part of the Randle cycle.

Keywords:  Acetylation; Fatty acids; Glucose uptake; Insulin; Randle cycle

DOI:  https://doi.org/10.1152/ajpheart.00449.2022
JACC Heart Fail. 2023 Jan;pii: S2213-1779(22)00524-8. [Epub ahead of print]11(1): 76-89

Blood Pressure and Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: DELIVER.

Senthil Selvaraj, Muthiah Vaduganathan, Brian L Claggett, Zi Michael Miao, James C Fang, Orly Vardeny, Akshay S Desai, Sanjiv J Shah, Carolyn S P Lam, Felipe A Martinez, Silvio E Inzucchi, Rudolf A de Boer, Magnus Petersson, Anna Maria Langkilde, John J V McMurray, Scott D Solomon.

   BACKGROUND: Optimizing systolic blood pressure (SBP) in heart failure (HF) with preserved ejection fraction carries a Class I recommendation but with limited evidence. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have antihypertensive effects across cardiovascular disease.
OBJECTIVES: The authors examined the interplay between SBP and treatment effects of dapagliflozin on SBP and cardiovascular outcomes.
METHODS: The authors analyzed 6,263 DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure) participants and related baseline and mean achieved SBP categories (<120, 120-129, 130-139, ≥140 mm Hg) to the primary outcome (cardiovascular death or worsening HF), secondary outcomes, and safety events. They analyzed whether the blood pressure-lowering effects of dapagliflozin accounted for its treatment effects by adjusting for the change in SBP from baseline to 1 month.
RESULTS: The average age was 72 ± 10 years and 44% were women. SBP <120 mm Hg was associated with higher HF and mortality events, although amputation and stroke risk increased with higher SBP. Dapagliflozin reduced SBP by 1.8 (95% CI: 1.1-2.5) mm Hg compared with placebo at 1 month. The treatment effect of dapagliflozin on the primary outcome and Kansas City Cardiomyopathy Questionnaire total symptom score was consistent across SBP (interaction P = 0.15 and P = 0.98, respectively). Adverse events between arms were similar across SBP categories. The treatment effect was not accounted for by reducing blood pressure.
CONCLUSIONS: In DELIVER, risk by SBP was augmented in the lowest and highest categories and varied by endpoint examined. Dapagliflozin modestly decreased SBP compared with placebo. Dapagliflozin was similarly efficacious and safe across the range of baseline SBP. The beneficial effects of dapagliflozin were not accounted for the changes in SBP. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).

Keywords:  SGLT2; blood pressure; dapagliflozin; heart failure hospitalization; heart failure with preserved ejection fraction

DOI:  https://doi.org/10.1016/j.jchf.2022.09.002
J Cardiovasc Pharmacol. 2023 Jan 01. 81(1): 4-14

Mechanisms of SGLT2 Inhibitors in Heart Failure and Their Clinical Value.

Yafei Xie, Yujie Wei, Dan Li, Jie Pu, Hong Ding, Xiaowei Zhang.

ABSTRACT: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are widely used to treat diabetes mellitus. Abundant evidence has shown that SGLT2 inhibitors can reduce hospitalization for heart failure (HF) in patients with or without diabetes. An increasing number of studies are being conducted on the mechanisms of action of SGLT2 inhibitors in HF. Our review summarizes a series of clinical trials on the cardioprotective effects of SGLT2 inhibitors in the treatment of HF. We have summarized several classical SGLT2 inhibitors in cardioprotection research, including empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, and sotagliflozin. In addition, we provided a brief overview of the safety and benefits of SGLT2 inhibitors. Finally, we focused on the mechanisms of SGLT2 inhibitors in the treatment of HF, including ion-exchange regulation, volume regulation, ventricular remodeling, and cardiac energy metabolism. Exploring the mechanisms of SGLT2 inhibitors has provided insight into repurposing these diabetic drugs for the treatment of HF.

DOI: https://doi.org/10.1097/FJC.0000000000001380
Free Radic Biol Med. 2022 Dec 30. pii: S0891-5849(22)01131-5. [Epub ahead of print]195 219-230

ALDH2 attenuates ischemia and reperfusion injury through regulation of mitochondrial fusion and fission by PI3K/AKT/mTOR pathway in diabetic cardiomyopathy.

Xin Tan, Yong-Feng Chen, Shi-Ying Zou, Wei-Jie Wang, Ning-Ning Zhang, Zheng-Yu Sun, Wei Xian, Xiao-Rong Li, Bi Tang, Hong-Ju Wang, Qin Gao, Pin-Fang Kang.

  The function of mitochondrial fusion and fission is one of the important factors causing ischemia-reperfusion (I/R) injury in diabetic myocardium. Aldehyde dehydrogenase 2 (ALDH2) is abundantly expressed in heart, which involved in the regulation of cellular energy metabolism and stress response. However, the mechanism of ALDH2 regulating mitochondrial fusion and fission in diabetic myocardial I/R injury has not been elucidated. In the present study, we found that the expression of ALDH2 was downregulated in rat diabetic myocardial I/R model. Functionally, the activation of ALDH2 resulted in the improvement of cardiac hemodynamic parameters and myocardial injury, which were abolished by the treatment of Daidzin, a specific inhibitor of ALDH2. In H9C2 cardiomyocyte hypoxia-reoxygenation model, ALDH2 regulated the dynamic balance of mitochondrial fusion and fission and maintained mitochondrial morphology stability. Meanwhile, ALDH2 reduced mitochondrial ROS levels, and apoptotic protein expression in cardiomyocytes, which was associated with the upregulation of phosphorylation (p-PI3KTyr458, p-AKTSer473, p-mTOR). Moreover, ALDH2 suppressed the mitoPTP opening through reducing 4-HNE. Therefore, our results demonstrated that ALDH2 alleviated the ischemia and reperfusion injury in diabetic cardiomyopathy through inhibition of mitoPTP opening and activation of PI3K/AKT/mTOR pathway.

Keywords:  Aldehyde dehydrogenase 2; Apoptosis; Mitochondrial fusion and fission; Mitochondrial permeability transition pore; PI3K/AKT/mTOR; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.12.097
Front Cardiovasc Med. 2022 ;9 1086672

Pleiotropic effect of sodium-glucose cotransporter 2 inhibitors on blood pressure.

Ting-Wei Kao, Chin-Chou Huang.

  Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been incorporated as guideline-directed medical therapy for heart failure with reduced ejection fraction. Recent trials clearly established the efficacy of SGLT2 inhibitors on cardiac remodeling while preventing renal function decline in patients with or without diabetes mellitus. Blood pressure reduction during SGLT2 inhibitors use has been proposed through pleiotropic pathways and as a potential contributor that translates to cardiovascular benefits. The mechanisms underlying this decrease in blood pressure are not simply glycemic control. Orchestrating fluid status, modulation of sodium content and renin-angiotensin-activation system, anti-fibrosis and anti-inflammatory effect, ameliorating the characteristics of metabolic syndrome, as well as restoration of circadian rhythm all contributed to the BP lowering effect by SGLT2 inhibitors. Although SGLT2 inhibitors has not been demonstrated as anti-hypertensive agents thus far, their effects on BP alteration are clinically significant. In this review, we revisited the evidence correlating SGLT2 inhibitor use with blood pressure level. Future research directions will focus on the signaling pathway of SGLT2 inhibitors for fluid removal, atherosclerosis, vasoconstriction, and eventually hypertension.

Keywords:  SGLT2 inhibitor; blood pressure; diabetes; heart failure; hypertension; pleiotropy

DOI:  https://doi.org/10.3389/fcvm.2022.1086672
Am J Physiol Heart Circ Physiol. 2023 Jan 06.

A high-sucrose diet exacerbates the left ventricular phenotype in a high fat-fed streptozotocin rat model of diabetic cardiomyopathy.

Anida Velagic, Mandy Li, Minh Deo, Jasmin Chendi Li, Helen Kiriazis, Daniel G Donner, Dovile Anderson, Miles J De Blasio, Owen L Woodman, Barbara K Kemp-Harper, Cheng Xue Qin, Rebecca H Ritchie.

  Left ventricular (LV) dysfunction is an early, clinically detectable sign of cardiomyopathy in type 2 diabetes mellitus (T2DM) that precedes the development of symptomatic heart failure. Pre-clinical models of diabetic cardiomyopathy are essential to develop therapies that may prevent or delay the progression of heart failure. This study examined the molecular, structural, and functional cardiac phenotype of two rat models of T2DM induced by a high-fat diet (HFD) with a moderate- or high-sucrose content (containing 88.9 or 346 g/Kg sucrose, respectively), plus administration of low-dose streptozotocin (STZ). At eight weeks of age, male Sprague-Dawley rats commenced a moderate- or high-sucrose HFD. Two weeks later, rats received low-dose STZ (35 mg/kg i.p. for two days) and remained on their respective diets. LV function was assessed by echocardiography one week prior to endpoint. At 22 weeks of age, blood and tissues were collected post-mortem. Relative to chow-fed sham rats, diabetic rats on a moderate- or high-sucrose HFD displayed cardiac reactive oxygen species dysregulation, perivascular fibrosis, and impaired LV diastolic function. The diabetes-induced impact on LV adverse remodeling and diastolic dysfunction was more apparent when a high-sucrose HFD was superimposed on STZ. In conclusion, a high-sucrose HFD in combination with low-dose STZ produced a cardiac phenotype that more closely resembled T2DM-induced cardiomyopathy than STZ diabetic rats subjected to a moderate-sucrose HFD.

Keywords:  diabetic cardiomyopathy; diastolic dysfunction; high-fat diet; streptozotocin; type 2 diabetes mellitus

DOI:  https://doi.org/10.1152/ajpheart.00390.2022
Metabolism. 2022 Dec 30. pii: S0026-0495(22)00274-8. [Epub ahead of print] 155396

Effects of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on substrate metabolism in prediabetic insulin resistant individuals: A randomized, double-blind crossover trial.

Anna Veelen, Charlotte Andriessen, Yvo Op den Kamp, Edmundo Erazo-Tapia, Marlies de Ligt, Julian Mevenkamp, Johanna A Jörgensen, Esther Moonen-Kornips, Gert Schaart, Russell Esterline, Bas Havekes, Jan Oscarsson, Vera B Schrauwen-Hinderling, Esther Phielix, Patrick Schrauwen.

   AIMS/HYPOTHESIS: Sodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment in type 2 diabetes mellitus patients results in glucosuria, causing an energy loss, and triggers beneficial metabolic adaptations. It is so far unknown if SGLT2i exerts beneficial metabolic effects in prediabetic insulin resistant individuals, yet this is of interest since SGLT2is also reduce the risk for progression of heart failure and chronic kidney disease in patients without diabetes.
METHODS: Fourteen prediabetic insulin resistant individuals (BMI: 30.3 ± 2.1 kg/m2; age: 66.3 ± 6.2 years) underwent 2-weeks of treatment with dapagliflozin (10 mg/day) or placebo in a randomized, placebo-controlled, cross-over design. Outcome parameters include 24-hour and nocturnal substrate oxidation, and twenty-four-hour blood substrate and insulin levels. Hepatic glycogen and lipid content/composition were measured by MRS. Muscle biopsies were taken to measure mitochondrial oxidative capacity and glycogen and lipid content.
RESULTS: Dapagliflozin treatment resulted in a urinary glucose excretion of 36 g/24-h, leading to a negative energy and fat balance. Dapagliflozin treatment resulted in a higher 24-hour and nocturnal fat oxidation (p = 0.043 and p = 0.039, respectively), and a lower 24-hour carbohydrate oxidation (p = 0.048). Twenty-four-hour plasma glucose levels were lower (AUC; p = 0.016), while 24-hour free fatty acids and nocturnal β-hydroxybutyrate levels were higher (AUC; p = 0.002 and p = 0.012, respectively) after dapagliflozin compared to placebo. Maximal mitochondrial oxidative capacity was higher after dapagliflozin treatment (dapagliflozin: 87.6 ± 5.4, placebo: 78.1 ± 5.5 pmol/mg/s, p = 0.007). Hepatic glycogen and lipid content were not significantly changed by dapagliflozin compared to placebo. However, muscle glycogen levels were numerically higher in the afternoon in individuals on placebo (morning: 332.9 ± 27.9, afternoon: 368.8 ± 13.1 nmol/mg), while numerically lower in the afternoon on dapagliflozin treatment (morning: 371.7 ± 22.8, afternoon: 340.5 ± 24.3 nmol/mg).
CONCLUSIONS/INTERPRETATION: Dapagliflozin treatment of prediabetic insulin resistant individuals for 14 days resulted in significant metabolic adaptations in whole-body and skeletal muscle substrate metabolism despite being weight neutral. Dapagliflozin improved fat oxidation and ex vivo skeletal muscle mitochondrial oxidative capacity, mimicking the effects of calorie restriction.
TRIAL REGISTRATION: ClinicalTrials.gov NCT03721874.

Keywords:  Energy metabolism; Glycogen; Human(s); Insulin resistance; Mitochondrial function; SGLT2 inhibitor

DOI:  https://doi.org/10.1016/j.metabol.2022.155396
Front Physiol. 2022 ;13 1111156

Acetate suppresses myocardial contraction via the short-chain fatty acid receptor GPR43.

Xuan Jiang, Ying Zhang, Huaxing Zhang, Xiaoguang Zhang, Xiaopeng Yin, Fang Yuan, Sheng Wang, Yanming Tian.

  The heart has high energy requirements, with an estimated 40%-60% of myocardial ATP production derived from the oxidation of fatty acids under physiological conditions. However, the effect of short-chain fatty acids on myocardial contraction remains controversial, warranting further research. The present study sought to investigate the effects and mechanisms of acetate, a short-chain fatty acid, on myocardial contraction in rat ventricular myocytes. Echocardiography and Langendorff heart perfusion were used to evaluate cardiac function. Cell shortening and calcium transient were measured in isolated cardiomyocytes. The patch-clamp method determined the action potential and L-type Ca2+ current in cardiomyocytes. Moreover, the expression of GPR43, a type of short-chain fatty acid receptors in cardiomyocytes was examined by immunofluorescent staining and Western blot. We demonstrated that acetate transiently reduced left ventricular developmental pressure in isolated Langendorff heart perfusion model, with no effect on stroke volume and cardiac output in vivo. In addition, acetate transiently and reversibly inhibited cardiomyocyte contraction and calcium transient. Acetate did not affect the action potential and L-type Ca2+ currents in cardiomyocytes. As a short-chain fatty acid receptor, GPR43 was expressed in rat cardiomyocytes. Furthermore, the GPR43 antagonist GLPG0974 prevented the acetate-induced inhibitory effect on myocardial contraction. We conclude that acetate transiently inhibits contraction via the short-chain fatty acid receptor GPR43 in cardiomyocytes.

Keywords:  FFAR2; GPR43; acetate; calcium handling; cardiac contractility; short-chain fatty acids

DOI:  https://doi.org/10.3389/fphys.2022.1111156
Acta Physiol (Oxf). 2023 Jan 04. e13912

WNT/β-catenin pathway is a key regulator of cardiac function and energetic metabolism.

Volodymyr V Balatskyi, Adrian Sowka, Pawel Dobrzyn, Oksana O Piven.

  The WNT/β-catenin pathway is a master regulator of cardiac development and growth, and its activity is low in healthy adult hearts. However, even this low activity is essential for maintaining normal heart function. Acute activation of the WNT/β-catenin signaling cascade is considered to be cardioprotective after infarction through the upregulation of prosurvival genes and reprogramming of metabolism. Chronically high WNT/β-catenin pathway activity causes profibrotic and hypertrophic effects in the adult heart. New data suggest more complex functions of β-catenin in metabolic maturation of the perinatal heart, establishing an adult pattern of glucose and fatty acid utilization. Additionally, low basal activity of the WNT/β-catenin cascade maintains oxidative metabolism in the adult heart, and this pathway is reactivated by physiological or pathological stimuli to meet the higher energy needs of the heart. This review summarizes the current state of knowledge of the organization of canonical WNT signaling and its function in cardiogenesis, heart maturation, adult heart function, and remodeling. We also discuss the role of the WNT/β-catenin pathway in cardiac glucose, lipid metabolism, and mitochondrial physiology.

Keywords:  WNT/β-catenin signaling; cardiac metabolism; glucose metabolism; lipid metabolism; β-oxidation

DOI:  https://doi.org/10.1111/apha.13912
Medicine (Baltimore). 2022 Dec 23. 101(51): e32489

Clinical efficacy of SGLT2 inhibitors with different SGLT1/SGLT2 selectivity in cardiovascular outcomes among patients with and without heart failure: A systematic review and meta-analysis of randomized trials.

Mei-Chuan Lee, Yi-Ming Hua, Chun-Ting Yang, Fang-Hsiu Kuo, Wei-Ting Chang, Hsin-Ju Tang, Han Siong Toh, Yu-Min Lin, Sih-Yao Chen, Hung-Yu Chang, Chia-Te Liao.

BACKGROUND: Some sodium-glucose co-transporter-2 (SGLT2) inhibitors showed benefits on heart failure (HF), but different SGLT2/SGLT1 selectivity might influence the treatment effect. This study aimed to meta-analyze the treatment effects of SGLT2 inhibitors and the diversity of receptor selectivity for patients with and without HF.
METHODS: Randomized controlled trials were searched in PubMed, Embase, Cochrane databases and ClinicalTrials.gov registry from inception to October 2020. The interest outcomes were analyzed with random-effects models and presented with a risk ratio (RR) and 95% confidence interval (CI). Subgroup analyses examined the treatment effects among SGLT2 inhibitors with different SGLT2/SGLT1 selectivity.
RESULTS: The final analyses included 10 trials and 52,607 patients. The RR of total cardiovascular (CV) death or hospitalization for HF (HHF) between SGLT2 inhibitors and placebo was 0.79 (95% CI 0.74-0.84, I2 = 31%). With SGLT2 inhibitors, HF patients had reduced mortality risks (RR 0.89, 95% CI 0.80-0.99, I2 = 0), and non-HF patients had lower risks of major adverse CV events (RR 0.92, 95% CI 0.85-0.99, I2 = 0). The risk reduction of HHF was consistent in groups of HF (RR 0.72, 95% CI 0.64-0.80, I2 = 8%) and non-HF (RR 0.74, 95% CI 0.61-0.89, I2 = 0), but the effect of the low SGLT2/SGLT1 selectivity inhibitor was insignificant in non-HF patients.
CONCLUSION: The efficacy of SGLT2 inhibitors on risk reduction of total CV death or HHF is consistent with the previous studies. The regimen is beneficial for reducing mortality in patients with HF and major adverse CV events in those without HF. Different SGLT2/SGLT1 selectivity may differ in the treatment effects in patients with and without HF.

DOI: https://doi.org/10.1097/MD.0000000000032489
Clin Res Cardiol. 2023 Jan 02.

Cardiovascular and renal effects of SGLT2 inhibitor initiation in acute heart failure: a meta-analysis of randomized controlled trials.

Pedro E P Carvalho, Thiago M A Veiga, Ana C Simões E Silva, Douglas M Gewehr, Caroline S Dagostin, Amanda Fernandes, Guilherme Nasi, Rhanderson Cardoso.

   BACKGROUND: We sought to compare cardiovascular outcomes, renal function, and diuresis in patients receiving standard diuretic therapy for acute heart failure (AHF) with or without the addition of SGLT2i.
METHODS AND RESULTS: Systematic search of three electronic databases identified nine eligible randomized controlled trials involving 2,824 patients. The addition of SGLT2i to conventional therapy for AHF reduced all-cause death (odds ratio [OR] 0.75; 95% CI 0.56-0.99; p = 0.049), readmissions for heart failure (HF) (OR 0.54; 95% CI 0.44-0.66; p < 0.001), and the composite of cardiovascular death and readmissions for HF (hazard ratio 0.71; 95% CI 0.60-0.84; p < 0.001). Furthermore, SGLT2i increased mean daily urinary output in liters (mean difference [MD] 0.45; 95% CI 0.03-0.87; p = 0.035) and decreased mean daily doses of loop diuretics in mg of furosemide equivalent (MD -34.90; 95% CI [- 52.58, - 17.21]; p < 0.001) without increasing the incidence worsening renal function (OR 0.75; 95% CI 0.43-1.29; p = 0.290).
CONCLUSION: SGLT2i addition to conventional diuretic therapy reduced all-cause death, readmissions for HF, and the composite of cardiovascular death or readmissions for HF. Moreover, SGLT2i was associated with a higher volume of diuresis with a lower dose of loop diuretics.

Keywords:  Acute heart failure; Diuresis; Renal function; Sodium-glucose cotransporter-2 (SGLT2) inhibitors

DOI:  https://doi.org/10.1007/s00392-022-02148-2
Eur J Heart Fail. 2023 Jan 04.

Biomarker signature and pathophysiological pathways in chronic heart failure patients with metabolic syndrome.

Camilla C S van der Hoef, Eva M Boorsma, Johanna E Emmens, Bart J van Essen, Marco Metra, Leong L Ng, Stefan D Anker, Kenneth Dickstein, Ify R Mordi, Adel Dihoum, Chim C Lang, Dirk J van Veldhuisen, Carolyn S P Lam, Adriaan A Voors.

   AIM: The comorbidities that collectively define metabolic syndrome are common in patients with heart failure. However, the role of metabolic syndrome in the pathophysiology of heart failure is not well understood. We therefore investigated the clinical and biomarker correlates of metabolic syndrome in patients with heart failure.
METHODS: In 1103 patients with heart failure, we compared the biomarker expression using a panel of 363 biomarkers among patients with (n = 468[42%]) and without (n = 635[58%]) metabolic syndrome. Subsequently, a pathway overrepresentation analysis was performed to identify key biological pathways. Findings were validated in an independent cohort of 1433 patients with heart failure of whom 615 (43%) had metabolic syndrome. Metabolic syndrome was defined as the presence of ≥ three of five criteria, including central obesity, elevated serum triglycerides, reduced high-density lipoprotein cholesterol, insulin resistance and hypertension.
RESULTS: The most significantly elevated biomarkers in patients with metabolic syndrome were leptin (log2 fold change 0.92,P = 5.85 × 10-21 ), fatty acid-binding protein 4 (log2 fold change 0.61,P = 1.21 × 10-11 ), interleukin-1 receptor antagonist (log2 fold change 0.47,P = 1.95 × 10-13 ), tumour necrosis factor receptor superfamily member 11a (log2 fold change 0.35,P = 4.16 × 10-9 ), and RET proto-oncogene (log2 fold change 0.31,P = 4.87 × 10-9 ). Network analysis identified 10 pathways in the index cohort and 6 in the validation cohort, all related to inflammation. The primary overlapping pathway in both the index and validation cohort was up-regulation of the natural killer cell-mediated cytotoxicity pathway.
CONCLUSION: Metabolic syndrome is highly prevalent in heart failure and is associated with biomarkers and pathways relating to obesity, lipid metabolism and immune responses underlying chronic inflammation. This article is protected by copyright. All rights reserved.

Keywords:  Biomarkers; Chronic Heart Failure; Metabolic Syndrome

DOI:  https://doi.org/10.1002/ejhf.2760