Acid In Heart Failure Research Articles

Prognostic Significance of Serum Uric Acid in Heart Failure

Prognostic Significance of Serum Uric Acid in Heart Failure

Genome-wide association and multi-trait analyses characterize the common genetic architecture of heart failure

Heart failure is a leading cause of cardiovascular morbidity and mortality. However, the contribution of common genetic variation to heart failure risk has not been fully elucidated, particularly in comparison to other common cardiometabolic traits. We report a multi-ancestry genome-wide association study meta-analysis of all-cause heart failure including up to 115,150 cases and 1,550,331 controls of diverse genetic ancestry, identifying 47 risk loci. We also perform multivariate genome-wide association studies that integrate heart failure with related cardiac magnetic resonance imaging endophenotypes, identifying 61 risk loci. Gene-prioritization analyses including colocalization and transcriptome-wide association studies identify known and previously unreported candidate cardiomyopathy genes and cellular processes, which we validate in gene-expression profiling of failing and healthy human hearts. Colocalization, gene expression profiling, and Mendelian randomization provide convergent evidence for the roles of BCKDHA and circulating branch-chain amino acids in heart failure and cardiac structure. Finally, proteome-wide Mendelian randomization identifies 9 circulating proteins associated with heart failure or quantitative imaging traits. These analyses highlight similarities and differences among heart failure and associated cardiovascular imaging endophenotypes, implicate common genetic variation in the pathogenesis of heart failure, and identify circulating proteins that may represent cardiomyopathy treatment targets.

Uric acid and cardiovascular risk stratification in the acute coronary syndromes: a friend we should mind

Uric acid (UA) is the end product of purine metabolism. Whilst being primarily known as the leading risk factor for the onset of gout [ [1] Dalbeth N. Choi H.K. Joosten L.A.B. Khanna P.P. Matsuo H. Perez-Ruiz F. Stamp L.K. Gout. Nat Rev Dis Primers. 2019; 5 Crossref PubMed Scopus (114) Google Scholar ], UA has also been acknowledged as a significant CV risk factor [ [2] Virdis A. Masi S. Casiglia E. et al. Identification of the uric acid thresholds predicting an increased total and cardiovascular mortality over 20 years. Hypertension. 2020; 75: 302-308 Crossref PubMed Scopus (62) Google Scholar ]. However, international guidelines report as pathological threshold only the saturation point of UA (6.0 mg/dL in women and ≥7.0 mg/dL in men) [ [3] Li Q. Li X. Wang J. et al. Diagnosis and treatment for hyperuricemia and gout: a systematic review of clinical practice guidelines and consensus statements. BMJ Open. 2019; 9 Crossref Scopus (44) Google Scholar ], yet failing to identify a specific CV prevention cut-off [ [4] Visseren F.L.J. Mach F. Smulders Y.M. et al. 2021 ESC guidelines on cardiovascular disease prevention in clinical practice. Europe J Prev Cardiol. 2021; Crossref Google Scholar ]. This somewhat neglects UA predictive role in CV disease [ [5] Kaufman M. Guglin M. Uric acid in heart failure: a biomarker or therapeutic target?. Heart Fail Rev. 2013; 18: 177-186 Crossref PubMed Scopus (31) Google Scholar ]. In a large (n=22,714) Italian-population based observation cohort study, we have described how UA markedly impact all-cause and CV mortality starting from lower serum levels (respectively, 4.7 and 5.6 mg/dL) [ [2] Virdis A. Masi S. Casiglia E. et al. Identification of the uric acid thresholds predicting an increased total and cardiovascular mortality over 20 years. Hypertension. 2020; 75: 302-308 Crossref PubMed Scopus (62) Google Scholar ]. Several other observations have also found that UA enhances the CV mortality and morbidity risk stratification across the totality of the cardiometabolic spectrum using the same lower cut-offs [ [6] Pugliese N.R. Mengozzi A. Virdis A. et al. The importance of including uric acid in the definition of metabolic syndrome when assessing the mortality risk. Clin Res Cardiol. 2021; 110: 1073-1082 Crossref PubMed Scopus (7) Google Scholar , [7] Muiesan M.L. Salvetti M. Virdis A. et al. Serum uric acid, predicts heart failure in a large Italian cohort: search for a cut-off value the uric acid right for heart health study. J Hypertens. 2021; 39: 62-69 Crossref PubMed Scopus (12) Google Scholar ]. However, whilst in the current literature the relationship between UA in CV disease has been explored mainly in a chronic context (i.e. diabetes, hypertension, chronic kidney disease), little evidence is available to help us in defining whether the predictive power of UA holds true also for the acute setting, such as the acute coronary syndrome (ACS) [ [8] Maloberti A. Biolcati M. Ruzzenenti G. et al. The role of uric acid in acute and chronic coronary syndromes. J Clin Med. 2021; 10 Crossref Scopus (2) Google Scholar ].

Abstract 13773: Hyperuricemia is Associated With Increased Mortality in Heart Failure Patients With Preserved Ejection Fraction: A Systematic Review and Meta-Analysis

Introduction: Recent data has emerged suggesting prognostic value of serum uric acid in heart failure with preserved ejection fraction (HFpEF), however, there are conflicting data. This is the first meta-analysis to assess the associations of serum uric acid and clinical outcomes in patients with HFpEF. Methods: Comprehensive literature search was conducted from MEDLINE and EMBASE through November 2020. We included cohort studies and post-hoc analyses of randomized controlled trials that investigated the associations between serum uric acid and clinical outcomes in patients with HFpEF. Data was combined using the random-effects, generic inverse variance method of DerSimonian and Laird to calculate hazard ratios and 95% confidence intervals (CI). Only studies using multivariable analyses were included. Results: Six studies were included in this meta-analysis, including 12,976 patients with HFpEF. The studies dated from 2015 to 2020. We found that in patients with HFpEF, hyperuricemia was associated with an increased risk of overall mortality (pooled adjusted HR 1.236, 95% CI 1.002-1.525, p=0.048, I 2 =84.6%) and cardiac mortality (pooled adjusted HR 1.589, 95% CI 1.273-1.984, p<0.05, I 2 = 0%) after multivariable adjustments. The results were significant on sensitivity analysis. Conclusions: Our meta-analysis suggested that hyperuricemia was associated with increased mortality in patients with HFpEF. Further studies are warranted to elucidate mechanism underlying this association and possible therapeutic interventions for HFpEF patients with hyperuricemia.

Abstract 13834: The Effect of Dapagliflozin on Serum Uric Acid in Heart Failure With Reduced Ejection Fraction: Insights From DAPA-HF

Introduction: Elevated serum uric acid (sUA) levels are common in patients with heart failure and reduced ejection fraction (HFrEF). sUA, in part, reflects the use of diuretics, and higher sUA is associated with a higher risk of adverse outcomes in HFrEF. We examined the effect of dapagliflozin on sUA, and the efficacy of dapagliflozin according to baseline sUA, in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial. Methods: Patients in NYHA class II-IV with a LVEF ≤40%, and elevated plasma NT-proBNP were included in DAPA-HF. Key exclusions included hypotension, systolic BP <95 mmHg, and eGFR <30 ml/min/1.73m 2 . The primary outcome was a composite of worsening HF (hospitalization for HF or an urgent HF visit requiring iv therapy) or CV death. sUA was measured pre-randomization and at 52 weeks. The effect of dapagliflozin on sUA was assessed using a linear regression model adjusted for baseline value. The efficacy of dapagliflozin was assessed using baseline sUA as a continuous variable. Results: Of the 4744 randomized patients, 3119 (65.7%) had sUA measured at baseline, with a mean of 6.10±1.70 (median 5.9, IQR 4.9-7.1) mg/dL. The placebo-corrected change in sUA at 52 weeks was -0.83 mg/dL (95% CI -0.93, -0.74); p<0.001.In adjusted models including diuretic use/dose, higher sUA was associated with an elevated risk of the primary endpoint; hazard ratio 1.09 (1.03-1.14) per 1mg/dL sUA; p=0.0015 Figure, Panel A .The benefit of dapagliflozin, compared with placebo, on the primary endpoint was consistent across the range of sUA studied ( Figure, Panel B ; P interaction=0.77). Conclusions: In DAPA-HF, higher sUA was associated with worse outcomes and dapagliflozin significantly reduced sUA. The efficacy of dapagliflozin on outcomes was consistent across the range of sUA studied.

The prognostic impact of uric acid in acute heart failure according to coexistence of diabetes mellitus

Background and aimsIncreased uric acid levels predict higher mortality in heart failure (HF) patients. Patients with diabetes mellitus (DM) appear to have increased xanthine oxidase activity. We aimed to study if the association between uric acid and mortality in acute HF was different according to the coexistence of DM. Methods and resultsWe studied a cohort of patients hospitalized due to acute HF in 2009–2010. Patients with no uric acid measurement upon admission were excluded from the analysis. Follow-up: 2 years; endpoint: all-cause mortality. Patients with elevated uric acid (>80.0 mg/L) were compared with those with lower values. We used a multivariate Cox-regression analysis to assess the prognostic impact of uric acid (both continuous and categorical variable: cut-off 80.0 mg/L). The analysis was stratified according to coexistence of DM. We studied 569 acute HF patients, 44.6%male, mean age 76 years, 290 were diabetic. Median admission uric acid: 81.2 mg/L and 52.2%had uric acid >80.0 mg/L. Elevated uric acid predicted all-cause mortality in acute HF only in patients with DM. The multivariate-adjusted HR of 2-year mortality was 1.68 (95 % CI: 1.15–2.46) for diabetic HF patients with uric acid>80.0 mg/L compared to those with lower levels (p = 0.008) and 1.10 (95 % CI: 1.03–1.18) per each 10 mg/L increase in uric acid (p = 0.007). In non-diabetic HF patients, uric acid was not associated with mortality. ConclusionsIncreased uric acid predicts ominous outcome in acute HF patients with diabetes, however, it is not prognostic associated in non-diabetics. Uric acid may play a different role in acute HF depending on DM status.

Clinical Implications of Uric Acid in Heart Failure: A Comprehensive Review.

Affecting more than 26 million people worldwide and with rising prevalence, heart failure (HF) represents a major global health problem. Hence, further research is needed in order to abate poor HF outcomes and mitigate significant expenses that burden health care systems. Based on available data, experts agree that there is an urgent need for a cost-effective prognostic biomarker in HF. Although a significant number of biomarkers have already been investigated in this setting, the clinical utility of adding biomarker evaluation to routine HF care still remains ambiguous. Specifically, in this review we focused on uric acid (UA), a purine metabolism detriment whose role as cardiovascular risk factor has been exhaustingly debated for decades. Multiple large population studies indicate that UA is an independent predictor of mortality in acute and chronic HF, making it a significant prognostic factor in both settings. High serum levels have been also associated with an increased incidence of HF, thus expanding the clinical utility of UA. Importantly, emerging data suggests that UA is also implicated in the pathogenesis of HF, which sheds light on UA as a feasible therapeutic target. Although to date clinical studies have not been able to prove the benefits of xanthine oxidase in HF patients, we discuss the putative role of UA and xanthine oxidase in the pathophysiology of HF as a therapeutic target.

Gallic acid attenuates pulmonary fibrosis in a mouse model of transverse aortic contraction-induced heart failure

Gallic acid, a trihydroxybenzoic acid found in tea and other plants, attenuates cardiac hypertrophy, fibrosis, and hypertension in animal models. However, the role of gallic acid in heart failure remains unknown. In this study, we show that gallic acid administration prevents heart failure-induced pulmonary fibrosis. Heart failure induced in mice, 8weeks after transverse aortic constriction (TAC) surgery, was confirmed by echocardiography. Treatment for 2weeks with gallic acid but not furosemide prevented cardiac dysfunction in mice. Gallic acid significantly inhibited TAC-induced pathological changes in the lungs, such as increased lung mass, pulmonary fibrosis, and damaged alveolar morphology. It also decreased the expression of fibrosis-related genes, including collagen types I and III, fibronectin, connective tissue growth factor (CTGF), and phosphorylated Smad3. Further, it inhibited the expression of epithelial-mesenchymal transition (EMT)-related genes, such as N-cadherin, vimentin, E-cadherin, SNAI1, and TWIST1. We suggest that gallic acid has therapeutic potential for the treatment of heart failure-induced pulmonary fibrosis.

Uric Acid in Heart Failure: Controversy Factor in The Multiple Pathogenesis of The Disease

Uric Acid in Heart Failure: Controversy Factor in The Multiple Pathogenesis of The Disease

Abstract 323: Metabolic Transformation of Fatty Acids Defines Resolving Versus Non-Resolving Inflammation in Obesity-Associated Heart Failure

Whether and how fat intake contributes to persistent inflammation in obesity is unclear. Here, we report the differential metabolic transformation of fatty acids in heart failure (HF) pathology in the setting of obesity. We used permanent coronary ligation to induce myocardial infarction (MI) leading to acute (d1), healing phase (d5) and subsequent chronic HF phase (d28) in male C57BL/6J mice, while maintaining naïve controls at day (d)0. Prior to MI, 100 two month-old mice were subjected to n-6 fatty acids (safflower oil; SO; 22Kcal) for 3 months, with subsequent randomized allocation of 50 mice to docosahexaenoic acid (DHA; 22Kcal) enriched n-3 fatty acids for the next 2 months, while maintaining SO control in the remaining 50 mice. Both groups gained significant weight and fat mass independent of lean mass confirmed by magnetic resonance imaging. Post-MI survival and left ventricular (LV) function was decreased in SO-fed mice with downregulation of multiple inflammation resolution mechanisms in the spleen, infarcted LV, and kidney. DHA increased Ly6C low macrophages, MRC, Arg-1, YM1 and FFAR4 (GPR120) during the acute and resolving phase from d1 to d5 post-MI as compared with SO-fed mice. DHA-improved post-MI survival at d28, together with increased levels of D-series resolvins (RvD1, RvD2, RvD4, RvD5), maresin 1, and RvE3, and lower levels of prostaglandins (PGD 2 , PGE 2 , PGF2 α ), leukotriene B 4 (LTB 4 ), 20-OH-LTB 4 , thromboxane B2 and lipoxin A 4 in the resolving phase. During chronic HF at d28 post-MI, DHA increased CD4 + /CD127 - with increased expression of FOXp3 in the LV. DHA reduced FFAR1-3 , neprilysin activity and simultaneously increased FFAR4 in the kidney as compared with SO post-MI. In contrast, SO-induced overactivation of pro-inflammatory FFAR1 (GPR40) and reduction of anti-inflammatory FFAR4 tracked with increased serum creatinine and IL-1β, and decreased ALX/ FPR2 in kidney at d28 post-MI. Overall, DHA intake modulates the splenocardiac resolving phase with generation of proresolving mediators, augmentation of Ly6C low macrophages, and suppression of prostaglandins post-MI. Thus, the metabolic transformation of n-3 and -6 fatty acids can regulate resolution versus non-resolution of inflammation in HF post-MI in the setting of obesity.

The Role of Omega-3 Polyunsaturated Fatty Acids in Heart Failure: A Meta-Analysis of Randomised Controlled Trials.

Many new clinical trials about the effect of omega-3 polyunsaturated fatty acids (PUFAs) in heart failure (HF) patients have shown inconsistent results. Therefore, a meta-analysis of randomised controlled trials (RCTs) was performed to determine the benefits of omega-3 PUFAs in HF patients. Articles were obtained from PubMed, EMBASE, and the Cochrane Library. RCTs comparing omega-3 PUFAs with placebo for HF were included. Two reviewers independently extracted the data from the selected publications. The I2 statistic was used to assess heterogeneity. The pooled mean difference and associated 95% confidence intervals were calculated, and a fixed or random-effects model was used for the meta-analysis. A total of nine RCTs involving 800 patients were eligible for inclusion. Compared with patients taking placebo, HF patients who received omega-3 PUFAs experienced decreased brain natriuretic peptide levels and serum norepinephrine levels. Although the left ventricular ejection fraction (LVEF) and clinical outcomes (Tei index, peak oxygen consumption) did not improve, subgroup analysis showed that the LVEF increased in dilated cardiomyopathy (DCM) patients. Overall, omega-3 PUFA supplements might be beneficial in HF patients, especially in DCM patients, but further studies are needed to confirm these benefits.

Polyunsaturated Fatty Acids in Heart Failure

Polyunsaturated Fatty Acids in Heart Failure

Polyunsaturated Fatty Acids in Heart Failure

Polyunsaturated Fatty Acids in Heart Failure

Abstract 86: Catabolic Remodeling of Branched Chain Amino Acids in Heart Failure

Metabolic remodeling is an integral part of heart failure. Although glucose and fatty acids metabolism have been extensively studied, little is known about the role of amino acids homeostasis in heart physiology and pathology. Branched chain amino acids (BCAAs), including leucine, isoleucine, and valine, are essential amino acids for both protein synthesis and cellular signaling. Elevated levels of BCAAs have been linked with heart failure. However, the underlying regulatory mechanism and functional significance of abnormal BCAA catabolism in heart failure have not been established. We found that genes involved in BCAA catabolism, including a key regulatory protein PP2Cm, are significantly down-regulated at mRNA as well as protein level in pressure-overload induced failing heart in mice. Furthermore, the concentrations of BCAA catabolic products branched-chain keto acids (BCKAs) are also elevated in heart tissues of post TAC mice. Interestingly, the down-regulation of BCAA catabolic genes mimics a similar expression pattern observed in fetal heart, suggesting that decreased BCAA catabolic activity is part of the metabolic remodeling in pathologically stressed heart from an adult to a fetal-like state. Genetic ablation of PP2Cm in mouse leads to defect in BCAA catabolism and accumulation of BCAAs and BCKAs in cardiac tissue and serum. PP2Cm deficient mice had lower cardiac contractility and higher susceptibility to develop heart failure under pressure overload. In addition, BCKAs treatment to isolated mitochondria resulted in lower oxygen consumption rate and ATP production. PP2Cm deficiency as well as BCKAs treatment induced oxidative stress in cardiomyocyte and antioxidant treatment ameliorated the development of heart failure in PP2Cm deficient animals. Together, these data indicated that BCAA catabolic remodeling is likely an integrated component of metabolic remodeling during heart failure. More importantly, mis-regulation of BCAA catabolism in heart promoted heart failure progression, involving direct impact on mitochondrial function and redox homeostasis in cardiomyocytes.

The Use of ω-3 Poly-Unsaturated Fatty Acids in Heart Failure: A Preferential Role in Patients with Diabetes

To review the evidence for a beneficial effect of ω-3 PUFAs in heart failure (HF) and its co-morbidities, their possible preferential effect in diabetes and the potential mechanism for their benefit. We summarize the clinical studies which investigated the use of ω-3 PUFAs in patients with HF with an emphasis on diabetes. We briefly summarize the evidence for an effect of ω-3 PUFAs in patients with coronary artery disease (CAD), atrial fibrillation (AF) and ventricular arrhythmias. We also discuss the proposed mechanisms of ω-3 PUFA action in cardiovascular diseases. While there is emerging evidence for a beneficial effect of ω-3 PUFA supplementation in patients with HF, the evidence for other indications have been variable and conflicting. In HF patients with diabetes, ω-3 PUFAs may have a preferential therapeutic benefit. Randomized controlled trials did not show considerable beneficial effects of ω-3 PUFAs in other conditions such as CAD and AF. In a diabetic and insulin-resistant state, ω-3 PUFAs bind to the G-protein coupled receptor, GPR120, resulting in reduced cytokine production from inflammatory macrophages and improved signaling in adipocytes, leading to a reduction in insulin resistance. There is promising evidence showing that use of ω-3 PUFA supplementation improves clinical outcomes of HF patients with diabetes. Further clinical trials are needed in this regard.

Uric acid in heart failure: a biomarker or therapeutic target?

There is a need for a cost-effective prognostic biomarker in heart failure (HF). Substantial evidence suggests that uric acid (UA) is an independent marker for adverse prognosis in acute and chronic HF of varying severity. Whether UA is a merely a marker of poor prognosis or is an active participant in disease pathogenesis is currently unknown. In the setting of HF, at least two different processes can be responsible for increased UA: increased production, which may result from oxidative stress, and decreased excretion due to renal insufficiency, which can be a consequence of cardio-renal syndrome, renal congestion, or comorbidities. While pioneer studies have raised the possibility of preventing HF through the use of UA lowering agents, namely xanthine oxidase inhibitors and uricosurics, the literature is still conflicting on whether the reduction in UA will result in a measurable clinical benefit. In this review, we examine the evidence relating UA to HF prognosis, the mechanisms that contribute to increased UA levels in HF, and future novel treatments aimed at reducing UA levels.

The role of uric acid in heart failure

Complications and mortality of heart failure are high, despite the availability of several forms of treatment. Uric acid, the end product of purine metabolism would actively participate in the pathophysiology of heart failure. However, there is no consensus about its action in cardiovascular disease. Serum uric acid would have a protective antioxidant activity. This action could help to reduce or counteract the processes that cause or appear as a result of heart failure. However, these protective properties would vanish in the intracellular environment or in highly hydrophobic areas such as atherosclerotic plaques and adipose tissue. This review discusses the paradoxical action of uric acid in the pathophysiology of heart failure.

Catabolism of Branched-Chain Amino Acids in Heart Failure: Insights from Genetic Models

Genetic defects in amino acid metabolism are major causes of newborn diseases that often lead to abnormal development and function of the central nervous system. Their direct impact on cardiac development and function has rarely been investigated. Recently, the authors have established that a mitochondrial targeted 2C-type ser/thr protein phosphatase, PP2Cm, is the endogenous phosphatase of the branched-chain alpha keto acid-dehydrogenase complex (BCKD) and functions as a key regulator in branched-chain amino acid catabolism and homeostasis. Genetic inactivation of PP2Cm in mice leads to significant elevation in plasma concentrations of branched-chain amino acids and branched-chain keto acids at levels similar to those associated with intermediate mild forms of maple syrup urine disease. In addition to neuronal tissues, PP2Cm is highly expressed in cardiac muscle, and its expression is diminished in a heart under pathologic stresses. Whereas phenotypic features of heart failure are seen in PP2Cm-deficient zebra fish embryos, cardiac function in PP2Cm-null mice is compromised at a young age and deteriorates faster by mechanical overload. These observations suggest that the catabolism of branched-chain amino acids also has physiologic significance in maintaining normal cardiac function. Defects in PP2Cm-mediated catabolism of branched-chain amino acids can be a potential novel mechanism not only for maple syrup urine disease but also for congenital heart diseases and heart failure.

Marine polyunsaturated fatty acids in heart failure Are the theoretical benefits matched by the clinical data?

Chronic heart failure (CHF) is a common condition, which despite major advances, is still characterized by high mortality (with sudden arrhythmic death a particular risk), poor quality of life due to exercise intolerance and frequent hospitalizations. Epidemiological studies suggest that populations with a high intake of marine polyunsaturated fatty acids (PUFAs or fish oils) have low levels of cardiovascular mortality. Animal and human studies of fish oil supplementation have demonstrated improved endothelial function and myocardial relaxation, reduced vascular tone and platelet aggregability, and a stabilization of myocyte excitability by prolongation of the refractory period. Marine PUFAs also have potentially important immune-modulating effects, reducing cytokine production and release, and altering prostaglandin metabolism. Data from patients following acute myocardial infarction have suggested that marine PUFA supplementation may reduce early mortality, mostly by reducing the risk of sudden arrhythmic death. Until recently, data in patients with chronic heart failure was lacking, but the recent publication of the GISSI-HF study, randomizing more than 7000 CHF patients to marine PUFA supplementation or placebo has clarified somewhat the role of these agents. The aim of this article is to review the theoretical benefits of marine PUFAs and to discuss the implications of the GISSI-HF study for the management of patients with CHF.

Response to Letter Regarding Article “Acute Administration of Fish Oil Inhibits Triggered Activity in Isolated Myocytes From Rabbits and Patients With Heart Failure”

We thank Drs Pignier and LeGrand for their interest in our work.1 In their letter, Drs Pignier and LeGrand express their belief that inhibition of the persistent component of the sodium current (INa,P) constitutes a key mechanism of the antiarrhythmic properties of ω3-polyunsaturated fatty acids in heart failure in our study,1 a …