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Impact of plasma xanthine oxidoreductase activity in patients with heart failure with preserved ejection fraction.

ABSTRACT: AIMS:Reactive oxygen species are reportedly involved in the mechanism underlying heart failure with preserved ejection fraction (HFpEF); however, the disease pathophysiology remains poorly understood. Xanthine oxidoreductase (XOR), the rate-limiting enzyme of purine metabolism, plays an important role in uric acid production and generates reactive oxygen species. However, the impact of plasma XOR activity on the clinical outcomes of patients with HFpEF remains unclear. The aim of this study was to investigate whether plasma XOR activity is associated with major adverse cardiovascular events (MACEs) in patients with HFpEF. METHODS AND RESULTS:The plasma XOR activity was measured in 257 patients with HFpEF, who were then divided into three groups according to the activity levels: low XOR group (<33 pmol/h/mL, n = 45), normal XOR group (33-120 pmol/h/mL, n = 160), and high XOR group (>120 pmol/h/mL, n = 52). During the median follow-up period of 809 days, there were 74 MACEs. Kaplan-Meier analysis revealed that the high XOR group was at the highest risk for MACEs. Multivariate analysis by Cox's proportional hazard regression approach showed that high XOR activity was significantly associated with MACEs, after adjustment for confounding factors. The patients were also divided into four groups according to the absence/presence of high XOR activity and/or hyperuricaemia. According to the multivariate Cox regression analysis, high XOR activity was associated with MACEs, regardless of the hyperuricaemia status. CONCLUSIONS:Elevated plasma XOR activity is significantly associated with adverse clinical outcomes in patients with HFpEF.

SUBMITTER: Watanabe K

PROVIDER: S-EPMC7373896 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Impact of plasma xanthine oxidoreductase activity in patients with heart failure with preserved ejection fraction.

Watanabe Ken K Watanabe Tetsu T Otaki Yoichiro Y Shishido Tetsuro T Murase Takayo T Nakamura Takashi T Kato Shigehiko S Tamura Harutoshi H Nishiyama Satoshi S Takahashi Hiroki H Arimoto Takanori T Watanabe Masafumi M

ESC heart failure 20200520 4

<h4>Aims</h4>Reactive oxygen species are reportedly involved in the mechanism underlying heart failure with preserved ejection fraction (HFpEF); however, the disease pathophysiology remains poorly understood. Xanthine oxidoreductase (XOR), the rate-limiting enzyme of purine metabolism, plays an important role in uric acid production and generates reactive oxygen species. However, the impact of plasma XOR activity on the clinical outcomes of patients with HFpEF remains unclear. The aim of this st ...[more]

PMID: 32432414

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Project description:BACKGROUND:The role of coronary microvascular disease and its impact on functional and energetic reserve in heart failure with preserved ejection fraction (HFpEF) remains unclear. We hypothesized that in response to submaximal pharmacologic stress (dobutamine), patients with HFpEF have impairment in left ventricular (LV) myocardial mechanical (external work [EW]), energetic (myocardial O2 consumption [MVO2]), and myocardial blood flow (MBF) reserve. We further assessed whether coupling of MBF to EW is impaired in HFpEF and associated with compensatory increases or pathological decreases in myocardial O2 extraction. Lastly, we assessed whether coupling of MVO2 to EW (mechanical efficiency) was impaired in HFpEF. METHODS AND RESULTS:In prospectively enrolled patients with HFpEF (n=19) and age/sex-matched healthy controls (n=19), we performed 11C-acetate positron emission tomography assessing MVO2 and MBF at rest and during dobutamine infusion. EW was calculated as stroke volume (echo)×end-systolic pressure×heart rate. At rest, compared with controls, patients with HFpEF had higher LV EW, MVO2, and MBF. With dobutamine, LV EW, MVO2, and MBF increased in both HFpEF and controls; however, the magnitude of increases was significantly smaller in HFpEF. In both groups, MBF increased in relation to EW, but in HFpEF, the slope of the relationship was significantly smaller than in controls. Myocardial O2 extraction was increased in HFpEF. Mechanical efficiency was similar in HFpEF and controls. In a post hoc analysis, HFpEF patients with LV hypertrophy (n=10) had significant reductions in LV mechanical efficiency relative to controls. CONCLUSIONS:In HFpEF during submaximal dobutamine stress, there is myocardial mechanical-, energetic- and flow-reserve dysfunction with impaired coupling of blood flow to demand and slight increases in myocardial O2 extraction. These findings provide evidence that coronary microvascular dysfunction is present in HFpEF, limits O2 supply relative to demand, and is associated with reserve dysfunction.

Project description:Nitrates are commonly prescribed to enhance activity tolerance in patients with heart failure and a preserved ejection fraction. We compared the effect of isosorbide mononitrate or placebo on daily activity in such patients.In this multicenter, double-blind, crossover study, 110 patients with heart failure and a preserved ejection fraction were randomly assigned to a 6-week dose-escalation regimen of isosorbide mononitrate (from 30 mg to 60 mg to 120 mg once daily) or placebo, with subsequent crossover to the other group for 6 weeks. The primary end point was the daily activity level, quantified as the average daily accelerometer units during the 120-mg phase, as assessed by patient-worn accelerometers. Secondary end points included hours of activity per day during the 120-mg phase, daily accelerometer units during all three dose regimens, quality-of-life scores, 6-minute walk distance, and levels of N-terminal pro-brain natriuretic peptide (NT-proBNP).In the group receiving the 120-mg dose of isosorbide mononitrate, as compared with the placebo group, there was a nonsignificant trend toward lower daily activity (-381 accelerometer units; 95% confidence interval [CI], -780 to 17; P=0.06) and a significant decrease in hours of activity per day (-0.30 hours; 95% CI, -0.55 to -0.05; P=0.02). During all dose regimens, activity in the isosorbide mononitrate group was lower than that in the placebo group (-439 accelerometer units; 95% CI, -792 to -86; P=0.02). Activity levels decreased progressively and significantly with increased doses of isosorbide mononitrate (but not placebo). There were no significant between-group differences in the 6-minute walk distance, quality-of-life scores, or NT-proBNP levels.Patients with heart failure and a preserved ejection fraction who received isosorbide mononitrate were less active and did not have better quality of life or submaximal exercise capacity than did patients who received placebo. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02053493.).

Project description:Approximately half of heart failure patients have a normal ejection fraction, a condition designated as heart failure with preserved ejection fraction (HFpEF). This heart failure subtype disproportionately affects women and the elderly and is commonly associated with other cardiovascular comorbidities, such as hypertension and diabetes. HFpEF is increasing at a steady rate and is predicted to become the leading cause of heart failure within a decade. HFpEF is characterized by impaired diastolic function, thought to be due to concentric remodeling of the heart along with increased stiffness of both the extracellular matrix and myofilaments. In addition, oxidative stress and inflammation are thought to have a role in HFpEF progression, along with endothelial dysfunction and impaired nitric oxide-cyclic guanosine monophosphate-protein kinase G signaling. Surprisingly a number of clinical studies have failed to demonstrate any benefit of drugs effective in heart failure with systolic dysfunction in HFpEF patients. Thus, HFpEF is one of the largest unmet needs in cardiovascular medicine, and there is a substantial need for new therapeutic approaches and strategies that target mechanisms specific for HFpEF. This conclusion is underscored by the recently reported disappointing results of the RELAX trial, which assessed the use of phosphodiesterase-5 inhibitor sildenafil for treating HFpEF. In animal models, endothelial nitric oxide synthase activators and If current inhibitors have shown benefit in improving diastolic function, and there is a rationale for assessing matrix metalloproteinase 9 inhibitors and nitroxyl donors. LCZ696, a combination drug of angiotensin II receptor blocker and neprilysin inhibitor, and the aldosterone receptor antagonist spironolactone are currently in clinical trial for treating HFpEF. Here we present an overview of the etiology and diagnosis of HFpEF that segues into a discussion of new therapeutic approaches emerging from basic research and drugs currently in clinical trial that primarily target diastolic dysfunction or imbalanced ventricular-arterial coupling.

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Impact of plasma xanthine oxidoreductase activity in patients with heart failure with preserved ejection fraction.

Publications

Impact of plasma xanthine oxidoreductase activity in patients with heart failure with preserved ejection fraction.

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