Probenecid Improves Cardiac Function in Patients With Heart Failure With Reduced Ejection Fraction In Vivo and Cardiomyocyte Calcium Sensitivity In Vitro

Abstract

BackgroundTransient receptor potential vanilloid 2 is a calcium channel activated by probenecid. Probenecid is a Food and Drug Administration–approved uricosuric drug that has recently been shown to induce positive lusitropic and inotropic effects in animal models through cardiomyocyte transient receptor potential vanilloid 2 activation. The aim of this study was to test the hypothesis that oral probenecid can improve cardiac function and symptomatology in patients with heart failure with reduced ejection fraction and to further elucidate its calcium‐dependent effects on myocyte contractility.Methods and ResultsThe clinical trial recruited stable outpatients with heart failure with reduced ejection fraction randomized in a single‐center, double‐blind, crossover design. Clinical data were collected including a dyspnea assessment, physical examination, ECG, echocardiogram to assess systolic and diastolic function, a 6‐minute walk test, and laboratory studies. In vitro force generation studies were performed on cardiomyocytes isolated from murine tissue exposed to probenecid or control treatments. The clinical trial recruited 20 subjects (mean age 57 years, mean baseline fractional shortening of 13.6±1.0%). Probenecid therapy increased fractional shortening by 2.1±1.0% compared with placebo −1.7±1.0% (P=0.007). Additionally, probenecid improved diastolic function compared with placebo by decreasing the E/E′ by −2.95±1.21 versus 1.32±1.21 in comparison to placebo (P=0.03). In vitro probenecid increased myofilament force generation (92.36 versus 80.82 mN/mm2, P<0.05) and calcium sensitivity (pCa 5.67 versus 5.60, P<0.01) compared with control.ConclusionsProbenecid improves cardiac function with minimal effects on symptomatology and no significant adverse effects after 1 week in patients with heart failure with reduced ejection fraction and increases force development and calcium sensitivity at the cardiomyocyte level.Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT01814319.

Effect of Uric Acid-Lowering Agents on Patients With Heart Failure: A Systematic Review and Meta-Analysis of Randomised Controlled Trials

“…Probenecid is an agonist of transient receptor potential vanilloid 2 (TRPV2), which may increase myocardial contractility via increased calcium cycling on a beat-tobeat basis (26). It increased the force generation and calcium sensitivity of single cardiomyocytes, consistent with improved cardiac function observed in patients with HFrEF (25). Even though the results of Robbins et al were compatible with most pooled results of included studies, it was a source of underlying heterogeneity.…”

“…Hence, the random sequence generation and allocation concealment were unclear. One study was deemed to have a high risk of incomplete outcome data ( 25 ). Figure 2 summarised the risk of bias.…”

“…Six studies (20)(21)(22)(23)(24)(25), with a total of 864 participants, fulfilled the inclusion criterion (Figure 1). SUA was assessed in five studies, LVEF in three studies, BNP/NT-BNP in five studies, 6MWT in four studies, and mortality in two studies.…”

“…Five studies did not provide enough details regarding the method of randomisation other than just stating that it was a randomised trial (20)(21)(22)(23)25). Hence, the random sequence generation and allocation concealment were unclear.…”

Probenecid treatment improves outcomes in a novel mouse model of peripartum cardiomyopathy

“…Probenecid has been previously demonstrated to improve outcomes in an animal model of ischemic cardiomyopathy [27], in patients with HFrEF [37]. More recently, in a large population study of almost 40,000 elderly patients that were treated for gout, probenecid therapy was PLOS ONE found to be associated with decreased risk of heart failure and heart failure related hospitalization (as well as decreased incidence of myocardial infarction and stroke) in comparison to patients treated with allopurinol [38].…”