Abstract
IntroductionParoxetine is a GRK2 inhibitor that has been widely used to treat depression and anxiety over the last few decades. The inhibition of GRK2 has been studied extensively in vivo; however, evidence of its impact on heart failure remains scarce.MethodsTo assess the association between paroxetine use and mortality in patients with heart failure. We conducted a retrospective longitudinal cohort study from 2008 to 2019, with a follow-up time of 28 days for all groups. This is a single-center study using the Medical Information Mart for Intensive Care IV database with 11,657 heart failure patients identified. We performed genetic matching to adjust for the covariates. Heart failure patients prescribed paroxetine for >24 h after hospital admission were categorized into the paroxetine group (77 patients), with remaining heart failure patients making up the matched control group (231 patients). The primary outcome was 28-day all-cause mortality from the date of hospital admission. Secondary outcomes included length of intensive care unit stay, length of hospital stay, and in-hospital mortality. The Kaplan–Meier survival estimator, logistic regression, Cox regression, and restricted mean survival time were used to detect the association between paroxetine therapy and outcomes.ResultsPatients who received paroxetine during one hospital admission lived, on average, 0.7 lesser days (95% CI −2.53 to 1.1, p = 0.46) than patients who did not use it in a 28-day truncation time point. Multivariable logistic regression, including all matched covariates, demonstrated that the adjusted odds ratio of 28-day mortality of the paroxetine administration group was 1.1 (95% CI 0.37–2.9, p = 0.90). Multivariable Cox regression of 28-day mortality presented an adjusted hazard ratio of 1.00 (95% CI 0.42–2.62, p = 0.92). Paroxetine was associated with an increased survival time at a 3,000-day truncation time point (203 days, 95% CI −305.69 to 817.8, p = 0.37).ConclusionsIn patients with heart failure, treatment with paroxetine did not significantly reduce 28-day all-cause mortality.
Highlights
Paroxetine is a G protein-coupled receptors (GPCRs) kinase 2 (GRK2) inhibitor that has been widely used to treat depression and anxiety over the last few decades
Heart failure (HF) often results from different CVDs and other conditions that lead to myocardial and vascular damage. βadrenergic receptors (β-ARs), which belong to the superfamily of G protein-coupled receptors (GPCRs), regulate cardiac contractility and heart rate in response to catecholamine release
The patients who were prescribed paroxetine for longer than 24 h in the initial prescription after their hospital admission were categorized into the paroxetine group, with the remaining HF patients making up the control group
Summary
Paroxetine is a GRK2 inhibitor that has been widely used to treat depression and anxiety over the last few decades. The inhibition of GRK2 has been studied extensively in vivo; evidence of its impact on heart failure remains scarce. HF patients have higher preload and afterload, resulting in increased cardiac work, which escalates catecholamine release from the adrenal medulla via sympathetic nerve fibers [1]. Chronic exposure to catecholamines stimulates GPCR kinase 2 (GRK2) upregulation in the heart. Dysregulated GRK2 expression during established HF leads to agonist-occupied βAR desensitization and downregulation, diminishing cardiac reserves [3, 4]. Cardiomyopathic mice expressing βARKct (a cardiac GRK2 inhibitor) exhibited a significant increase in mean survival age, showed less cardiac dilation, improved cardiac function, and left ventricular end-diastolic dimension compared to the control group [2, 3]
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