Blunted beta-adrenoceptor-mediated inotropy in valvular cardiomyopathy: Another piece of the puzzle in human aortic valve disease

Abstract

OBJECTIVES: Heart failure induced by valvular cardiomyopathy occurs in a substantial proportion of patients undergoing heart valve surgery. We aimed (i) to quantify beta-adrenoceptor (beta-AR) function by measuring the inotropic effect of isoprenaline in left ventricular (LV) tissue and (ii) to correlate beta-AR-mediated inotropy with clinical markers of heart failure. METHODS: A total of 179 LV myocardial samples were obtained from 104 consecutive patients who underwent aortic valve (AV) surgery between 2017 and 2019. Beta-ARs were stimulated by increasing the concentrations of isoprenaline, followed by a single high concentration of forskolin and calcium. Beta-AR sensitivity was estimated as the concentration to achieve half maximum effects (EC50). Maximum effect size was calculated as the relative beta-AR-mediated inotropic response compared to the force in the presence of high calcium [FISO/Ca (%)]. In vitro data were correlated with the clinical indicators of LV disease. RESULTS: FISO/Ca was independent of age and sex and amounted to 79.6 ± 20.5%. In a multivariate regression model, we found a significant inverse association between FISO/Ca and preoperative left ventricular end-diastolic diameter increase per 10 mm (OR -9.24, 95% CI -16.66 to -1.82; P = 0.015). Furthermore, patients with end-stage heart failure showed a strong tendency towards more severe reduction of max beta-AR response, as indicated by reduced FISO/Ca in a multivariate model (OR -29.60, 95% CI -61.92 to 2.72; P = 0.055). CONCLUSIONS: Our study indicates that in vitro myocardial contractility testing can quantify beta-AR dysfunction in patients with AV disease. We found a significant association between reduced beta-AR sensitivity and increased LV diameter, which may indicate a role of beta-AR dysfunction in the development of heart failure in patients with AV disease.