Effect of beta-blockade on ventricular/atrial morphodynamics

Background. Abnormal left ventricular (LV) relaxation and left ventricular diastolic dysfunction (LVDD) are early quantifiable features of myocardial end-organ damage seen in patients who have hypertension and precedes the development of LV hypertrophy. Nearly 50% of patients who develop diastolic heart failure suffer long standing LVDD due to isolated hypertension as the underlying etiology. Ongoing studies have therefore redirected efforts on understanding the effects of intervening earlier in patients with LVDD before features of diastolic heart failure develop. The significance of LV twist mechanics and vortex ring formation in human hearts using novel high resolution speckle and contrast particle tracking echocardiography have been recently characterized. Although data on a favorable effects of beta-adrenergic receptor blockade on transmitral LV diastolic filling exists the effects of beta-blocker therapy on LV regional and global relaxation mechanics, blood flow propagation sequence, hemodynamics and symptomatic improvement by intervening early in patients with hypertension who have evidence of LVDD remains incompletely characterized. Aims. To evaluate systematically if treatment with beta-blockers for 6 months in patients with hypertension and left ventricular diastolic dysfunction improves exercise time by enhancing: LV deformation, torsion and untwisting mechanics; Left atrium (LA) -to-LV blood flow transport and characteristics of intra-cavitary vortex formation; LA reservoir and booster pump function and LA-LV interaction during the conduit phase. Methods. The study will be conducted as a single-arm clinical trial involving 85 adults with a history of mild-to- moderate hypertension and baseline echocardiographic evidence of LVDD. Subjects (stratified by age, sex, and baseline diastolic function grade) will be treated with beta-blockers for 6 months. Exercise echo with contrast will be performed at baseline and at 6 months after treatment initiation. Total exercise duration, rate-pressure product, early diastolic transmitral flow velocity to mitral annular tissue Doppler velocity ratio (E/e`) and untwisting velocity at rest and under stress will be recorded. Changes in blood flow and its relationship to muscle mechanics will be determined by speckle tracking echocardiography and high temporal resolution echo-contrast particle imaging velocimetry. Significance. Patients with LVDD are asymptomatic at rest and often become markedly symptomatic with exertion. This pilot study is the first that could show a correlation between the improvement in exercise capacity seen with the use of beta-blockers and changes in LV relaxation, torsional mechanics, LV vortex formation and LA-LV transport functions. The preliminary data will be essential for understanding the underlying pathophysiological mechanisms through which beta-blocker therapy improves exercise hemodynamics. Furthermore, it could provide data for the design of subsequent larger randomized multicenter trials.