Effects of incremental beta-blocker dosing on myocardial mechanics of the human left ventricle: MRI 3D-tagging insight into pharmacodynamics supports theory of inner antagonism. Am J Physiol Heart Circ Physiol 309: H45-H52, 2015. First published April 17, 2015; doi:10.1152/ajpheart.00746.2014.-Beta-blockers contribute to treatment of heart failure. Their mechanism of action, however, is incompletely understood. Gradients in beta-blocker sensitivity of helically aligned cardiomyocytes compared with counteracting transversely intruding cardiomyocytes seem crucial. We hypothesize that selective blockade of transversely intruding cardiomyocytes by lowdose beta-blockade unloads ventricular performance. Cardiac magnetic resonance imaging (MRI) 3D tagging delivers parameters of myocardial performance. We studied 13 healthy volunteers by MRI 3D tagging during escalated intravenous administration of esmolol. The circumferential, longitudinal, and radial myocardial shortening was determined for each dose. The curves were analyzed for peak value, time-to-peak, upslope, and area-under-the-curve. At low doses, from 5 to 25 g·kg Ϫ1 ·min Ϫ1 , peak contraction increased while timeto-peak decreased yielding a steeper upslope. Combining the values revealed a left shift of the curves at low doses compared with baseline without esmolol. At doses of 50 to 150 g·kg Ϫ1 ·min Ϫ1 , a right shift with flattening occurred. In healthy volunteers we found more pronounced myocardial shortening at low compared with clinical dosage of beta-blockers. In patients with ventricular hypertrophy and higher prevalence of transversely intruding cardiomyocytes selective lowdose beta-blockade could be even more effective. MRI 3D tagging could help to determine optimal individual beta-blocker dosing avoiding undesirable side effects. left ventricular hypertrophy; beta-blockers; MRI HEART FAILURE IS A MAJOR CAUSE of morbidity and mortality all over the world. Therapeutic beta-blockade is known to have long-term beneficial effects in patients suffering heart failure in terms of reduced hospitalization, improved left ventricular function, slowing of progression, and increased life expectancy (7). Such beta-blockade is now established as part of standard therapy, together with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Beta-blockade, nonetheless, requires careful monitoring, with appropriate titration of dosing to minimize adverse effects (3). A major goal of beta-blockade is reduction of heart rate to prolong myocardial rest at diastole. This desired negative chronotropic effect often necessitates high doses and often comes with undesired negative inotropic and bathmotropic and side effects. Thus it is optimal to determine the appropriate individual dose at which better ventricular function is achieved, with avoidance of other effects, especially negative inotropy.To quantify global and regional myocardial contraction, MRI 3D tagging can be used. This method uses the threedimensional (3D) Complementary Spatial Modulation of M...