Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis.
LVEDD and LVESD decreased by 2.6 (0.4) mm and 4.9 (0.5) mm, respectively (mean (SEM)), and LVFS increased by 4.3 (0.5)% (all p < 0.0001 v baseline). Simple regression revealed no significant relation between BHR or HRR and the changes in LVEDD, LVESD, or LVFS. Stratification of patients into high and low BHR groups (above and below the mean) or according to the baseline heart rhythm (sinus rhythm v atrial fibrillation) showed no differences between groups in the extent of reverse left ventricular remodelling. Improvements in left ventricular function and dimensions were associated with significant improvements in New York Heart Association functional class.
The heart rate slope for the non-optimized group was derived from the points 0.949+/-0.088 (0 intercept) and 1.055+/-0.128 (1 intercept), p<0.0001. The heart rate slope for the optimized group was derived from the points 1.026+/-0.108 (0 intercept) and 1.012+/-0.108 (1 intercept), p=0.47. Regression linear plots for the heart rate slope for each patient in the non-optimized and optimized groups revealed a slope of 0.986 (almost perfect) for the optimized group, but the regression analysis for the non-optimized group was 0.030 (far from perfect, which occurs at 1).
Oxidative stress in polymorphonuclear cells and mononuclear cells was increased significantly in hypertensive patients compared with in normotensive controls. After 6 months of treatment, carvedilol decreased oxidative stress significantly in polymorphonuclear cells by a mean of 45 arbitrary units (95% confidence interval [CI]: 32 to 59 arbitrary units; P <0.001) and propranolol decreased oxidative stress significantly by 20 arbitrary units (95% CI: 7 to 33 arbitrary units; P <0.003; P = 0.001 for difference between treatments). Carvedilol also decreased oxidative stress significantly in mononuclear cells by 23 arbitrary units (95% CI: 15 to 31 arbitrary units; P <0.001), whereas propranolol decreased oxidative stress by 2 arbitrary units (95% CI: 7 to 12 arbitrary units; P = 0.62; P = 0.002 for difference between treatments). Carvedilol decreased C-reactive protein levels significantly by a median of 0.073 mg/dL (interquartile range, 0.034 to 0.112 mg/dL; P <0.001), whereas propranolol decreased levels by 0.012 mg/dL (interquartile range, 0.009 to 0.032 mg/dL; P = 0.26; P = 0.003 for difference between treatments).
For inherited cardiomyopathies, abnormal sensitivity to intracellular calcium (Ca(2+) ), incurred from genetic mutations, initiates subsequent molecular events leading to pathological remodeling. Here, we characterized the effect of β-adrenergic stress in familial dilated cardiomyopathy (DCM) using human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) from a patient with RBM20 DCM. Our findings suggest that β-adrenergic stimulation accelerated defective Ca(2+) homeostasis, apoptotic changes, and sarcomeric disarray in familial DCM hiPSC-CMs. Furthermore, pharmacological modulation of abnormal Ca(2+) handling by pretreatment with β-blocker, carvedilol, or Ca(2+) -channel blocker, verapamil, significantly decreased the area under curve, reduced percentage of disorganized cells, and decreased terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-positive apoptotic loci in familial DCM hiPSC-CMs after β-adrenergic stimulation. These translational data provide patient-based in vitro analysis of β-adrenergic stress in RBM20-deficient familial DCM hiPSC-CMs and evaluation of therapeutic interventions to modify heart disease progression, which may be personalized, but more importantly generalized in the clinic.
Recently, several randomised controlled studies have demonstrated improvement in survival of patients with non ischemic cardiomyopathy (Bisoprolol, Metoprolol, Carvedilol) and ischemic cardiomyopathy (Carvedilol). It is not quite clear, whether the observed difference in mortality after beta-blockade on top of diuretics, digitalis and ACE-inhibitors is due to some as yet unknown pathophysiological changes. Certainly, beta-blocking agents have an established efficacy in arrhythmia. Irrespective of the acknowledged benefit in survival, one should note, that the risk reduction in mortality by 65% by Carvedilol has to be viewed critically-as the risk reductions in several other large scale trials. If the mortality in the group receiving digitalis, diuretics and ACE-inhibitors was 7.8%, the mortality after addition of Carvedilol was 3.2%. This means a difference of 4.6%. If however, percent from percent is calculated, than the risk reduction amounts to 65%. One can easily understand, why this larger latter, number usually is being published.
These findings identify a novel cardioprotective role for AKAP5 that is mediated by regulating the activities of cardiac CaN and CaMKII and highlight a significant role for cardiac β-ARs in this phenomenon.
To evaluate the antianginal efficacy of carvedilol, a beta-blocker with vasodilating activity, we performed a randomized double-blind placebo-controlled study of two single doses of carvedilol. Twelve patients (eight males, four females, mean age 57 years) with stable effort angina and a positive exercise ECG with angina underwent treadmill exercise testing 2 h after either placebo, or carvedilol 25 or 50 mg. Both doses of carvedilol reduced resting heart rate but only the 50 mg dose reduced resting blood pressure. Exercise time and time to angina increased by 24% and 35%, respectively, after carvedilol, and ST depression at both maximal and submaximal work levels was reduced. The time to 1 mm ST depression was increased by carvedilol but the heart rate at 1 mm ST depression and maximum ST/heart rate slope were unchanged. Maximum heart rate, systolic pressure, and rate-pressure product were significantly reduced by carvedilol. The 50 mg dose was significantly better than 25 mg in prolonging exercise time and reducing subjective and objective measurements of ischemia, and this was related to significantly greater hemodynamic effects. Carvedilol appears to be effective in preventing or reducing effort angina due to reduced myocardial oxygen demand, and it exhibits an important dose-response effect.