Effects of the oral endothelin-receptor antagonist bosentan on echocardiographic and doppler measures in patients with pulmonary arterial hypertension

OBJECTIVES The purpose of this study was to investigate the effects of bosentan (125 or 250 mg twice daily) on echocardiographic and Doppler variables in 85 patients with World Health Organization class III or IV pulmonary arterial hypertension (PAH). BACKGROUND Bosentan, an orally active dual endothelin-receptor antagonist, improves symptoms, exercise capacity, and hemodynamics in patients with PAH. METHODS Patients had primary pulmonary hypertension (84%) or PAH associated with connective tissue disease. Of these, 29 patients received placebo and 56 received bosentan (1:2 randomization). Six-minute walk tests and echocardiograms were performed at baseline and after 16 weeks of treatment. RESULTS Baseline characteristics were similar in the placebo and bosentan groups, and echocardiographic and Doppler findings were consistent with marked abnormalities of right ventricular (RV) and left ventricular (LV) structure and function that were due to PAH. The treatment effect on 6-min walking distance was 37 m in favor of bosentan (p = 0.036). Treatment effects of bosentan compared with placebo on other parameters were as follows: Doppler-derived cardiac index = + 0.4 l/min/m2(p = 0.007), LV early diastolic filling velocity = + 10.5 cm/s (p = 0.003), LV end-diastolic area = + 4.2 cm2(p = 0.003), LV systolic eccentricity index = -0.12 (p = 0.047), RV end-systolic area = -2.3 cm2(p = 0.057), RV:LV diastolic areas ratio = -0.64 (p = 0.007), Doppler RV index = -0.06 (p = 0.03), and percentage of patients with an improvement in pericardial effusion score = 17% (p = 0.05). CONCLUSIONS Bosentan improves RV systolic function and LV early diastolic filling and leads to a decrease in RV dilation and an increase in LV size in patients with PAH

Effects of the oral endothelin-receptor antagonist bosentan on echocardiographic and doppler measures in patients with pulmonary arterial hypertension

OBJECTIVES The purpose of this study was to investigate the effects of bosentan (125 or 250 mg twice daily) on echocardiographic and Doppler variables in 85 patients with World Health Organization class III or IV pulmonary arterial hypertension (PAH). BACKGROUND Bosentan, an orally active dual endothelin-receptor antagonist, improves symptoms, exercise capacity, and hemodynamics in patients with PAH. METHODS Patients had primary pulmonary hypertension (84%) or PAH associated with connective tissue disease. Of these, 29 patients received placebo and 56 received bosentan (1:2 randomization). Six-minute walk tests and echocardiograms were performed at baseline and after 16 weeks of treatment. RESULTS Baseline characteristics were similar in the placebo and bosentan groups, and echocardiographic and Doppler findings were consistent with marked abnormalities of right ventricular (RV) and left ventricular (LV) structure and function that were due to PAH. The treatment effect on 6-min walking distance was 37 m in favor of bosentan (p = 0.036). Treatment effects of bosentan compared with placebo on other parameters were as follows: Doppler-derived cardiac index = + 0.4 l/min/m2(p = 0.007), LV early diastolic filling velocity = + 10.5 cm/s (p = 0.003), LV end-diastolic area = + 4.2 cm2(p = 0.003), LV systolic eccentricity index = -0.12 (p = 0.047), RV end-systolic area = -2.3 cm2(p = 0.057), RV:LV diastolic areas ratio = -0.64 (p = 0.007), Doppler RV index = -0.06 (p = 0.03), and percentage of patients with an improvement in pericardial effusion score = 17% (p = 0.05). CONCLUSIONS Bosentan improves RV systolic function and LV early diastolic filling and leads to a decrease in RV dilation and an increase in LV size in patients with PAH

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Non-compaction cardiomyopathy : a genetically and clinically heterogeneous disorder : presentation of two cases and review of the literature

Left ventricular non-compaction (LVNC) is a rare disease that can occur isolated or in association with other disorders, including congenital heart disease and musculoskeletal disorders. It is characterized by a two-layered myocardium with excessive trabeculation of the left ventricle. Diagnosis is challenging as left ventricular trabeculations can be pathological yet can also be a normal finding in athletes and black people, leading to overdiagnosis. Echocardiography and CMR are important diagnostic tools. LVNC is often complicated by ventricular dysfunction, arrhythmias and thromboembolic events. Based on two cases, we review the pathogenesis, genetic background, clinical features and treatment of LVNC according to the available guidelines

Calciphylaxis in a cardiac patient without renal disease

Calciphylaxis is a rare complication that occurs in 1% of patients with end-stage renal disease (ESRD) each year. Extensive microvascular calcification and occlusion/thrombosis lead to violaceous skin lesions, which progress to nonhealing ulcers with secondary infection, often leading to sepsis and death. The lower extremities are predominantly involved (roughly 90% of patients). Although most calciphylaxis patients have abnormalities of the calcium-phosphate axis or elevated levels of parathyroid hormone, these abnormalities do not appear to be fundamental to the pathophysiology of the disorder. We report on a case of histologically proven calciphylaxis in a 54-year-old woman with normal renal function and normal calcium-parathyroid homeostasis. She had a history of alcoholic cardiomyopathy, and was treated with warfarin anticoagulation. She has been successfully treated with antibiotics, i.v. biophosphonates and intensive locale wound care. We recorded a complete wound healing in contrast to what is reported in other series

Light chain deposition disease as a rare cause of restrictive cardiomyopathy

We report an unusual case of a 47-year-old Caucasian woman who presented with severe dyspnoea as a manifestation of restrictive cardiomyopathy, found to be due to myocardial deposition of kappa light chains. Non-routine specific immunofluorescence stainings of endomyocardial biopsy specimens were key for the diagnosis of myocardial light chain deposition disease. We discuss non-amyloidotic cardiac immunoglobulin deposition disease in contrast to cardiac amyloidosis

DISTURBANCES OF λ-TRIAD ARE MORE PREDICTIVE FOR PROARRHTHMIA THAN QT PROLONGATION: A CASE STUDY OF TERFENADINE

BACKGROUND – Terfenadine was withdrawn because of proarrhythmia. Its therapeutic anti-histamine concentration is normally below 1 nM, while IKr and INa block have IC50 > 200 nM. Thus, IKr block singly is an unlikely proarrhythmic cause. METHODS AND RESULTS – Rabbit hearts were perfused with 1-10,000 nM terfenadine for 10-450 min. Terfenadine (1 nM, 450 min) insignificantly shortened APD60; at 10 nM APD60 prolonged 46±11 ms (P < 0.05; n = 6), but 1 hour washout further prolonged APD60. Above 30 nM, APD60 shortening was followed by prolongation (23±7 ms; 300 nM;10 min; P < 0.05; n = 23). In the µM range, APD60 declined and conduction slowed (14±2%; 3 µM; 10 min; P < 0.05; n = 24). Terfenadine disturbed repolarization (TRIaD: triangulation, reverse use depen-dence, instability and dispersion) from 1 to 1000 nM, increasing with concentration (450 min: 1 nM yields 50%, 10 nM 100%) and exposure time (100 nM: 10 min yields 16%, 30 min yields 33%, 90 min 83%). TRIaD with APD prolongation yielded 2 TdP; TRIaD with APD shortening yielded 7 VT and 5 VF. CONCLUSIONS –In the low nM and µM range TRIaD is accompanied by little change or shortening of APD; in the mid nM range APD shortening is followed by prolongation. TRIaD with APD prolongation preferentially induces TdP, but VT/VF in its absence. In patients ter-fenadine causes normally little QT prolongation and according to FDA records, VT/VF ap-pears indeed the primary tachycardia. Thus, TRIaD predicts proarrhythmia, while QT diffe-rentiates between VT/VF or TdP