Impact of the ß1-adrenoceptor Arg389Gly polymorphism on heart-rate responses to bisoprolol and carvedilol in heart-failure patients.

This pharmacogenetic substudy of the prospective, double-blind, randomized CIBIS-ELD trial determined the impact of the ß1-adrenoceptor Arg189Gly polymorphism on heart-rate responses to bisoprolol or carvedilol in elderly patients with heart failure (421 with sinus rhythm, 107 with atrial fibrillation). Patients were randomized 1:1 to bisoprolol or carvedilol with a fortnightly dose-doubling scheme and guideline target doses. Patients with sinus rhythm responded essentially identically to bisoprolol and carvedilol, independent of genotype. Atrial fibrillation patients homozygous for Arg389 had a much smaller response to carvedilol than carriers of at least one Gly389 allele (mean difference 12 bpm, P < 0.00001). Carvedilol up to 2 × 12.5 mg did not reduce heart rate in Arg389Arg homozygotes at all. Interestingly, the immediate response to carvedilol did not differ between genotypes. The Arg389Gly polymorphism has a major impact on the heart-rate response to carvedilol (but not bisoprolol) in patients with heart failure plus atrial fibrillation.

Parathyroid hormone response to vitamin D insufficiency in elderly males with chronic heart failure.

Secondary hyperparathyroidism (SHPT) may contribute to the systemic illness that accompanies chronic heart failure (CHF). Healthy elderly with vitamin D deficiency who did not develop hyperparathyroidism (functional hypoparathyroidism, FHPT) had lower mortality than those who did. This study was designed to examine determinants of the PTH response in the vitamin D insufficient CHF patients. Sixty five vitamin D insufficient males with NYHA class II and III and 20 control subjects age >/=55 years were recruited. Echocardiography, physical performance, NT-pro-BNP, PTH, 25-hydroxyvitamin D (25(OH)D), adiponectin and bone activity surrogate markers (OPG, RANKL, OC, beta-CTx) were assessed. Increased NYHA class was associated with SHPT, while physical performance was inferior compared to FHPT. SHPT was associated with lower left ventricular ejection fraction (LVEF) and flow mediated dilatation, but with higher left heart dimensions, left ventricular mass index and right ventricular systolic pressure. CHF patients with SHPT had increased NT-pro-BNP, adiponectin and bone markers, but decreased 25(OH)D compared to those with FHPT. Independent determinants for SHPT in CHF patients with vitamin D insufficiency were LVEF, adiponectin and beta-CTx, irrespective of renal function and serum vitamin D levels. In conclusion, increased PTH levels, but not low vitamin D, demonstrated close relation to CHF severity.

Association of increased parathyroid hormone with neuroendocrine activation and endothelial dysfunction in elderly men with heart failure.

High PTH levels have been reported in patients with chronic heart failure (CHF). Similarly, its levels increase with aging and are related to impaired survival in elderly adults. However, its relationship with neuroendocrine activation and endothelial dysfunction in CHF has not been previously studied. Seventy-three CHF males with New York Heart Association (NYHA) classes II and III and 20 control subjects aged ≥ 55 yr were recruited. PTH, 25-hydroxyvitamin D [25(OH)D], N-terminal pro-brain natriuretic peptide (NT-pro-BNP), adiponectin, and osteoprotegerin were measured. Endothelial function (brachial flow mediated dilation), echocardiography, physical performance, and quality of life were assessed, as well. CHF patients had markedly increased serum PTH (77 ± 33 vs 40 ± 11 pg/ml, p<0.0001), NT-pro-BNP [1809 (2742) vs 67 (74) pg/ml, p<0.0001], adiponectin (17 ± 9 vs 10 ± 2 µg/ml, p<0.0001), osteoprotegerin, whereas 25(OH)D levels were decreased compared to controls. Increased PTH is positively correlated with NTpro- BNP (r=0.399, p<0.0001), adiponectin (r=0.398, p<0.0001), and osteoprotegerin, whereas negatively with 25(OH)D in CHF patients. Additionally, increased serum PTH was associated with endothelial dysfunction, echocardiographic variables of heart failure progression, impaired physical performance, and deteriorated quality of life. In a multivariate linear regression analysis, increased serum PTH was independently associated with neuroendocrine activation (NT-pro-BNP, adiponectin) and endothelial dysfunction in elderly CHF men (R2=0.455). Additionally, demonstrated relations with other well-established variables of heart failure severity suggest the potential role of serum PTH in the pathogenesis and non-invasive monitoring of heart failure progression. Future studies are needed to evaluate the predictive value of serum PTH for clinical outcomes as well as beneficial potential of PTH suppression in CHF patients.

Isolated ventricular noncompaction in patients with chronic renal failure.

Isolated ventricular noncompaction is a rare congenital disorder characterized by the presence of numerous prominent trabeculations and deep intratrabecular recesses which communicate with the ventricular cavity. This disease has a very bad prognosis. Two cases of isolated ventricular noncompaction in patients with chronic renal failure have been described. The first case is a 65-year-old male, on regular hemodialysis for 3.5 years due to mesangioproliferative glomerulonephritis. He was symptomless regarding signs of congestive heart failure, angina pectoris, systemic embolization or arrhythmia. The second case is a patient with chronic renal failure (due to renal calculosis) admitted because of non-ST elevation acute myocardial infarction. In both cases echocardiography revealed an enlarged left ventricle, with extremely thickened walls with two layers: a thin, compacted myocardium on the epicardial side, and a thicker noncompaction endocardial layer. Ratio between noncompaction part of the wall and compaction part was 2.56 in the first and 4.94 in the second case. Blood flow from the left ventricular cavity into recesses was recorded with Color Doppler. Oral anticoagulation therapy was introduced in both of them. Holter ECG in the first patient revealed an intermittent right bandle branch block and in the second patient, premature ventricular contractions. Neurological examination findings were normal in both patients. Echocardiography of first-degree relatives was performed in the first case and it was normal in all 5 relatives. In the second case it was not performed due to technical reasons (relatives live abroad). Regular echocardiographic follow-up of all patients with chronic renal failure is necessary in order to diagnose cardiovascular comorbidities including this rare abnormality and its complications.

Antihypertensive effect of indapamide given in conjunction with captopril in severe hypertension.

The efficacy of captopril alone or in combination with indapamide was evaluated in 17 patients with severe hypertension (diastolic greater than 120 mmHg) previously treated with triple antihypertensive therapy, i.e. diuretic, beta-blocker and a vasodilator. After a wash-out period of 1 week, captopril was given initially as 75 mg/day for 2 weeks; at the end of this period, the dosage was doubled to 150 mg/day and continued at this level for a further 2 weeks. Indapamide (2.5 mg/day) was then added to the regimen and administered for 1 month. The results showed that captopril alone lowered, but did not normalize the blood pressure. The mean diastolic pressure was reduced to 117 and 103.8 mmHg after dosages of captopril of 75 mg and 150 mg, respectively. On the addition of indapamide, the blood pressure was normalized to 93.82 mmHg mean diastolic pressure. Systolic readings were similarly reduced. Two patients developed skin rashes while on captopril alone: no other treatment-related side-effects were reported once indapamide therapy had commenced.