Kalkidan Bishu

Proteinuria, Chronic Kidney Disease, and the Effect of an Angiotensin Receptor Blocker in Addition to an Angiotensin-Converting Enzyme Inhibitor in Patients With Moderate to Severe Heart Failure

Background— Chronic kidney disease (CKD) is an established risk factor for poor outcomes in heart failure (HF). Whether proteinuria provides additional prognostic information is not known. Renin-angiotensin blockade medications improve outcomes in HF but are underutilized in HF patients with renal dysfunction because of safety concerns and a lack of evidence of their effectiveness. Methods and Results— In the Valsartan in Heart Failure Trial (Val-HeFT), 5010 patients with class II, III, or IV heart failure were randomly assigned to receive valsartan or placebo. The 2 primary outcomes were death and first morbid event, defined as death, sudden death with resuscitation, hospitalization for HF, or administration of intravenous inotropic or vasodilator drugs for 4 hours or more without hospitalization. The study cohort was divided into subgroups according to the presence of CKD (estimated glomerular filtration rate <60 mL · min−1 · 1.73 m−2) and proteinuria (positive dipstick). Multivariable Cox proportional hazards regression models were used to examine the relationships between study outcomes and proteinuria, including its interaction with CKD. The interaction between valsartan and CKD was also tested. The effect of valsartan on estimated glomerular filtration rate was estimated by generalized linear models, including tests of interactions between treatment and CKD. At baseline, CKD was found in 58% and dipstick-positive proteinuria in 8% of patients. Dipstick-positive proteinuria was independently associated with mortality (hazard ratio [HR] 1.28, 95% confidence interval [CI] 1.01 to 1.62, P=0.05) and first morbid event (HR 1.28, 95% CI 1.06 to 1.55, P=0.01). The increased risk of death associated with dipstick-positive proteinuria was similar for those with and without CKD (HR 1.26, 95% CI 0.96 to 1.66 versus HR 1.37, 95% CI 0.83 to 2.26; P=0.94), as was the hazard for first morbid event (HR 1.26, 95% CI 1.01 to 1.57 versus HR 1.42, 95% CI 0.98 to 2.07; P=0.71). Valsartan reduced estimated glomerular filtration rate compared with placebo to a similar extent (P=0.52) in the subgroups with CKD (mean reduction −3.6 mL · min−1 · 1.73 m−2) and without CKD (mean reduction −4.0 mL · min−1 · 1.73 m−2) and by −3.8 mL · min−1 · 1.73 m−2 in both groups combined. The beneficial effect of valsartan on first morbid events was similar in those with and without CKD (HR 0.86, 95% CI 0.74 to 0.99 versus HR 0.91, 95% CI 0.73 to 1.12; P=0.23) and was significant in the subgroup with CKD. The effect of valsartan on mortality did not differ in patients with and without CKD (HR 1.01, 95% CI 0.85 to 1.20 versus HR 0.91, 95% CI 0.69 to 1.25; P=0.08). Conclusions— CKD was common and dipstick-positive proteinuria was infrequent in this sample of patients with HF. After controlling for other risk factors, including CKD, the relatively small subgroup with dipstick-positive proteinuria did have worse outcomes. Valsartan reduced the estimated glomerular filtration rate by the same amount in patients with and without CKD and reduced the risk of the first morbid event in patients with CKD, which suggests its beneficial effects in patients with HF and CKD.

Telephone titration of heart failure medications.

Background:In clinical practice, heart failure (HF) medications are underused and prescribed at lower than recommended doses. Telephone care is an option that could help to titrate HF medication in a timely manner. We describe our experience of a nurse-run, cardiologist- or nurse practitioner-supervised clinic to up-titrate HF medications via telephone. Methods:Patients with the diagnosis of HF, New York Heart Association classes I to III, were referred to a registered nurse-run, cardiologist-/nurse practitioner-supervised HF medication titration clinic. Clinical and medication data collected at enrollment to the clinic and at 3 to 6 months after optimization of HF medications in patients who did or did not reach the target doses were compared. Effect on left ventricular (LV) function was also evaluated. Results:There were 79 patients in the evaluation: 64 with HF and LV systolic dysfunction (LVSD) and the remaining 15 with HF and preserved ejection fraction (EF). Seventy-two percent of patients with LVSD were on an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), and 61% were on a &bgr;-blocker at baseline, and this increased to 98% and 97%, respectively, after optimization. Target doses was achieved in 50% of patients for ACEI or ARB, and in 41% for &bgr;-blockers. The median time to optimization was 54 days (interquartile range, 20-97 days). The average number of phone calls at the time of optimization were 5.4 (SD, 3.7), and the average number of clinic visits was 1.9 (SD, 1.3). Reasons for not reaching the target doses included hypotension, hyperkalemia, and renal dysfunction for ACEI and bradycardia for &bgr;-blockers. Overall, the EF increased by 10% (SD, 10%) after 6 months, and 35% or greater in 42% of patients whose baseline EF was less than 35%. There were no adverse events related to the dose up-titration. Conclusion:Telephonic titration of HF medications was feasible and safe and was achieved in 97% patients on ACEI/ARB and &bgr;-blockers. Medication titration was associated with significant improvement in LV function, avoiding the need for device therapy in many patients.

Sildenafil and B-Type Natriuretic Peptide Acutely Phosphorylate Titin and Improve Diastolic Distensibility In VivoClinical Perspective

Background— In vitro studies suggest that phosphorylation of titin reduces myocyte/myofiber stiffness. Titin can be phosphorylated by cGMP-activated protein kinase. Intracellular cGMP production is stimulated by B-type natriuretic peptide (BNP) and degraded by phosphodiesterases, including phosphodiesterase-5A. We hypothesized that a phosphodiesterase-5A inhibitor (sildenafil) alone or in combination with BNP would increase left ventricular diastolic distensibility by phosphorylating titin. Methods and Results— Eight elderly dogs with experimental hypertension and 4 young normal dogs underwent measurement of the end-diastolic pressure-volume relationship during caval occlusion at baseline, after sildenafil, and BNP infusion. To assess diastolic distensibility independently of load/extrinsic forces, the end-diastolic volume at a common end-diastolic pressure on the sequential end-diastolic pressure-volume relationships was measured (left ventricular capacitance). In a separate group of dogs (n=7 old hypertensive and 7 young normal), serial full-thickness left ventricular biopsies were harvested from the beating heart during identical infusions to measure myofilament protein phosphorylation. Plasma cGMP increased with sildenafil and further with BNP (7.31±2.37 to 26.9±10.3 to 70.3±8.1 pmol/mL; P<0.001). Left ventricular diastolic capacitance increased with sildenafil and further with BNP (51.4±16.9 to 53.7±16.8 to 60.0±19.4 mL; P<0.001). Changes were similar in old hypertensive and young normal dogs. There were no effects on phosphorylation of troponin I, troponin T, phospholamban, or myosin light chain-1 or -2. Titin phosphorylation increased with sildenafil and BNP, whereas titin-based cardiomyocyte stiffness decreased. Conclusion— Short-term cGMP-enhancing treatment with sildenafil and BNP improves left ventricular diastolic distensibility in vivo, in part by phosphorylating titin.