endothelin-1 and Sleep-Apnea--Central

Patients with heart failure have high levels of central sympathetic outflow and also have a high prevalence of sleep-related breathing disorders, predominantly central sleep apnea. The options for treating central sleep apnea in heart failure are limited and include theophylline. Whether theophylline alters sympathetic activity in heart failure patients is not known.. Using a single-blinded, randomized, placebo-controlled study design, we investigated the sympathetic, hemodynamic, neurohumoral, and ventilatory effects of theophylline in patients with congestive heart failure compared with healthy control subjects closely matched for age, sex, and body mass index. Theophylline increased muscle sympathetic nerve activity and lowered transcutaneous CO2 in the control subjects but only lowered transcutaneous CO2 in the heart failure patients. Theophylline nearly doubled plasma renin concentration in both the healthy subjects (P<0.01) and the heart failure patients (P<0.02).. Our study shows that in heart failure patients, there are differential effects of theophylline: in contrast to healthy subjects, theophylline does not increase sympathetic activity in heart failure, whereas increases in plasma renin and ventilation are still evident. These novel findings may have important implications for understanding the potential harmful and beneficial effects of theophylline and related substances in heart failure patients.

Topics: Adolescent; Adult; Aged; Aldosterone; Atrial Natriuretic Factor; Cardiovascular Agents; Endothelin-1; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Renin; Respiration; Single-Blind Method; Sleep Apnea, Central; Sympathetic Nervous System; Theophylline

Elevated plasma endothelin-1 (ET-1) levels have been reported in association with hypoxia and congestive heart failure (CHF). Furthermore, Cheyne-Stokes respiration-central sleep apnea (CSR-CSA) has been found to correlate with the degree of pulmonary hypertension and the severity of CHF; however, the association between ET-1 levels and CSR-CSA has not been investigated previously.. Veterans Affairs Medical Center.. We studied 46 consecutive patients with CHF (left ventricular function < or = 40%) who underwent right-heart catheterization and overnight polysomnography. Thirty-nine patients completed the study. Sixteen patients (41%) had CSR-CSA, 5 patients (13%) had obstructive apnea, and 18 patients (46%) had no sleep-disordered breathing. Circulating plasma ET-1 levels were assayed in patients with CSR-CSA and in patients with no sleep-disordered breathing using commercially available enzyme-linked immunosorbent assay kits.. ET-1 levels were significantly elevated in patients with CSR-CSA (mean +/- SD, 5.4 +/- 1.3 pg/mL) compared to those without central apnea (3.9 +/- 1.1 pg/mL; p < 0.01), and correlated with mean pulmonary artery pressure (r = 0.66, p < 0.01), pulmonary capillary wedge pressure (r = 0.56, p < 0.03), and central apnea frequency (r = 0.66, p < 0.01). In multivariate analysis, the severity of CSR-CSA was the only variable independently associated with plasma ET-1.. We conclude that elevated plasma ET-1 levels are linked to the severity of CSR-CSA. Whether ET-1 represents an important pathogenic factor in CSR-CSA or marker of its occurrence requires further evaluation.

Topics: Aged; Cheyne-Stokes Respiration; Endothelin-1; Heart Failure; Hemodynamics; Humans; Male; Sleep Apnea, Central