Chronotherapy in Coronary Heart Disease: Comparison of Two Nitrate Treatments

Abstract

The purpose of this study was to assess the ischemic burden and the hemodynamic changes during daily activities in patients with coronary heart disease. Three exercise tests were performed during the day (10:00 a.m., 2:00 p.m., 6:00 p.m.), recording ST-segment depression, pulmonary artery pressure, pulmonary wedge pressure, and cardiac output as well as heart rate and systemic blood pressure during placebo and nitrate therapy. With placebo as well as nitrate therapy there was a gradual increase of ischemia and preload and a decrease of cardiac output during the day. High nitrate concentrations led to a significant reduction of both preload and ST depression with a marked circadian phase dependency of cardiovascular effects.

Chronobiology and chronotherapy of ischemic heart disease

“…Exercise-induced ST-segment depression appeared to depend on circadian time, the most pronounced depression occurring in the late afternoon [87]. The antiischemic effect of ISDN did not differ between times of exercise testing; whereas, those of IS-5-MN achieved statistical significance only when ergometry was performed in the morning [87]. The lack of anti-ischemic effect of the mononitrate at noon could be due to declining plasma concentrations several hours after drug intake at 8 a.m., to circadian variation in vessel sensitivity to nitrovasodilators, ormost likelyto both of these factors.…”

“…Quyyumi et al [86] compared the antianginal efficacy of atenolol, nifedipine, and IS-5-MN and observed a similar reduction in nocturnal ischemia by each of the medications; whereas, daytime episodes were less affected by nifedipine and the mononitrate compared to atenolol. In patients with stable angina pectoris, the effects of a 20 mg dose of IS-5-MN administered at 12-h intervals twice daily and 120 mg ISDN once daily were compared on ergometric STsegment depression at different circadian times (10 a.m., 2 p.m., and 6 p.m.) [87]. Exercise-induced ST-segment depression appeared to depend on circadian time, the most pronounced depression occurring in the late afternoon [87].…”

“…In patients with stable angina pectoris, the effects of a 20 mg dose of IS-5-MN administered at 12-h intervals twice daily and 120 mg ISDN once daily were compared on ergometric STsegment depression at different circadian times (10 a.m., 2 p.m., and 6 p.m.) [87]. Exercise-induced ST-segment depression appeared to depend on circadian time, the most pronounced depression occurring in the late afternoon [87]. The antiischemic effect of ISDN did not differ between times of exercise testing; whereas, those of IS-5-MN achieved statistical significance only when ergometry was performed in the morning [87].…”

Influence of the Circadian System on Disease Severity

“…In contrast, long acting nitrates are designed for once per day dosing and should normally be administered at bedtime to maintain a therapeutic concentration in the plasma throughout the night and the subsequent vulnerable morning hours60.…”

Cardiovascular Chronobiology: Do You Know What Time It Is?

“…In one study, the circadian pattern of ischemia and infarction was blunted in patients receiving ß blockers or calcium channel blockers, but not nitrates 86 . Isosorbide dinitrate (ISDN) has a maximal anti‐ischemic effect in the morning 87 . However, in contrast to doses of ISDN administered throughout the day, a dose of ISDN administered at 2 a.m. causes greater nocturnal orthostasis, which could place a patient at increased risk for a fall 88,89 .…”