To define the long-term variability of serial coronary flow reserve (CFR) catheter and intracoronary papaverine. Initial CFR measurements were highly correlated with repeat measurements obtained 11±0.6 months later (r=0.95; mean absolute difference, 0.3±0.1; n=17). Differences in CFRbetween studies were related to changes in heart rate (r=0.61,p=0.01) but not to changes in mean arterial pressure (r=0.25, p=0.33). To define the effects of rapid changes in heart rate, mean arterial pressure, and preload on CFR, these variables were altered by atrial pacing, handgrip exercise, and volume expansion, respectively. Atrial pacing produced a rate-related increase in rCBFV but did not change hCBFV. Consequently, CFR was significantly reduced as heart rate was increased progressively from 76±2 in sinus rhythm (4.5+±0.2) to 100 (3.8±0.2, p<0.05, n=32) to 120 beats/min (3.2±0.1, p<0.05, n=7). Despite a 19±2 mm Hg rise in mean arterial pressure during handgrip exercise, CFR was unchanged from baseline (3.7±0.3 vs. 3.7±0.4, p=NS, n=7) because rCBFV rose proportionally with hCBFV. When pulmonary capillary wedge pressure was increased from 9±1 to 16±1 mm Hg after volume expansion, CFR was significantly decreased (from 3.8±0.2 to 2.9+±0.2, p<0.05, n=9) because rCBFV was increased while hCBFV remained unchanged. Hence, serial CFR measurements in humans are highly reproducible in the absence of conditions known to affect resting or hyperemic coronary blood flow. Increases in heart rate or preload reduced CFR because rCBFV was increased while hCBFV was unchanged. In contrast, changes in mean arterial pressure did not alter CFR. Proper interpretation of CFR measurements should take into account the hemodynamic conditions at which they are obtained. (Circulation 1990;81:1319-1330 The concept of coronary flow reserve, introduced 30 years ago by Coffman and Gregg,' provides a method for describing the capacity of the coronary circulation to conduct maximal hyperemic blood flow. The subsequent development
Sympathetic reinnervation after cardiac transplantation is regionally heterogeneous. SN reinnervation is not associated necessarily with LV reinnervation, and LV reinnervation can involve the anterior and posterior walls together or separately.
Stimulation of reinnervating sympathetic neurons with tyramine in transplant recipients causes a significant but subnormal increase in dP/dt and a transient decrease in CBFV, suggesting that reinnervating sympathetic neurons can produce physiologically meaningful changes in left ventricular function and coronary artery tone.
This multiple-dose study of DMP 504, a hydrogel bile acid sequestrant, employed a randomized, double-blind, sequential-cohort design with placebo (blinded) and open-label cholestyramine (CS) controls. Ninety-three healthy primary hypercholesterolemic subjects (serum LDL cholesterol 130 to 200 mg/dL; triglycerides ≤280 mg/dL) maintaining a stable diet (NCEP Step One) for 3 weeks received either DMP 504 or placebo DMP 504 in capsules, or CS powder for suspension (16 g/d). The DMP 504 dose (0.9, 1.8, 2.7, 3.6, 5.4, 7.2 g/d) escalated with sequential enrollment of cohorts (DMP 504 n = 10, placebo n = 2, and CS n = 3 for Cohorts I-V; DMP 504 n = 8, placebo n = 2 for Cohort VI). An additional cohort (VII) included DMP 504 3.6 g/d, n = 9, and placebo, n = 2.LDL cholesterol (LDL-C) decreased in a dose-dependent manner (-15.8% to -34.1%; r = -0.56; P < 0.001) over the dose range 0.9 g/d to 7.2 g/d after 2 weeks of dosing with DMP 504 and +0.8% to -19.7% (r = -0.48; P < 0.001) over doses 0.9 g/d to 5.4 g/d after 6 weeks. LDL-C did not change with placebo but declined with cholestyramine by -28.3% at 2 weeks and -23.9% at 6 weeks. Plasma 7-α-hydroxy-4-cholesten-3-one, a marker of hepatic cholesterol 7-α-hydroxylase activity, increased dose-dependently with DMP 504 and with CS; change in LDL-C correlated inversely with 7-α-hydroxy-4-cholesten-3-one (r = -0.46; P < 0.001).There was no dose-limiting toxicity with DMP 504. One subject (DMP 504 2.7 g/d) withdrew because of gastrointestinal disturbance. Subject complaints were largely gastrointestinal in nature (flatulence, abdominal discomfort, diarrhea/constipation) occurring in 53% of the 64 DMP 504, 60% of 15 CS, and 29% of 14 placebo subjects.The novel hydrogel DMP 504 can induce significant LDL cholesterol lowering at doses of several grams/ day with an acceptable side effect profile. Drug Dev. Res. 41:76-84, 1997.
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