Meta-analysis methods and models with applications in evaluation of cholesterol-lowering drugs.
In cardiac allograft rejection, histopathologic changes suggesting that myocardial ischemia is a component of the rejection process have been documented. To further define the coronary vascular reactivity of human heart transplant, coronary sinus blood flow and coronary resistance were measured before and after intravenous dipyridamole within the first year after transplantation in 8 patients without rejection (group II) and in 5 patients with rejection (group III). All had normal coronary arteriograms. Results were compared to those of 8 control subjects (group I). After dipyridamole, coronary sinus blood flow was increased in groups I, II and III by 303, 212 (p less than 0.01 vs group I) and 45%, respectively (p less than 0.001 vs groups I and II). Coronary resistance was reduced by 77, 73 (not significant vs group I) and 36%, respectively (p less than 0.001 vs groups I and II). Concomitantly, coronary sinus blood oxygen content was increased by 172, 145 (not significant vs group I) and 78%, respectively (p less than 0.001 vs group I, not significant vs group II). Thus, the coronary flow reserve evaluated by the dipyridamole/basal coronary sinus blood flow ratio and the coronary resistance reserve evaluated by the basal/dipyridamole coronary resistance ratio were dramatically impaired in group III (1.56 +/- 0.09 and 1.63 +/- 0.30, respectively, p less than 0.001 vs groups I and II). In contrast, they were almost normal in group II (3.11 +/- 0.42 vs 4.03 +/- 0.52 in group I, p less than 0.02, and 3.83 +/- 0.78 vs 4.45 +/- 0.81 in group I, difference not significant). Thus, the impairment of coronary reserve during heart rejection should be linked to abnormalities of the coronary microvaculature. This emphasizes the important involvement of the coronary circulation in the rejection process.
Recent studies suggest that angiographic measurements of coronary arterial stenosis are poorly correlated with direct measurements of the capacity of the artery to conduct hyperemic blood flow. Direct measurement of coronary blood flow and the flow reserve capacity of individual coronary vessels in conscious humans, however, has been hampered by methodologic limitations. We have developed and validated a coronary Doppler catheter capable of subselectively measuring coronary blood flow velocity at the time of cardiac catheterization. Studies in seven calves demonstrated that measurements of the change in coronary blood flow velocity assessed using the Doppler catheter were highly correlated with simultaneous measurements of the change in coronary sinus blood flow (r = 0.97, slope = 1.06) and changes in blood flow velocity assessed using an epicardial Doppler probe (r = 0.95, slope = 1.04). Additional studies demonstrated that the catheter did not produce physiologically significant obstruction to coronary blood flow. Subsequent studies in 215 humans undergoing catheterization have shown that acceptable signals of phasic coronary blood flow velocity could be recorded in 176 patients. Subsequent dose response kinetic studies demonstrated that intracoronary administration of papaverine can rapidly produce maximal coronary hyperemia, equivalent in magnitude to intravenous dipyridamole, but short enough in duration to permit multiple measurements of coronary flow reserve during a single catheterization. Measurements of coronary flow reserve in patients with obstructive coronary artery disease have permitted characterization of the physiologic significance of individual obstructive coronary lesions. The development of this coronary Doppler catheter system and technique for measurement of maximal coronary flow reserve should facilitate characterization of the physiologic impact of coronary arterial lesions on coronary blood flow and studies of the coronary circulation in conscious humans.
Intracellular accumulation of ZDV was rapid, reaching equilibrium within 20 min; nigericin increased accumulation by 1.9-fold, but this did not alter the generation of ZDV mono-, di- and triphosphate. The accumulation and metabolism were pH dependent, being maximal at pH 7.4 and least at pH 5.1. Monensin, carbonyl cyanide p-trifluoromethoxy) phenyl hydrazone, brefeldin A, bafilomycin A1 and concanamycin A increased accumulation; 2-deoxyglucose, dipyridamole, thymidine and tetraphenylphosphonium inhibited accumulation. The accumulation was saturable; the derived K(d) and capacity of binding were 250 nmol per 10(6) cells and 265 nM respectively. 3T3-F442A cells express P-gp; inhibitors of P-gp (XR9576 and verapamil), P-gp/BCRP (GF120918), multidrug resistance protein (MRP) (MK571) and MRP/OATP (probenecid) increased the accumulation of ZDV. Saquinavir, ritonavir, amprenavir and lopinavir increased accumulation.
Myocardial perfusion studies have a sensitivity of 97% for identifying patients with acute coronary syndrome, with precordial pain and normal or doubtful ischemic ECG. For the intermediate or low risk patients with acute coronary syndrome the non-invasive diagnostic techniques of SPECT and GSPECT systems of evaluating myocardial perfusion achieve a high degree diagnostic accuracy, safety and reduces unnecessary admissions and costs.