Myocardial Blood Flow Response Research Articles

Coronary vasoregulation in patients with various risk factors in response to cold pressor testing: Contrasting myocardial blood flow responses to short- and long-term vitamin C administration

ObjectivesWe sought to determine whether abnormal myocardial blood flow (MBF) responses to the cold pressor test (CPT) in patients with various risk factors may involve different mechanisms that could lead to varying responses of short- and long-term administration of antioxidants. BackgroundThere is a growing body of evidence that increased vascular production of reactive oxygen species markedly reduces the bioavailability of endothelium-derived nitric oxide, leading to impaired vasodilator function. It is unknown whether increased oxidative stress is the prevalent mechanism underlying endothelial dysfunction in patients with different coronary risk factors. MethodsFifty patients with normal coronary angiograms were studied. The MBF responses to CPT was determined by means of positron emission tomography before and after intravenous infusion of 3 g vitamin C or saline (placebo), as well as after 3 months and 2 years of 2 g vitamin C or placebo supplementation daily. ResultsIn hypertensive patients, the change in MBF (ΔMBF) was not modified significantly by short-term vitamin C administration challenges (0.20 ± 0.20 ml/g/min; p = NS) but was significantly increased after three months and two years of treatment with vitamin C versus baseline (0.58 ± 0.27 and 0.63 ± 0.17 vs. 0.14 ± 0.18 ml/g/min; both p ≤ 0.001). In smokers, ΔMBF in response to CPT was significantly increased after short-term vitamin C infusion and long-term vitamin C treatment (0.52 ± 0.10, 0.54 ± 0.13, 0.50 ± 0.07 vs. −0.08 ± 0.10 ml/g/min; all p ≤ 0.001). In hypercholesterolemic patients, no improvement in ΔMBF during CPT was observed after short- and long-term vitamin C treatment (0.05 ± 0.14, 0.08 ± 0.18, 0.02 ± 0.19 vs. 0.08 ± 0.16 ml/g/min; p = NS). The CPT-induced ΔMBF in hypertensive patients and smokers after follow-up was significant as compared with placebo and control subjects (p ≤ 0.001). ConclusionsThe present study revealed marked heterogeneous responses in MBF changes to short- and long-term vitamin C treatment in patients with various risk factors, which highlights the quite complex nature underlying abnormal coronary vasomotion.

Cardiac autonomic dysinnervation and myocardial blood flow in long-term Type 1 diabetic patients.

The aim of the study was to assess scintigraphically the relationship between myocardial blood flow response and sympathetic dysinnervation in long-term Type 1 diabetic patients. Effects of the iron chelator deferoxamine on myocardial blood flow were studied and they were investigated according to the presence of cardiac sympathetic dysfunction. Myocardial blood flow (MBF) was assessed with N-13 ammonia positron emission tomography in 13 long-term Type 1 diabetic patients and 13 control subjects at rest and in response to sympathetic stimulation (cold pressor test (CPT)). In diabetic patients, the study was repeated after preinfusion with deferoxamine. Furthermore, 123I metaiodobenzylguanidine (MIBG) scintigraphy was applied to assess regional cardiac sympathetic dysinnervation (uptake score 1 = normal, homogeneous uptake em leader 6 = no uptake). In diabetic patients, MBF increased in response to CPT from 78 +/- 18 ml/100 g/min to 84 +/- 26 ml/100 g (8%, P < 0.001). Control subjects demonstrated an increase from 63 +/- 17 ml/100 g to 84 +/- 26 ml/100 g (33%, P < 0.001), respectively. Resting MBF was higher in diabetic patients than in control subjects (P < 0.001). In diabetic patients, increase in MBF in response to CPT was significant in regions with a MIBG uptake score of <or= 3. Regions with a MIBG uptake score of > 3 did not exhibit a significant increase in MBF in response to CPT. After administration of deferoxamine, the increase in MBF in response to CPT was 23% and the magnitude of increase was related to the MIBG uptake score (r = 0.40, P < 0.0001). Myocardial blood flow response to sympathetic stimulation is significantly impaired in long-term Type 1 diabetes. After preinfusion with deferoxamine the impairment is partially reversed and a relationship between myocardial blood flow and the extent of cardiac sympathetic dysfunction is observed.

Homocysteine impairs coronary microvascular dilator function in humans

ObjectivesWe sought to use positron emission tomography (PET) to test the hypothesis that hyperhomocysteinemia adversely effects coronary microvascular dilator function. BackgroundHyperhomocysteinemia is associated with abnormal endothelium-dependent vasodilation in peripheral human arteries. However, its effect on the coronary circulation is not known. MethodsEighteen healthy humans, age 24 to 56 years, were enrolled in a double-blind, crossover trial. Basal and adenosine-stimulated myocardial blood flow (MBF) was determined by PET: after ingestion of placebo and after methionine-induced hyperhomocysteinemia. Further, brachial ultrasonography was used to assess flow-mediated vasodilation. Additionally, to assess the role of nitric oxide (NO) in adenosine-mediated vasodilation, the MBF response to adenosine was measured in the presence and absence of the NO synthase antagonist NG-monomethyl-l-arginine (l-NMMA) (0.3 mg/kg/min intravenously). ResultsHyperhomocysteinemia resulted in a reduction in the MBF dose-response curve to adenosine (p < 0.05). This was most apparent with low dose adenosine, where MBF augmentation was significantly blunted during hyperhomocysteinemia (1.06 ± 1.00 ml/min/g vs. 0.58 ± 0.78 ml/min/g, placebo vs. methionine, p < 0.05). Similarly, flow-mediated brachial artery vasodilation was impaired during hyperhomocysteinemia (4.4 ± 2.6% vs. 2.6 ± 2.3%, placebo vs. methionine, p < 0.05). In a separate series of experiments, MBF during adenosine was reduced in the presence of l-NMMA (p < 0.05 analysis of variance). This was most apparent at the low dose of adenosine, where MBF response to adenosine was blunted in the presence of l-NMMA (2.08 ± 1.34 ml/min/g vs. 1.48 ± 1.32 ml/min/g, placebo vs. l-NMMA, p < 0.05). ConclusionsThe data, therefore, support the hypothesis that acute hyperhomocysteinemia impairs microvascular dilation in the human coronary circulation as a result of reduced NO bioavailability.

Effects of gestational age on myocardial blood flow and coronary flow reserve in pressure-loaded ovine fetal hearts.

To test the hypothesis that coronary flow and coronary flow reserve are developmentally regulated, we used fluorescent microspheres to investigate the effects of acute (6 h) pulmonary artery banding (PAB) on baseline and adenosine-enhanced right (RV) and left ventricular (LV) blood flow in two groups of twin ovine fetuses (100 and 128 days of gestation, term 145 days, n = 6 fetuses/group). Within each group, one fetus underwent PAB to constrict the main pulmonary artery diameter by 50%, and the other twin served as a nonbanded control. Physiological measurements were made 6 h after the surgery was completed; tissues were then harvested for analysis of selected genes that may be involved in the early phase of coronary vascular remodeling. Within each age group, arterial blood gas values, heart rate, and mean arterial blood pressure were similar between control and PAB fetuses. Baseline endocardial blood flow in both ventricles was greater in 100 than 128-day fetuses (RV: 341 +/- 20 vs. 230 +/- 17 ml*min(-1)*100 g(-1); LV: 258 +/- 18 vs. 172 +/- 23 ml*min(-1)*100 g(-1), both P < 0.05). In both age groups, RV and LV endocardial blood flows increased significantly in control animals during adenosine infusion and were greater in PAB compared with control fetuses. After PAB, adenosine further increased RV blood flow in 128-day fetuses (from 416 +/- 30 to 598 +/- 33 ml*min(-1)*g(-1), P < 0.05) but did not enhance blood flow in 100-day animals (490 +/- 59 to 545 +/- 42 ml*min(-1)*100 g(-1), P > 0.2). RV vascular endothelial growth factor and Flk-1 mRNA levels were increased relative to controls (P < 0.05) in 128 but not 100-day PAB fetuses. We conclude that in the ovine fetus, developmentally related differences exist in 1) baseline myocardial blood flows, 2) the adaptive response of myocardial blood flow to acute systolic pressure load, and 3) the responses of selected genes involved in vasculogenesis to increased load in the fetal myocardium.

Dose-dependent vasodilating effects of insulin on adenosine-stimulated myocardial blood flow.

In the peripheral vasculature, insulin induces time- and dose-dependent vasodilation. We have recently demonstrated that insulin potentiates adenosine-stimulated myocardial blood flow. However, it is unknown whether insulin's effects on the coronary vasculature are dose dependent. In this study, we quantitated myocardial blood flow and adenosine-stimulated coronary flow (140 microg.kg(-1).min(-1) for 5 min) in 10 healthy men (age, 32 +/- 6 years; BMI, 24.1 +/- 1.8 kg/m(2)) using positron emission tomography and (15)O-labeled water. Hyperemic myocardial blood flow was measured in the basal state, during euglycemic physiological hyperinsulinemia (serum insulin approximately 65 mU/l) and during supraphysiological hyperinsulinemia (serum insulin approximately 460 mU/l). Basal myocardial blood flow was 0.84 +/- 0.17 ml.g(-1).min(-1). Physiological hyperinsulinemia increased the adenosine-stimulated flow by 20% (from 3.92 +/- 1.17 to 4.72 +/- 0.96 ml.g(- 1).min(-1); P < 0.05). Supraphysiological hyperinsulinemia further enhanced the adenosine-stimulated flow by 19% (to 5.61 +/- 1.03 ml.g(-1).min(-1); P < 0.05). These effects were not explained by changes in systemic hemodynamics, since coronary resistance decreased during each insulin infusion (P < 0.05). In addition, hyperemic myocardial blood flow responses during insulin stimulation were positively correlated with whole-body glucose uptake. The results demonstrate that insulin is able to enhance hyperemic myocardial blood flow in a dose-dependent manner in healthy subjects. These effects might contribute to the known beneficial dose-dependent effects of insulin on myocardial ischemia.

Modulation of catecholamine responsiveness and beta-adrenergic receptor/adenylyl cyclase pathway during cardiac allograft rejection1 2.

This study investigated the changes of catecholamine responsiveness and beta-adrenergic receptor/adenylyl cyclase pathway during acute cardiac transplant rejection. Isogeneic Lewis to Lewis and allogeneic Dark Agouti (DA) to Lewis rat cardiac transplants were studied 3 and 5 days after heterotopic intraabdominal transplantation (n=6/group). Myocardial blood flow (MBF), left ventricular systolic pressure (LVSP), maximum pressure development (+dP/dt), and end-diastolic pressure (LVEDP) were measured using an intraventricular balloon. Contractile response to dobutamine (5 microg/kg/min) was also assessed. In separate groups beta-adrenergic receptor density and adenylyl cyclase activity were measured in the grafts, in the recipients' native hearts and in native hearts of sham-operated controls. During mild to moderate rejection cardiac function indices remained unchanged, although MBF and contractile response to dobutamine decreased significantly (P<0.05) in the allogeneic group. The beta-adrenergic receptor density was significantly (P<0.05) increased in both isografts and allografts and in the native hearts of allografted recipients in comparison to native hearts of controls. Adenylyl cyclase activity showed a significant decrease (P<0.05) only in allografts. During severe rejection, LVSP and +dP/dt decreased and LVEDP increased in allografts in comparison to isografts (P<0.05). This was accompanied by a significant decrease in MBF, contractile response to dobutamine, beta-adrenergic receptor density, and adenylyl cyclase activity (P<0.05). Both microcirculatory disturbances and primary alteration in adenylyl cyclase activity may contribute to decreased contractile reserve in mild to moderate cardiac allograft rejection, whereas beta-adrenergic receptor density seems to be also influenced by cardiac denervation. Severe rejection leads to systolic and diastolic heart failure with complex dysregulation of the beta-adrenergic receptor/adenylyl cyclase pathway and impaired microcirculation.

Minimal impairment of myocardial blood flow responses to exercise in the remodeled left ventricle early after myocardial infarction, despite significant hemodynamic and neurohumoral alterations.

Previous studies have demonstrated a decreased flow reserve in the surviving hypertrophied left ventricle (LV) early after myocardial infarction. We hypothesized that exacerbation of hemodynamic abnormalities and neurohumoral activation during exercise could exhaust coronary flow reserve and thereby impair myocardial O(2) supply. Consequently, we studied hemodynamic, neurohumoral and regional myocardial perfusion and metabolic responses to exercise in pigs with LV hypertrophic remodeling 3 weeks after a myocardial infarction produced by permanent left circumflex coronary artery ligation. Chronically instrumented pigs were exercised on a treadmill up to 85% of maximum heart rate. Pigs with a myocardial infarction (MI) had a lower cardiac output (21%), stroke volume (28%), LVdP/dt(max) (18%), systemic (22%) and pulmonary (20%) vascular conductance, and increased left atrial (225%) and pulmonary artery (75%) pressures, compared to normal pigs. In MI, the exercise-induced increases in cardiac pump function, and systemic and pulmonary vasodilation were blunted compared to normals. Consequently, perfusion of visceral organs became impaired during strenuous exercise, but cerebral and skeletal muscle blood flows were maintained. Exercise-induced increases in norepinephrine and endothelin levels were exacerbated and, while relative sympathetic drive was maintained, cardiac responsiveness to norepinephrine was blunted. Despite lower capillary densities in the hypertrophied non-infarcted LV and relative subendocardial hypoperfusion during strenuous exercise, which necessitated a slight increase in O(2) extraction, there was no metabolic evidence of overt myocardial ischemia during strenuous exercise as indicated by the arterio-coronary venous pH difference. LV dysfunction and neurohumoral activation were present in pigs with a 3-week-old infarction, particularly during exercise. However, although myocardial perfusion and O(2) supply were slightly impaired, myocardial ischemia did not occur even during exercise up to 85% of maximum heart rate, suggesting that perfusion abnormalities do not contribute to LV dysfunction early after infarction.

Myocardial blood-flow response during mental stress in patients with coronary artery disease

Positron emission tomography was used to quantify changes in myocardial blood flow during mental stress in patients with and without coronary artery disease. Blunted augmentation of myocardial blood flow during mental stress was observed in regions without significant epicardial stenosis.

Regulation of myocardial blood flow response to mental stress in healthy individuals

Mental stress testing has been proposed as a noninvasive tool to evaluate endothelium-dependent coronary vasomotion. In patients with coronary artery disease, mental stress can induce myocardial ischemia. However, even the determinants of the physiological myocardial blood flow (MBF) response to mental stress are poorly understood. Twenty-four individuals (12 males/12 females, mean age 49 +/- 13 yr, range 31-74 yr) with a low likelihood for coronary artery disease were studied. Serum catecholamines, cardiac work, and MBF (measured quantitatively with N-13 ammonia and positron emission tomography) were assessed. During mental stress (arithmetic calculation) MBF increased significantly from 0.70 +/- 0.14 to 0.92 +/- 0.21 ml x min(-1) x g(-1) (P < 0.01). Mental stress caused significant increases (P < 0.01) in serum epinephrine (26 +/- 16 vs. 42 +/- 17 pg/ml), norepinephrine (272 +/- 139 vs. 322 +/- 136 pg/ml), and cardiac work [rate-pressure product (RPP) 8,011 +/- 1,884 vs. 10,416 +/- 2,711]. Stress-induced changes in cardiac work were correlated with changes in MBF (r = 0.72; P < 0.01). Multiple-regression analysis revealed stress-induced changes in the RPP as the only significant (P = 0.0001) predictor for the magnitude of mental stress-induced increases in MBF in healthy individuals. Data from this group of healthy individuals should prove useful to investigate coronary vasomotion in individuals at risk for or with documented coronary artery disease.

L-Arginine normalizes coronary vasomotion in long-term smokers.

Noninvasive measurements of myocardial blood flow (MBF) with PET revealed an abnormal coronary vasomotor response to cold pressor test in healthy long-term smokers. If coronary endothelial dysfunction accounted for this abnormality, we hypothesized that it could be reversed by L-arginine as the substrate for NO synthase. MBF was quantified with 13N-labeled ammonia and PET in 11 healthy smokers (age, 45+/-10 years; 27+/-10 years of smoking) and in 12 age-matched nonsmokers on 2 separate days. On day 1, MBF was measured at rest and, after intravenous L-arginine, during cold pressor test. On day 2, MBF was measured during cold pressor test and then at rest during L-arginine. Baseline rate-pressure product (RPP) (6559+/-1590 versus 7144+/-1157 bpmxmm Hg) and MBF (0.65+/-0.14 versus 0.73+/-0.13 mL x g-1 x min-1) were similar in nonsmokers and smokers. Cold pressor test increased RPP similarly in both groups (53+/-26% versus 46+/-26%), whereas MBF increased in nonsmokers (to 0.93+/-0.25 mL x g-1 x min-1; P<0.05) but not in smokers (0.80+/-0.16 mL x g-1 x min-1). The percent MBF increase differed between nonsmokers and smokers (44+/-25% versus 11+/-14%; P=0.0017). However, after L-arginine, the magnitude of MBF response to cold pressor test no longer differed between groups (48+/-36% versus 48+/-28%), whereas RPP again increased similarly in the 2 groups (59+/-30% versus 44+/-16%). L-Arginine had no effect on resting MBF in smokers or nonsmokers. Our findings implicate the coronary endothelium as the major site of the abnormal vasomotor response in long-term smokers. Cold pressor test combined with PET imaging may allow the noninvasive identification of coronary endothelial dysfunction in humans.

Myocardial blood flow and perfusion reserve in infarcted patients with stress-induced normalization of previously negative T waves: A positron emission tomography study

Background. The clinical correlations between stress-induced normalization of previously negative T waves (NTW) and regional myocardial blood flow (MBF) regulation and tissue viability remain debatable. Methods and Results. To confirm these correlations, 14 patients with previous anterior myocardial infarction (13 Q waves) and NTW on baseline electrocardiographic precordial leads and 10 healthy subjects were studied by means of positron emission tomography (PET). The MBF values were obtained in the anterior infarcted myocardial regions in either resting condition or during dipyridamole infusion, using N-13 ammonia as a flow tracer. Seven subjects had normalization of NTW (Group 1) and 7 had persistent NTW (Group 2) during dipyridamole infusion. The resting MBF values were similar for both Group 1 and Group 2 (0.43 ± 0.13 versus 0.51 ± 0.15 mL·min −1·g −1, respectively; P = not significant) and were significantly lower than in the anterior myocardial regions of healthy subjects (1.03 ± 0.23 mL·min −1·g −1, P < .001). After administration of dipyridamole, the MBF was significantly higher in Group 1 than in Group 2 (0.88 ± 0.37 versus 0.55 ± 0.17 mL·min −1·g −1, respectively; P < .05) and markedly lower than in healthy subjects (3.78 ± 0.64 mL·min −1·g −1, P < .001). Coronary reserves (dipyridamole/resting MBF) were 2.03 ± 0.40 and 1.14 ± 0.44 in Group 1 and Group 2, respectively ( P < .002). Conclusion. Despite similar values of resting perfusion, infarcted dysfunctional areas with or without NTW during stress may present different regional MBF responses; normalization of NTW demonstrates higher coronary flow reserve than persistent NTW, suggesting a better preserved coronary microcirculatory function in the former, indicative of the presence of myocardial viability.

Effects of dobutamine at maximally tolerated dose on myocardial blood flow in humans with ischemic heart disease.

This study tests the hypothesis in humans with ischemic heart disease that myocardial blood flow response to dobutamine is linearly correlated with blood flow response to adenosine. PET with [13N]ammonia was used to measure myocardial blood flow at rest and during adenosine and dobutamine at the maximally tolerated dose. Myocardial segments were defined physiologically on the basis of blood flow response to adenosine: normal, > or = 2 mL x min(-1) x g(-1); abnormal, < 2 mL x min(-1) x g(-1); and "steal," decline versus baseline > or = 0.15 mL x min(-1) x g(-1). The patient population consisted of 11 men and 2 women. Dobutamine increased heart rate (79+/-22 to 115+/-28 bpm) and rate-pressure product (9748+/-2862 to 15,157+/-3433 mm Hg/min) significantly (both P<.01). Myocardial blood flow at rest in abnormal segments (0.50+/-0.23 mL x min(-1) x g(-1)) was reduced (P<.001) versus normal (0.90+/-0.45) and steal (0.92+/-0.60). Nevertheless, in abnormal segments, blood flow increased versus rest (P<.001) with dobutamine (0.83+/-0.43) and adenosine (0.90+/-0.49). In steal segments, myocardial blood flow declined versus baseline (P<.001) with dobutamine (0.68+/-0.46) and adenosine (0.50+/-0.45). In normal segments, myocardial blood flow increased (P<.001) with dobutamine (2.16+/-0.99) and adenosine (3.10+/-0.90). Over the range of flows, the correlation between adenosine and dobutamine was good (r=.78, P<.0001). Although flow with dobutamine in normal segments correlated with rate-pressure product (r=.81, P<.05), the slope of the line was 2.7+/-0.8 (P<.02), and normalized blood flow (3.3+/-2.5 x rest) exceeded normalized rate-pressure product (1.9+/-0.8 x rest; P<.05). In humans with ischemic heart disease, myocardial blood flow responses to dobutamine and adenosine are linearly correlated over a wide range. The hyperemic response to dobutamine is in excess of that predicted by rate-pressure product and reflects the unmeasured inotropic, oxygen-wasting, and beta2-agonist effects of the drug. Dobutamine induces coronary steal with a frequency approaching that of adenosine.

Comparative Effects of Enalapril and Verapamil on Myocardial Blood Flow in Systemic Hypertension

The comparative effects of calcium channel blockers and ACE inhibitors on myocardial blood flow (MBF) in hypertensive patients after long-term treatment are still unknown. Twenty hypertensive subjects with normal coronary arteries were randomly assigned to verapamil 240 to 480 mg/d or enalapril 10 to 40 mg/d. MBF was quantified at rest, during pacing tachycardia, and after dipyridamole by positron emission tomography and 13N-ammonia before and 6 months after treatment after 1 week of pharmacological washout. In both groups, blood pressure and heart rate during flow measurements were not different before and after therapy. Before treatment, mean MBF at rest, during pacing tachycardia, and after dipyridamole infusion was similar in the two groups; however, pacing and dipyridamole flows were significantly lower than those obtained in a control group of normotensive subjects. After treatment, in the enalapril-treated patients, MBF did not change in the three study conditions. In the verapamil-treated patients, MBF did not change at rest and significantly increased during pacing and after dipyridamole. The inhomogeneity of regional MBF distribution, evaluated from the coefficient of variation, decreased at rest after both treatments and, in the enalapril group, also during pacing. No relation was found between changes in MBF and changes in left ventricular mass. In arterial hypertension, MBF during pacing tachycardia and after dipyridamole is impaired. Successful therapy with verapamil increases MBF response to these stimuli, independent of changes in perfusion pressure and left ventricular mass. These results suggest that verapamil directly improves coronary microcirculatory function in hypertension. Enalapril does not significantly change MBF but reduces the inhomogeneity of regional flow distribution.

Myocardial Blood Flow Response to Pacing Tachycardia and to Dipyridamole Infusion in Patients With Dilated Cardiomyopathy Without Overt Heart Failure

Myocardial blood flow (MBF) impairment has been documented in advanced dilated cardiomyopathy (DCM) in which hemodynamic factors, secondary to severe ventricular dysfunction, may limit myocardial perfusion. To assess whether MBF impairment in DCM may also be present independent of hemodynamic factors, the present study was designed to quantify myocardial perfusion in patients with mild disease without overt heart failure. Absolute regional MBF (milliliters per minute per gram) was measured by positron emission tomography and 13N-ammonia in resting conditions, during pacing-induced tachycardia, and after dipyridamole infusion (0.56 mg/kg over 4 minutes) in 22 DCM patients and in 13 healthy subjects. Patients were in New York Heart Association functional class I-II and showed depressed left ventricular (LV) ejection fraction by radionuclide angiography (35 +/- 8%; range, 21% to 48%), normal coronary angiography, and normal or moderately increased LV end-diastolic pressure (9.2 +/- 5.5 mm Hg; range, 2 to 20 mm Hg). There were no differences in arterial blood pressure, heart rate, and rate-pressure product between patients and control subjects in the three study conditions. Compared with control subjects, DCM patients had lower mean MBF at rest (0.80 +/- 0.25 versus 1.08 +/- 0.20 mL.min-1.g-1, P < .01), during atrial pacing tachycardia (1.21 +/- 0.59 versus 2.03 +/- 0.64 mL.min-1.g-1, P < .01), and after dipyridamole infusion (1.91 +/- 0.76 versus 3.78 +/- 0.86 mL.min-1.g-1, P < .01). LV MBF values were related to baseline LV end-diastolic pressure at rest (r = -.57, P < .01) and during pacing (r = -.67, P < .01) but not after dipyridamole infusion (r = .19, P = .40). Five patients had LV end-diastolic pressure > 12 mm Hg; in 4, myocardial perfusion was severely depressed both at baseline and in response to stress. In patients with DCM without overt heart failure, myocardial perfusion is impaired both at rest and in response to vasodilating stimuli. The abnormalities in vasodilating capability can be present despite normal hemodynamics; progression of the disease is associated with more depressed myocardial perfusion.

Effects of dobutamine on myocardial blood flow, contractile function, and bioenergetic responses distal to coronary stenosis: Implications with regard to dobutamine stress testing

To determine the effects of dobutamine stimulation on myocardium distal to a coronary stenosis, transmural spatially localized phosphorus 31 nuclear magnetic resonance measurements of myocardial high-energy phosphate compounds (adenosine triphosphate and phosphocreatine), inorganic phosphate, and blood flow and systolic wall thickening were made in 8 open-chested dogs. Data were collected under (1) control conditions, (2) after the application of a moderate coronary stenosis, (3) during infusion of dobutamine with continuing stenosis, and (4) after the release of the stenosis with continuing dobutamine. Stenosis was associated with concordant reductions of subendocardial blood flow, wall thickening, and high-energy phosphate, and mild elevation of inorganic phosphate; subepicardial measurements were essentially unchanged. During dobutamine infusion, blood flow increased in all myocardial layers. Wall thickening returned to control values in the subendocardium and increased nonsignificantly in the subepicardium. Additional loss of high-energy phosphate occured only in the subepicardium. The data suggest that improved contractile function associated with dobutamine infusion resulted from the inotropic effects of dobutamine and was made possible by the improved blood flow it produced. The data indicate that measurements of blood flow and contractile function do not reliably predict the transmural myocardial metabolic responses to inotropic perturbations in the hypoperfused heart. Taken together, the present findings yield insights with regard to the interpretation of diagnostic dobutamine stimulation testing with single photon emission tomography, radionuclide angiography, and echocardiography.

Impairment of myocardial vascular responsiveness after transient myocardial ischemia and reperfusion

Coronary vascular responses after brief periods of myocardial ischemia are impaired. Whereas some studies suggest that the ischemic insult selectively depresses endothelium-dependent vasodilator mechanisms, other studies indicate that even responses to direct vascular smooth-muscle relaxants such as adenosine may be decreased. This study was undertaken to measure regional myocardial blood flow (RMBF) responses to adenosine (a direct coronary vasodilator) and serotonin (an indirect, endothelium-dependent vasodilator) in myocardium subjected to regional ischemia followed by reperfusion. Temporary regional ischemia was achieved by 20 minutes of occlusion of the left anterior descending coronary artery (LAD) followed by 20 minutes of reflow in 10 open-chest anesthetized dogs. In the left circumflex coronary artery (LCX) territory, which served as a nonischemic control, RMBF (measured with radioactive microspheres) increased significantly in response to left atrial infusions of adenosine (1.29 ± 0.27 to 3.89 ± 2.15 ml/min/gm; p < 0.001) and serotonin (1.29 ± 0.27 to 3.29 ± 1.49 ml/min/gm; p < 0.001) and the percent reduction in coronary vascular resistant (%ΔCVR) was comparable for these two pharmacologic probes (65% ± 26% ± 19%; difference not significant [NS]). In contrast, in the myocardium supplied by the LAD, which was subjected to ischemia followed by reperfusion, the augmentation of RMBF by adenosine (1.07 ± 0.29 to 1.82 ± 1.35 ml/min/gm; p < 0.001) and serotoinin (1.07 ± 0.29 to 2.37 ± 1.21 ml/min/gm; p < 0.001) was blunted. The absolute increase in RMBF after adenosine infusion was significantly less than that for serotonin infusion ( p < 0.001), and the %ΔCVR also was significantly less (43% ± 24% vs 56% ± 22%; p < 0.001). Thus despite comparable values for heart rate (147 ± 21 vs 146 ± 19 beats/min; NS), mean arterial pressure (90 ± 20 vs 101 ± 26 mm Hg; NS),cardiac output (3.2 ± 1.0 vs 3.5 ± 1.41/min; NS), and %ΔCVR in the control LCX territory during left atrial infusions of adenosine and serotonin, in the previously ischemic LAD bed the vasodilator response to adenosine was significantly more depressed than the vasodilator response to serotonin. In conclusion, a brief period of regional myocardial ischemia followed by reperfusion, insufficient to cause structural alterations in the microvasculature, causes a profound depression of vasodilator responses to adenosine and serotonin. Contrary to the notion that ischemia selectively depresses endothelium-dependent vasodilation, RMBF responses to serotonin, a putative indirect vasodilator, were better preserved than were RMBF responses to adenosine, a direct smooth-muscle relaxant. The complex interrelation between ischemia followed by reperfusion and the functional vasodilator responses of the microvasculature (at least with respect to these two pharmacologic probes) is more complex than previously recognized.

Global alteration in perfusion response to increasing oxygen consumption in patients with single-vessel coronary artery disease.

Recent evidence suggests that, in coronary artery disease (CAD), myocardial blood flow (MBF) regulation is abnormal in regions supplied by apparently normal coronary arteries. However, the relation between this alteration and MBF response to increasing metabolic demand has not been fully elucidated. MBF was assessed at baseline, during atrial pacing tachycardia, and after dipyridamole (0.56 mg/kg IV over 4 minutes) in 9 normal subjects and in 24 patients with ischemia on effort, no myocardial infarction, and isolated left anterior descending (n = 19) or left circumflex (n = 5) coronary artery stenosis (> or = 50% diameter narrowing). Perfusion of both poststenotic (S) and normally supplied (N) areas was measured off therapy by positron emission tomography and [13N]ammonia. Normal subjects and CAD patients showed similar rate-pressure products at baseline, during pacing, and after dipyridamole. In CAD patients, MBF was lower in S than in N territories at rest (0.68 +/- 0.14 versus 0.74 +/- 0.18 mL.min-1.g-1, respectively, P < .05), during pacing (0.92 +/- 0.29 versus 1.16 +/- 0.40 mL.min-1.g-1, respectively, P < .01), and after dipyridamole (1.18 +/- 0.34 versus 1.77 +/- 0.71 mL.min-1.g-1, respectively, P < .01). However, normal subjects showed significantly higher values of MBF both at rest (0.92 +/- 0.13 mL.min-1.g-1, P < .05 versus both S and N areas), during pacing tachycardia (1.95 +/- 0.64 mL.min-1.g-1, P < .01 versus both S and N areas), and after dipyridamole (3.59 +/- 0.71 mL.min-1.g-1, P < .01 versus both S and N areas). The percent change in flow was strictly correlated with the corresponding change in rate-pressure product in normal subjects (r = .85, P < .01) but not in either S (r = .04, P = NS) or N regions (r = .08, P = NS) of CAD patients. Besides epicardial stenosis, further factors may affect flow response to increasing metabolic demand and coronary reserve in patients with CAD.

Neutrophil elastase inhibitor ICI 200,880 protects against attenuation of coronary flow reserve and myocardial dysfunction following temporary coronary artery occlusion in the dog

Diminished coronary flow reserve and myocardial dysfunction following coronary artery occlusion and reperfusion have been attributed to neutrophil infiltration into the reperfused regions. Release of free radicals and elastase during reperfusion may also contribute to ischaemia-reperfusion induced changes. The aim of this study was to determine the effect of an elastase inhibitor on reperfusion induced attenuated coronary flow reserve and myocardial dysfunction. Anaesthetised dogs were subjected to 1 h of left anterior descending coronary artery occlusion and 2 h of reperfusion. Ten minutes before reperfusion, dogs were randomly given saline or the neutrophil elastase inhibitor ICI 200,880 (10 mg.kg-1) and treatment was continued for the next 70 min. While the regional myocardial shortening fraction and coronary blood flow responses to acetylcholine and glyceryl trinitrate were attenuated following coronary reperfusion in saline treated dogs, similar reductions were not observed in the ICI 200,880 treated dogs (p < 0.01). Histopathology showed myocardial injury and extensive neutrophil infiltration in the reperfused regions in saline treated animals. In contrast, neutrophil infiltration was minimal in the ICI 200,880 treated dogs, in spite of myocardial injury. Myeloperoxidase, an index of neutrophil infiltration, was increased (p < 0.02 v control regions) in the reperfused regions in saline treated dogs, but not in the ICI 200,880 treated dogs. Flow cytometry also showed diminished neutrophil infiltration and oxidative burst in reperfused myocardium of ICI 200,880 treated (v saline treated) dogs. The elastase inhibitor ICI 200,880 protects against ischaemia-reperfusion induced attenuated coronary flow reserve and myocardial dysfunction, and this protective effect is associated with decreased neutrophil infiltration into the reperfused regions.

Severe right ventricular pressure loading in fetal sheep augments global myocardial blood flow to submaximal levels.

It has previously been shown that the fetal right ventricle (RV) is sensitive to changes in arterial pressure and that its stroke volume is significantly reduced with acute increases in pulmonary arterial pressure. However, the myocardial blood flow (MBF) response to increases in pulmonary arterial pressure have not been investigated in the fetus. To assess whether the RV afterload sensitivity to arterial pressure is associated with limitation in MBF, seven fetal lambs were instrumented at 130 days of gestation with a pulmonary arterial occluder and intravascular catheters. RV stroke volume was measured by an electromagnetic flow probe and MBF by 15-microns labeled microspheres. MBF was determined at baseline and during incremental increases in pulmonary arterial pressure. Maximal MBF was determined in seven additional fetuses during adenosine infusion. The highest tolerated pressure was associated with a 50% reduction in RV stroke volume. The highest pulmonary arterial occlusion pressure resulted in a doubling of MBF to all regions of the heart (266 +/- 99 to 504 +/- 158, 193 +/- 69 to 387 +/- 100, and 171 +/- 66 to 338 +/- 134 ml/min/100 g for the RV, septum, and left ventricle, respectively). The best correlation for increases in both RV and global MBF was the RV heart rate-systolic pulmonary pressure product. Adenosine infusion was associated with a threefold increase in global MBF that was significantly greater than the MBF achieved during pulmonary arterial occlusion. The fetal RV sensitivity to acute pressure loading is not associated with limitation of MBF. The fetal myocardium has a remarkable flow reserve that allows for preservation of function during acute increases in arterial pressure.

Regional Myocardial Blood Flow and Coronary Reserve in Hypertensive Patients

Patients with essential arterial hypertension demonstrate abnormal vasodilator capacity either during increased cardiac metabolic demand or during pharmacological vasodilation. Structural and functional damage to the coronary microcirculation has been proposed as one of the major causes of impaired coronary reserve in this disease. To assess the role of microvascular impairment in regional myocardial blood flow (MBF), 27 patients with essential hypertension were evaluated by dynamic positron emission tomography (PET) at rest, during atrial pacing and after dipyridamole infusion and compared with 13 healthy subjects. All patients had normal coronary arteries, 17 had moderate to severe hypertension and 10 had mild hypertension. Baseline mean MBF of 0.97 +/- 0.25 ml/min/g was significantly increased to 1.60 +/- 0.38 during atrial pacing and 2.35 +/- 0.95 after dipyridamole infusion (p < 0.01); however, mean flow during atrial pacing and after dipyridamole infusion was significantly lower than in healthy subjects (2.15 +/- 0.73 and 3.71 +/- 0.86 ml/min/g, p < 0.05 and p < 0.01, respectively). The MBF response to atrial pacing and dipyridamole infusion was similarly depressed in patients with mild and severe hypertension. The study was repeated after 6 months of antihypertensive treatment with the calcium antagonist verapamil or the angiotensin converting enzyme (ACE) inhibitor enalapril in a subgroup of 20 patients as part of a randomised, single-blind clinical trial. This study is still in progress; the initial 16 patients treated with verapamil or enalapril showed an obvious improvement in MBF values during atrial pacing and after dipyridamole infusion after 6 months of therapy (mean MBF: 2.10 +/- 0.64 and 2.99 +/- 1.63 ml/min/g, respectively, p < 0.05 vs pretreatment values). In conclusion, obvious impairment of MBF during atrial pacing and after dipyridamole infusion was observed in hypertensive patients with normal coronary arteries and this appeared unrelated to the severity of hypertension. Therapy with verapamil or enalapril improved coronary reserve and MBF response to an increase in myocardial oxygen demand.