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

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: Besides epicardial stenosis, further factors may affect flow response to increasing metabolic demand and coronary reserve in patients with CAD.     

Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension

BACKGROUND: Patients with essential hypertension have abnormal endothelium-dependent vasodilation. Because the endothelium exerts its action on the vascular smooth muscle through the release of several substances, it is important to identify which of these factors is involved in the abnormal response of hypertensive arteries. METHODS AND RESULTS: To investigate the role of endothelium-derived nitric oxide in this abnormality, we studied the vascular effect of the arginine analogue NG-monomethyl-L-arginine, an inhibitor of the endothelial synthesis of nitric oxide, under baseline conditions and during infusion of acetylcholine, an endothelium-dependent vasodilator, and sodium nitroprusside, a direct smooth muscle dilator. The study included 11 hypertensive patients (seven men; age, 46.5 +/- 9 years) and 10 normal control subjects (seven men; age, 45.7 +/- 7 years). Drugs were infused into the brachial artery, and the response of the forearm vasculature was measured by strain-gauge plethysmography. Basal blood flow was similar in normal control subjects and hypertensive patients (2.97 +/- 0.7 versus 2.86 +/- 1.1 mL.min-1.100 mL-1, respectively). NG-monomethyl-L-arginine produced a significantly greater decrease in blood flow in control subjects than in patients (1.08 +/- 0.6 versus 0.32 +/- 0.4 mL.min-1.100 mL-1; p < 0.004). The vasodilator response to acetylcholine was reduced in patients compared with control subjects (maximum flow, 8.2 +/- 4 versus 16.4 +/- 8 mL.min-1.100 mL-1; p < 0.001). NG-monomethyl-L-arginine blunted the vasodilator response to acetylcholine in control subjects (maximum flow decreased from 16.4 +/- 8 to 7.01 +/- 3 mL.min-1.100 mL-1; p < 0.004); however, the arginine analogue did not significantly alter the response to acetylcholine in hypertensive patients (maximum flow, 8.2 +/- 4 versus 8.01 +/- 5 mL.min-1.100 mL-1). NG-monomethyl-L-arginine did not modify the vasodilator response to sodium nitroprusside in either control subjects or patients. CONCLUSIONS: These findings indicate that patients with essential hypertension have a defect in the endothelium-derived nitric oxide system that may at least partly account for both the increased vascular resistance under basal conditions and the impaired response to endothelium-dependent vasodilators.     

Syncope and ventricular arrhythmias in hypertrophic cardiomyopathy are not related to the derangement of coronary microvascular function

Non-sustained ventricular tachycardia on Holter and syncope have been considered risk factors for sudden death in hypertrophic cardiomyopathy. AIMS: In these patients the coronary vasodilator reserve is impaired despite normal coronaries, so we evaluated the correlation between the severity of coronary vasodilator reserve impairment and the occurrence of syncope and non-sustained ventricular tachycardia. METHODS AND RESULTS: Eighty-four patients with hypertrophic cardiomyopathy (62 males, age 43 +/- 12 years) had a two-dimensional echocardiographic study and a 48-h Holter. Myocardial blood flow was measured by positron emission tomography, at baseline and after dipyridamole, and the coronary vasodilator reserve was computed as dipyridamole myocardial blood flow/baseline myocardial blood flow. In 27 patients, subendocardial and subepicardial myocardial blood flow was measured in the septum and the subendocardial/subepicardial ratio was computed. Twenty of 84 patients had at least one syncopal episode, and 26 had at least one run of non-sustained ventricular tachycardia on Holter. Baseline and dipyridamole myocardial blood flow, coronary vasodilator reserve, and baseline and dipyridamole subendocardial/subepicardial myocardial blood flow ratio were similar in patients with and without syncope and with and without non-sustained ventricular tachycardia on Holter. However, patients with non-sustained ventricular tachycardia had larger left ventricular end-diastolic (47 +/- 6 vs 44 +/- 5 mm, P < 0.05) and end-systolic diameters (30 +/- 6 vs 27 +/- 4 mm, P < 0.05). CONCLUSIONS: (1) Coronary vasodilation is not more severely impaired in patients with hypertrophic cardiomyopathy and syncope or non-sustained ventricular tachycardia. (2) The left ventricle is more dilated in hypertrophic cardiomyopathy with non-sustained ventricular tachycardia.     

L-Arginine normalizes coronary vasomotion in long-term smokers

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.     

Changes in cardiac autonomic activities in patients with syndrome X. A study of spectral analysis of heart rate variability

The present study was designed to assess cardiac autonomic activities, coronary microvascular function, and their relationship in patients with syndrome X. Control of coronary blood flow is complex, and impaired coronary flow reserve has been attributed as the cause of myocardial ischemia in patients with syndrome X. It is unknown whether cardiac autonomic activities are altered in the presence of coronary microvascular dysfunction in patients with syndrome X. Eighteen patients with syndrome X were studied. Great cardiac vein flow was measured by the thermodilution method and the coronary flow reserve was determined by intravenous dipyridamole (0.56 mg/kg) infusion. Twenty-four-hour ambulatory electrocardiograms were obtained in a drug-free state. Another 14 age- and sex-matched normal subjects served as a control group. The amplitude (in ms) of ultralow (ULF), very-low (VLF), low (LF), and high (HF) frequency bands and total spectra of heart rate variability were measured for twenty-four-hour and every four-hour interval of the day.     

Structural and functional alterations of the intramyocardial coronary arterioles in patients with arterial hypertension

BACKGROUND: In hypertensive patients with angina pectoris, the coronary vasodilator reserve is frequently impaired despite a normal coronary angiogram. Experimental data indicate that structural alterations of the intramyocardial coronary vasculature contribute to an increased minimal coronary resistance and a diminished coronary flow reserve. METHODS AND RESULTS: In 14 patients (10 men and 4 women) with arterial hypertension and 8 normotensive subjects, minimal coronary resistance and vasodilator reserve (dipyridamole: 0.5 mg/kg body wt, gas chromatographic argon method) were determined after the angiographic exclusion of relevant coronary artery disease. Coronary reserve was depressed in hypertensive patients (2.7 +/- 2.3 vs 4.6 +/- 1.3, P < or = .05) due to increased minimal coronary resistance (0.64 +/- 30 vs 0.24 +/- 0.055 mm Hg.min.100 g.mL-1, p < or = 0.002). In right septal biopsies, mean external arteriolar diameter (21.6 +/- 2.3 vs 17.2 +/- 2.5 microns, P < or = .001), mean arteriolar wall area (271 +/- 61 vs 172 +/- 62 microns 2, P < or = .01), percent medial wall area (69.9 +/- 4.0 vs 66.0 +/- 3.2%W, P < or = .05), mean periarteriolar fibrosis area (216 +/- 122 vs 104 +/- 68 microns 2, P < or = .05), and volume density of total interstitial fibrosis (3.6 +/- 1.8 vs 1.9 +/- 0.5Vv% fibrosis, P < or = .05) were increased in hypertensive patients compared with normotensive subjects. Minimal coronary resistance correlated with %W (r = .6, P < or = .003) and Vv% fibrosis (r = .62, P < or = .002). Left ventricular mass index (111 +/- 21 vs 97 +/- 17 g/m2, P = NS) and left ventricular end-diastolic pressure (12 +/- 6 vs 8 +/- 3 mm Hg, P = NS) did not correlate significantly with minimal coronary resistance. In multivariate analysis, both %W and Vv% fibrosis explained half of the variability of minimal coronary resistance (r2 = .5, P < or = .002). CONCLUSIONS: Structural remodeling of the intramyocardial coronary arterioles and the accumulation of fibrillar collagen are decisive factors for a reduced coronary dilatory capacity in patients with arterial hypertension and angina pectoris in the absence of relevant coronary artery stenoses.     

Effects of short-term treatment of hyperlipidemia on coronary vasodilator function and myocardial perfusion in regions having substantial impairment of baseline dilator reverse

BACKGROUND: We tested the hypothesis that correction of hyperlipidemia improves coronary vasodilator response and maximal perfusion in myocardial regions having substantial impairment of pretreatment vasodilator capacity. METHODS AND RESULTS: Measurements of myocardial blood flow were made with PET [13N]ammonia in 12 patients with ischemic heart disease (11 men; age, 65+/-8 years [mean+/-SD]) at rest and during adenosine at 70 and then 140 microg . kg-1 . min-1 for 5 minutes each before and approximately 4 months after simvastatin treatment (40 mg daily). Simvastatin reduced LDL (171+/-13 before versus 99+/-18 mg/dL after simvastatin, P<0.001) and increased HDL (39+/-8 versus 45+/-9 mg/dL, P<0.05). Myocardial segments were classified on the basis of pretreatment blood flow response to 140 microg . kg-1 . min-1 adenosine as normal (flow >/=2 mL . min-1 . g-1) or abnormal (flow <2 mL . min-1 . g-1). In normal segments, baseline myocardial blood flow (0.95+/-0.32) increased (P<0.001) at both low- (1.62+/-0.81) and high- (2.63+/-0.41) dose adenosine and was unchanged both at rest and with adenosine after simvastatin. In abnormal segments, myocardial blood flow at rest (0. 73+/-0.19) increased at low- (1.06+/-0.59, P<0.02) and high- (1. 29+/-0.33, P<0.01) dose adenosine. After simvastatin, myocardial blood flow increased more compared with pretreatment at both low- (1. 37+/-0.66, P<0.05 versus pretreatment) and high- (1.89+/-0.79, P<0. 01 versus pretreatment) dose adenosine. CONCLUSIONS: Short-term lipid-lowering therapy increases stenotic segment maximal myocardial blood flow by approximately 45%. The mechanism involves enhanced, flow-mediated dilation of stenotic epicardial conduit vessels and may account at least in part for the efficacy of lipid lowering in secondary prevention trials and in reducing ischemic episodes in ambulatory patients.     

Alterations of the architecture of subendocardial arterioles in patients with hypertrophic cardiomyopathy and impaired coronary vasodilator reserve: a possible cause for myocardial ischemia

OBJECTIVES: The study was designed to investigate the architecture of subendocardial arterioles of patients with hypertrophic cardiomyopathy (HCM) and angina pectoris with respect to coronary vasodilator reserve. BACKGROUND: There is growing evidence that the coronary microvasculature is abnormal in HCM. Arterioles, which mainly regulate intramyocardial blood flow, are especially suspect. METHODS: Thirteen patients with HCM (50.1+/-12.6 years old, mean value +/- SD) were studied after exclusion of any relevant coronary stenoses. Subendocardial arterioles (density [n/mm2], wall area [microm2], percent lumen area [%lumen], periarteriolar collagen area [microm2]), myocyte diameter (microm) and interstitial collagen fraction (Vv%) were evaluated by means of stereologic morphometry of transvenous biopsy samples. Coronary blood flow was measured quantitatively with the inert chromatographic argon method at basal conditions and after dipyridamole (0.5 mg/kg body weight over 4 min intravenously), and coronary vasodilator reserve was calculated as the ratio of coronary resistance at basal conditions and after pharmacologic vasodilation. Data from five normotensive subjects (45.4+/-11 years old, p = NS) served as control data. RESULTS: Arteriolar density was diminished by 38% (p = 0.004) and %lumen by 13% (p = 0.009) in patients with HCM compared with control subjects. Coronary reserve was impaired in patients with HCM (2.28+/-0.6 vs. 5.34+/-1.49, p = 0.003) because of higher coronary resistance after vasodilation (0.48+/-0.14 vs. 0.22+/-0.06 mm Hg x min x 100 g/ml, p = 0.004). Coronary vasodilator reserve correlated with arteriolar density (r = +0.47, p = 0.045) and with %lumen (r = 0.65, p = 0.003). CONCLUSIONS: In HCM, the architecture of preterminal subendocardial arterioles is altered by a reduced total cross-sectional lumen area, corresponding to an impaired coronary vasodilator capacity that may predispose to myocardial ischemia.     

Assessment of blood flow distal to coronary artery stenoses. Correlations between myocardial positron emission tomography and poststenotic intracoronary Doppler flow reserve

BACKGROUND: Previous studies have correlated quantitative coronary angiographic stenosis severity with positron emission tomography (PET) myocardial perfusion and proximal measurements of intracoronary flow velocities in normal and diseased coronary arteries. The aim of this study was to correlate regional myocardial blood flow (RMBF) derived from [15O]H2O PET with directly measured poststenotic intracoronary Doppler flow velocity data acquired under basal conditions and dipyridamole-induced hyperemia. METHODS AND RESULTS: Eleven consecutive patients 53 +/- 13 years old with ischemic chest pain and isolated proximal left coronary artery stenoses (left anterior descending, 9; left circumflex, 2; mean, 59 +/- 23% diameter stenosis) underwent [15O]H2O myocardial PET and intracoronary Doppler flow velocity studies within 1 week. PET RMBF (mL.g-1.min-1) and myocardial perfusion reserve (MPR) were calculated in poststenotic and normal reference vascular beds. Poststenotic Doppler average peak flow velocities (APV; cm/s) and coronary flow velocity reserve (CFR) were compared with corresponding PET data and quantitative angiographic lesional parameters. PET RMBF and Doppler APV were linearly correlated (r = .60; P < .001), as were poststenotic PET MPR and Doppler CFR (r = .76; P < .0002). Relative coronary flow velocity and MPR ratios between poststenotic and angiographically normal vascular beds were comparably reduced (0.83 +/- 0.25 versus 0.86 +/- 0.21, respectively; P = NS). CONCLUSIONS: Intracoronary Doppler flow velocities acquired distal to isolated left coronary artery stenoses correlated with [15O]H2O PET regional myocardial perfusion and are useful for assessment of the physiological significance of coronary stenoses in humans.     

Assessing coronary stenosis. Quantitative coronary angiography versus visual estimation from cine-film or pharmacological stress perfusion images

Visual judgment of stenosis severity from cine-film or single-photon emission computed tomographic dipyridamole perfusion images was compared to assessment of stenosis severity as measured with digital quantitative coronary angiography. Thirty patients with angiographically verified single-vessel disease underwent dipyridamole thallium stress testing within 90 days of angiography. RESULTS: A percent diameter stenosis of > or = 50%, a percent area stenosis of > or = 75%, and a stenotic flow reserve of < 3.75 measured by quantitative coronary angiography (CMS, version 1.1, Medis Inc.) corresponded to haemodynamically significant stenosis as evaluated by visual estimates from cine-film or perfusion images. Quantitative coronary angiography percent diameter stenosis (51.2% +/- 12.6%) correlated closely (r = 0.74) but underestimated significantly visual assessment of stenosis severity from cine-film (69.3% +/- 21.2%; P = 0.0001). However, quantitative coronary angiography percent area stenosis (74.7% +/- 11.7%) more closely reflected visual estimates from cine-film (P = 0.19). Quantitative coronary angiography stenotic flow reserve showed the highest positive and negative predictive value regarding visual estimates from cine-film (88%, 86%) or perfusion images (88%, 64%) followed by percent diameter stenosis (86%, 75% 86%, 56%) and percent area stenosis (87%, 80%, 87%, 60%), respectively. CONCLUSION: Evaluation of coronary lesions by quantitative coronary angiography corresponds closely with visual estimates from cine-film and haemodynamic significance as evaluated by dipyridamole perfusion images.     

Myocardial perfusion reserve studied by single-photon emission-computed tomography with thallium-201 and a drug stress test with adenosine triphosphate in patients with cardiovascular risk factors

INTRODUCTION AND OBJECTIVE: Recent studies have suggested that the evaluation of coronary reserve is a sensitive method in the early detection of vascular alterations before plaques exist, and certainly before clinical detection of atherosclerotic lesions. Single-photon emission-computed tomography (SPECT) with thallium-201 (201Tl) provides a noninvasive tool for evaluating myocardial perfusion reserve. The objective of this study was to measure the myocardial perfusion reserve in two groups of subjects, some with and some without cardiovascular risk factors and in a group of patients with coronary artery disease. METHODS: Seventy-four subjects, divided into three groups, were recruited to assess regional and global myocardial perfusion reserve. The control group consisted of 11 asymptomatic individuals without cardiovascular risk factors. The second group was composed of 49 patients with one or more risk factors. Finally, the third group included 14 patients with coronary artery disease. 201Tl-SPECT at rest and after pharmacological stress with a 7 minute adenosine triphosphate (ATP) infusion (140 micrograms/kg/min) was performed in all patients. ATP minus rest value subtraction was applied in order to obtain the stress data. Relative myocardial perfusion reserve indices were calculated as the ratio between stress and rest values. RESULTS: Global and regional myocardial perfusion reserves of the vascular territories were significantly lower in patients with cardiovascular risk factors than in control subjects (Global: 1.48 +/- 0.19 vs 1.81 +/- 0.08, LAD: 1.52 +/- 0.21 vs 1.85 +/- 0.09, CX: 1.45 +/- 0.2 vs 1.79 +/- 0.86, RCA: 1.47 +/- 0.2 vs 1.79 +/- 0.86) and higher than in patients with coronary artery disease (Global: 1.48 +/- 0.19 vs 1.31 +/- 0.14, LAD: 1.52 +/- 0.21 vs 1.35 +/- 0.15, CX: 1.45 +/- 0.2 vs 1.2 +/- 0.24). Univariate linear regression analysis in a group of 40 patients with high risk lipid profiles revealed a significant negative correlation between myocardial perfusion reserve and total cholesterol (r = -0.35; p = 0.01), LDL-cholesterol (r = -0.38; p = 0.036) and LDL/HDL ratio (r = -0.39; p = 0.029). CONCLUSION: Determination of myocardial perfusion reserve with 201Tl-SPECT allows the detection of abnormal vasodilatory response to intravenous ATP in patients with cardiovascular risk factors. These patients have higher reserves than patients with coronary disease, which might suggest an early phase of atherosclerosis.     

The graft flow and 201Tl-myocardial scintigram in patients with saphenous vein graft or left internal thoracic artery graft

To evaluate myocardial perfusion in patients with saphenous vein graft (SVG) or internal thoracic artery graft (ITA-G), we studied 38 patients (14: SVG, 10 males and 4 females, mean age 66 +/- 9 y-o; 24: ITA-G, 18 males and 6 females, mean age 64 +/- 7 y-o) by digital subtraction angiography (DSA) of ITA-G or SVG, and thallium-201 myocardial perfusion scintigraphy on exercise or dipyridamole stress. The grafting sites were left anterior descending artery (LAD) in all patients. Normal controls (n = 22) were defined by normal coronary angiogram and no evidence of myocardial ischemia. The graft flow and flow reserve on dipyridamole were measured by Rutishauser's formula. The basal blood flow of native normal ITA, SVG and ITA-G were respectively 72 +/- 24 ml/min, 51 +/- 23 ml/min, and 36 +/- 20 ml/min. The basal ITA-G flow was significantly lower than SVG-flow (p < 0.05). The flow reserves of SVG and ITA-G were respectively 2.32 +/- 0.65 and 1.78 +/- 0.59 (p < 0.02). The incidence of moderate hypoperfusion of thallium-201 SPECT was 14.3% in SVG and 12.5% in ITA-G on exercise stress, and 35% in SVG and 50% in ITA-G on dipyridamole stress. The incidence of reversible myocardial ischemia on dipyridamole stress was significant. The graft flow in patients with normal and abnormal thallium-201 SPECT were respectively 61 +/- 21 ml/min and 33 +/- 15 ml/min in SVG (p < 0.01), 46 +/- 19 ml/min and 27 +/- 16 ml/min in ITA-G (p < 0.02). The graft flow reserve were respectively 2.69 +/- 0.38 and 1.65 +/- 0.49 in SVG (p < 0.001), 2.25 +/- 0.40 and 1.31 +/- 0.28 in ITA-G (p < 0.001). We concluded that the basal blood flow and flow reserve of ITA-G were significantly lower than those of SVG. The myocardial ischemia was occasionally documented by the thallium-201 myocardial SPECT on dipyridamole stress in patients with patent ITA-G.     

Changes in coronary vasodilation in hypertensive patients with angiographically normal coronary arteries

In normal subjects, coronary arteries dilate in response to sympathetic stimulation evoked by the cold pressor test. Similarly, in normal coronary arteries the increase in blood flow velocity induced by papaverine results in flow-dependent coronary dilation. In order to assess the coronary responses to both stimuli in hypertensive patients, variations of proximal left anterior descending coronary artery diameters and coronary blood flow velocity have been measured using quantitative coronary angiography and intracoronary Doppler in 10 control subjects and in 12 hypertensive patients. All the patients had angiographically normal coronary arteries. Total serum cholesterol, triglycerides, HDL- and LDL-cholesterol were within normal range in all patients. All patients were nonsmokers and none of them had diabetes mellitus. During the cold pressor test (hands immersed in ice water for 120 s), the rate-pressure product and coronary blood flow velocity increased respectively by 33 +/- 9% (p < 0.001) and 51 +/- 26% (p < 0.05) in control subjects, by 28 +/- 18% (p < 0.001) and 68 +/- 52% (p < 0.05) in hypertensive patients. In control subjects, coronary arteries dilated by + 12.0 +/- 4.4% (p < 0.001), and constricted by -10.3 +/- 8.5% (p < 0.001) in hypertensive patients. After injection of 10 mg of papaverine into the distal left anterior descending coronary artery, proximal left anterior descending coronary artery dilated by + 17.0 +/- 10.6% (p < 0.001) in control subjects, and did not vary (-0.7% +/- 10.6%) in hypertensive patients, when blood flow velocity was increased respectively by 449 +/- 97% and 383 +/- 103% (p < 0.001 in both groups).(ABSTRACT TRUNCATED AT 250 WORDS)     

CD9, but not other tetraspans, associates with the beta1 integrin precursor

Insulin resistance is common in patients with angina pectoris, a positive exercise electrocardiogram, and normal coronary angiograms (syndrome X). It is still not known whether insulin resistance affects the cardiac muscle itself and, if so, whether insulin resistance involves myocardial hemodynamics and energy metabolism. We investigated hemodynamics as well as metabolite exchanges across the heart and the forearm in eight patients with syndrome X and eight control subjects during a baseline period after an overnight fast and during a hyperinsulinemic-euglycemic clamp. Myocardial hemodynamics and metabolism were studied at rest, during pace stress, and in the recovery period after pacing. Neither coronary sinus blood flow nor forearm blood flow differed between the groups before and during the clamp. Whole body insulin-stimulated glucose uptake was decreased in the patients (15.6+/-2.1 vs. 23.1+/-2.0 micromol x kg-1 x min-1). Insulin-stimulated glucose uptake in the forearm and the cardiac muscle was equally reduced in the patients (46+/-5 and 48+/-5%). Myocardial glucose uptake correlated with total arterial delivery in the control subjects (r = 0.63, P < 0.01), but not in patients (r = 0.22, P = 0.13). Carbohydrate and lipid oxidation was similar in the two groups at rest, and changes during the clamp were not different in control subjects and patients either at rest, during pacing, or in the recovery period. Patients with syndrome X exhibit myocardial insulin resistance, but cardiac energy metabolism remains unaffected. In patients with syndrome X, insulin-stimulated glucose uptake is independent from myocardial blood flow.     

Assessment of transmyocardial perfusion in alligator hearts

BACKGROUND: Techniques for achieving myocardial perfusion directly from the left ventricular chamber are currently under investigation. Although originally based on the anatomy of reptilian hearts, which are rich in transmural channels and reported to have a poorly developed coronary vasculature, the blood flow capacity of a transmyocardial blood supply has not been studied in these hearts. With the ultimate goal of providing insight into the potential for achieving transmyocardial perfusion in human hearts, we studied the relative contribution of transmyocardial and coronary perfusion in alligator hearts. METHODS AND RESULTS: After explanation from six American alligators, the left ventricle was instrumented, and coronary arteries were perfused with oxygenated physiological solution. Using microspheres to estimate regional myocardial perfusion in the beating hearts, we show that although the epicardium was well perfused by the coronary arteries (0.20 +/- 0.08 versus 0.07 +/- 0.01 mL.min-1.g-1 owing to flow from the ventricular chamber), a significant proportion of endocardial perfusion was from the ventricular chamber (0.21 +/- 0.07 mL.min-1.g-1 from the left ventricle versus 0.13 +/- 0.04 mL.min-1.g-1 from coronary arteries). CONCLUSIONS: A significant amount of direct transmyocardial perfusion is present in alligator hearts. The conditions that apparently permit this situation in reptilian hearts are reviewed, and their implications for aiding in the optimization of techniques for achieving transmyocardial flow in humans are discussed.     

18F-2-deoxyglucose deposition and regional flow in pigs with chronically dysfunctional myocardium. Evidence for transmural variations in chronic hibernating myocardium

BACKGROUND: Hibernating myocardium in patients with collateral-dependent myocardium is characterized by relative reductions in resting flow and increases in the uptake of 18F-2-deoxyglucose (FDG) in the fasting state. We performed the present study to examine whether these key physiological alterations could be produced in a porcine model of chronic coronary occlusion and to assess whether the adaptations consistent with hibernation varied across the myocardial wall. METHODS AND RESULTS: We chronically instrumented pigs (n = 18) with a fixed occluder on the proximal left anterior descending coronary artery (LAD). Three months later, ventricular function, regional myocardial perfusion, and FDG deposition (by excised tissue counting or positron emission tomography) were assessed in pigs after an over-night fast in the closed-chest anesthetized state. Total LAD occlusion with angiographic collaterals was present in the majority of animals. Left ventriculography showed severe anterior hypokinesis, and resting perfusion was significantly reduced in the hibernating LAD region in comparison with the normal remote regions (subendocardium: 0.80 +/- 0.06 versus 1.07 +/- 0.06 mL.min-1.g-1, P < .001; full-thickness: 0.87 +/- 0.04 versus 0.99 +/- 0.06 mL.min-1.g-1, P < .01). There was a twofold increase in full-thickness fasting FDG uptake in the dysfunctional LAD region (1.8 +/- 0.2 by positron emission tomography versus 1.9 +/- 0.1 by ex vivo counting). Ex vivo tissue counting revealed a pronounced transmural variation in FDG uptake in the hibernating region (LAD/normal), which averaged 2.5 +/- 0.2 in the subendocardium, 1.9 +/- 0.2 in the midmyocardium, and 1.4 +/- 0.1 in the subepicardium. CONCLUSIONS: These results demonstrate that pigs instrumented with a proximal LAD stenosis develop hibernating myocardium characterized by relative reductions in resting function and perfusion in association with increased uptake of FDG in the fasting state. The transmural variations in relative resting flow and FDG uptake suggest that myocardial adaptations consistent with hibernation are most pronounced in the subendocardial layers and vary in relation to local coronary flow reserve.     

Relation among stenosis severity, myocardial blood flow, and flow reserve in patients with coronary artery disease

BACKGROUND: Coronary arteriography is considered the "gold standard" for evaluating the severity of a coronary stenosis. Because the resistance to blood flow through a stenotic lesion depends on a number of lesion characteristics, the physiological significance of coronary lesions of intermediate severity is often difficult to determine from angiography alone. This study of patients with coronary artery disease seeks to determine the relation between myocardial blood flow and flow reserve measured by positron emission tomography (PET) and the percent area stenosis on quantitative coronary arteriography. METHODS AND RESULTS: We studied 28 subjects: 18 patients with coronary artery disease (66 +/- 8 years) and 10 age-matched healthy volunteers (64 +/- 13 years) with dynamic N-13 ammonia PET imaging at rest and after dipyridamole (0.56 mg/kg). The percent cross-sectional area stenosis was quantified on the coronary arteriograms as described by Brown et al. In the 18 patients, a total of 41 non-infarct-related coronary vessels were analyzed. Myocardial blood flows in normal regions of patients with coronary artery disease were not different than those in healthy volunteers, both at rest and after dipyridamole. As a result, the myocardial flow reserve was also similar in both groups (2.4 +/- 0.4 versus 2.6 +/- 0.7, respectively; P = NS). Quantitative PET estimates of hyperemic blood flow (r = .81, P < .00001), flow reserve (r = .78, P < .00001), and an index of the "minimal coronary resistance" (r = .78, P < .00001) were inversely and nonlinearly correlated with the percent area stenosis on angiography. Of note, PET estimates of myocardial flow reserve successfully differentiated coronary lesions of intermediate severity (50% to 70% and 70% to 90%; 2.4 +/- 0.4 versus 1.8 +/- 0.5, respectively; P = .04). CONCLUSIONS: In patients with coronary artery disease, non-invasive measurements of myocardial blood flow and flow reserve by PET are inversely and nonlinearly related to stenosis severity as defined by quantitative angiography. Importantly, coronary lesions of intermediate severity have a differential flow reserve that decreases as stenosis increases that can be detected noninvasively by PET, thus allowing better definition of the functional importance of known coronary stenosis.     

Impact of impaired coronary flow reserve and insulin resistance on myocardial energy metabolism in patients with syndrome X

To evaluate the role of a decreased coronary flow reserve in the genesis of angina pectoris in patients with syndrome X, we studied myocardial hemodynamics and metabolism at rest, during pace stress, and in the recovery period after pacing in 18 consecutive patients with syndrome X and in 10 control subjects. By means of positron emission tomography or the intracoronary flow-wire method, patients were subclassified as having microvascular angina (MA, n = 8) when coronary flow reserve was reduced (<2.5) or no microvascular angina (non-MA, n = 10) when coronary flow reserve was preserved (> or =2.5). At rest, coronary sinus blood flow was increased in MA patients. During pace stress, coronary sinus blood flow increased by 39 +/- 6% in MA patients versus 67 +/- 12% in non-MA patients and 69 +/- 7% in controls (p <0.05). Patients with non-MA revealed fasting hyperinsulinemia, increased arterial concentration of free fatty acids, and a similar tendency for beta-hydroxybutyrate. Oxygen extraction and carbon dioxide release did not differ between groups. Net myocardial lactate release was not observed in any patient during pace stress and myocardial energy metabolism was preserved in all patients with syndrome X. During pacing, myocardial uptake of free fatty acids and beta-hydroxybutyrate was increased in non-MA patients. Myocardial uptake of free fatty acids correlated positively and myocardial glucose and lactate uptake correlated inversely with arterial concentrations of free fatty acids in all subjects. Metabolic evidence of myocardial ischemia is uncommon in patients with syndrome X, irrespective of a globally reduced coronary flow reserve. Although patients with syndrome X can be subclassified according to presence of a microvascular or a metabolic disorder, angina pectoris and ST-segment depressions coexist with a preserved global myocardial energy efficiency in all patients.     

Chemical modulation of in situ intrinsic cardiac neurones influences myocardial blood flow in the anaesthetised dog

OBJECTIVE: The aim was to determine whether modulation of intrinsic cardiac neurones influences the distribution of myocardial blood flow in canine anaesthetised open chest experimental preparations. METHODS: Intrinsic cardiac neurones were modified by locally applied nicotine (100 micrograms) or bradykinin (50 micrograms) while changes were recorded in cardiac haemodynamics and myocardial blood flow (radiolabelled microspheres). Right and left ventricular intramyocardial tissue pressures were measured with high fidelity microtip transducers. RESULTS: Control injections of saline (vehicle; 0.1 ml) into active loci did not produce cardiovascular responses. Nicotine modulation of intrinsic cardiac neurones did not change coronary artery conductance, but total myocardial blood flow [116(SEM 17) v 532(97) ml.min-1.100 g-1; p = 0.001 v baseline] and oxygen consumption [7.92(1.10) v 20.14(1.86) ml.min-1.100 g-1; p = 0.001] increased in direct relation to heart rate-blood pressure product changes. Locally administered bradykinin increased coronary artery conductance [2.62(0.39) v 4.71(1.07) ml.min-1.100 g-1.mm Hg-1], total myocardial blood flow, to 263(72) ml.min-1.100 g-1, and oxygen consumption, to 14.9(4.4) ml.min-1.100 g-1; however, heart rate-blood pressure product did not change. CONCLUSIONS: These results support earlier findings that intrinsic neurones are involved in cardiac regulation. Furthermore, modification of intrinsic cardiac neurones by nicotine or bradykinin significantly alters the distribution of myocardial blood flow, possibly because of increased myocardial metabolism.     

Value of intracoronary ultrasound and Doppler in the differentiation of angiographically normal coronary arteries: a prospective study in patients with angina pectoris

BACKGROUND: A substantial proportion of patients undergoing heart catheterization for suspected coronary artery disease have normal angiograms. Coronary morphology and blood flow velocity can be assessed very accurately with intracoronary ultrasound and Doppler. The purpose of this study was to use both methods to classify further patients with suspected coronary artery disease but with coronary angiograms adjudged normal at the time. METHODS AND RESULTS: In forty-four patients with suspected coronary artery disease and normal coronary angiograms, intracoronary ultrasound and intracoronary Doppler were performed in the left anterior descending and left main coronary arteries. Coronary flow reserve was obtained by calculating the ratio of the maximal coronary flow mean velocity after the intracoronary administration of 10 mg papaverine to the coronary flow mean velocity at rest. Of 44 patients, 16 (36%) (group I) were found to have normal coronary morphology by intracoronary ultrasound and normal (> 3.0) coronary flow reserve (5.3 +/- 1.8). In seven patients (16%) (group II) there were normal intracoronary ultrasonic findings but a reduced coronary flow reserve (2.1 +/- 0.4). Plaque formation was found in a total of 21 (48%) of the 44 patients; mean plaque sizes were 3.6 +/- 1.6 mm2 for those in group III (normal coronary flow reserve) and 5.0 +/- 2.3 mm2 for those in group IV (reduced coronary flow reserve). Vessel area in both of these groups (16.3 +/- 8.0 mm2 and 19.2 +/- 6.1 mm2) was significantly larger than that of group I (14.6 +/- 5.7 mm2, P < 0.01). Plaque calcification was found in 25% of those in group III and 44% of those in group IV. Thus, only 36% of the patients with normal angiograms were true normal, 48% exhibited early stage of coronary atherosclerosis, and the other 16% might be considered as syndrome X. CONCLUSION: Intracoronary ultrasound and Doppler can be used to differentiate further heart disease in patients with normal coronary angiograms. Only a minority were true normal. Early signs of atherosclerosis cannot be detected by coronary angiography. This may have important therapeutic and prognostic implications.