Coronary Vasodilator Reserve Research Articles

Analysis of coronary blood flow velocity dynamics in angiographicaily normal and stenosed arteries before and after endolumen enlargement by angioplasty

Objectives. This study was designed to assess whether the spectral waveform of coronary velocity on Doppler study is characteristically altered in the presence of significant stenosis with normalization of the spectral waveform after relief of endolumen obstruction.Background. Although coronary flow reserve determinations have provided physiologic information complementary to the angiographic percent diameter narrowing, flow velocity measurements have been limited to proximal arteries with inconsistent results after angioplasty. A 12-MHz Doppler guide wire permits flow velocity determination in the proximal and distal coronary artery with fast Fourier spectral analysis.Methods. With the Doppler guide wire, proximal arterial flow velocity and flow reserve measurements in 17 angiographically normal arteries were compared with measurements in 29 significantly stenosed arteries. Proximal and distal flow velocity measurements were also obtained before and after angioplasty of the 29 abnormal arteries. Velocity spectrum was digitized to compute peak diastolic velocity, peak systolic velocity, mean velocity, diastolic/systolic velocity ratio and first third and first half flow fraction.Results. Compared with proximal stenosed arteries, proxtmal normal arteries had significantly higher peak diastolic velocity (64 ± 26 cm/s vs. 41 ± 26 cm/s) and higher coronary vasodilator reserve (2.3 ± 0.8 vs. 1.6 ± 0.7). Normal arteries had higher flows in the first third and first half of the coronary cycle (46 ± 3% vs. 39 ± 7% and 65 ± 2% vs. 56 ± 10%, respectively). Before angioplasty, coronary velocity variables were significantly lower distal than proximal to the stenosis. After angioplasty, there was a greater mean increase in distal velocities (200% vs. 90% for the proximal arteries) that resulted in near equalization of proximal and distal mean velocity and a significant reduction in proximal/ distal mean velocity ratio (2.4 ± 1.7 vs. 1.2 ± 0.4).Conclusions. Before angioplasty, abnormal coronary flow velocity dynamics are more marked distal than proximal to the stenosis. Greater increase in coronary flow velocities in the distal circulation after relief of endolumen obstruction results in a significant reduction in the proximal/distal flow velocity ratio. Thus, normalization of Doppler-derived flow velocity variables with marked reduction of the proximal/distal flow velocity ratios parallels angiographic success and may prove useful as an additional end point measurement in interventional cases with questionable angiographic findings.

Changes in coronary vasodilatory reserve induced by pressure overload during post-natal development: effects on post-ischemic perfusion.

Several congenital heart defects result in increased hemodynamic load on one or both ventricles. We have investigated the effects of left ventricular (LV) pressure overload during post-natal development on the coronary vasodilatory reserve in isolated rat hearts (i) during aerobic perfusion, and (ii) following cardioplegic arrest and hypothermic ischemia. The LV pressure overload was induced in 1-week-old Wistar rats by abdominal aortic constriction (AC), with controls (C) undergoing sham operations. Relative to C, the LV weight/body weight in AC increased by 45% and 100% at 3 and 6 weeks of age, respectively. At these ages, the hearts (n = 8/group) were isolated and Langendorff-perfused. Minimal coronary vascular resistance per gram dry weight (MCVR/g) was measured during maximal vasodilation with adenosine (10 mumol/l) before cardioplegic arrest and hypothermic (15 degrees C) ischemia (210 min) and again after reperfusion (45 min). Before ischemia, MCVR/g was greater in AC than in C both at 3 weeks of age (0.48 +/- 0.03 vs 0.31 +/- 0.01 mmHg/ml per min/g dry wt) and at 6 weeks of age (1.20 +/- 0.05 vs 0.46 +/- 0.01 mmHg/ml per min/g dry wt). In the post-ischemic period, MCVR/g increased in all groups. Post-ischemic MCVR/g was similar in C and AC at 3 weeks of age (0.52 +/- 0.12 and 0.66 +/- 0.05 mmHg/ml per min/g dry wt, respectively) but was significantly greater in AC than in C at 6 weeks of age (2.42 +/- 0.22 vs. 0.54 +/- 0.02 mmHg/ml per min/g dry wt).(ABSTRACT TRUNCATED AT 250 WORDS)

Left ventricular pressure overload during postnatal development: Effects on coronary vasodilator reserve and tolerance to hypothermic global ischemia

The effect of pressure overload during postnatal development on (1) coronary reserve and (2) tolerance to cardioplegic arrest and hypothermic ischemia was investigated. Left ventricular pressure overload was induced in 1-week-old rats by aortic constriction (group AC), with control rats (group C) undergoing sham operation. Relative to group C rats, left ventricular weight/body weight ratio in group AC increased by 50% to 80% at 3 weeks of age and by 100% to 120% at 6 weeks of age. At these ages, hearts were isolated from group C and AC rats and Langendorff-perfused with bicarbonate buffer at perfusion pressures of 75 and 110 mm Hg, respectively. In the first study, minimal coronary vascular resistance was assessed during perfusion with adenosine (10 mumol/L). There was no difference in total minimal coronary vascular resistance between groups C and AC at 3 weeks of age. Total minimal coronary vascular resistance decreased with increasing cardiac mass between 3 and 6 weeks of age in group C (from 6.9 +/- 0.4 to 4.5 +/- 0.2 mm Hg/ml/min, p < 0.05), but not in group AC. Between these ages, minimal coronary vascular resistance per unit heart weight increased to a greater extent in group AC (from 2.9 +/- 0.2 to 7.0 +/- 0.3 mm Hg/ml/min/gm, p < 0.05) than in group C (from 1.8 +/- 0.0 to 2.7 +/- 0.1 mm Hg/ml/min/gm, p < 0.05). In the second study, hearts were arrested with St. Thomas' Hospital cardioplegic solution (15 degrees C) and subjected to hypothermic (15 degrees C) global ischemia (210 minutes at 3 weeks and 180 minutes at 6 weeks) followed by 65 minutes of reperfusion. At 3 weeks of age, coronary resistance profiles, changes in left ventricular end-diastolic pressure, and recoveries of left ventricular developed pressure during reperfusion were similar in groups C and AC. At 6 weeks of age, however, group AC had greater coronary resistance during reperfusion, a greater increase in left ventricular end-diastolic pressure (28 +/- 5 versus 1 +/- 1 mm Hg, p < 0.05), and consequently a reduced recovery of left ventricular developed pressure (50.7% +/- 3.6% versus 75.9% +/- 4.0%, p < 0.05) relative to group C. Thus 2 weeks of left ventricular pressure overload during neonatal development in the rat has little effect on coronary reserve and ischemic tolerance. Prolonged (5 weeks) pressure overload, however, results in postischemic diastolic dysfunction, which may be due to perfusion abnormalities during reperfusion.

Evidence for a systemic defect of resistance-sized arterioles in hypertrophic cardiomyopathy.

To investigate whether the abnormalities of coronary arterioles observed in association with hypertrophic cardiomyopathy represent a generalized phenomenon, both forearm and coronary vasodilator reserve were measured in 12 patients with hypertrophic cardiomyopathy. Forearm vasodilator reserve was evaluated by measuring minimal forearm vascular resistance (Rmin, the ratio of mean intra-arterial pressure to peak forearm blood flow measured by venous plethysmography) under conditions of maximal postocclusive reactive hyperemia. In a subgroup (n = 5) of patients, the intra-arterial infusion of sodium nitroprusside combined with arterial occlusion did not produce additional vasodilation, indicating that the ischemic stimulus was indeed maximal. Coronary reserve was quantitated by measuring left ventricular blood flow (13N-ammonia and positron emission tomography) and coronary resistance at baseline and after intravenous dipyridamole (0.56 mg/kg). Rmin was significantly greater in patients than in a group of age- and sex-matched controls. The percentage change in coronary resistance after dipyridamole was significantly related to Rmin, whereas no correlation was found between change in coronary resistance and individual septal thickness values. Independent of cardiac hypertrophy, systemic and coronary arterioles of patients with hypertrophic cardiomyopathy are affected by an abnormality that may contribute to the clinical evolution of this syndrome.

The significance of a dipyridamole induced 99mTc-MIBI perfusion abnormality on single photon emission tomography: a quantitative validation with labelled water and positron emission tomography.

To relate technetium-99m 2-methoxy-isobutyl-isonitrile (99mTc-MIBI) uptake to regional myocardial blood flow (rMBF), 99mTc-MIBI single photon emission tomography (SPET) and H2(15)O positron emission tomography (PET) scans were obtained at rest and after dipyridamole infusion in six patients with single vessel coronary artery disease. 99mTc-MIBI and H2(15)O data sets were created for each segment perfused by the stenotic vessel and for a normal reference area, assigning regions on the SPET tomograms to comparable regions on the PET by similar transaxial image reconstructions. All patients demonstrated post-dipyridamole 99mTc-MIBI perfusion defects in the territories supplied by the stenotic arteries. Resting rMBF in these regions was slightly lower than that in the normal areas (0.82 +/- 0.05 vs 0.90 +/- 0.09 ml/g/min, P = NS). A 43% +/- 14% reduction in 99mTc-MIBI activity in the area at risk was coupled with on average a 60% +/- 9% reduction in post-dipyridamole rMBF compared with control regions (0.98 +/- 0.08 vs 2.52 +/- 0.51 ml/g/min, P < 0.001). Thus, SPET assessment of 99mTc-MIBI uptake tends to underestimate the perfusion contrast between areas with normal and areas with low coronary vasodilatory reserve when compared to PET. However, these findings may still not affect the clinical usefulness of 99mTc-MIBI and more extensive studies are required to confirm these results in the clinical environment.

Pharmacotherapeutic effects of antihypertensive agents on myocardium and coronary arteries in hypertension

Hypertensive left ventricular hypertrophy comprises myocyte hypertrophy, interstitial fibrosis and structural alterations in the coronary microcirculation. This leads to impairment of diastolic function in the left ventricle and coronary flow reserve despite normal epicardial arteries. Consequently, antihypertensive treatment should aim at (1) reversing myocyte hypertrophy, (2) restoring myocardial structure and (3) improving coronary flow reserve without lowering blood pressure. In recent years many clinical studies have shown that regression of hypertensive hypertrophy can be induced by long-term treatment with ACE inhibitors, calcium-channel blockers, beta-receptor blockers and antisympathonic drugs. However, vasodilators and diuretics, which stimulate adrenoceptor activity and increase angiotensin II levels, were found to be less effective in reversing left ventricular hypertrophy. The trophic influence of catecholamines and angiotensin II on the myocardium counteracts the effect of systolic wall stress reduction due to blood pressure lowering. As regards reversal of interstitial fibrosis, ACE inhibitors seem to be effective, because fibroblast growth was found to be stimulated by angiotensin II. Recently, clinical studies have confirmed previous experimental data that improvement in impaired coronary vasodilator reserve can be realized by long-term antihypertensive therapy. In adopting an antihypertensive treatment strategy prime consideration should be given to reversal of cardiac remodelling through restoration of myocardial structure and repair of the coronary microcirculation.

Coronary reserve and exercise ECG in patients with chest pain and normal coronary angiograms.

Coronary vasodilator reserve is reduced in some patients with a history of chest pain and angiographically normal coronary arteries. ECG changes suggestive of myocardial ischemia during exercise also can be demonstrated in a subset of these patients. We have investigated the correlation between coronary vasodilator reserve, assessed with 13N-labeled ammonia and positron emission tomography, and the ECG during exercise stress in 45 patients with a history of chest pain, angiographically normal coronary arteries, and a negative ergonovine test. ST segment depression on the ECG during exercise was present in 29 of 45 patients. Mean resting left ventricular blood flow was 1.04 +/- 0.22 ml.min-1.g-1; it increased to 1.32 +/- 0.47 ml.min-1.g-1 (p less than 0.01 versus baseline value) during atrial pacing and to 2.52 +/- 0.96 ml.min-1.g-1 (p less than 0.01 versus baseline value) after dipyridamole (0.56 mg/kg i.v.). No regional flow defects could be demonstrated in any patient during pacing or after dipyridamole. Myocardial flows after dipyridamole, however, did not show a normal frequency distribution (Kolmogorov-Smirnov test), and two patient populations could be identified. Twenty-nine (67%) patients had a mean left ventricular flow of 3.02 +/- 0.33 ml.min-1.g-1 after dipyridamole (range, 2.13-5.46 ml.min-1.g-1), and 14 (33%) patients had a mean flow of 1.48 +/- 0.29 ml.min-1.g-1 (range, 1.06-2.04 ml.min-1.g-1, p less than 0.01 versus the "high-flow group"). Approximately one third of patients in our series showed a reduced coronary vasodilator reserve. Although 12 of 14 patients in the "low-flow group" had ST segment depression during exercise stress, 16 of 29 patients in the high-flow group also had ST segment depression during exercise stress. Therefore, despite a good sensitivity (86%) in identifying patients with a blunted increment of coronary flow, the ECG response during exercise stress appears to have a rather low specificity (45%). This suggests that factors other than reduced coronary reserve and myocardial ischemia may play a role in the genesis of the ST segment depression in these patients.

Interpretation of cardiac pathophysiology from pressure waveform analysis: Coronary hemodynamics, part III: Coronary hyperemia

Basal patterns (systolic/diastolic components) of coronary flow velocity as previously described are generally maintained during hyperemia and can be easily recorded in the catheterization laboratory during pharmacologic stimulation. The interpretation of the clinical significance of coronary vasodilatory reserve may be complicated by both coronary and myocardial diseases. Distal coronary artery hyperemic responses measured with ultrasound Doppler-tipped guidewires will provide new information on traditional observations of coronary physiology in humans.

Myocardial contrast echocardiography can depict thebesian vein outflow in humans

17. ventricular pulsus alternans during acute increase in afterload during balloon pulmonic valvuloplasty. Am J Cardiol 1987; 601412-3. Gleason WL, Braunwald E. Studies on Starling’s law of the heart. VI. Relationship between left ventricular end-diastolic volume and stroke volume in man with observations on the mechanism of pulsus alternans. Circulation 1962;25:841-7. Lab MJ, Lee JA. Changes in intracellular calcium during mechanical alternans in isolated ferret ventricular muscle. Circ Res 1990;66:585-95. Wilson RF, Laughlin DE, Ackell PH, et al. Transluminal, subselective measurement of coronary artery blood flow velocity and vasodilator reserve in man. Circulation 1985;72:8292. Wilson RF, Marcus ML, White CW. Pulmonary inflation reflex: its lack of physiologic significance in coronary circulation of humans. Am J Physiol 1988;255(Heart Circ Physiol 24): H866-71. Wilson RF, White CW. Intracoronary papaverine: an ideal coronary vasodilator for studies of the coronary circulation in conscious humans. Circulation 1986;73:444-51.

Current Medical therapy for esophageal motility disorders

Treatment of patients with an esophageal source of chest pain remains a challenging problem. Although a variety of measures--including nitrates, anticholinergics, sedatives, calcium channel antagonists, esophageal dilation, and psychological reassurance--are available for the management of esophageal chest pain, none has emerged as the treatment of choice. Studies of nitrate preparations for the treatment of painful motility disorders are limited by a small number of patients and the lack of randomized, placebo-controlled investigations. The efficacy of anticholinergic drugs in hypercontractile esophageal motility disorders has not been reported. In the only prospective placebo-controlled trial using an anti-depressant, trazodone was superior to placebo in relieving symptoms in patients with a variety of esophageal motility disorders. Conflicting results have been described in placebo-controlled trials of the calcium channel antagonists nifedipine and diltiazem in patients with "nutcracker esophagus" or diffuse spasm. Information about the efficacy of verapamil and hydralazine is limited. Esophageal dilation has been useful in selected patients. For many patients, esophageal chest pain may be associated with gastroesophageal reflux. Treatment of these patients with nitrates, calcium channel antagonists, or anticholinergics may aggravate their reflux. The mechanisms of esophageal chest pain remain unknown. Recent studies have suggested that abnormal motility may not be the only factor associated with chest pain. An important number of patients have behavioral abnormalities, increased nociception, impaired coronary vasodilatory reserve, or a diffuse abnormality of smooth muscle. Research into rational therapy for chest pain patients should take into account the contribution of these other factors.

Investigation of impaired coronary vasodilator reserve in the guinea pig heart with pressure induced hypertrophy.

Impaired coronary reserve and increased minimal coronary resistance have been documented in several animal models of left ventricular hypertrophy. There is controversy whether the increased minimal coronary resistance is due to vascular or extravascular causes. To test the hypothesis that pressure-overloaded left ventricular hypertrophy (LVH) is associated with a vascular defect, studies were performed using isolated buffer-perfused guinea pig hearts taken 72 +/- 6 days post-aortic banding (LVH n = 13) and compared to sham-operated controls (n = 12). The pressure flow relationship was determined over the range 30-70 mmHg. We defined an extravascular compression index as the percentage increase in flow during maximal arteriolar dilation when systolic forces were excluded during prolonged diastole (2 +/- 0.2 s). In LVH, coronary reserve was reduced (141 +/- 5.5% v 231.7 +/- 24.1%) P less than 0.01 and minimal coronary resistance was increased (4.55 +/- 0.44 v 3.70 +/- 0.37 mmHg.ml-1.min-1.g-1) P less than 0.05. The extravascular compression index was increased in LVH (36.8 +/- 1.4 v 30.5 +/- 2.3%) P less than 0.05. Systole caused a greater increase in resistance in the LVH group than in controls (1.73 +/- 0.26 v 0.95 +/- 0.14 mmHg.ml-1.min-1.g-1) P less than 0.05. These data indicate that during diastole there is impaired minimal coronary resistance of vascular origin. Systole impaired flow to a greater extent in hypertrophied hearts, further reducing the coronary reserve.

The effect of ergonovine on coronary vasodilatory reserve in patients with angiographically normal coronary arteries

Ergonovine produces physiologic coronary artery narrowing in many patients without focal coronary spasm. The effect of ergonovine-induced coronary vasoconstriction on coronary vasodilatory reserve is unknown. Therefore we studied 10 patients with atypical chest pain and angiographically normal coronary arteries. The heart rate and blood pressure were recorded continuously and coronary Doppler flow velocity was measured continuously with a 20 MHz Doppler-tipped catheter. Ergonovine caused diffuse narrowing of the vessels in all patients, with a 12% ± 5% change in diameter of the left anterior descending coronary artery ( p < 0.001). There was a significant change in systolic (17% ± 12% change; p < 0.05) and mean arterial pressure (13% ± 13% change; p < 0.05), with no significant change in mean coronary flow velocity with ergonovine. Ergonovine also did not attenuate the maximal hyperemic response with papaverine. Thus despite an increase in myocardial demand and a decrease in caliber of conductance coronary vessels, the coronary autoregulatory flow responses were intact after the administration of ergonovine.

The effects of ionic and nonionic radiographic contrast media on coronary hyperemia in patients during coronary angiography

The purpose of this study was to compare the differential effects of ionic, high-osmolar meglumine diatrizoate; ionic, low-osmolar ioxaglate meglumine; and nonionic, low-osmolar iohexol (all radiographic contrast agents) on coronary blood flow velocity and hyperemic responses during diagnostic coronary angiography. Coronary flow velocity and arterial pressure were measured at baseline and during maximal hyperemia after contrast media were randomly injected (4 to 6 ml into left coronary artery) in 22 patients with the use of a Judkins-style 20 MHz Doppler-tipped angiographic catheter. Contrast media-induced hyperemic responses were compared to those induced with intracoronary nitroglycerin (200 μg) and papaverine (10 mg). There were no significant differences in systolic, diastolic, or mean arterial pressure measurements among the three contrast agents. The increase in mean coronary flow velocity during hyperemia was 118 ± 93%, 133 ± 73%, and 136 ± 86% for iohexol, ioxaglate meglumine, and diatrizoate, respectively ( p = NS among agents vs 264 ± 109% for papaverine; p < 0.05 for all). Coronary vasodilatory reserve (calculated as the ratio of hyperemic to basal mean flow velocity) was also similar among agents. It was comparable to the coronary vasodilatory reserve with nitroglycerin (2.1 ± 1.0 to 2.2 ± 1.1) and significantly less than that with papaverine (3.3 ± 2.2, p < 0.05). These data indicate that the clinical advantages of nonionic or low-osmolar contrast media are not mechanistically related to significant attenuation of the coronary hyperemic response.

Abnormal endothelium-dependent coronary vasomotion in hypertensive patients

Coronary vasomotion is abnormal in hypertensive patients, as evidenced by reduced coronary vasodilator reserve, but endothelium dependent coronary vasomotion in hypertensive patients has not been studied. To assess the integrity of endothelium-dependent vasodilation, the response of coronary arteries to acetylcholine (an endothelium-dependent vasodilator) and nitroglycerin (an endothelium-independent vasodilator) was studied in 14 patients undergoing cardiac catheterization. Eight patients with essential hypertension were compared with six normotensive patients. None had obstructive disease detectable by coronary arteriography. Coronary artery diameter was measured with digital-subtracted arteriography and coronary blood flow velocity with a Doppler flow velocity catheter.At baseline, coronary artery diameter was similar in the hypertensive and the normotensive control patients (2.4 ±0.3 vs. 2.8 ± 0.7 mm). During intracoronary acetylcholine infusion (30 μg/min), coronary artery diameter decreased to 1.3 ± 0.7 mm in the hypertensive patients (p < 0.005), but was unchanged (2.7 ± 0.8 mm) in the normotensive patients. With intracoronary nitroglycerin (203 μg), coronary artery diameter increased significantiy in both groups. Calculated coronary blood flow decreased during acetylcholine infusion by 59 ± 31% in the hypertensive patients but increased by 3 ± 3% in the normotensive group (p < 0.005). There was a significant negative correlation between the percent change in estimated coronary blood flow during acetylcholine infusion and mean arterial pressure measured at baseline (r = 0.67, p < 0.02).Therefore, these hypertensive patients exhibited marked coronary vasoconstriction in response to intracoronary acetylcholine but normal vasodilation in response to nitroglycerin, suggesting abnormal endothelium-dependent vasodilation. The latter may be a mechanism contributing to reduced coronary vasodilator reserve and angina pectoris in hypertensive patients.

Coronary vasodilator reserve in ischemic myocardium of the exercising dog.

Previous work has reported that coronary vasodilator reserve may persist in myocardium rendered ischemic by hypoperfusion. This study investigated the presence and extent of residual coronary vasomotor tone in myocardial regions made acutely ischemic by a flow-limiting coronary stenosis during exercise. Studies were done in chronically instrumented dogs undergoing treadmill exercise in the presence of a coronary stenosis that decreased distal left circumflex coronary artery perfusion pressure to approximately 40 mm Hg. Measurements of myocardial blood flow were made with radioactive microspheres during exercise (6.5 km/hr, 6% grade) before and during intracoronary infusion of the potent coronary vasodilator adenosine (40 micrograms/kg/min). Distal coronary perfusion pressure was held equal before and during intracoronary adenosine infusion (43 +/- 5 versus 42 +/- 5 mm Hg) by adjusting the hydraulic coronary occluder. During exercise in the presence of a coronary stenosis, myocardial blood flow (milliliter per minute per gram) was significantly reduced in all layers of the ischemic posterior region compared with the nonischemic anterior region. During intracoronary adenosine infusion, with no change in coronary perfusion pressure, myocardial blood flow was significantly increased compared with preadenosine flows for both the subendocardial layer flow (1.03 +/- 0.74 versus 0.66 +/- 0.50; p less than 0.05) and mean transmural flow (1.54 +/- 0.59 versus 1.16 +/- 0.36; p less than 0.05). In the presence of a coronary stenosis, regional myocardial segment shortening in the ischemic region during exercise fell significantly to 49 +/- 8% of shortening in the absence of a coronary stenosis but improved modestly during adenosine infusion (65 +/- 7 versus 49 +/- 8%; p less than 0.05). These results indicate that adenosine-responsive coronary vasodilator reserve persists during exercise-induced myocardial ischemia and suggest that residual microvascular vasoconstrictor tone may affect the extent of myocardial hypoperfusion occurring consequent to a flow-limiting coronary stenosis.

Medical Repair of Hypertensive Left Ventricular Remodeling

Hypertensive left ventricular (LV) hypertrophy leads to myocytic hypertrophy, interstitial fibrosis, and structural alterations of the coronary microcirculation. This structural remodeling of the myocardium results in an impairment of diastolic function of the left ventricle and of coronary flow reserve despite normal epicardial arteries. Consequently, an antihypertensive treatment should aim at (a) reversing myocytic hypertrophy, (b) regression of myocardial fibrosis, and (c) improvement of coronary flow reserve apart from blood pressure lowering. In recent years many clinical studies have shown that regression of hypertensive hypertrophy can be induced by long-term treatment with angiotensin-converting enzyme (ACE) inhibitors, calcium-channel blockers, beta-receptor blockers, and antisympathonic drugs. However, vasodilators and diuretics, which stimulate adrenoceptor activity and increase angiotensin II levels, were found to be less effective in reversing LV hypertrophy. The trophic influence of catecholamines and angiotensin II on the myocardium counteracts the effect of systolic wall stress reduction due to blood pressure lowering. In respect of reversal of interstitial fibrosis, ACE inhibitors seem to be effective because the growth of fibroblasts was found to be stimulated by angiotensin II. Recently, clinical studies have confirmed previous experimental data that an improvement of the impaired coronary vasodilator reserve can be realized by long-term antihypertensive therapy. An antihypertensive treatment strategy which fully restores myocardial structure and completely repairs coronary microcirculation has to be considered as a causative treatment of hypertensive heart disease.

Morphologic, hemodynamic and coronary perfusion characteristics in severe left ventricular hypertrophy secondary to systemic hypertension and evidence for nonatherosclerotic myocardial ischemia

Patients with the clinical diagnosis of ischemic heart disease who were found to be free of significant coronary artery atherosclerotic disease (n = 150) underwent coronary vasodilator reserve testing, 2-dimensional echocardiography, and dipyridamole limited-stress thallium testing. After exclusions (predominantly for technically poor coronary artery Doppler signals or suboptimal echocardiography), 100 patients formed the study population. The purpose was to characterize typical cardiac and coronary artery findings in hypertensive patients with severe left ventricular (LV) hypertrophy (n = 15) and to investigate the evidence for myocardial ischemia unrelated to coronary atherosclerosis in early and advanced hypertensive heart disease. Normotensive and hypertensive control groups without LV hypertrophy (n = 12 and 34, respectively) were used for comparison. Severe LV hypertrophy was defined as LV mass index ≥50% above established gender specific norms using 2-dimensional-directed M-mode echocardiography and the cube equation corrected to agree with necropsy estimates of mass. Clinical characteristics more often associated with severe LV hypertrophy were black race (67%), diabetes mellitus (33%), proteinuria (47%) and elevated creatinine (1.5 ± 0.9 mg/dl). Baseline electrocardiograms and dipyridamole limited-stress thallium scans were highly likely to be abnormal (94 and 73%, respectively). Both eccentric and concentric cardiac hypertrophies were found in the severe group. Ejection fraction was significantly lower (0.51 vs 0.68, p = 0.002) and basal coronary flow velocity higher (12.0 vs 5.0 cm/s, p = 0.0004) among these patients when compared with normotensive control patients. Coronary flow reserve did not differ between control groups but was significantly depressed in patients with severe LV hypertrophy (2.5 vs 3.9, p = 0.001). This, together with the prevalent evidence of resting and stress-induced ischemia, strongly supports the concept of myocardial ischemia unrelated to coronary atherosclerosis in this group.

Cardiovascular complications in renal failure.

Cardiovascular diseases are a leading cause of death in end-stage renal disease (ESRD) largely as a result of the progressively increasing age of ESRD patients and the broad constellation of uremia-associated factors that can adversely affect cardiac function. Hypertension, one of the leading causes of renal failure, is a major culprit in this process, causing left ventricular hypertrophy, cardiac chamber dilation, increased left ventricular wall stress, redistribution of coronary blood flow, reduced coronary artery vasodilator reserve, ischemia, myocardial fibrosis, heart failure, and arrhythmias. In addition to impairing the coronary microcirculation, hypertension may contribute to the development of atherosclerotic coronary artery disease, particularly in the presence of the many lipid abnormalities observed in ESRD. These patients have reduced high-density lipoprotein cholesterol and increased plasma triglyceride concentrations, and there is a defect in cholesterol transport. Other abnormalities that may contribute to atherosclerotic coronary artery disease in ESRD are reduced high-density lipoprotein cholesterol synthesis and reduced activity of the reverse cholesterol pathway. Treatment with fibric acids, nicotinic acids, and lovastatin may be useful in lowering cholesterol and triglyceride concentrations in some of these patients. The incidence of coronary artery disease in ESRD populations is difficult to determine. About 25 to 30% of ESRD patients with angina have no evidence of significant coronary artery disease, and an undetermined number have silent coronary disease. The presence of resting electrocardiographic abnormalities caused by hypertension or conduction defects makes it difficult to accurately diagnosis coronary artery disease in ESRD populations by noninvasive methods, including exercise testing and thallium scintigraphy with or without the use of dipyridamole. Hypotension is a frequent complication of the dialytic process. Many factors have been implicated, including autonomic neuropathy. There is no consensus on the function of the efferent limb of the sympathetic nervous system. The afferent limb (arterial baroreflex function) is felt to be impaired. Further, there may be defects in the ability of the cardiovascular system to respond to sympathetic nerve activity. Most studies of autonomic function have used indirect measurements. Studies are underway that use techniques to assess sympathetic function directly. Such experiments with microneuropathy suggest greater skeletal sympathetic muscle discharge in uremic patients than in normal patients.

Influx of neutrophils into the walls of large epicardial coronary arteries in response to ischemia/reperfusion.

There are several clinical situations in which large epicardial coronary arteries are deprived of blood flow, such as occurs when an obstructing thrombus or embolus lodges within a vessel or during coronary dissection. There is little information concerning the effect of flow deprivation on large epicardial coronary arteries. We studied a model in which a segment of a large epicardial coronary artery was deprived of blood flow using both proximal and distal clamps for 3 hours followed by reperfusion. On examination by light microscopy of cross sections of the arteries, 19 +/- 6 neutrophils were present in the intima of ischemic/reperfused vessels, whereas only a mean of 4 +/- 3 (SEM) were present in the intima of nonischemic vessels (p less than 0.02). On average, there were 17 +/- 9 neutrophils just under the elastic lamina in ischemic/reperfused vessels versus none in the nonischemic vessels (p less than 0.05); there were 16 +/- 10 neutrophils present within the media of ischemic/reperfused vessels, and none (p less than 0.05) in the nonischemic vessels. Electron microscopic analysis revealed that neutrophils in the ischemic/reperfused vessels were often "sandwiched" between the endothelial cells and the elastic lamina. Ultrastructural abnormalities within the myocardium also revealed damage to the microvasculature, including the presence of neutrophils within the vessels and erythrocyte stasis. To rule out the possibility that findings in the large epicardial arteries were due to toxic substances from static blood within the isolated arterial segment, a protocol was performed in which blood was removed from the isolated segment. Again, neutrophil infiltration into the vessel was observed. Resting mean epicardial coronary artery blood flow before coronary occlusion was 19 +/- 3 ml/min; mean coronary blood flow 2.5 hours after reperfusion was identical at 19 +/- 3 ml/min. Response to both endothelial-dependent vasodilation (acetylcholine) and endothelial-independent vasodilation (nitroglycerin) challenges was normal early after reperfusion but was depressed late after reperfusion, suggesting progressive vascular dysfunction and hence a form of vascular reperfusion injury in this model. When large epicardial coronary arteries are deprived of blood flow, followed by reperfusion in this model, neutrophils migrate into the vessel wall as well as into the microvasculature. These abnormalities are associated with reduced endothelial-dependent and endothelial-independent coronary vasodilator reserve.

Intravenous adenosine: Continuous infusion and low dose bolus administration for determination of coronary vasodilator reserve in patients with and without coronary artery disease

To assess the use of adenosine as an alternative agent for determination of coronary vasodilator reserve, hemodynamics and coronary blood flow velocity were measured at rest and during peak hyperemic responses to continuous intravenous adenosine infusion (50, 100 and 150 μg/kg per min for 3 min) and intracoronary papaverine (10 mg) in 34 patients (17 without [group 1]and 17 with [group 2]significant left coronary artery disease), and in 17 patients (11 without and 6 with left coronary artery disease) after low dose (2.5 mg) intravenous bolus injection of adenosine.The maximal adenosine dose did not change mean arterial pressure (−10 ± 14% and −6 ± 12% for groups 1 and 2, respectively) but increased the heart rate (15 ± 18% and 13 ±16%, respectively). For continuous adenosine infusions, mean coronary flow velocity increased 64 ± 104%, 122 ± 94% and 198 ± 59% and 15 ± 51%, 110 ± 95% and 109 ± 86% in groups 1 and 2, respectively for each of the three doses. Mean coronary flow velocity increased significantly after 100 and 150 μg/kg of adenosine and 10 mg of intracoronary papaverine (48 ± 25, 52 ±19 and 54 ± 21 cm/s, respectively; all p < 0.05 vs. baseline) and was significantly higher than in group 2 (37 ± 24, 32 ± 16, 41 ± 23 cm/s; all p < 0.05 vs. group 1). The coronary vasodilator reserve ratio (calculated as the ratio of hyperemic to basal mean flow velocity) for adenosine and papaverine was 2.94 ± 1.50 and 2.94 ± 1.00, respectively, in group 1 and was significantly and similarly reduced in group 2 (2.16 ± 0.81 and 2.38 ± 0.78, respectively; both p < 0.05 vs. group 1). Low dose bolus injection of adenosine increased mean velocity equivalenty to that after continuous infusion of 100 μg/kg, but less than after papaverine. There was a strong correlation between adenosine infusion and papaverine for both mean coronary flow velocity and coronary vasodilator reserve ratio (r2= 0.871 and 0.325; SEE = 0.068 and 0.189, respectively; both p < 0.0005).No patient had significant arrhythmias or prolongation of the corrected QT (QTc) interval with adenosine, but papaverine increased the QTc interval from 445 ± 44 to 501 ± 43 ms (p < 0.001 vs. both maximal adenosine and baseline) and produced nonsustained ventricular tachycardia in one patient.These data indicate that intravenous adenosine in doses >100 μg/kg (and in low dose bolus injections) for most patients is nearly equivalent to intracoronary papaverine without producing QTc prolongation, making this agent a potentially superior and safer alternative to intracoronary papaverine for determination of coronary vasodilator reserve.