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 micrograms/min), coronary artery diameter decreased to 1.3 +/- 0.7 mm in the hypertensive patients (p less than 0.005), but was unchanged (2.7 +/- 0.8 mm) in the normotensive patients. With intracoronary nitroglycerin (200 micrograms), coronary artery diameter increased significantly 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 less than 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 less than 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional extraction of circulating norepinephrine, DOPA, and dihydroxyphenylglycol in humans.

Dihydroxyphenylglycol (DHPG) is the main intraneuronal metabolite of the sympathetic neurotransmitter, norepinephrine (NE), and dihydroxyphenylalanine (DOPA) the immediate product of the rate-limiting step in catecholamine biosynthesis. Simultaneous measurements of regional rates of appearance (spillovers) of NE, DOPA, and DHPG in plasma have the potential to provide unique information about aspects of sympathoneural function but have not actually been measured in humans. In the present study, spillovers of DHPG, DOPA, and NE in the heart, head, leg, and lungs, were estimated from regional extraction fractions of infused [3H]-1-NE, DHPG, and [13C6]DOPA or unlabelled DOPA in humans during cardiac catheterization. There was little cardiac extraction of DHPG (7 +/- SEM 2%) or DOPA (8 +/- 4%) but substantial extraction of NE (69 +/- 4%). Values for cardiac spillover of DHPG and DOPA therefore were similar to values for the arteriovenous increment times plasma flow (arteriovenous production rate), whereas the cardiac spillover of NE averaged about 7-times the NE arteriovenous production rate. Cardiac DHPG spillover (28 +/- 3 ng/min) exceeded the spillovers of NE (9 +/- 2 ng/min) and DOPA (15 +/- 4 ng/min). In contrast, cranial DOPA spillover (159 ng/min) exceeded those of NE and DHPG by 8- and 2-fold and accounted for about 1/10 of the total spillover of DOPA into arterial plasma. In the femoral vascular bed, arteriovenous production rates of NE and DHPG were unrelated to femoral spillovers of NE and DHPG. Arterial and regional clearances of [13C6]DOPA were similar to those of unlabelled DOPA. The results suggest that (1) endogenous NE, DOPA, and DHPG all are released into the bloodstream by the heart, head, and limbs of humans; (2) DHPG and DOPA are not co-released with NE; (3) cardiac arteriovenous production rates of DOPA and DHPG can be used to indicate cardiac spillover of these catechols, whereas the cardiac NE arteriovenous production rate substantially underestimates cardiac NE spillover; and (4) estimates of limb spillover of NE and DHPG require concurrent measurements of the corresponding regional clearances.

Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension.

BACKGROUND: Endothelium regulates vascular tone by influencing the contractile activity of vascular smooth muscle. This regulatory effect of the endothelium on blood vessels has been shown to be impaired in atherosclerotic arteries in humans and animals and in animal models of hypertension. METHODS: To determine whether patients with essential hypertension have an endothelium-dependent abnormality in vascular relaxation, we studied the response of the forearm vasculature to acetylcholine (an endothelium-dependent vasodilator) and sodium nitroprusside (a direct dilator of smooth muscle) in 18 hypertensive patients (mean age [+/- SD], 50.7 +/- 10 years; 10 men and 8 women) two weeks after the withdrawal of antihypertensive medications and in 18 normal controls (mean age, 49.9 +/- 9; 9 men and 9 women). The drugs were infused at increasing concentrations into the brachial artery, and the response in forearm blood flow was measured by strain-gauge plethysmography. RESULTS: The basal forearm blood flow was similar in the patients and controls (mean +/- SD, 3.4 +/- 1.3 and 3.7 +/- 0.8 ml per minute per 100 ml of forearm tissue, respectively; P not significant). The responses of blood flow and vascular resistance to acetylcholine were significantly reduced in the hypertensive patients (P less than 0.0001); maximal forearm flow was 9.1 +/- 5 ml per minute per 100 ml in the patients and 20.0 +/- 8 ml per minute per 100 ml in the controls (P less than 0.0002). However, there were no significant differences between groups in the responses of blood flow and vascular resistance to sodium nitroprusside. Because the vasodilator effect of acetylcholine might also be due to presynaptic inhibition of the release of norepinephrine by adrenergic nerve terminals, the effect of acetylcholine was assessed during phentolamine-induced alpha-adrenergic blockade. Under these conditions, it was also evident that the responses to acetylcholine were significantly blunted in the hypertensive patients (P less than 0.03). CONCLUSIONS: Endothelium-mediated vasodilation is impaired in patients with essential hypertension. This defect may play an important part in the functional abnormalities of resistance vessels that are observed in hypertensive patients.

Beneficial and detrimental effects of lidoflazine in microvascular angina.

Lidoflazine, a piperazine derivative calcium antagonist, was investigated as therapy in 22 patients with microvascular angina (chest pain, angiographically normal coronary arteries and left ventricle, microvascular constrictor response to pacing after ergonovine administration and limited coronary flow response to dipyridamole). Eighteen of 22 patients reported symptom benefit while taking lidoflazine 360 mg daily. Compared to baseline exercise treadmill testing, lidoflazine resulted in significant improvement in exercise duration (812 +/- 337 vs 628 +/- 357 seconds, p less than 0.01) and time to onset of chest pain (530 +/- 343 vs 348 +/- 246 seconds, p less than 0.01). The 5 patients with ischemic ST-segment changes during baseline testing demonstrated an almost 4-minute delay in ST-segment depression (3 patients) or no ST-segment depression (2 patients) while taking lidoflazine. Repeat invasive study of coronary flow in 11 patients taking lidoflazine demonstrated significantly greater coronary vasodilation at rest, during pacing, during pacing after ergonovine and after dipyridamole administration (all p less than 0.03), compared to the initial drug-free study. During the randomized, placebo-controlled phase of the study with 7-week treatment periods, 9 of 11 patients who completed this phase of the study preferred lidoflazine and all demonstrated improved exercise capacity with lidoflazine compared to placebo. However, 3 patients developed malignant ventricular arrhythmias, and 1 died while taking lidoflazine, resulting in termination of the study. Limited coronary vasodilator response in microvascular angina has a reversible vasoconstrictor component and may be due to elevated systolic calcium levels. Despite the hemodynamic, symptom and exercise benefit, lidoflazine may be unsafe for clinical use because of its propensity to cause potentially fatal ventricular arrhythmias.

Differences in the neuronal removal of circulating epinephrine and norepinephrine.

Neuronal uptake is an important mechanism for the removal of norepinephrine, but its contribution to the removal of epinephrine is unknown. This study compared the neuronal removal of circulating epinephrine and norepinephrine by examination of the cardiac extractions or plasma clearances of [3H]norepinephrine and endogenous or 3H-labeled epinephrine in healthy subjects, patients with cardiovascular disorders, and subjects administered desipramine to block neuronal uptake. In rabbits the plasma clearances of [3H]epinephrine and [3H] norepinephrine by neuronal uptake and the formation of dihydroxyphenylglycol (DHPG) from simultaneously infused [3H] norepinephrine and epinephrine were compared. In normal patients 51 +/- 3% of plasma epinephrine was extracted during one pass through the coronary circulation, significantly less than the cardiac extraction of [3H]norepinephrine (78 +/- 1%). In patients with cardiovascular disorders extractions of epinephrine (34 +/- 3%) remained lower than those of [3H]norepinephrine (63 +/- 2%). After desipramine, cardiac extraction of epinephrine was reduced to 12 +/- 2% and [3H]norepinephrine to 20 +/- 3%. In subjects infused simultaneously with [3H]epinephrine and [3H] norepinephrine, desipramine reduced the cardiac extraction of [3H]epinephrine by 28 +/- 6%, significantly less than the 49 +/- 7% reduction in [3H]epinephrine extraction; the plasma clearance of [3H]epinephrine was reduced by 4 +/- 5%, significantly less than the 20 +/- 6% reduction in [3H]norepinephrine clearance. In rabbits desipramine reduced the plasma clearance of [3H] epinephrine by 18%, significantly less than the 42% reduction in [3H]norepinephrine clearance; production of DHPG from epinephrine was less than half the production of [3H]DHPG from [3H]norepinephrine. The above differences indicated that epinephrine was removed 44-64% less avidly than norepinephrine by uptake into and metabolism within sympathetic neurons.

Left ventricular hypertrophy and impaired diastolic filling in essential hypertension. Diastolic mechanisms for systolic dysfunction during exercise.

Left ventricular ejection fraction is normal at rest but may respond abnormally to exercise in many patients with essential hypertension. To assess the determinants of the abnormal ejection fraction response to exercise, we performed radionuclide angiography at rest and during exercise in 41 hypertensive patients without coronary artery disease. In 22 patients (group 1), the ejection fraction increased more than 5% during exercise; in the other 19 patients (group 2), the ejection fraction either increased by less than 5% or decreased with exercise. Left ventricular diastolic filling was impaired at rest in patients in group 2 compared with group 1, with reduced peak filling rate (2.5 +/- 0.4 vs. 3.1 +/- 0.7 end-diastolic volume/sec; p less than 0.01) and prolonged time to peak filling rate (175 +/- 28 vs. 153 +/- 22 msec; p less than 0.01). Impaired diastolic filling in group 2 was associated with less augmentation in end-diastolic volume during exercise compared with group 1 (p less than 0.01). These observations were not dependent on the threshold value that was arbitrarily chosen to define an abnormal ejection fraction response, as there were significant correlations for the entire group between the magnitude of change in ejection fraction with exercise and both the resting peak filling rate (r = 0.46) and the change in end-diastolic volume with exercise (r = 0.62).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative effects of verapamil and nitroprusside on left ventricular function in patients with hypertension.

The effects of verapamil were compared with those of nitroprusside at matched mean arterial pressures and heart rates in 10 symptomatic hypertensive patients during cardiac catheterization. Simultaneous radionuclide angiography and micromanometer pressure measurements were obtained to assess left ventricular pressure-volume relations. Compared with control conditions, verapamil increased left ventricular end-diastolic volume index from 57 +/- 16 to 70 +/- 28 ml/m2 (p = 0.05) without a significant increase in left ventricular end-diastolic pressure (from 10 +/- 4 to 13 +/- 6 mm Hg). Despite a downward and rightward shift in the end-systolic pressure-volume relation indicating negative inotropic effects, ejection fraction did not decrease significantly (from 52 +/- 9% to 46 +/- 9%); cardiac index and stroke volume index remained unchanged. The change in stroke volume index with verapamil was directly related to the magnitude of change in end-diastolic volume index (r = 0.82, p less than 0.005), suggesting that the increase in end-diastolic volume did not arise purely from negative inotropic effects. Systemic vascular resistance index decreased from 42 +/- 8 to 34 +/- 7 mm Hg.min.m2/liter (p less than 0.05). In contrast, nitroprusside decreased left ventricular end-diastolic volume index from 57 +/- 16 to 41 +/- 10 ml/m2 (p less than 0.05), cardiac index from 3.2 +/- 0.7 to 2.8 +/- 0.6 liters/min per m2 (p less than 0.05) and stroke volume index from 28 +/- 6 to 24 +/- 5 ml/m2 (p less than 0.01), with no change in systemic vascular resistance index (40 +/- 10 mm Hg.min.m2).(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac norepinephrine kinetics in hypertrophic cardiomyopathy.

We examined the uptake and release of norepinephrine in the cardiac circulation and other regional vascular beds in 11 patients with hypertrophic cardiomyopathy (HCM) and in 10 control subjects during simultaneous infusion of tracer-labeled norepinephrine and isoproterenol. Cardiac neuronal uptake of norepinephrine was assessed by comparing regional removal of tracer-labeled norepinephrine with that of tracer-labeled isoproterenol (which is not a substrate for neuronal uptake) and by the relation between production of dihydroxyphenylglycol (DHPG), an exclusively intraneuronal metabolite of norepinephrine, and regional spillover of norepinephrine. Cardiac extraction of norepinephrine averaged 59 +/- 17% in the patients with HCM, significantly less than in the control subjects (79 +/- 13%, p less than 0.05), whereas cardiac extraction of isoproterenol was similar in the two groups (13 +/- 23% versus 13 +/- 14%), indicating that neuronal uptake of norepinephrine was decreased in the patients with HCM. The cardiac arteriovenous difference in norepinephrine was significantly larger in the patients with HCM than in the control subjects (73 +/- 77 versus 13 +/- 50 pg/ml, p less than 0.05), as was the product of the arteriovenous difference in norepinephrine and coronary blood flow (7.3 +/- 7.3 versus 0.8 +/- 3.0 ng/min, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Implications of plasma levels of catechols in the evaluation of sympathoadrenomedullary function.

This report summarizes new techniques for examining aspects of sympathoadrenomedullary function. Tracer pharmacokinetic methods are more accurate than measurements of antecubital venous norepinephrine (NE) in assessing sympathoneural responsiveness. During mental challenge (playing a video game), patients with essential hypertension had significantly larger increments of NE spillover into arterial blood than did normotensive control subjects, whereas responses of antecubital venous and even arterial NE did not differ significantly between the groups. The rate of neuronal reuptake of endogenous NE can be measured in vivo using plasma levels of NE and of the intraneuronal NE metabolite, dihydroxyphenylglycol (DHPG). Regional production of dihydroxyphenylalanine (DOPA) may reflect catecholamine biosynthesis, and DOPA may be an indirectly acting natriuretic neurohormone. Positron emission tomography after injection of positron-emitting fluorodopamine may allow in vivo, noninvasive assessments of regional sympathetic function.

Plasma dihydroxyphenylalanine and total body and regional noradrenergic activity in humans.

Dihydroxyphenylalanine (DOPA) is the immediate product of the rate-limiting step in catecholamine biosynthesis, hydroxylation of tyrosine. This study examined whether plasma concentrations of DOPA are related to tyrosine hydroxylase activity. Plasma concentrations of DOPA, norepinephrine, and the norepinephrine metabolites 3,4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured in arterial blood and blood draining the heart, brain, and forearm of 21 patients undergoing cardiac catheterization. Rates of entry of norepinephrine into arterial plasma and plasma draining the heart were estimated using infusions of radioactive norepinephrine. Arterial plasma DOPA correlated positively with arterial plasma DHPG (r = 0.63), MHPG (r = 0.47), norepinephrine (r = 0.67), and the rate of entry of norepinephrine into arterial plasma (r = 0.62). There were significant arteriovenous increments in plasma DOPA: 28% across the heart, 18% across the brain, and 32% across the forearm. Arteriovenous increments in plasma DOPA across the brain correlated positively with increments in plasma DHPG (r = 0.83), but not with increments in norepinephrine or MHPG. In the arm, where MHPG was the major metabolite, arteriovenous increments in DOPA correlated positively with increments in MHPG (r = 0.52) and with the combined increments in MHPG, DHPG, and norepinephrine (r = 0.60). In the heart, where DHPG was the major metabolite, arteriovenous increments in DOPA correlated positively with increments in DHPG (r = 0.72) and the combined increments in DHPG, MHPG, and norepinephrine (r = 0.62). The rate at which norepinephrine entered the great cardiac venous plasma from tissues of the heart correlated positively with the rate at which DOPA overflowed from the heart into the systemic circulation (r = 0.56). The relationships between plasma DOPA and norepinephrine metabolism and the rates of norepinephrine entry into plasma support the view that plasma DOPA reflects tyrosine hydroxylase activity.

Angina due to coronary microvascular disease in hypertensive patients without left ventricular hypertrophy.

When angina occurs in patients with hypertension, it is usually attributed to coronary artery disease or left ventricular hypertrophy. To determine the contribution of coronary microvascular abnormalities to angina in patients with hypertension, we evaluated hypertensive patients without coronary artery disease or left ventricular hypertrophy by measuring the coronary responses to rapid atrial pacing before and after administration of ergonovine. We compared 12 hypertensive patients who had pacing-induced angina with 13 normotensive subjects without such angina. The two groups had similar coronary flow (in the great cardiac vein) at rest; however, pacing increased coronary flow less in hypertensive patients with angina than in normotensive subjects (48 vs. 83 percent; P = 0.05). In the hypertensive patients with angina, pacing after ergonovine increased coronary flow by only 32 percent (as compared with 48 percent before ergonovine; P less than 0.05) and decreased coronary resistance by 15 percent (as compared with 28 percent before ergonovine; P less than 0.05), indicating the presence of ergonovine-induced vasoconstriction. In normotensive subjects, in contrast, cardiac pacing after ergonovine increased coronary flow by 112 percent (P less than 0.001), and its effect on coronary resistance was not different from that of pacing before ergonovine. The hypertensive patients with angina had a significant increase in myocardial oxygen extraction during pacing after ergonovine and less of an increase in myocardial lactate consumption - a response consistent with the presence of myocardial ischemia. Thus, angina in hypertensive patients without epicardial coronary disease may be caused by myocardial ischemia, which appears to be due to an abnormally elevated resistance of the coronary microvasculature.

Relation of peak creatine kinase levels during acute myocardial infarction to presence or absence of previous manifestations of myocardial ischemia (angina pectoris or healed myocardial infarction).

The hypothesis that acute myocardial infarction (MI) is more extensive in patients without previous angina or healed MI was evaluated in 177 patients with documented recent acute MI. Ninety-nine patients (56%) had no previous angina or healed MI (negative history group), and the remaining 78 patients (44%) had a previous history of angina or healed MI (positive history group). The mean peak creatine kinase (CK) level in the negative history group was 784 compared with 419 IU in the positive history group (p less than 0.0001). The mean peak CK-MB level in the negative history group was 128 compared with 76 IU in the positive history group (p less than 0.001). The mean peak CK-MB level was higher in the negative history group after controlling for age, streptokinase administration, previous coronary artery bypass grafting or treatment with beta-blocking agents. Despite the high frequency of healed MI in the positive history group (73%), the rates of in-hospital complications were similar for the 2 groups. Patients with acute MI without previous angina or healed MI have substantially higher peak CK and CK-MB levels; this implies a larger MI than in patients with previous angina or healed MI.

In vivo measurement of neuronal uptake of norepinephrine in the human heart.

Neuronal uptake (Uptake-1) of the sympathetic neurotransmitter norepinephrine from the circulation in the human heart was assessed in vivo with three techniques. 1) Cardiac removal of intravenously infused tracer-labeled norepinephrine was measured before and after Uptake-1 blockade with desipramine; 2) the difference between the fractional extraction of radioactive norepinephrine and of radioactive isoproterenol, which is not a substrate for neuronal uptake, was used to estimate the removal of norepinephrine by Uptake-1 in the heart compared with other vascular beds (arm, leg, brain, and lungs); and 3) regional arteriovenous differences in radioactive and endogenous dihydroxyphenylglycol (DHPG), an exclusively intraneuronal metabolite of norepinephrine, were compared in these beds. In untreated patients, cardiac removal of radioactive norepinephrine averaged 79%, whereas in desipramine-treated patients, cardiac removal of radioactive norepinephrine averaged 19%, a value similar to that of isoproterenol in untreated patients (14%), confirming that in the heart the non-neuronal removals of isoproterenol and norepinephrine were similar. In the heart, 69% of delivered norepinephrine was estimated to be removed by Uptake-1, a much higher percentage than that in the arm (14%), leg (7%), brain (10%), and lungs (4%). The cardiac arteriovenous increment in endogenous DHPG (137%) far exceeded that of the other beds (49%, 26%, 39%, and -19%, respectively), and radioactive DHPG in the great cardiac vein exceeded arterial levels by 113%, whereas in the other beds, arterial radioactive DHPG exceeded venous levels. The results indicate that the human heart is exceptionally dependent on neuronal uptake for in vivo removal of circulating norepinephrine.

Differences in coronary flow and myocardial metabolism at rest and during pacing between patients with obstructive and patients with nonobstructive hypertrophic cardiomyopathy.

Fifty patients with hypertrophic cardiomyopathy underwent invasive study of coronary and myocardial hemodynamics in the basal state and during the stress of pacing. The 23 patients with basal obstruction (average left ventricular outflow gradient, 77 +/- 33 mm Hg; left ventricular systolic pressure, 196 +/- 33 mm Hg, mean +/- 1 SD) had significantly lower coronary resistance (0.85 +/- 0.18 versus 1.32 +/- 0.44 mm Hg X min/ml, p less than 0.001) and higher basal coronary flow (106 +/- 20 versus 80 +/- 25 ml/min, p less than 0.001) in the anterior left ventricle, associated with higher regional myocardial oxygen consumption (12.4 +/- 3.6 versus 8.9 +/- 3.3 ml oxygen/min, p less than 0.001) compared with the 27 patients without obstruction (mean left ventricular systolic pressure 134 +/- 18 mm Hg, p less than 0.001). Myocardial oxygen consumption and coronary blood flow were also significantly higher at paced heart rates of 100 and 130 beats/min (the anginal threshold for 41 of the 50 patients) in patients with obstruction compared with those without. In patients with obstruction, transmural coronary flow reserve was exhausted at a heart rate of 130 beats/min; higher heart rates resulted in more severe metabolic evidence of ischemia with all patients experiencing chest pain, associated with an actual increase in coronary resistance. Patients without obstruction also demonstrated evidence of ischemia at heart rates of 130 and 150 beats/min, with 25 of 27 patients experiencing chest pain. In this group, myocardial ischemia occurred at significantly lower coronary flow, higher coronary resistance and lower myocardial oxygen consumption, suggesting more severely impaired flow delivery in this group compared with those with obstruction. Abnormalities in myocardial oxygen extraction and marked elevation in filling pressures during stress were noted in both groups. Thus, obstruction to left ventricular outflow is associated with high left ventricular systolic pressure and oxygen consumption and therefore has important pathogenetic importance to the precipitation of ischemia in patients with hypertrophic cardiomyopathy. Patients without obstruction may have greater impairment in coronary flow delivery during stress.

Use of the initial electrocardiogram to predict in-hospital complications of acute myocardial infarction.

We evaluated the initial electrocardiogram as a predictor of complications in 469 patients with suspected acute myocardial infarction. An electrocardiogram was classified as positive if it showed one or more of the following: evidence of infarction, ischemia, or strain; left ventricular hypertrophy; left bundle-branch block; or paced rhythm. Forty-two (14 per cent) of 302 patients with positive electrocardiograms had at least one life-threatening complication (ventricular fibrillation, sustained ventricular tachycardia, or heart block), as compared with 1 (0.6 per cent) of 167 patients with a negative electrocardiogram. Life-threatening complications were therefore 23 times more likely if the initial electrocardiogram was positive (P less than 0.001). Other complications were 3 to 10 times more likely (P less than 0.01), interventions were 4 to 10 times more likely (P less than 0.05), and death was 17 times more likely (P less than 0.001) in patients with a positive electrocardiogram. We conclude that patients with a negative initial electrocardiogram have a low likelihood of complications and could be admitted to an intermediate care unit instead of a coronary care unit. This would reduce admissions to the coronary care unit by 36 per cent and thereby save considerable hospital costs without compromising patient care.