Julio A. Panza

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.

Acute vascular effects of estrogen in postmenopausal women.

BackgroundAlthough hormone replacement therapy has been associated with reduction of cardiovascular events in postmenopausal women, the mechanisms that mediate this apparent benefit are unclear. Because improvement in vaso-motor function may represent one of the beneficial effects of estrogen administration, we investigated the acute effects of physiological levels of estrogen on the vascular responses of estrogen-deficient postmenopausal women. Methods and ResultsThe study included 40 postmeno-pausal women 60±8 years old (mean±SD), 20 of whom had one or more conditions associated with vascular dysfunction (hypertension, hypercholesterolemia, diabetes, or coronary artery disease). The forearm vascular responses to the endo-thelium-dependent vasodilator acetylcholine were studied before and during infusion of 17β-estradiol into the ipsilateral brachial artery. In 31 subjects, the effect of estradiol on the responses to the endothelium-independent vasodilator sodium nitroprusside was also studied. Women with risk factors for vascular dysfunction had significantly reduced vasodilator responses to acetylcholine (P=.01) and to sodium nitroprusside (P<.001) compared with healthy subjects. Intra-arterial infusion of 17β-estradiol increased the forearm venous estradiol concentration from 16±10 to 318±188 pg/mL, levels typical of reproductive-age women at midcycle, but caused no vasodilation. However, estradiol potentiated the forearm vasodilation induced by acetylcholine by 18±30% (P<.001) in women with risk factors for vascular dysfunction and by 14±23% (P=.03) in healthy women. Estradiol also potentiated the forearm vasodilation induced by sodium nitroprusside in women with risk factors for vascular dysfunction by 14±21% (P<.001) but not in healthy women. ConclusionsPhysiological levels of 17,3-estradiol selectively potentiate endothelium-dependent vasodilation in healthy postmenopausal women and potentiate both endothelium-dependent and endothelium-independent vasodilation in post-menopausal women with risk factors for atherosclerosis and evidence of impaired vascular function. These vascular effects may be partly responsible for the long-term benefit of estrogen therapy on cardiovascular events in postmenopausal women.

Myocardial Viability and Survival in Ischemic Left Ventricular Dysfunction

BACKGROUND The assessment of myocardial viability has been used to identify patients with coronary artery disease and left ventricular dysfunction in whom coronary-artery bypass grafting (CABG) will provide a survival benefit. However, the efficacy of this approach is uncertain. METHODS In a substudy of patients with coronary artery disease and left ventricular dysfunction who were enrolled in a randomized trial of medical therapy with or without CABG, we used single-photon-emission computed tomography (SPECT), dobutamine echocardiography, or both to assess myocardial viability on the basis of prespecified thresholds. RESULTS Among the 1212 patients enrolled in the randomized trial, 601 underwent assessment of myocardial viability. Of these patients, we randomly assigned 298 to receive medical therapy plus CABG and 303 to receive medical therapy alone. A total of 178 of 487 patients with viable myocardium (37%) and 58 of 114 patients without viable myocardium (51%) died (hazard ratio for death among patients with viable myocardium, 0.64; 95% confidence interval [CI], 0.48 to 0.86; P=0.003). However, after adjustment for other baseline variables, this association with mortality was not significant (P=0.21). There was no significant interaction between viability status and treatment assignment with respect to mortality (P=0.53). CONCLUSIONS The presence of viable myocardium was associated with a greater likelihood of survival in patients with coronary artery disease and left ventricular dysfunction, but this relationship was not significant after adjustment for other baseline variables. The assessment of myocardial viability did not identify patients with a differential survival benefit from CABG, as compared with medical therapy alone. (Funded by the National Heart, Lung, and Blood Institute; STICH ClinicalTrials.gov number, NCT00023595.).

Circadian Variation in Vascular Tone and Its Relation to α-Sympathetic Vasoconstrictor Activity

Abstract Background. The frequency of several cardiovascular events, such as myocardial infarction, sudden death, and stroke, is increased during the early morning hours. There is also a similar circadian pattern in several physiologic variables, including blood pressure, suggesting that certain dynamic processes may contribute to the circadian distribution and onset of acute events. Methods. To determine whether there are circadian variations in vascular tone and to investigate their underlying mechanisms, we measured blood flow and vascular resistance in the forearm and their responses to phentolamine (an α-adrenergic—antagonist drug) and sodium nitroprusside (a direct vasodilator) in 12 normal subjects (7 men and 5 women; mean age [±SD], 44±9 years) at three different times of day (7 a.m., 2 p.m., and 9 p.m.). The drugs were infused into the brachial artery, and the responses were measured by strain-gauge plethysmography. Results. The basal forearm vascular resistance was significantly higher, and the ...

Impaired Endothelium-Dependent Vasodilation in Patients With Essential Hypertension Evidence That Nitric Oxide Abnormality Is Not Localized to a Single Signal Transduction Pathway

BACKGROUND Patients with essential hypertension have abnormal endothelium-dependent vascular relaxation, largely related to reduced bioactivity of nitric oxide (NO). The purpose of the present investigation was to determine whether this defect is due to a deficit at the specific intracellular signal-transduction pathway level or is a consequence of a more generalized endothelial abnormality. METHODS AND RESULTS The responses of the forearm vasculature to acetylcholine and bradykinin (endothelium-dependent agents that act through different signal transduction pathways) and to sodium nitroprusside (a direct dilator of vascular smooth muscle) were studied in 10 hypertensive patients (5 men, 5 women; aged 48 +/- 9 years old [mean +/- SD]) and 12 control subjects (6 men, 6 women; aged 48 +/- 7 years old). To determine the contribution of NO to bradykinin-induced vasodilation, the vascular responses to bradykinin were also measured after administration of NG-monomethyl-L-arginine, an arginine analogue that inhibits the synthesis of NO. Drugs were infused into the brachial artery, and forearm blood flow was measured by strain-gauge plethysmography. The response to acetylcholine was significantly blunted in hypertensive patients (maximal blood flow, 7.5 +/- 2 versus 16.6 +/- 8 mL.min-1.100 mL-1 in control subjects [mean +/- SD]; P < .005). Similarly, the vasodilator effect of bradykinin was significantly reduced in hypertensive patients compared with control subjects (maximal blood flow, 8.7 +/- 2 versus 15.8 +/- 6 mL.min-1.100 mL-1 in control subjects; P < .005). A significant correlation was found between the maximal blood flow with acetylcholine and that with bradykinin (r = .89). No significant differences were found between the two groups for vascular response to sodium nitroprusside. NG-monomethyl-L-arginine significantly blunted the response to bradykinin in control subjects (maximal blood flow decreased from 15.8 +/- 6 to 10.1 +/- 2 mL.min-1.100 mL-1, P < .003). In contrast, inhibition of NO synthesis did not modify the response to bradykinin in hypertensive patients (maximal blood flow, 8.7 +/- 2 and 8.5 +/- 3 before and during infusion of NG-monomethyl-L-arginine, respectively; P = NS). As a consequence, the response to bradykinin after inhibition of NO synthesis was not significantly different between the two groups. CONCLUSIONS Patients with essential hypertension have impaired endothelium-dependent vasodilator responses to both acetylcholine and bradykinin. These findings indicate that the endothelial dysfunction in this condition is not related to a specific defect of a single intracellular signal-transduction pathway and suggest a more generalized abnormality of endothelial vasodilator function.

The role of nitric oxide in endothelium-dependent vasodilation of hypercholesterolemic patients.

BackgroundPatients with hypercholesterolemia have a reduced response to endothelium-dependent vasodilators. However, the regulatory function of the endothelium on vascular tone is mediated through the release of several vasoactive substances; therefore, a reduced response to endothelium-dependent agents does not identify which of the factors released by the endothelium is involved in this abnormality. Methods and Result. To investigate the role of nitric oxide in the endothelium-dependent vasodilation in hypercholesterolemia, we studied the effect of NG-monomethylRL-arginine (L-NMMA), an inhibitor of endothelial nitric oxide synthesis, on basal vascular tone and on the responses to acetylcholine, an endothelium-dependent vasodilator, and to sodium nitroprusside, a direct smooth muscle dilator. The study included 33 hypercholesterolemic patients (17 men; 51±8 years; plasma cholesterol, .240 mg/dL) and 23 normal controls (12 men; 48±7 years; plasma cholesterol, <210 mgldL). Drugs were infused into the brachial artery, and the response of the forearm vasculature was measured by strain-gauge plethysmography. Basal blood flow and vascular resistance were similar in hypercholesterolemic patients and normal controls (3.1±1 versus 2.6±0.8 mL/min per 100 mL and 32.1±13 versus 36.1±12 mm Hg/mL-1 min−1. 100 mL-1, respectively). The reduction in basal blood flow and increase in vascular resistance produced by L-NMMA were not significantly different between the two groups. L-NMMA markedly blunted the response to acetylcholine in normals (maximum flow decreased from 16.4±8 to 7.0±3; P<.005); however, the arginine analogue did not significantly modify the response to acetylcholine in the hypercholesterolemic patients (maximum flow, 11.1±8 versus 10.0±8). L-NMMA did not modify the vasodilator response to sodium nitroprusside in either controls or patients. ConclusionsThese findings indicate that hypercholesterolemic patients have a defect in the bioactivity of nitric oxide that may explain their impaired endothelium-dependent vascular relaxation.

Long-term results of dual-chamber (DDD) pacing in obstructive hypertrophic cardiomyopathy. Evidence for progressive symptomatic and hemodynamic improvement and reduction of left ventricular hypertrophy.

BackgroundWe previously reported that 6 to 12 weeks of dual-chamber (DDD) pacing results in clinical and hemodynamic improvement in obstructive hypertrophic cardiomyopathy (HCM). This study examines the long-term results of DDD pacing in obstructive HCM. Methods and ResultsDDD devices were implanted in 84 patients (mean age, 49 ± 16 years) with obstructive HCM and severe drug-refractory symptoms. At a mean follow-up of 2.3 ± 0.8 years (maximum, 3.5 years), the New York Heart Association (NYHA) functional class had improved significantly (1.6 ± 0.6 versus 3.2 ± 0.5, P < .00001). Symptoms were eliminated in 28 patients (33%), improved in 47 patients (56%), but remained unchanged in 7 patients (8%). Two patients died suddenly (97% cumulative 3-year survival rate). In 74 patients with significant left ventricular outflow tract (LVOT) obstruction at rest, the LVOT gradients were significantly reduced at follow-up (27 ± 31 versus 96 ± 41 mm Hg, P < .00001). Symptoms and provokable LVOT gradients were also reduced in all 10 patients without significant resting but with provokable LVOT obstruction. Persistence of the LVOT obstruction and symptoms was attributed to inability to pre-excite the interventricular septum (n = 8) and onset of atrial fibrillation (n = 7). Fifty patients had two cardiac catheterization evaluations, 3 ± 1 and 16 ± 4 months after implantation of a pacemaker. In this subgroup, the NYHA functional class improved from 3.2 ± 0.5 at baseline to 1.8 ± 0.7 at the initial evaluation (P < .00001), but with a further significant improvement at the second evaluation: 1.4 ± 0.6, P < .001. This symptomatic improvement was associated with progressive reduction of LVOT gradient at the two evaluations: baseline, 100 ± 47 mm Hg; first evaluation, 41 ± 36 mm Hg (P < .0001); and second evaluation, 29 ± 34 mm Hg (P < .01). Despite the presence of left bundle branch block, DDD pacing reduced LVOT obstruction significantly in 15 patients (LVOT gradient, baseline 89 ± 36 mm Hg versus 18 ± 26 mm Hg at follow-up, P < .0001). There was a weak but significant correlation between the reduction in LVOT gradients accomplished by AV pacing before implantation of DDD device and the eventual reduction in LVOT gradients recorded at the follow-up evaluation (r = .38, P = .0017). Echocardiography demonstrated significant thinning of the anterior septum and distal anterior LV wall in the absence of deterioration of LV systolic function. Conclusions(1) Although most of the improvement of symptoms and hemodynamic indexes occurs during the first few months of DDD pacing, further changes are often observed a year later; (2) DDD pacing is associated with an excellent prognosis in a subgroup of severely disabled patients, many of whom present with syncope or presyncope; (3) baseline pacing studies are not essential to identify patients who may benefit from pacing; (4) preexisting left bundle branch block is compatible with severe LVOT obstruction, and DDD pacing is also beneficial in this subgroup; (5) DDD pacing reduces both resting and provokable LVOT obstruction; (6) additional therapy, for example, radiofrequency ablation of the AV node, may be necessary in some patients either to preexcite the interventricular septum or to control atrial fibrillation; and (7) although LV hypertrophy has been considered a primary feature of HCM, pacing appears to reverse LV wall thickness in a significant subset of adult HCM patients.

Contribution of Nitric Oxide to Metabolic Coronary Vasodilation in the Human Heart

BACKGROUND The vascular endothelium contributes to smooth muscle relaxation by tonic release of nitric oxide. To investigate the contribution of nitric oxide to human coronary epicardial and microvascular dilation during conditions of increasing myocardial oxygen requirements, we studied the effect of inhibiting nitric oxide synthesis with NG-monomethyl-L-arginine (L-NMMA) on the coronary vasodilation during cardiac pacing in patients with angiographically normal coronary arteries with and without multiple risk factors for coronary atherosclerosis. METHODS AND RESULTS In 26 patients with angiographically normal or near-normal epicardial coronary arteries, metabolic vasodilation was assessed as a change in coronary vascular resistance and diameter during cardiac pacing (mean heart rate, 141 beats per minute). Endothelium-dependent vasodilation was estimated with intracoronary acetylcholine and endothelium-independent dilation with intracoronary sodium nitroprusside and adenosine. These measurements were repeated after 64 mumol/min intracoronary L-NMMA. At rest, L-NMMA produced a 16 +/- 25% (mean +/- SD) increase in coronary vascular resistance (P < .05) and an 11% reduction in distal epicardial coronary artery diameter (P < .01), indicating tonic basal release of nitric oxide from human coronary epicardial vessels and microvessels. Significant inhibition of pacing-induced metabolic coronary vascular dilation occurred with L-NMMA, coronary vascular resistance was 38 +/- 56% higher (P < .03), and epicardial coronary dilation during control pacing (9 +/- 13%) was converted to constriction after L-NMMA and pacing (-6 +/- 9%, P < .04). L-NMMA specifically inhibited endothelium-dependent vasodilation with acetylcholine (coronary vascular resistance was 72% higher [P < .01]) but did not alter endothelium-independent dilation with sodium nitroprusside and adenosine. Nine patients had no major risk factors for atherosclerosis, defined as serum cholesterol > 240 mg/dL, hypertension, or diabetes. The remaining 17 patients with one or more of these risk factors had depressed microvascular vasodilation during cardiac pacing (coronary vascular resistance decreased by 13% versus 36% in those without risk factors, P < .05). The inhibitory effect of L-NMMA on pacing-induced coronary epicardial and microvascular vasodilation was observed only in patients without risk factors, whereas those with risk factors had an insignificant change, indicating that nitric oxide contributes significantly to pacing-induced coronary vasodilation in patients free of risk factors and without endothelial dysfunction. Patients with risk factors also had reduced vasodilation with acetylcholine (40 +/- 28% versus 68 +/- 8% decrease in coronary vascular resistance, P < .01), but the responses to sodium nitroprusside were similar in both groups. CONCLUSIONS During metabolic stimulation of the human heart, nitric oxide release contributes significantly to microvascular vasodilation and is almost entirely responsible for the epicardial vasodilation. This contribution of nitric oxide is reduced in patients exposed to risk factors for coronary atherosclerosis and leads to a net reduction in vasodilation during stress. An important implication of these findings is that reduced nitric oxide bioavailability during stress in patients with atherosclerosis or risk factors for atherosclerosis may contribute to myocardial ischemia by limiting epicardial and microvascular coronary vasodilation.

Contribution of endothelium-derived nitric oxide to exercise-induced vasodilation.

BackgroundEndothelium-derived nitric oxide is an important modulator of resting vascular tone in animals and humans. However, the contribution of nitric oxide to exercise-induced vasodilation is unknown. Methods and ResultsThe effect of NG-monomethyl-L-arginine (L- NMMA), an inhibitor of nitric oxide synthesis, on exercise-induced vasodilation was studied in 18 healthy subjects (mean ± SD, 40 ± 10 years; 10 women). Acetylcholine was used to test the efficacy of L-NMMA in inhibiting stimulation of nitric oxide synthesis and sodium nitroprusside to test the specificity of L-NMMA in inhibiting endothelium-dependent vasodilation. Intermittent handgrip exercise and infusions of acetylcholine and sodium nitroprusside were performed during intra-arterial infusion of 5% dextrose (control) and L-NMMA (4 to 16 μmol/min). Forearm blood flow was determined by strain-gauge plethysmography. Forearm oxygen extraction was measured from arterial and venous oxygen saturations. In a separate study, 10 subjects performed exercise during infusions of 5% dextrose, L-arginine (the substrate for nitric oxide production), and D-arginine (the stereoisomer that is not a substrate for nitric oxide production). L-NMMA reduced exercise blood flow by 7 ± 13% (P = .04), increased exercise resistance by 18 ± 20% (P = .02), and increased exercise oxygen extraction by 16 ± 17% (P < .001). The degree of inhibition of acetylcholine-induced vasodilation with L-NMMA correlated positively with the degree of reduction in exercise blood flow (r = .55, P = .02). The highest dose of L-NMMA (16 μmol/min) produced the greatest effect; exercise blood flow was reduced by 11 ± 14% (P = .03), and vascular resistance increased by 26 ± 23% (P = .005). L-NMMA did not affect the forearm vasodilation produced by sodium nitroprusside. Exercise blood flow, resistance, and oxygen extraction were not significantly modified by infusions of either L- or D-arginine. ConclusionsInhibition of nitric oxide synthesis reduces exercise-induced vasodilation in the human forearm, indicating that nitric oxide plays a role in exercise-induced vasodilation. Increased availability of nitric oxide substrate does not enhance exercise-induced vasodilation in healthy subjects. These findings have important implications for disease states in which endothelium-derived nitric oxide production is impaired.

Effect of increased availability of endothelium-derived nitric oxide precursor on endothelium-dependent vascular relaxation in normal subjects and in patients with essential hypertension.

Background. Patients with essential hypertension have a deficit in the endothelium‐derived nitric oxide system that results in impaired endothelium‐dependent vascular relaxation. The objective of this study was to determine whether this abnormality is caused by a deficiency of substrate for nitric oxide synthesis. Methods and Results. The vascular responses to acetylcholine (an endothelium‐dependent vasodilator infused at 7.5, 15, and 30 &mgr;g/min) and sodium nitroprusside (a direct smooth muscle dilator infused at 0.8, 1.6, and 3.2 &mgr;g/min) were studied during combined administration of dextrose 5% or l‐arginine (substrate for nitric oxide synthesis infused at 40 &mgr;mol/min) in 12 normal control subjects (seven men and five women; age, 49.3±7 years) and 14 hypertensive patients (nine men and five women; age, 48.4±7 years). In addition, the effect of d‐arginine (stereoisomer of arginine that is not a precursor of nitric oxide) on the vascular responses to acetylcholine was studied in eight normal control subjects and seven hypertensive patients. Drugs were infused into the brachial artery, and the response of the forearm vasculature was measured by strain gauge plethysmography. The vasodilator response to acetylcholine was significantly blunted in hypertensive patients compared with normal control subjects (maximum flow, 8.9±5 versus 15.7±6 mL · min‐1 · 100 mL‐1, respectively; p<0.007); however, no difference was observed in the response to sodium nitroprusside (11.4±6 and 11.7±mL · min‐1 · 100 mL‐1, respectively). l‐Arginine did not significantly change basal blood flow or vascular resistance in either group. In normal control subjects, the infusion of l‐arginine significantly augmented the vasodilator response to acetylcholine (maximum flow, 15.7±6 versus 21.4±8 mL · min‐1 · 100 mL‐1 before and after l‐arginine, respectively; p<0.001). In contrast, in hypertensive patients, the infusion of l‐arginine did not alter the response to acetylcholine (maximum flow, 8.9±5 and 8.4±4 mL · min‐1 · 100 mL‐1 before and after l‐arginine, respectively). The administration of l‐arginine did not modify the response to sodium nitroprusside in either group. Similarly, the infusion of d‐arginine did not alter the response to acetylcholine in either group. Conclusions. In normal humans, availability of substrate for production of nitric oxide is a rate‐limiting step for endothelium‐dependent vascular relaxation. In contrast, increased availability of nitric oxide precursor does not modify endothelium‐mediated vasodilation in hypertensive patients. These findings provide further evidence of a defect in the endothelium‐derived nitric oxide system in hypertension and indicate that this abnormality is not related to decreased availability of substrate for nitric oxide production. (Circulation 1993;87:1475‐1481)