HIV, highly active antiretroviral therapy and the heart: a cellular to epidemiological review.

The advent of potent highly active antiretroviral therapy (HAART) for persons infected with HIV-1 has led to a "new" chronic disease with complications including cardiovascular disease (CVD). CVD is a significant cause of morbidity and mortality in persons with HIV infection. In addition to traditional risk factors such as smoking, hypertension, insulin resistance and dyslipidaemia, infection with HIV is an independent risk factor for CVD. This review summarizes: (1) the vascular and nonvascular cardiac manifestations of HIV infection; (2) cardiometabolic effects of HAART; (3) atherosclerotic cardiovascular disease (ASCVD) risk assessment, prevention and treatment in persons with HIV-1 infection.

Tetrahydrobiopterin: a novel antihypertensive therapy.

Tetrahydrobiopterin (BH(4)) is a cofactor for the nitric oxide (NO) synthase enzymes, such that its insufficiency results in uncoupling of the enzyme, leading to release of superoxide rather than NO in disease states, including hypertension. We hypothesized that oral BH(4) will reduce arterial blood pressure (BP) and improve endothelial function in hypertensive subjects. Oral BH(4) was given to subjects with poorly controlled hypertension (BP >135/85 mm Hg) and weekly measurements of BP and endothelial function made. In Study 1, 5 or 10 mg kg(-1) day(-1) of BH(4) (n=8) was administered orally for 8 weeks, and in Study 2, 200 and 400 mg of BH(4) (n=16) was given in divided doses for 4 weeks. Study 1: significant reductions in systolic (P=0.005) and mean BP (P=0.01) were observed with both doses of BH(4). Systolic BP was 15+/-15 mm Hg (P=0.04) lower after 5 weeks and persisted for the 8-week study period. Study 2: subjects given 400 mg BH(4) had decreased systolic (P=0.03) and mean BP (P=0.04), with a peak decline of 16+/-19 mm Hg (P=0.04) at 3 weeks. BP returned to baseline 4 weeks after discontinuation. Significant improvement in endothelial function was observed in Study 1 subjects and those receiving 400 mg BH(4). There was no significant change in subjects given the 200 mg dose. This pilot investigation indicates that oral BH(4) at a daily dose of 400 mg or higher has a significant and sustained antihypertensive effect in subjects with poorly controlled hypertension, an effect that is associated with improved endothelial NO bioavailability.

Nitric oxide activity in the human coronary circulation. Impact of risk factors for coronary atherosclerosis.

The bioavailability of nitric oxide (NO) in the human coronary circulation at rest and after acetylcholine (ACH)-induced vasodilation was investigated in 32 patients with angiographically normal coronary arteries. The effects of intracoronary L-NG monomethyl arginine (L-NMMA) were investigated at rest and after ACH, sodium nitroprusside, and adenosine. L-NMMA (64 mumol/min) increased resting coronary vascular resistance by 22% (P < 0.001), reduced distal epicardial coronary artery diameter by 12.6% (P < 0.001), and inhibited ACH-induced coronary epicardial and microvascular vasodilation. These effects were reversed with intracoronary L-arginine. L-NMMA did not inhibit dilation in response to sodium nitroprusside and adenosine. 23 patients were exposed to one or more coronary risk factors. The vasoconstrictor effect of L-NMMA on the epicardial and microvessels was greater in patients free of risk factors: Coronary vascular resistance was 36% higher in patients without risks, compared to 17% higher in patients with risks (P < 0.05). Both epicardial and microvascular dilator effects of ACH were greater in patients without risk factors, and the inhibition of these effects by L-NMMA was also greater in patients without risk factors. Thus: (a) NO contributes importantly to resting epicardial and coronary microvascular tone, (b) coronary vascular dilation in response to ACH is predominantly due to increased production of NO, and (c) despite the absence of angiographic evidence of atherosclerosis, exposure to coronary risk factors is associated with reduced resting and stimulated bioavailability of NO from the human coronary circulation.

Coronary vasodilation and improvement in endothelial dysfunction with endothelin ET(A) receptor blockade.

The endothelium-derived peptide endothelin-1 (ET-1) causes vasoconstriction predominantly via smooth muscle ET(A) receptor activation. We hypothesized that ET(A) receptor inhibition would improve human coronary vascular function. We studied unobstructed coronary arteries of 44 patients with atherosclerosis or its risk factors. Epicardial diameter (D) and Doppler flow velocity were measured, and coronary vascular resistance (CVR) was calculated during intracoronary infusions of acetylcholine (ACH) and sodium nitroprusside (SNP), and during cold pressor testing, before and after a 60-minute intracoronary infusion of the ET(A) receptor antagonist BQ-123. BQ-123 dilated the coronary circulation; D increased by 5.6+/-1.0% (P<0.0001), and CVR fell by 12+/-3% (P<0.01). The D response to ACH, corrected for the SNP response, improved in segments that constricted with ACH at baseline (P=0.03), whereas segments that initially dilated with ACH did not change with BQ-123 (P=NS). Improvement in D and CVR responses to ACH with BQ-123 inversely correlated with baseline ACH responses (r=-0.44 [P=0.006] and r=-0.78 [P=0.001], respectively), indicating greater improvement in those with endothelial dysfunction. Similarly, cold pressor testing-mediated epicardial vasoconstriction (-2.0+/-1.1%) was reversed after BQ-123 (+1.0+/-0.7%), especially in dysfunctional segments (from -5.6+/-0.9% to +2.2+/-0.9%, P<0.001). There was no correlation between any risk factor and the response to BQ-123. An arteriovenous difference in ET-1 levels developed after BQ-123, which was consistent with enhanced cardiac clearance of ET-1, probably via ET(B) receptors. Thus, ET-1 acting via the ET(A) receptor contributes to basal human coronary vasoconstrictor tone and endothelial dysfunction. This suggests that ET(A) receptor antagonism may have therapeutic potential in the treatment of endothelial dysfunction and atherosclerosis.

Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis.

Fractalkine, a chemokine expressed by inflamed endothelium, induces leukocyte adhesion and migration via the receptor CX3CR1, and the CX3CR1 polymorphism V249I affects receptor expression and function. Here we show that this polymorphism is an independent risk factor for atherosclerotic coronary artery disease (CAD). Genotyping of the CX3CR1-V249I polymorphism was performed in a cohort of 339 white individuals who underwent cardiac catheterization (n=197 with and n=142 without CAD, respectively). In 203 patients, intracoronary acetylcholine 15 microg/min) and sodium nitroprusside (20 microg/min) were administered to test endothelium-dependent and -independent coronary vascular function, respectively. Change in coronary vascular resistance (DeltaCVR) was measured as an index of microvascular dilation. An association was observed between presence of the CX3CR1 I249 allele and reduced prevalence of CAD, independent of established CAD risk factors (odds ratio=0.54 [95% confidence interval, 0.30 to 0.96], P=0.03). Angiographic severity of CAD was also lower in these subjects (P=0.01). Furthermore, endothelium-dependent vasodilation was greater in these individuals compared with individuals homozygous for the CX3CR1-V249 allele (DeltaCVR during acetylcholine = -46+/-3% versus -36+/-3%, respectively, P=0.02), whereas DeltaCVR with sodium nitroprusside was similar in both groups (-55+/-2% versus -53+/-2%, P=0.45). The association between CX3CR1 genotype and endothelial function was independent of established risk factors and presence of CAD by multivariate analysis (P=0.02). Thus, the CX3CR1 I249 allele is associated with decreased risk of CAD and improved endothelium-dependent vasodilation. This suggests that CX3CR1 may be involved in the pathogenesis of CAD.

Endothelial progenitor cells as putative targets for angiostatin.

Angiostatin, a product of the proteolytic cleavage of plasminogen, possesses potent antitumor and antiangiogenic properties in vivo. Studies with cultured endothelial cells suggest that under certain conditions, angiostatin inhibits the migration and proliferation of these cells or, alternatively, increases their rate of apoptosis. In general, the effects of angiostatin have been considerably less potent in vitro than in vivo. One potential explanation for this disparity is that the in vivo target of angiostatin is not the mature endothelial cell. Recently, evidence has accumulated to show that circulating endothelial progenitor cells (EPCs) contribute to neovascularization. In this study, we have isolated EPCs from human subjects and demonstrated that, in contrast to that of mature endothelial cells, the growth of EPCs is exquisitely sensitive to angiostatin. These results suggest that angiostatin and related compounds may exert their biological effects by inhibiting the contribution of EPCs to angiogenesis and not by altering the growth of mature endothelial cells.

Antibodies to human heat-shock protein 60 are associated with the presence and severity of coronary artery disease: evidence for an autoimmune component of atherogenesis.

BACKGROUND: Antibodies to mycobacterial heat-shock protein (HSP) 65 have been reported to be associated with carotid artery thickening. We examined whether antibodies to human HSP60 are associated with the risk of coronary artery disease (CAD). METHODS AND RESULTS: Blood samples from 391 patients (62% men, mean age 57 years) being evaluated for CAD by coronary angiography were tested for IgG antibodies to human HSP60 by ELISA. We found that 75% of the study subjects had anti-HSP60 antibodies. The prevalence of CAD was increased in seropositive compared with seronegative patients (68% versus 49%, P:=0.0009). Mean titers of HSP60 antibodies were higher in CAD patients than in non-CAD patients (P:=0.008). No association between HSP60 antibodies and infection or inflammation was found. Importantly, HSP60 antibodies were related to disease severity. The prevalence of HSP60 antibodies was 76%, 80%, and 85% in patients with 1-, 2-, and 3-vessel disease, compared with 64% in patients without CAD (P: for trend=0.003). A similar association between increasing antibody titers and number of diseased vessels was also found (P:=0.03). Significant associations between antibodies to HSP60 and CAD severity persisted after adjustment for traditional risk factors by age, race, sex, smoking, diabetes, hypercholesterolemia, hypertension, and C-reactive protein levels. Adjusted OR for number of vessels diseased was 1.86 (95% CI 1.13 to 3.04). CONCLUSIONS: This is the first study demonstrating a significant association between human HSP60 antibodies and both the presence and severity of CAD.

Insertion-deletion polymorphism of the ACE gene modulates reversibility of endothelial dysfunction with ACE inhibition.

BACKGROUND: The aim of this study was to examine whether angiotensin-converting enzyme (ACE) inhibition improves coronary endothelial dysfunction in patients with atherosclerosis and its risk factors and whether this was related to the ACE insertion-deletion (I/D) polymorphism. METHODS AND RESULTS: In 56 patients with atherosclerosis or its risk factors, we studied endothelium-dependent responses with acetylcholine and endothelium-independent function with sodium nitroprusside, before and after ACE inhibition with enalaprilat. Enalaprilat did not alter either resting coronary tone or vasodilation with sodium nitroprusside. However, it potentiated the coronary microvascular and epicardial responses with acetylcholine; coronary blood flow increased from 82+/-7 to 90+/-8 mL/min (P=0.05) after enalaprilat. Patients with depressed endothelial function (P<0.001) and those with ACE DD or ID genotypes (P=0.002) but not those homozygous for the I allele had the greatest improvement by multivariate analysis. Similarly, acetylcholine-mediated epicardial vasomotion improved in segments that initially constricted (endothelial dysfunction): from -10.1+/-1% to -1.4+/-2% (P<0.001) after enalaprilat. No augmentation was observed in segments that dilated (normal endothelial dysfunction) with acetylcholine. Patients with the D allele, hypercholesterolemia, and smokers (all P<0.05) had greater improvement. CONCLUSIONS: Acute ACE inhibition improves coronary epicardial and microvascular endothelium-dependent vasomotion in patients with atherosclerosis or its risk factors who have endothelial dysfunction and presence of the D allele.

Host response to cytomegalovirus infection as a determinant of susceptibility to coronary artery disease: sex-based differences in inflammation and type of immune response.

BACKGROUND: Positive and negative associations between cytomegalovirus (CMV) infection and coronary artery disease (CAD) have been reported. We postulated that the susceptibility to CMV-induced CAD might relate to patterns of inflammatory and immune responses to CMV infection and that sex might have an effect on these responses. METHODS AND RESULTS: In 151 men and 87 women being evaluated for CAD, blood samples were tested for humoral (Ab+) and cellular (Tc+) responses to CMV and for C-reactive protein (CRP). In men, an elevated CRP level was a significant determinant of CAD even after adjustment for CAD risk factors (OR, 3.1; 95% CI, 1.21 to 7. 97). CMV seropositivity was associated with elevated CRP levels on multivariate analysis (P:=0.006). In contrast, in women, CMV seropositivity was independently predictive of CAD (OR, 41.8; 95% CI, 4.12 to 423.74). CRP level in women with CAD was >25% higher than those without CAD, but the difference did not reach statistical significance. Importantly, compared with CMV Ab-/Tc- women, CAD prevalence was higher in Ab+/Tc- and Ab+/Tc+ (13% versus 68% and 64%, both P:<0.005) but not in Ab-/Tc+ women (25%). There were no differences in age, smoking, diabetes, hypertension, and hypercholesterolemia among women with different types of immune responses to CMV infection. CONCLUSIONS: The mechanisms by which CMV predisposes to CAD in men and women may be different. In men, CMV appears to contribute to CAD risk, insofar as it predisposes to inflammation. In women, other mechanisms, possibly related to the type of immune response generated by the host, appear to be responsible for the proatherogenic effects of CMV.

Acute and chronic angiotensin-1 receptor antagonism reverses endothelial dysfunction in atherosclerosis.

BACKGROUND: The renin-angiotensin system may contribute to atherogenesis through the promotion of endothelial dysfunction. The present study was performed to determine whether angiotensin-1 (AT(1)) receptor inhibition improves endothelial dysfunction. METHODS AND RESULTS: In the femoral circulation of 19 patients with atherosclerosis and of 9 control subjects, we studied microvascular responses to reactive hyperemia, angiotensin II, acetylcholine, and sodium nitroprusside before and after the administration of intra-arterial losartan (10 mg). Femoral artery flow velocity was measured with a Doppler flow wire, and the femoral vascular resistance index (FVRI) was calculated as mean arterial pressure divided by flow velocity. Losartan induced a minor (5.9+/-2%, P=0. 02) reduction in FVRI and inhibited angiotensin II-mediated vasoconstriction in both patient groups (P<0.01). After the administration of losartan, acetylcholine-mediated vasodilation was augmented in patients (44+/-5% to 58+/-4% reduction in FVRI with infusion at a rate of 150 microgram/min, P<0.001) but not control subjects. Vasodilation during reactive hyperemia was also greater after AT(1) receptor inhibition (P=0.03) in patients, but the response to sodium nitroprusside remained unchanged. In a separate group of 31 patients with atherosclerosis, we investigated the effect of 8 weeks of oral losartan therapy on brachial artery flow-mediated vasodilation with the use of high-resolution ultrasound. Oral losartan therapy improved flow-mediated brachial artery dilation (1.4+/-0.9% to 3.2+/-0.8%, P=0.03) but had no effect on the nitroglycerin response. Serum nitrogen oxide levels increased from 21.6+/-1.7 to 26.7+/-2.4 micromol/L (P=0.008). CONCLUSIONS: The results of the present study indicate that inhibition of the AT(1) receptor in patients with atherosclerosis reverses endothelial dysfunction by improving NO availability and therefore may have long-term therapeutic benefits.

Prostacyclin and pathogenesis of hemodynamic abnormalities of diabetic ketoacidosis in rats.

The pathogenesis of the hemodynamic abnormalities of diabetic ketoacidosis (DKA) is not well understood. Previous studies suggest that prostacyclin (PGI2) production by adipose tissue is increased in DKA. We investigated the role of PGI2 in the pathogenesis of the reduced vascular resistance in DKA. Rats with streptozocin-induced DKA were anesthetized with pentobarbital sodium, and flow was measured with an electromagnetic probe on the infradiaphragmatic aorta. The plasma level of 6-keto-PGF1 alpha (stable derivative of PGI2) was higher (mean +/- SE 0.91 +/- 0.05 ng/ml) and vascular resistance lower (4.9 +/- 0.2 mmHg.ml-1.min-1.100 g-1 [resistance units, RU]) in 67 rats with DKA than in 21 normal rats (0.34 +/- 0.03 ng/ml, P less than .01, and 9.0 +/- 0.7 RU, P less than .01, respectively). Inhibition of cyclooxygenase activity with either indomethacin or meclofenamic acid reduced the plasma 6-keto-PGF1 alpha level but failed to raise vascular resistance. Infusions of PGI2 in rats with DKA demonstrated that the vasculature was responsive to PGI2. Inhibition of cyclooxygenase activity not only reduced PGI2 production but also suppressed renin release. When the effects of the renin-angiotensin system were excluded by bilateral nephrectomy, indomethacin caused a significant increase (P less than .05) in vascular resistance. Thus, the failure of cyclooxygenase inhibitors to raise vascular resistance in DKA was a result of concurrent suppression of vasodilator (PGI2) and vasoconstrictor (renin-angiotensin system) mechanisms that are activated in DKA. Insulin administration increased vascular resistance (P less than .01) and decreased the level of plasma 6-keto-PGF1 alpha (P less than .01). Combined administration of PGI2 and insulin did not alter vascular resistance, suggesting that the increase in vascular resistance with insulin was predominantly due to the reduction of circulating PGI2. Thus, vascular resistance is decreased in DKA primarily as a result of the vasodilator effects of PGI2 produced by adipose tissue. The activation of the renin-angiotensin system represents a partial compensation. The increase in PGI2 production may contribute to the hypotension and mortality of DKA.

Does acute improvement of endothelial dysfunction in coronary artery disease improve myocardial ischemia? A double-blind comparison of parenteral D- and L-arginine.

OBJECTIVES: Parenteral L-arginine will improve myocardial ischemia in patients with obstructive coronary artery disease. BACKGROUND: Endothelial dysfunction causes coronary arterial constriction during stress, and L-arginine improves endothelial dysfunction. METHODS: Twenty-two patients with stable coronary artery disease and exercise-induced ST-segment depression underwent assessment of forearm endothelial function with acetylcholine and symptom-limited treadmill exercise testing during dextrose 5% infusion and after double-blind intravenous administration of L- and D-arginine (5 mg/kg/min) for 20 min. RESULTS: Forearm blood flow increased with both L- and D-arginine (33%+/-6% and 38%+/-7%, respectively, p < 0.001). Acetylcholine-mediated forearm vasodilation also improved with both L- and D-arginine (p < 0.0001). The magnitude of improvement was similar with both enantiomers and was observed in patients throughout the range of acetylcholine responses and cholesterol levels. Heart rate and blood pressure at rest and during each stage of exercise and exercise duration remained unchanged with L- and D-arginine compared to control. Ischemic threshold, measured either as the rate-pressure product or the duration of exercise at the onset of 1-mm ST-segment depression during exercise, also remained unchanged. Serum arginine, insulin and prolactin levels (p < 0.01) increased with both enantiomers. CONCLUSIONS: Parenteral arginine produces non-stereo-specific peripheral vasodilation and improves endothelium-dependent vasodilation in patients with stable coronary artery disease by stimulation of insulin-dependent nitric oxide release or by nonenzymatic nitric oxide generation. Despite enhanced endothelial function, there was no improvement in myocardial ischemia during stress with either enantiomer. Whether parenteral arginine will be of therapeutic benefit in acute coronary syndromes and oral arginine in myocardial ischemia needs to be studied further.

N-acetylcysteine improves coronary and peripheral vascular function.

OBJECTIVES: We investigated whether N-acetylcysteine (NAC), a reduced thiol that modulates redox state and forms adducts of nitric oxide (NO), improves endothelium-dependent vasomotion. BACKGROUND: Coronary atherosclerosis is associated with endothelial dysfunction and reduced NO activity. METHODS: In 16 patients undergoing cardiac catheterization, seven with and nine without atherosclerosis, we assessed endothelium-dependent vasodilation with acetylcholine (ACH) and endothelium-independent vasodilation with nitroglycerin (NTG) and sodium nitroprusside (SNP) before and after intracoronary NAC. In 14 patients femoral vascular responses to ACH, NTG and SNP were measured before and after NAC. RESULTS: Intraarterial NAC did not change resting coronary or peripheral vascular tone. N-acetylcysteine potentiated ACH-mediated coronary vasodilation; coronary blood flow was 36 +/- 11% higher (p < 0.02), and epicardial diameter changed from -1.2 +/- 2% constriction to 4.7 +/- 2% dilation after NAC (p = 0.03). Acetylcholine-mediated femoral vasodilation was similarly potentiated by NAC (p = 0.001). Augmentation of the ACH response was similar in patients with or without atherosclerosis. N-acetylcysteine did not affect NTG-mediated vasodilation in either the femoral or coronary circulations and did not alter SNP responses in the femoral circulation. In contrast, coronary vasodilation with SNP was significantly greater after NAC (p < 0.05). CONCLUSIONS: Thiol supplementation with NAC improves human coronary and peripheral endothelium-dependent vasodilation. Nitroglycerin responses are not enhanced, but SNP-mediated responses are potentiated only in the coronary circulation. These NO-enhancing effects of thiols reflect the importance of the redox state in the control of vascular function and may be of therapeutic benefit in treating acute and chronic manifestations of atherosclerosis.

Anti-ischemic effects of angiotensin- converting enzyme inhibition in hypertension.

OBJECTIVES: We investigated whether augmentation of bradykinin (BK) bioavailability with angiotensin-converting enzyme (ACE) inhibition is associated with reduced exercise-induced myocardial ischemia in hypertension. BACKGROUND: Bradykinin responses are depressed in hypertension, and endothelial dysfunction contributes to myocardial ischemia by promoting abnormal coronary vasomotion during stress. METHODS: Fourteen hypertensive (HT) and 17 normotensive (NT), mildly symptomatic patients with coronary artery disease (CAD) and ST-segment depression during exercise were studied before and after seven days of oral enalapril (EN), which was titrated from 2.5 to 20 mg daily. Patients underwent two treadmill exercise tests and determination of forearm vasodilator response to BK. RESULTS: Despite receiving a lower dose of EN (7.8 vs. 14.8 mg, p < 0.001), NT patients had a significant reduction in blood pressure compared to HT patients. Compared to pre-EN, the ischemic threshold, defined as the rate-pressure product at the onset of 1-mm ST depression (p = 0.045), the duration of exercise to 1-mm ST depression (180 +/- 54 s, p = 0.007) and the maximum exercise duration (94 +/- 18 s, p < 0.001) were greater after EN in HT patients, but not in NT subjects (all p > or = 0.3). Patients with a greater drop in blood pressure experienced no improvement in exercise-induced ischemia. Forearm blood flow responses to BK were improved with EN in all patients to a similar extent. Moreover, no correlation was observed between the basal response to BK or the magnitude of its improvement with EN and with either the dose of EN or the improvement in exercise ischemic threshold. CONCLUSIONS: Exercise-induced myocardial ischemia is ameliorated in HT patients with CAD by ACE inhibition.

Abnormal flow-mediated epicardial vasomotion in human coronary arteries is improved by angiotensin-converting enzyme inhibition: a potential role of bradykinin.

OBJECTIVES: This study was performed to determine whether angiotensin converting enzyme (ACE) inhibition improves endothelium-dependent flow-mediated vasodilation in patients with atherosclerosis or its risk factors and whether this is mediated by enhanced bradykinin activity. BACKGROUND: Abnormal coronary vasomotion due to endothelial dysfunction contributes to myocardial ischemia in patients with atherosclerosis, and its reversal may have an antiischemic action. Previous studies have shown that ACE inhibition improves coronary endothelial responses to acetylcholine, but whether this is accompanied by improved responses to shear stress remains unknown. METHODS: In 19 patients with mild atherosclerosis, metabolic vasodilation was assessed during cardiac pacing. Pacing was repeated during separate intracoronary infusions of low-dose bradykinin (BK) and enalaprilat. Endothelium-dependent and -independent vasodilation was estimated with intracoronary BK and sodium nitroprusside respectively. RESULTS: Enalaprilat did not alter either resting coronary vascular tone or dilation with sodium nitroprusside, but potentiated BK-mediated dilation. Epicardial segments that constricted abnormally with pacing (-5+/-1%) dilated (3+/-2%) with pacing in the presence of enalaprilat (p = 0.002). Similarly, BK at a concentration (62.5 ng/min) that did not alter resting diameter in the constricting segments also improved the abnormal response to a 6+/-1% dilation (p < 0.001). Cardiac pacing-induced reduction in coronary vascular resistance of 27+/-4% (p < 0.001) remained unchanged after enalaprilat. CONCLUSIONS: Thus ACE inhibition: A) selectively improved endothelium-dependent but not-independent dilation, and B) abolished abnormal flow-mediated epicardial vasomotion in patients with endothelial dysfunction, in part, by increasing endogenous BK activity.

The insertion/deletion polymorphism of the angiotensin-converting enzyme gene determines coronary vascular tone and nitric oxide activity.

OBJECTIVES: We investigated whether the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene modulates vasomotor tone and endothelial function. BACKGROUND: The deletion allele of the ACE I/D polymorphism has been associated with increased incidence of cardiovascular pathology. The risk is synergistically increased in patients who also possess the C allele at position 1,166 of the angiotensin type I (AT1) receptor gene. METHODS: In 177 patients with coronary atherosclerosis or its risk factors, we investigated endothelial function with intracoronary acetylcholine (ACH), endothelium-independent smooth muscle function with sodium nitroprusside (SNP) and basal nitric oxide activity with L-NG monomethyl arginine. RESULTS: Compared with ACE II genotype, patients with the ACE DD genotype had lower coronary microvascular and epicardial responses with SNP (coronary blood flow increase 196 +/- 26% vs. 121 +/- 11%, p = 0.003, and diameter increase 21.9 +/- 2% vs. 17 +/- 1%, p = 0.03, ACE II vs. DD, respectively). L-NG monomethyl arginine induced greater constriction in patients with the ACE DD compared with ACE II genotype (coronary blood flow -10 +/- 4% vs. 11 +/- 5%, p = 0.003, ACE DD vs. II and diameter constriction -6.3 +/- 1.2% vs. -1.9 +/- 1.2%, p = 0.01, respectively, in patients with atherosclerosis). No difference in ACH-mediated vasomotion was detected between the three ACE genotypes. The AT1 receptor polymorphism did not influence responses to either SNP or ACH. CONCLUSIONS: Patients possessing the D allele of the ACE gene have increased vascular smooth muscle tone. The enhanced tone appears to be counterbalanced by an increase in basal nitric oxide activity in patients with atherosclerosis.

Blood pressure changes during transient myocardial ischemia: insights into mechanisms.

OBJECTIVES: We investigated the contribution of changes in systemic blood pressure to the genesis of spontaneous myocardial ischemia. BACKGROUND: Although increases in heart rate often precede the development of spontaneous myocardial ischemia, it remains a subject of controversy whether these are accompanied by simultaneous changes in blood pressure. METHODS: Using an ambulatory monitoring device that triggered blood pressure recordings from the level of the ST segment, we documented systolic and diastolic blood pressure and heart rate changes related to episodes of ST segment depression in 17 patients with stable coronary artery disease. RESULTS: Systolic blood pressure and heart rate, but not diastolic pressure, increased significantly before the onset of ST segment depression and persisted throughout the ischemic episode. There was a significant correlation between the changes in heart rate and systolic blood pressure during episodes of myocardial ischemia (r = 0.5, p = 0.0005) and between heart rate and systolic blood pressure changes at 1-mm ST segment depression during treadmill exercise testing and ambulatory monitoring (r = 0.73, p = 0.0005 for heart rate; r = 0.77, p = 0.0008 for systolic blood pressure), indicating that patients with a low heart rate threshold during ischemic episodes also had a lower systolic blood pressure threshold before ischemia during both tests. Circadian changes in systolic blood pressure paralleled the variations in heart rate and ischemic episodes, with the lowest values at night. CONCLUSIONS: Significant increases in myocardial oxygen demand, including systolic blood pressure, occur during episodes of spontaneous myocardial ischemia. Patients with a lower heart rate threshold during ischemic episodes had a lower systolic blood pressure threshold during both ambulatory monitoring and treadmill exercise. The effects of antianginal therapy on blood pressure changes during ischemia need to be explored further.

Platelet inhibitory effect of nitric oxide in the human coronary circulation: impact of endothelial dysfunction.

OBJECTIVES: We sought to determine whether coronary vascular nitric oxide (NO) release in vivo modulates platelet activation. BACKGROUND: Nitric oxide modulates vasodilator tone and platelet activity via the cyclic guanosine monophosphate (cGMP) pathway, but whether coronary endothelial dysfunction influences platelet activation in humans is unknown. METHODS: In 26 patients, we measured coronary blood flow, epicardial diameter and coronary sinus platelet cGMP content during intracoronary infusions of acetylcholine (ACH), L-NG monomethyl arginine (L-NMMA) and sodium nitroprusside. RESULTS: Acetylcholine increased platelet cGMP content (p = 0.013), but its magnitude was lower in patients with endothelial dysfunction; thus, patients with epicardial constriction with ACH had a 7 +/- 6%, p = ns change compared with a 32 +/- 13%, p = 0.05 increase in platelet cGMP in those with epicardial dilation. Similarly, patients with atherosclerosis or its risk factors had a smaller increase (9 +/- 6%) compared with those having normal coronary arteries without risk factors (51 +/- 22%, p = 0.019). L-NG monomethyl arginine decreased platelet cGMP content to a greater extent in patients with epicardial dilation with ACH (- 15 +/- 7%, p = 0.06) compared to those with constriction (+5 +/- 6% change, p = 0.5). Sodium nitroprusside produced a similar increase in platelet cGMP content in patients with and without endothelial dysfunction (p = 0.56). The effects of sodium nitroprusside, but not ACH or L-NMMA, were reproduced in vitro. CONCLUSIONS: Platelet cGMP levels can be modulated by basal and stimulated release of NO. The platelet inhibitory effect of NO is reduced in patients with endothelial dysfunction, which may explain their increased risk from thrombotic events and the improved survival associated with strategies designed to improve vascular function.

Impaired endothelium-dependent vasodilation in patients with essential hypertension: evidence that the abnormality is not at the muscarinic receptor level.

OBJECTIVES: The purpose of this study was to determine whether the impaired endothelium-dependent vasodilation of hypertensive patients is related to a specific defect of the muscarinic receptor or to a broader abnormality of the vascular endothelium. BACKGROUND: Patients with essential hypertension have abnormal endothelium-dependent vasodilator response to acetylcholine. However, whether this results from an isolated dysfunction of the endothelial cell muscarinic receptor is unknown. METHODS: The responses of the forearm vasculature to acetylcholine and substance P (endothelium-dependent agents acting on different receptors) and to sodium nitroprusside (a direct dilator of vascular smooth muscle) were studied in eight hypertensive patients (six men, two women; mean age [+/- SD] 50 +/- 12 years) and eight normal control subjects (four men, four women; mean age 49 +/- 9 years). To determine the nitric oxide contribution to substance P-induced vasodilation, the vascular responses to substance P were also measured after inhibition of nitric oxide synthesis with NG-monomethyl-L-arginine. Drugs were infused into the brachial artery, and forearm blood flow was measured by strain gauge plethysmography. RESULTS: The response to acetylcholine was significantly blunted in hypertensive patients (highest blood flow [mean +/- SD] 8.4 +/- 4 vs. 13.8 +/- 4 ml/min per 100 ml in control subjects, p < 0.03). Similarly, the vasodilator effect of substance P was significantly reduced in hypertensive patients (highest blood flow [mean +/- SD] 8.8 +/- 4 vs. 13.9 +/- 4 ml/min per 100 ml in control subjects, p < 0.03). A significant correlation was found between the maximal blood flow with acetylcholine and that with substance P (r = 0.68, p < 0.004). The vasodilator response to sodium nitroprusside was similar in patients and control subjects. The nitric oxide contribution to substance P-induced vasodilation was reduced in hypertensive patients, such that the responses to substance P measured during infusion of NG-monomethyl-L-arginine were not significantly different between the two groups. CONCLUSIONS: These findings indicate that the endothelial abnormality of patients with essential hypertension is not restricted to the muscarinic cell receptor.

Angiotensin type 1 receptor antagonism reverses abnormal coronary vasomotion in atherosclerosis.

OBJECTIVES: This study was performed to determine whether angiotensin type 1 (AT1) receptor inhibition improves abnormal coronary vasomotion and endothelial dysfunction in patients with atherosclerosis or its risk factors. BACKGROUND: Endothelial dysfunction, an early feature of atherosclerosis, contributes to abnormal vasomotion during stress. Angiotensin II may contribute to endothelial dysfunction in atherosclerosis. METHODS: In 25 patients, mean age 59 +/- 2 years, with atherosclerosis or its risk factors, we measured coronary vasomotion during flow-mediated dilation (FMD) in response to adenosine, cold pressor test (CPT) and exercise before and after AT1 receptor blockade with intracoronary losartan (5 mg). RESULTS: Losartan did not alter resting coronary vascular tone, but epicardial FMD improved from 5.6 +/- 1.5% to 8.9 +/- 1.8% (p = 0.02). Abnormal epicardial vasomotion during CPT and exercise also improved with losartan from -1.7 +/- 0.8% to 1.5 +/- 0.1% (p = 0.02) and -0.6 +/- 0.9% to 3.4 +/- 1.2% (p = 0.009), respectively. Improvement in epicardial vasomotion was most prominent in segments with baseline endothelial dysfunction evidenced as constriction during stress. Microvascular dilation during adenosine, an endothelium-independent response, was unchanged with losartan. CONCLUSIONS: Inhibition of the coronary vascular AT1 receptors in patients with atherosclerosis improves epicardial vasomotion during stress, probably by improving endothelial dysfunction. Whether AT1 receptor blockade will provide long-term therapeutic benefits in atherosclerosis needs further investigation.