Does cardiovascular phenotype explain the association between diabetes and incident heart failure? The Strong Heart Study.

BACKGROUND AND AIMS: Diabetes remains a predictor of incident heart failure (HF), independent of intercurrent myocardial infarction (MI) and concomitant risk factors. Initial cardiovascular (CV) characteristics, associated with incident heart failure (HF) might explain the association of diabetes with incident HF. METHODS AND RESULTS: Participants to the 2nd Strong Heart Study exam, without prevalent HF or coronary heart disease, or glomerular filtration rate <30 mL/min/1.73 m(2), were analyzed (n = 2757, 1777 women, 1278 diabetic). Cox regression of incident HF (follow-up 8.91 ± 2.76 years) included incident MI censored as a competing risk event. Acute MI occurred in 96 diabetic (7%) and 84 non-diabetic participants (6%, p = ns). HF occurred in 156 diabetic (12%) and in 68 non-diabetic participants (5%; OR = 2.89, p < 0.001). After accounting for competing MI and controlling for age, gender, BMI, systolic blood pressure, smoking habit, plasma cholesterol, antihypertensive treatment, heart rate, fibrinogen and C-reactive protein, incident HF was predicted by greater LV mass index, larger left atrium, lower systolic function, greater left atrial systolic force and urinary albumin/creatinine excretion. Risk of HF was reduced with more rapid LV relaxation and anti-hypertensive therapy. Diabetes increases hazard of HF by 66% (0.02 < p < 0.001). The effect of diabetes could be explained by the level of HbA1c. CONCLUSIONS: Incident HF occurs more frequently in diabetes, independent of intercurrent MI, abnormal LV geometry, subclinical systolic dysfunction and indicators of less rapid LV relaxation, and is influenced by poor metabolic control. Identification of CV phenotype at high-risk for HF in diabetes should be advised.

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.

Effects of inhaled nitric oxide on regional blood flow are consistent with intravascular nitric oxide delivery.

Nitric oxide (NO) may be stabilized by binding to hemoglobin, by nitrosating thiol-containing plasma molecules, or by conversion to nitrite, all reactions potentially preserving its bioactivity in blood. Here we examined the contribution of blood-transported NO to regional vascular tone in humans before and during NO inhalation. While breathing room air and then room air with NO at 80 parts per million, forearm blood flow was measured in 16 subjects at rest and after blockade of forearm NO synthesis with N(G)-monomethyl-L-arginine (L-NMMA) followed by forearm exercise stress. L-NMMA reduced blood flow by 25% and increased resistance by 50%, an effect that was blocked by NO inhalation. With NO inhalation, resistance was significantly lower during L-NMMA infusion, both at rest and during repetitive hand-grip exercise. S-nitrosohemoglobin and plasma S-nitrosothiols did not change with NO inhalation. Arterial nitrite levels increased by 11% and arterial nitrosyl(heme)hemoglobin levels increased tenfold to the micromolar range, and both measures were consistently higher in the arterial than in venous blood. S-nitrosohemoglobin levels were in the nanomolar range, with no significant artery-to-vein gradients. These results indicate that inhaled NO during blockade of regional NO synthesis can supply intravascular NO to maintain normal vascular function. This effect may have application for the treatment of diseases characterized by endothelial dysfunction.

Role of endothelial nitric oxide in shear stress-induced vasodilation of human microvasculature: diminished activity in hypertensive and hypercholesterolemic patients.

BACKGROUND: It has been proposed that flow-mediated shear stress regulates vascular tone; however, whether this operates in the human microcirculation is unknown. This study was designed to investigate the effect of shear stress on human microvascular tone, to assess the contribution of nitric oxide (NO), and to determine whether this mechanism is defective in hypertension and in hypercholesterolemia. METHODS AND RESULTS: In 9 normal controls (NC), 11 hypertensive patients (HT), and 12 hypercholesterolemic patients (HChol), arteries (internal diameter 201+/-26 microm) isolated from gluteal fat biopsies were cannulated and perfused in chambers. Shear stress was induced by increasing the flow rate from 1 to 50 microL/min after preconstriction with norepinephrine (NE). Arterial internal diameter was expressed as percent of NE-induced constriction. In NC, shear stress induced flow-dependent vasodilation from 23+/-9% at 1 microL/min to 53+/-14% at 50 microL/min (P<0.0001), which was abolished by endothelial removal. The NO synthase inhibitor Nomega-nitro-L-arginine (L-NNA) significantly blunted this response (mean vasodilation decreased from 27+/-6% to 6+/-9%; P=0.04). HT had significant impairment of flow-mediated dilation (mean vasodilation 5+/-6%; P=0.01 versus NC), which was not affected by L-NNA. HChol had preserved flow-mediated vasodilation (mean vasodilation 24+/-7%; P=0.56 versus NC), but this was not significantly modified by L-NNA. CONCLUSIONS: In the human microvasculature, shear stress induces endothelium-dependent, NO-mediated vasodilation. This phenomenon is blunted in HT patients because of reduced activity of NO. In contrast, the HChol microvasculature has preserved shear stress-induced dilation despite diminished NO activity.

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.

Oral L-arginine in patients with coronary artery disease on medical management.

BACKGROUND: Vascular nitric oxide (NO) bioavailability is reduced in patients with coronary artery disease (CAD). We investigated whether oral L-arginine, the substrate for NO synthesis, improves homeostatic functions of the vascular endothelium in patients maintained on appropriate medical therapy and thus might be useful as adjunctive therapy. METHODS AND RESULTS: Thirty CAD patients (29 men; age, 67+/-8 years) on appropriate medical management were randomly assigned to L-arginine (9 g) or placebo daily for 1 month, with crossover to the alternate therapy after 1 month off therapy, in a double-blind study. Nitrogen oxides in serum (as an index of endothelial NO release), flow-mediated brachial artery dilation (as an index of vascular NO bioactivity), and serum cell adhesion molecules (as an index of NO-regulated markers of inflammation) were measured at the end of each treatment period. L-Arginine significantly increased arginine levels in plasma (130+/-53 versus 70+/-17 micromol/L, P<0.001) compared with placebo. However, there was no effect of L-arginine on nitrogen oxides (19.3+/-7.9 versus 18. 6+/-6.7 micromol/L, P=0.546), on flow-mediated dilation of the brachial artery (11.9+/-6.3% versus 11.4+/-7.9%, P=0.742), or on the cell adhesion molecules E-selectin (47.8+/-15.2 versus 47.2+/-14.4 ng/mL, P=0.601), intercellular adhesion molecule-1 (250+/-57 versus 249+/-57 ng/mL, P=0.862), and vascular cell adhesion molecule-1 (567+/-124 versus 574+/-135 ng/mL, P=0.473). CONCLUSIONS: Oral L-arginine therapy does not improve NO bioavailability in CAD patients on appropriate medical management and thus may not benefit this group of patients.

Insulin stimulates both endothelin and nitric oxide activity in the human forearm.

BACKGROUND: The mechanism of the hemodynamic effect of insulin in the skeletal muscle circulation has not been fully elucidated. The purpose of this study was to assess whether the hemodynamic response to insulin involves the concurrent release of endothelin (ET-1) and nitric oxide (NO), 2 substances with opposing vasoactive properties. METHODS AND RESULTS: Bioactivity of ET-1 and NO was assessed without insulin and during insulin infusion in the forearm circulation of healthy subjects by use of blockers of ET-1 receptors and by NO synthesis inhibition. In the absence of hyperinsulinemia, ET-1 receptor blockade did not result in any significant change in forearm blood flow from baseline (P=0.29). Intra-arterial insulin administration did not significantly modify forearm blood flow (P=0. 88). However, in the presence of hyperinsulinemia, ET-1 receptor antagonism was associated with a significant vasodilator response (P<0.001). In the presence of ET-1 receptor blockade, the vasoconstrictor response to NO inhibition by N(G)-monomethyl-L-arginine was significantly higher after insulin infusion than in the absence of hyperinsulinemia (P=0.006). CONCLUSIONS: These findings suggest that in the skeletal muscle circulation, insulin stimulates both ET-1 and NO activity. An imbalance between the release of these 2 substances may be involved in the pathophysiology of hypertension and atherosclerosis in insulin-resistant states associated with endothelial dysfunction.

Vascular effects of estrogen and vitamin E therapies in postmenopausal women.

BACKGROUND: Estrogen and vitamin E therapies have been suggested to reduce cardiovascular risk, but comparison of the vascular effects of these therapies to determine mechanisms of potential benefit has not been performed in postmenopausal women. METHODS AND RESULTS: In a double-blind, 3-period crossover study, we randomly assigned 28 healthy postmenopausal women to conjugated equine estrogens (CE) 0. 625 mg/d, vitamin E 800 IU/d, and their combination, with measurements made before and after each 6-week treatment period. The ratio of LDL to HDL cholesterol and lipoprotein(a) decreased on therapies including CE but increased on vitamin E alone (P<0.001 and P=0.002, respectively, by ANOVA). Brachial artery flow-mediated dilation improved on all therapies (all P<0.001 versus pretreatment values) and to a similar degree (P=0.267 by ANOVA). No therapy improved the dilator response to nitroglycerin. CE lowered serum levels of cell adhesion molecules E-selectin, ICAM-1, and VCAM-1 (all P<0.05 versus pretreatment values). Vitamin E had no significant effect on levels of these markers of inflammation (P<0. 001 by ANOVA for E-selectin). CE alone or combined with vitamin E but not vitamin E alone lowered or showed a trend for lowering plasma levels of plasminogen activator inhibitor type-1 (P=0.069 by ANOVA). CONCLUSIONS: Estrogen and vitamin E therapies similarly improved arterial endothelium-dependent vasodilator responsiveness consistent with increased nitric oxide in healthy postmenopausal women, despite divergent effects on atherogenic lipoproteins. However, only estrogen reduced markers of vascular disease.

Effect of antihypertensive treatment on endothelium-dependent vascular relaxation in patients with essential hypertension.

OBJECTIVES: This study was designed to determine whether antihypertensive treatment can restore the impaired endothelium-dependent vasodilation of patients with essential hypertension. BACKGROUND: The endothelium regulates vascular tone through the release of vasoactive agents that act on the underlying vascular smooth muscle. This endothelial function is impaired in certain cardiovascular conditions, including essential hypertension. METHODS: The vascular responses to acetylcholine (endothelium-dependent vasodilator, 7.5, 15 and 30 micrograms/min) and sodium nitroprusside (direct dilator of smooth muscle, 0.8, 1.6, 3.2 micrograms/min) were studied in 15 patients (11 men and 4 women with a mean age of 54.1 +/- 12 years) on two occasions: after withdrawal of medications, when the patients were hypertensive, and during the medical treatment that reduced blood pressure to within normal limits in each patient. The results were compared with those obtained in 15 normal control subjects (10 men and 5 women with a mean age of 52.3 +/- 7 years). Drugs were infused into the brachial artery, and forearm blood flow response was measured by strain gauge plethysmography. RESULTS: The blood flow and vascular resistance responses to acetylcholine were significantly reduced in the hypertensive patients (p < 0.0001); maximal forearm flow (ml/min per 100 ml) was 7.0 +/- 4 ml in the patients and 16.7 +/- 5 in the control subjects (p < 0.005). However, no significant differences between groups were observed in the responses to sodium nitroprusside. In patients with essential hypertension, the vascular responses to acetylcholine and sodium nitroprusside were not modified by medical therapy. Maximal forearm flow with acetylcholine (ml/min per 100 ml) was 7.2 +/- 2 during antihypertensive therapy and 7.0 +/- 4 after medication withdrawal. CONCLUSIONS: Clinically effective antihypertensive therapy does not restore the impaired endothelium-dependent vascular relaxation of patients with essential hypertension. This indicates that such endothelial dysfunction is either primary or becomes irreversible once the hypertensive process has become established.

Utility of continuous wave Doppler echocardiography in the noninvasive assessment of left ventricular outflow tract pressure gradient in patients with hypertrophic cardiomyopathy.

Subaortic obstruction is an important determinant of the clinical presentation of and therapeutic approach to patients with hypertrophic cardiomyopathy. Therefore, assessment of the presence and magnitude of the intraventricular pressure gradient is paramount in the clinical evaluation of these patients. To establish the utility of continuous wave Doppler echocardiography in assessing the pressure gradient in hypertrophic cardiomyopathy, 28 patients representing the wide hemodynamic spectrum of this disease underwent simultaneous determination of the subaortic gradient by continuous wave Doppler ultrasound and cardiac catheterization. With use of the modified Bernoulli equation, the Doppler-estimated gradient showed a strong correlation with the maximal instantaneous pressure difference measured at catheterization, both under basal conditions (r = 0.93; p less than 0.0001) and during provocative maneuvers (r = 0.89; p less than 0.0001). In 26 of the 28 patients, all assessments of the subaortic gradient were in agreement within 15 mm Hg (average difference 5 +/- 3 mm Hg). In the other two patients there were substantial differences between these measurements (under basal conditions in one patient and after provocation in another), although the Doppler technique predicted the presence of marked subaortic obstruction in each. In both patients the erroneous interpretation was due to superimposition of the mitral regurgitation signal on that of left ventricular outflow. Doppler waveforms from the left ventricular outflow tract showed variability in contour among different patients and in individual patients. Hence, continuous wave Doppler echocardiography is a useful noninvasive method for estimating the subaortic gradient in patients with hypertrophic cardiomyopathy. However, technical factors such as contamination of the outflow tract jet with that of mitral regurgitation and variability in waveform configuration may importantly influence such assessments of the subaortic gradient.

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.

Impairment of the nitric oxide-mediated vasodilator response to mental stress in hypertensive but not in hypercholesterolemic patients.

OBJECTIVES: This study investigated whether mental stress-induced vasodilation mediated by endothelium-derived nitric oxide (NO) is defective in conditions with endothelial dysfunction, such as hypertension and hypercholesterolemia. BACKGROUND: Vascular release of NO modulates the vasodilator response to mental stress in healthy subjects. Previous studies have shown that hypertensive and hypercholesterolemic patients have impaired endothelium-dependent vasodilation to pharmacologic agents due to decreased NO activity. However, whether this abnormality also operates in response to physiologic stimuli such as mental stress has not been defined. METHODS: Forearm blood flow responses (plethysmography) to mental stress were compared in 12 normal subjects, 12 hypertensive patients and 10 hypercholesterolemic patients before and during NO synthesis inhibition with N(G)-monomethyl-L-arginine (4 micromol/min). Vascular responses to acetylcholine (7.5, 15 and 30 microg/min), an endothelium-dependent vasodilator, and sodium nitroprusside (0.8, 1.6 and 3.2 microg/min), an exogenous NO donor, were also assessed in each group. RESULTS: During saline the vasodilator response to mental stress was significantly blunted in hypertensive (37+/-11%; p=0.01) but not in hypercholesterolemic (85+/-21%; p=0.78) patients compared with controls (93+/-15%). N(G)-Monomethyl-L-arginine administration significantly blunted mental stress-induced vasodilation in healthy subjects (p=0.004 vs. saline) and hypercholesterolemic patients (p=0.03 vs. saline), but not in hypertensive patients (p=0.69 vs. saline). The vasodilator effect of the highest dose of acetylcholine was similarly blunted in hypertensive (215+/-44%; p=0.02) and hypercholesterolemic (172+/-71%; p=0.02) patients compared with controls (364+/-34), whereas the vasorelaxing response to sodium nitroprusside was similar in the three groups. CONCLUSIONS: Hypertensive but not hypercholesterolemic patients have impaired NO-dependent vasodilation during mental stress. These findings may be accounted for by different mechanisms underlying endothelial dysfunction in these two conditions and might explain an increased susceptibility of hypertensive patients to vascular damage over repeated exposure to stressful situations.

Increased activity of endogenous endothelin in patients with hypercholesterolemia.

OBJECTIVE: We sought to assess the activity of endogenous endothelin-1 (ET-1) in hypercholesterolemic patients using antagonists of ET-1 receptors. BACKGROUND: Endothelial dysfunction in hypercholesterolemic patients may contribute to their risk of premature atherosclerosis. Endothelin, a peptide released by endothelial cells, may be involved in this process by activating smooth muscle cell mitogenesis and leukocyte adhesion. METHODS: Forearm blood flow (FBF) responses (strain-gauge plethysmography) to intra-arterial infusion of a selective blocker of ETA receptors (BQ-123) and, on a separate occasion, to ET-1 were measured in 12 hypercholesterolemic patients and 12 normal control subjects. In addition, on a different day, six hypercholesterolemic patients received co-infusion of BQ- 123 and BQ-788 (a selective blocker of ETB receptors). RESULTS: In normal subjects, BQ-123 did not significantly modify FBF from baseline (p = 0.78); however, in hypercholesterolemic patients, BQ-123 administration resulted in a significant vasodilator response (p < 0.001). Administration of exogenous ET-1 resulted in similar vasoconstrictor responses in patients (37%) and control subjects (35%) (p = 0.83). In hypercholesterolemic patients, the vasodilator response to selective ETA blockade was reversed by nonselective blockade of ET-1 receptors obtained by co-infusion of BQ-123 and BQ-788. CONCLUSIONS: The vascular activity of endogenous ET-1 is enhanced in hypercholesterolemic patients, whereas their sensitivity to exogenous ET-1 is unchanged. These findings suggest increased production of ET-1, which may participate in the pathophysiology of vascular disease characteristic of hypercholesterolemia.

Investigation of decreased availability of nitric oxide precursor as the mechanism responsible for impaired endothelium-dependent vasodilation in hypercholesterolemic patients.

OBJECTIVES: The purpose of this study was to determine whether the impaired endothelium-dependent vasodilation of hypercholesterolemic patients is due to decreased availability of L-arginine, the substrate for nitric oxide. BACKGROUND: Patients with hypercholesterolemia have impaired endothelium-dependent vasodilation that is related to a defect in the endothelium-derived nitric oxide system. However, the precise location of this abnormality has not been determined. METHODS: The study included 12 hypercholesterolemic patients (6 men, 6 women; 52 +/- 9 years old; serum cholesterol > 240 mg/dl) and 15 normal volunteers (8 men, 7 women; 50 +/- 6 years old; serum cholesterol < 210 mg/dl). The forearm vascular responses to intraarterial infusion of acetylcholine, an endothelium-dependent vasodilator (7.5, 15, 30 micrograms/min), and sodium nitroprusside, a direct smooth muscle dilator (0.8, 1.6, 3.2 micrograms/min) were studied before and during infusion of L- or D-arginine (a stereoisomer of arginine that is not a nitric oxide precursor). RESULTS: The response to acetylcholine was lower in hypercholesterolemic patients than in control subjects. However, no significant difference was observed with sodium nitroprusside infusion. L-Arginine augmented the response to acetylcholine in normal subjects (maximal blood flow increased from 14.4 +/- 7 to 18.9 +/- 10 ml/min per 100 ml, p < 0.002). In contrast, in the hypercholesterolemic patients, only a mild but not significant improvement in the response to acetylcholine was observed with the infusion of L-arginine (maximal blood flow increased from 6.8 +/- 4 to 8.4 +/- 5 ml/min per 100 ml; p = 0.16); however, a similar mild but not significant change was also observed with D-arginine (maximal blood flow increased from 6.8 +/- 4 to 8.3 +/- 4 ml/min per 100 ml, p = 0.07). L-Arginine did not modify the response to sodium nitroprusside in either group. CONCLUSIONS: The augmentation of endothelium-dependent vasodilation by L-arginine, the nitric oxide precursor, is defective in hypercholesterolemic patients. This supports the concept of an abnormal endothelium-derived nitric oxide system in hypercholesterolemia and indicates that decreased availability of nitric oxide substrate is not responsible for the impaired endothelial function in this condition.

Prediction of the frequency and duration of ambulatory myocardial ischemia in patients with stable coronary artery disease by determination of the ischemic threshold from exercise testing: importance of the exercise protocol.

The relation between ambulatory myocardial ischemia and the results of exercise testing in patients with ischemic heart disease remains undefined, because of the dissimilar results of previous reports. To further investigate this issue and, in particular, to ascertain the importance of the exercise protocol in determining that relation, 70 patients with stable coronary artery disease underwent 48 h ambulatory electrocardiographic (ECG) monitoring and treadmill exercise tests after withdrawal of medications. Patients exercised using two different protocols with slow (National Institutes of Health [NIH] combined protocol) and brisk (Bruce protocol) work load increments. Exercise duration was longer with the NIH combined protocol (14.1 +/- 5 versus 6.8 +/- 2 min; p less than 0.0001), but the maximal work load and peak heart rate achieved were greater with the Bruce protocol (9.8 +/- 2 versus 6.5 +/- 2 METs, and 142 +/- 19 versus 133 +/- 22 beats/min, respectively; p less than 0.0001). A close inverse correlation between exercise testing and the results of ambulatory ECG monitoring was observed using the NIH combined protocol; the strongest correlation was observed between time of exercise at 1 mm of ST segment depression and number of ischemic episodes (r = -0.86; p less than 0.0001). With the Bruce protocol a significantly weaker inverse correlation was found (r = -0.35). The mean heart rate at the onset of ST segment depression was similar during monitoring and during exercise testing with the NIH combined protocol (97.2 +/- 13 versus 101.0 +/- 17 beats/min, respectively) but it was significantly higher (110.4 +/- 13) when using the Bruce protocol (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Relation between left ventricular function at rest and with exercise and silent myocardial ischemia.

The prognostic value of radionuclide measures of left ventricular function at rest and exercise is well established. Some studies have suggested that the frequency and duration of silent ischemia during ambulatory monitoring provide similar prognostic information; however, studies comparing these two techniques have not been performed. This study examines the relation between left ventricular function at rest and exercise-induced ischemia assessed by radionuclide ventriculography with myocardial ischemia during ambulatory electrocardiographic (ECG) monitoring. Of the 155 patients with coronary artery disease studied, 88% had left ventricular dysfunction with exercise, defined as failure of the ejection fraction to increase by greater than 4% with exercise, and 33% of patients had left ventricular dysfunction at rest (ejection fraction less than 45%); 52% had transient episodes of ST segment depression during 48-h ambulatory ECG monitoring. Exercise-induced left ventricular dysfunction during radionuclide ventriculography was extremely sensitive (94%) in detecting patients with ischemic episodes during ambulatory ECG monitoring; however, only 55% of patients with exercise-induced left ventricular dysfunction had ST segment depression during ambulatory monitoring. Moreover, patients with left ventricular dysfunction at rest had a lower prevalence of transient episodes of ST segment depression (31%) than did patients with normal left ventricular function at rest (62%) (p = 0.008). The relation between prognostically important variables during exercise radionuclide ventriculography and the number and duration of transient episodes of ST depression was examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of increases in heart rate in determining the occurrence and frequency of myocardial ischemia during daily life in patients with stable coronary artery disease.

OBJECTIVES: The goal of this study was to investigate the role of increases in heart rate in the development of ischemic episodes recorded during ambulatory electrocardiographic (ECG) monitoring in patients with stable coronary artery disease and to establish the importance of such increases in determining the frequency of ambulatory myocardial ischemia. BACKGROUND: The factors that determine the occurrence and frequency of episodes of myocardial ischemia that patients with stable coronary artery disease experience during daily life have not been clearly defined. In particular, the role of increases in heart rate in the development of myocardial ischemia is controversial. METHODS: To address these issues, 54 patients (42 men and 12 women, mean age 60.5 +/- 8 years) with proved coronary artery disease who had > or = 1 mm ST segment depression during exercise testing underwent an exercise treadmill test with use of the National Institutes of Health combined protocol and a 48-h period of ambulatory ECG monitoring. The exercise ischemic threshold was determined as the heart rate at the onset of ST segment depression during exercise testing. RESULTS: During monitoring, 48 (89%) of the 54 patients had at least one episode of ST segment depression (mean +/- SD 6.6 +/- 5 episodes, range 0 to 22). The majority (320 of 359 or 89%) of ischemic episodes were preceded by an increase in heart rate > or = 10 beats/min; the most significant increase (22.3 +/- 10 beats/min) occurred during the 5-min period before the onset of the episode. An ischemic episode occurred 80% of the times the heart rate reached the exercise ischemic threshold. A strong correlation was observed between the number of times the exercise ischemic threshold was reached during monitoring and both the number and the duration of ischemic episodes (r = 0.90 and 0.71, respectively, p < 0.0001). CONCLUSIONS: Increases in heart rate that exceed the exercise ischemic threshold are commonly observed before the onset of episodes of ambulatory myocardial ischemia in patients with stable coronary artery disease. Moreover, such increases constitute an important determinant of the frequency of myocardial ischemia during daily life. These findings may explain the variability observed in the number of ischemic episodes and may have important implications for the mechanisms that contribute to myocardial ischemia in daily life and for the clinical evaluation of patients with coronary artery disease.

Coexistence of mitral valve prolapse in a consecutive group of 528 patients with hypertrophic cardiomyopathy assessed with echocardiography.

Hypertrophic cardiomyopathy and mitral valve prolapse are both conditions that may be genetically transmitted and incur a risk for sudden cardiac death. Although the small left ventricular cavity and distorted geometry characteristic of hypertrophic cardiomyopathy might suggest a predisposition to mitral valve prolapse, the frequency with which these two entities coexist and the potential clinical significance of such an association are not known. To further define the relation of hypertrophic cardiomyopathy and mitral valve prolapse, 528 consecutive patients with hypertrophic cardiomyopathy were studied by echocardiography. Patients ranged in age from 1 to 86 years (mean 45); 335 (63%) were male. Unequivocal echocardiographic evidence of systolic mitral valve prolapse into the left atrium was identified in only 16 (3%) of the 528 patients. The mitral valve excised at operation from three of the patients had morphologic characteristics of a floppy mitral valve, which was judged to be responsible for the echocardiographic findings. Occurrence of clinically evident atrial fibrillation was common in patients with hypertrophic cardiomyopathy and mitral valve prolapse (9 [56%] of 16). Hence, in a large group of patients with hypertrophic cardiomyopathy, the association of echocardiographically documented mitral valve prolapse was uncommon. The coexistence of mitral valve prolapse in patients with hypertrophic cardiomyopathy appears to predispose such patients to atrial fibrillation.

Transesophageal dobutamine stress echocardiography for evaluation of patients with coronary artery disease.

OBJECTIVES: The present study was undertaken to determine the safety, feasibility and diagnostic accuracy of transesophageal dobutamine stress echocardiography for the evaluation of patients with known or suspected coronary artery disease. BACKGROUND: Dobutamine stress echocardiography has proved to be a valuable method for detecting and prognosticating ischemic heart disease. In addition, it may provide accurate information about myocardial viability in patients with systolic dysfunction. However, in some patients the technique may be limited by poor myocardial imaging with the conventional transthoracic approach. METHODS: Seventy-six patients (62 men, 14 women; mean age +/- SD 60 +/- 10 years) who underwent coronary angiography were included in the study. Transesophageal stress echocardiograms were performed after withdrawal of antianginal medications for > or = 48 h. Dobutamine was infused at a starting dose of 2.5 micrograms/kg body weight per min and was increased by 5-micrograms/kg per min increments every 5 min to a maximum of 40 micrograms/kg per min. Two-dimensional views were acquired at each stage and digitized for subsequent analysis. The left ventricle was divided into 16 segments, and each segment was assigned to a major coronary artery with the use of a model of regional distribution of coronary perfusion. RESULTS: Sixty-two of the 76 patients had angiographic evidence of coronary artery disease. New or worsening regional wall motion abnormalities developed during dobutamine infusion in 55 of these 62 patients and in none of the 14 patients with normal coronary arteries (sensitivity 89%, specificity 100%, overall accuracy 91%). Regional wall motion abnormalities in the distribution of more than one major coronary artery were seen in 3 of the 25 patients with single-vessel coronary artery disease and in 30 of the 37 patients with multivessel disease (p < 0.0001). The test was successfully completed in 73 (96%) of the 76 patients; it was discontinued in the remaining 3 patients because of intolerance to the probe. No major complications occurred in any patient. Minor complications developed in seven patients but did not affect the diagnostic accuracy of the test. CONCLUSIONS: Transesophageal dobutamine stress echocardiography is a safe, feasible and accurate method for assessing coronary artery disease. Its use should be considered in patients who have a suboptimal ultrasound window, and it provides an excellent tool for clinical investigations based on ultrasound imaging of the myocardium.

Effect of L-arginine on human coronary endothelium-dependent and physiologic vasodilation.

OBJECTIVES: We hypothesized that L-arginine would improve abnormal coronary vasodilation in response to physiologic stress in patients with atherosclerosis and its risk factors by reversing coronary endothelial dysfunction. BACKGROUND: Studies have demonstrated that physiologic coronary vasodilation correlates with endothelial function and that L-arginine, the substrate for nitric oxide synthesis, improves the response to acetylcholine (Ach). METHODS: Changes in coronary blood flow and epicardial diameter response to Ach, adenosine and cardiac pacing were measured in 32 patients with coronary atherosclerosis or its risk factors and in 7 patients without risk factors and normal coronary angiograms. RESULTS: Intracoronary L-arginine did not alter baseline coronary vascular tone, but the epicardial and microvascular responses to Ach were enhanced (both p < 0.001). The improvement after L-arginine was greater in epicardial segments that initially constricted with Ach; similarly, L-arginine abolished microvascular constriction produced by higher doses of Ach. Thus, there was a negative correlation between the initial epicardial and vascular resistance responses to Ach and the magnitude of improvement with L-arginine (r = -0.55 and r = -0.50, respectively, p < 0.001). D-Arginine did not affect the responses to Ach, and adenosine responses were unchanged with L-arginine. Cardiac pacing-induced epicardial constriction was abolished by L-arginine, but microvascular dilation remained unaffected. CONCLUSIONS: Thus, L-arginine improved endothelium-dependent coronary epicardial and microvascular function in patients with endothelial dysfunction. Prevention of epicardial constriction during physiologic stress by L-arginine in patients with endothelial dysfunction may be of therapeutic value in the treatment of myocardial ischemia.