Jay M. Sullivan

Postmenopausal estrogen use and coronary atherosclerosis

STUDY OBJECTIVE To determine whether estrogen replacement therapy affects the prevalence of severely obstructive coronary arterial lesions defined by selective coronary arteriography. DESIGN Case-control study. SETTING Large, urban, university-affiliated referral hospital. PATIENTS From a consecutive sample of 6452 women having coronary arteriography between 1972 and 1984, 2188 patients were eligible for study; others were excluded because they were nonmenopausal, had congenital heart defects, valvular heart disorders, primary myocardial disease, or no more than mild to moderate coronary artery disease. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Hospital nurses routinely obtained medication histories. Staff invasive cardiologists interpreted coronary arteriograms. Clinical, laboratory, and angiographic data were abstracted from the cardiac catheterization reports and entered into a computerized registry. Postmenopausal estrogen use for 1444 cases of coronary artery disease (70% stenosis) was compared to that 744 controls (0% stenosis). The odds ratio estimate of the risk of coronary artery disease for estrogen users relative to the risk of coronary artery disease for nonusers was 0.44 (95% confidence interval, 0.29 to 0.67) after adjustment for age, cigarette smoking, diabetes, cholesterol, and hypertension. Postmenopausal estrogen replacement was a significant independent protective factor for coronary artery disease in a multivariate logistic regression model (P = 0.037). CONCLUSION The data suggest that postmenopausal estrogen treatment reduces the risk for angiographically significant coronary artery disease.

Left ventricular hypertrophy: Effect on survival

OBJECTIVES The aim of the study was to determine whether left ventricular hypertrophy has an independent adverse effect on survival. BACKGROUND Left ventricular hypertrophy is considered to be a significant risk factor for coronary heart disease mortality; however, the impact of coexisting coronary artery stenosis on survival statistics is not clear. METHODS The relations among electrocardiographic (ECG) left ventricular hypertrophy, ST-T segment abnormality, coronary artery disease and survival were examined in 18,969 patients undergoing coronary arteriography between 1972 and 1985. Patients were excluded if they underwent coronary revascularization or had unstable angina, rheumatic or congenital heart disease, cardiomyopathy, pericardial disease or ECG changes other than left ventricular hypertrophy or repolarization abnormalities, leaving 4,824 patients for analysis. RESULTS Left ventricular hypertrophy was present in 249 patients, whereas 4,575 were free of left ventricular hypertrophy. Five-year survival was 90.2% in the group without left ventricular hypertrophy and was significantly lower (81.9%, p < 0.001) in the group with left ventricular hypertrophy. Five-year survival was significantly lower in patients with left ventricular hypertrophy, regardless of whether coronary artery disease was present: 84.4% versus 94.5% (p = 0.016) in the absence of coronary artery disease and 81.0% versus 87.7% (p < 0.001) in the presence of coronary artery disease. The presence of ST segment abnormalities was not associated with a significant reduction in survival in patients without coronary disease, although mortality was less in those without ST changes who had coronary disease (p = 0.012). CONCLUSIONS It is concluded that ECG left ventricular hypertrophy has an adverse effect on survival, even in patients who are free of coronary artery disease.

Double-blind, placebo-controlled study of the efficacy of flosequinan in patients with chronic heart failure

Objectives. The aim of this study was to assess the efficacy of flosequinan in chronic heart failure. Background. Flosequinan is a new vasodilator drug that acts by interfering with the inositol-triphosphate/protein kinase C pathway, an important mechanism of vasoconstriction. The drug dilates both peripheral arteries and veins, is orally active and has a long duration of action that permits once-daily dosing. Previous studies have shown that flosequinan produces sustained hemodynamic benefits in heart failure, but large scale studies evaluating its clinical efficacy have not been reported. Methods. One hundred ninety-three patients with chronic heart failure (New York Heart Association functional class II or III and left ventricular ejection fraction <40%) receiving digoxin and diuretic drugs were randomly assigned (double-blind) to the addition of flosequinan (100 mg once daily, n = 93) or placebo (n = 100) for 3 months. The clinical status and exercise tolerance of each patient was evaluated at the start of the study and every 2 to 4 weeks during the trial while background therapy remained constant. Results. After 12 weeks, maximal treadmill exercise time increased by 96 s in the flosequinan group but by only 47 s in the placebo group (p = 0.022 for the difference between groups). Maximal oxygen consumption increased by 1.7 ml/kg per in the flosequinan group (n = 17) but by only 0.6 ml/kg per min in the placebo group (n = 23), p = 0.05 between the groups. Symptomatically, 55% of patients receiving flosequinan but only 36% of patients receiving placebo benefited from treatment (p = 0.018). In addition, fewer patients treate with flosequinan had sufficiently severe worsening of heart failure to require a change in medication or withdrawal from the study (p = 0.07). By intention to treat, seven patients in the flosequinan group and two patients in the placebo group died. Conclusions. These findings indicate that flosequinan is an effective drug for patients with chronic heart failure who remain symptomatic despite treatment with digoxin and diuretic drugs. The effect of the drug on survival remains to be determined.

Attenuation of the microcirculation in young patients with high-output borderline hypertension.

Previous studies have shown abnormalities of the microvasculature in the spontaneously hypertensive rat and human subjects with established hypertension. We have studied the conjunctival microvasculature in relation to systemic and forearm hemodynamics in 24 normal subjects (NL) and 10 subjects with intermittent elevation of blood pressure (BHT). Macrophotographs of the conjunctival circulation were measured for arteriolar diameter and density of arterioles, capillaries, and venules. Blood pressure was measured by Arteriosonde, cardiac index by echocardiography, and forearm hemodynamics by mercury-filled strain-gauge venous occlusion plethysmography. Average diastolic blood pressure in the NL group was 74 +/- 1.7 mm Hg, while that of the BHT subjects was 89 +/- 3.1 mm Hg (p less than 0.005). Capillary density, venous density, and total vascular density were significantly lower in the BHT than NL group, while arteriolar density did not differ significantly. Cardiac index was significantly higher, and peripheral vascular resistance significantly lower, in the BHT as compared to the NL subjects. Forearm blood flow was higher in the NL subjects. The diameter of the preterminal arterioles of the BHT subjects was 27% greater than NL (p less than 0.02). The capillary density was inversely related to the cardiac index (r = -0.482, p less than 0.01), but was not related to blood pressure (r = -0.207). We conclude that the high cardiac output phase of early essential hypertension in humans is accompanied by a reduction in the number of filtering capillaries, and that the rarefaction of capillaries is more closely related to the elevation of cardiac output than to raised blood pressure.

Hemodynamic characteristics of sodium-sensitive human subjects.

Fifty-eight normal subjects and 51 subjects with borderline hypertension underwent microvascular and hemodynamic studies while on an ad libitum diet and during periods of sodium depletion (10 mEq/day) and repletion (200 mEq/day). Hemodynamic measurements included arterial blood pressure, cardiac index, total peripheral resistance, forearm blood flow, vascular resistance, venous compliance, and capillary filtration fraction. Studies of the microcirculation consisted of macrophotography of the bulbar conjunctiva with measurement of anteriolar, venular, and capillary density and diameter. During sodium repletion, cardiac index increased significantly in the normal subjects (2.35 +/- 0.7 vs 2.44 +/- 0.7 L/min/m2; p less than 0.01) and in the borderline hypertensive subjects (2.50 +/- 0.7 vs 2.70 +/- 0.8 L/min/m2; p less than 0.01). However, mean blood pressure rose by more than 5% in only 33 subjects, 13 with normal and 20 with borderline hypertension. When these sodium-sensitive subjects were compared with those whose blood pressure did not rise, the former were found to have significantly higher forearm vascular resistance (32.2 +/- 21 vs 17.9 +/- 12 mm Hg/ml/min/100 g; p less than 0.01), lower forearm blood flow (4.42 +/- 2.7 vs 7.47 +/- 5.0 ml/min/100 g) and lower conjunctival capillary density (3.72 +/- 1.7 vs 5.18 +/- 2.1 [SD] mm/mm2; p less than 0.05). These results indicate that sodium sensitivity in humans is accompanied by elevation of forearm vascular resistance and attenuation of the microcirculation.

The clinical aspects of estrogen and the cardiovascular system

Extensive epidemiologic and postmortem studies have identified a link between menopause and cardiovascular disease. The relation is especially strong in surgically menopausal women who do not receive estrogen replacement. More than 30 observational studies and one small randomized, controlled clinical trial have provided evidence that estrogen replacement reduces cardiovascular risk by approximately 50%. Four studies that used coronary arteriography to document the presence of coronary atherosclerosis have provided some of the most compelling evidence that estrogen replacement reduces cardiovascular risk in postmenopausal women. One study of survival in women undergoing coronary arteriography found that the greatest improvement in total mortality took place in those women with substantial coronary stenosis; less benefit was observed in those without disease. Angiographic studies have also confirmed the importance of high-density lipoprotein cholesterol in mediating the effect of estrogen and the beneficial effect of estrogen on endothelial function. Although the addition of progestins to estrogen attenuates estrogens effect on high-density lipoprotein cholesterol, limited observational daa have suggested that the cardioprotective effect is not reduced.

Sodium sensitivity in human subjects. Hemodynamic and hormonal correlates.

To investigate factors associated with sodium sensitivity, 157 subjects were studied while receiving 10 and 200 mEq sodium diets. Measurements included blood pressure (BP), forearm vascular resistance, plasma renin activity (PRA), and plasma aldosterone. Sodium repletion was associated with a greater than 5% increase in mean BP in 16% of the normotensive subjects and 29% of the borderline hypertensive subjects. Sodium-sensitive subjects were compared with sodiumresistant subjects in both the normotensive (n=92) and borderline hypertensive (n=65) groups. Forearm vascular resistance was significantly higher (p < 0.05) during sodium loading in the sodiumsensitive subgroups of both the normotensive and borderline hypertensive groups (35.8 ± 29 vs 23.8 ± 20 [SD] and 37.5 ± 29 vs 22.5 ± 14 mm Hg/ml/min/100 g, respectively. Venous capacitance was lower in the sodium-sensitive than in the sodium-resistant borderline hypertensive subjects (0.8 ± 0.21 vs 1.69 ± 0.24 ml/100 g). During sodium restriction, PRA was significantly lower (p < 0.01) in the sodium-sensitive subsets (2.56 ± 1.6 vs 4.04 ± 2.6; 2.65 ± 2.1 vs 3.88 ± 2.6 ng angiotensin I/ml/hr). Aldosterone was lower (p < 0.01) during sodium depletion in the sodium-sensitive subsets (17.3 ± 12 vs 26.3 ± 16; 18.5 ± 18 vs 27.9 ± 17 ng/ml). A significant inverse correlation existed between change in BP with sodium repletion and change in PRA or level of PRA during sodium depletion (p < 0.003). We conclude that both normotensive and borderline hypertensive sodiumsensitive subjects are characterized by an increase in forearm vascular resistance during high sodium intake and that this characteristic is associated with decreased responsiveness of the renin-aldosterone system during sodium depletion.

Sodium Sensitivity in Normotensive and Borderline Hypertensive Humans

The responses to sodium depletion and repletion were studied in subgroups of 92 normotensive and 65 borderline hypertensive individuals. The borderline hypertensives were characterized by significantly higher blood pressure, weight, cardiac output, hematocrit and decreased density of conjunctival capillaries and venules. Sodium-sensitivity was defined as an increase in mean arterial blood pressure exceeding 5% during sodium repletion. The prevalence of sodium-sensitivity was higher in blacks than in whites and greater in hypertensives than in normotensives. Sodium-sensitive individuals were characterized by significantly increased forearm vascular resistance and decreased plasma renin activity and aldosterone concentration. The resemblance of these changes to those reported in the Dahl salt-sensitive rat suggests a genetic basis for the response to sodium.

Association between the severity of diabetes mellitus and coronary arterial atherosclerosis

The relation between the severity of diabetes mellitus (DM) and the risk of significant coronary artery lesions were studied in 7,655 patients undergoing coronary arteriography for suspected coronary artery disease (CAD) between 1972 and 1982. The principal treatment regimen for DM was used to estimate the severity of DM. DM treated with insulin was defined as the most severe (n = 244), followed by DM treated with oral agents (n = 344) and with diet only (n = 380); 6,687 patients did not have DM. Severity of DM in patients with CAD (70% or greater diameter stenosis) was compared with that in control subjects without CAD (0% stenosis) for each of 9 anatomic locations (proximal, middle and distal portions of right, anterior descending and circumflex coronary arteries) using a retrospective case-control approach. The risk of CAD was highest in patients with DM treated with insulin (odds ratio estimate of the relative risk [OR = 3.0]), followed by patients with DM treated with oral agents (OR = 1.8) and lastly in those treated with diet alone (OR = 1.4). Severity of DM was a significant (p less than 0.05) independent predictor of CAD in a multivariate logistic regression model, whereas age at onset and duration of DM were not. The relative risk of CAD was the same (p greater than 0.05) for each of the 9 coronary segments. The data suggest that the risk of CAD increases with the severity of DM, which was a stronger predictor of CAD than duration of DM.(ABSTRACT TRUNCATED AT 250 WORDS)

Gender differences in labetalol kinetics: importance of determining stereoisomer kinetics for racemic drugs.

Study Objective. To evaluate the impact of gender on labetalol kinetics.