Immediate and short-term cardiovascular effects of fosinopril, a new angiotensin-converting enzyme inhibitor, in patients with essential hypertension.

Immediate and short-term cardiovascular effects of a new angiotensin-converting enzyme inhibitor, fosinopril, were assessed in 10 patients with mild to moderate essential hypertension. Administration of a 10 mg oral dose of fosinopril reduced mean arterial pressure (p less than 0.001) as a result of a 24% fall in total peripheral resistance (p less than 0.001). Short-term therapy (12 weeks) maintained the decrease in mean arterial pressure (p less than 0.05) by decreasing total peripheral resistance (p less than 0.01), without reflexive cardiac stimulation or expanding intravascular volume. Renal vascular resistance decreased (p less than 0.05) while renal blood flow, glomerular filtration rate and filtration fraction remained unchanged. The response pattern to mental, isometric and orthostatic stress was similarly unchanged. Left ventricular mass diminished by 11% (p less than 0.01); myocardial contractility was unaffected. Afterload was reduced (p less than 0.05), and velocity of circumferential fiber shortening and stroke volume increased (p less than 0.05). Thus, arterial pressure reduction produced by fosinopril was associated with improved systemic and renal hemodynamics and reduced left ventricular mass.

Hypertension and sudden death. Disparate effects of calcium entry blocker and diuretic therapy on cardiac dysrhythmias.

This study was designed to evaluate the impact of antihypertensive therapy on cardiac dysrhythmias in 13 hypertensive patients who received calcium entry blockers and in 10 hypertensive patients who received hydrochlorothiazide. Mean arterial pressure fell to a similar extent in both treatment groups; however, left ventricular mass index decreased (from 102 +/- 4 to 95 +/- 2 g/m2) only in patients receiving calcium entry blockers, but not in those taking hydrochlorothiazide. The prevalence of premature ventricular contractions decreased 74% from 21 +/- 14/h to 5.7 +/- 6/h in the calcium entry blocker group, but did not change in the hydrochlorothiazide group (15 +/- 17/h to 16 +/- 13/h). Couplets, multiform contractions, ventricular tachycardia, and supraventricular tachycardia were completely abolished after calcium entry blocker therapy, whereas the prevalence of these arrhythmias remained unchanged during treatment with hydrochlorothiazide. We conclude that antihypertensive therapy with calcium entry blockers (but not with thiazide diuretics) reduces left ventricular mass and the prevalence and severity of ventricular dysrhythmias. Whether this reduction will improve the ominous prognosis of left ventricular hypertrophy and diminish the risk of sudden death remains unknown.

Cardiac performance after reduction of myocardial hypertrophy.

PURPOSE: The current study was performed to assess the functional sequelae of reducing left ventricular hypertrophy in patients with essential hypertension. PATIENTS AND METHODS: To analyze left ventricular function and contractility in patients with essential hypertension after reduction of left ventricular hypertrophy, 14 patients with essential hypertension and left ventricular hypertrophy were studied prospectively by echocardiogram (1) before, (2) during, and (3) after left ventricular mass had been reduced by antihypertensive therapy of 19 +/- 3 months' duration. All drugs were discontinued four weeks before the first and the third study. RESULTS: At the time of the third study, arterial pressure had returned to pretreatment values, and mean, peak, and isovolumetric (but not end-systolic) wall stress increased, whereas left ventricular mass remained diminished. Despite the increased pressure load to the heart, myocardial contractility was maintained or improved after reduction of left ventricular hypertrophy, as indicated by the ratio of end-systolic wall stress to end-systolic volume index (p less than 0.02) and by the relation of fractional shortening to end-systolic wall stress (p less than 0.06). End-diastolic volume, an indicator of preload, remained reduced after therapy (p less than 0.05). As a result, pump function of the left ventricle improved as shown by an increase in the ejection fraction (p less than 0.05), fractional fiber shortening (p less than 0.05), and velocity of circumferential fiber shortening (p less than 0.01). CONCLUSION: Thus, in patients with essential hypertension, reduction of myocardial hypertrophy by antihypertensive therapy appears to be beneficial rather than detrimental to cardiac pump performance.

Does the renin-angiotensin-aldosterone system modify cardiac structure and function in essential hypertension?

To determine the impact of the renin-angiotensin-aldosterone system on left ventricular function and structure, 36 untreated patients with essential hypertension (WHO class I and II) were examined. Posterior wall thickness, relative wall thickness, and left ventricular mass were determined by M-mode echocardiography. Plasma renin activity, aldosterone, angiotensin I, and angiotensin II levels were measured by radioimmunoassay. Plasma renin activity was related to 24-hour urinary sodium excretion. Of all the endocrine parameters, only the angiotensin II level correlated with posterior wall thickness (r = 0.50, p less than 0.05) and relative wall thickness (r = 0.46, p less than 0.05). This relationship was confirmed by stepwise multiple regression analysis taking arterial pressure, obesity, and sodium excretion into account (p less than 0.05). Plasma renin activity but not the angiotensin II level correlated positively with the ejection fraction (r = 0.42, p less than 0.05) and velocity of circumferential fiber shortening (r = 0.57, p less than 0.01). Thus, angiotensin II emerged as a determinant of left ventricular structural adaptation in essential hypertension.

Hemodynamic, humoral and volume findings in systemic hypertension with isolated ventricular septal hypertrophy.

To analyze the hemodynamic, endocrine and volume characteristics of isolated septal hypertrophy (ISH) in established systemic hypertension, 22 patients with ISH were compared to 23 patients with symmetric hypertrophy and to 28 without left ventricular (LV) hypertrophy. Mean arterial pressure and 24-hour ambulatory pressure readings did not differ between the 2 groups. At the same level of arterial pressure, patients with ISH had a high cardiac index (p less than 0.02) and a faster heart rate (p less than 0.05); consequently, total peripheral resistance was decreased (p less than 0.05). Although there was no change in intravascular volume, central blood volume was expanded (p less than 0.02), and the ratio of central to peripheral blood volume was increased (p less than 0.02), thereby indicating peripheral venoconstriction. Patients with isolated ISH had greater responses of diastolic pressure and heart rate (p less than 0.05) to isometric stress than the other 2 groups. A hyperdynamic circulatory state is a hemodynamic hallmark of ISH in early essential hypertension that might be produced by increased sympathetic activity.

Myocardial contractility and left ventricular function in obese patients with essential hypertension.

Although the risk of developing congestive heart failure increases in parallel with the degree of obesity, load-dependent indexes of left ventricular function are found to be reduced in patients with morbid obesity only. We used the ratio of end-systolic wall stress to end-systolic volume index, which is load-independent, to assess myocardial contractility in 23 nonobese, 28 mildly obese and 26 moderately obese patients with mild to moderate essential hypertension. Although load-dependent indexes (i.e., ejection fraction, fractional fiber shortening and velocity of circumferential fiber shortening) were similar in the 3 groups, end-systolic wall stress to end-systolic volume index was lower in the moderately obese group (2.63 +/- 0.4, p less than 0.002) and even in the mildly obese group (2.88 +/- 0.8, p less than 0.05) than in the nonobese group (3.27 +/- 0.7). Further, there was a significant inverse relation between end-systolic wall stress to end-systolic volume index and body mass index (r = -0.34, p less than 0.005), diastolic diameter (r = -0.56, p less than 0.001) and left ventricular mass index (r = -0.55, p less than 0.001). Some obese patients have depressed myocardial contractility when compared with lean patients despite well-preserved pump function.

Immediate and short-term cardiovascular effects of a new converting enzyme inhibitor (lisinopril) in essential hypertension.

The immediate and short-term effects of lisinopril, a new converting enzyme inhibitor, on systemic and regional hemodynamics, cardiac structure and function and humoral indexes were evaluated in 10 patients with mild to moderate essential hypertension. A single oral dose of 5 mg lisinopril reduced mean arterial pressure from 118 to 104 mm Hg (p less than 0.01) and significantly increased (p less than 0.05) all load-dependent indexes of ventricular function (i.e., ejection fraction, velocity of circumferential fiber shortening and fractional fiber shortening rate). After 10 to 12 weeks of once-daily administration of lisinopril, mean arterial pressure remained reduced over a full 24-hour period (p less than 0.01), and was mediated through arteriolar dilation as expressed by the close correlation (r = 0.93, p less than 0.01) between changes in mean arterial pressure and changes in total peripheral resistance. Cardiac index decreased from 3.06 to 2.68 liters/min/m2 (p less than 0.01) without correlation to the decrease in arterial pressure (r = 0.06). Despite this reduction in cardiac index, renal blood flow increased from 861 to 1,053 ml/min (p less than 0.05) and renal vascular resistance decreased from 14 to 9 units (p less than 0.01). Left ventricular mass index decreased from 124 to 109 g/m2 (p less than 0.05), and left ventricular function remained unchanged. Thus, the decrease in arterial pressure produced by lisinopril was associated with improved renal hemodynamics and reduced left ventricular mass.

Cardiovascular effects of isradipine in essential hypertension.

The immediate and short-term cardiovascular effects of oral isradipine therapy were evaluated in 11 patients with mild to moderate systemic hypertension. Isradipine, 5 mg administered orally, induced a significant reduction in arterial pressure from 165 +/- 6/88 +/- 3 mm Hg to 140 +/- 5/76 +/- 2 mm Hg (p less than 0.001) within 2.5 hours by a decrease in total peripheral resistance associated with an increase in heart rate and cardiac output. Contrary to the acute effect, oral therapy with isradipine for 3 months reduced arterial pressure through a decrease in total peripheral resistance but without causing an increase in heart rate or cardiac output or activation of the sympathetic nervous system. Isradipine slightly reduced left ventricular mass and improved cardiac systolic function and left ventricular filling. Renal blood flow increased, and renal vascular resistance (p less than 0.01) and total blood volume (p less than 0.002) decreased without a change in either sodium excretion or body weight. Thus, isradipine, when given for 3 months, decreased arterial pressure by reducing total peripheral resistance without activation of reflexive mechanisms. Its favorable effects on systemic hemodynamics, total blood volume, renal blood flow, and cardiac structure and function suggest isradipine to be an excellent choice for antihypertensive therapy.

Disparate hemodynamic and sympathoadrenergic responses to isometric and mental stress in essential hypertension.

The hemodynamic and sympathoadrenergic responses during isometric handgrip and mental arithmetic tests were compared in 18 patients with mild essential hypertension. Mean blood pressure increased significantly after both maneuvers (27% during isometric stress and 10.7% during mental stress), but the increase was significantly higher during isometric stress (p less than 0.001). Both stressors increased the heart rate (p less than 0.001) and cardiac output (p less than 0.001). However, the total peripheral resistance behaved differently, for it increased during isometric stress (p less than 0.05) and remained unchanged during mental stress. Both stressors increased the epinephrine levels (p less than 0.005), but only isometric stress increased the norepinephrine levels (p less than 0.001). It is concluded that both stressors increase cardiac output by way of an increase in heart rate, but isometric stress also increases total peripheral resistance and thus causes a greater increase in arterial pressure. Isometric stress activates both the adrenergic and noradrenergic systems, thereby accounting for the exaggerated response in arterial pressure, whereas mental stress stimulates the adrenergic system only.

Comparison of diastolic left ventricular filling and cardiac dysrhythmias in hypertensive patients with and without isolated septal hypertrophy.

Although many patients with hypertension develop isolated septal hypertrophy (ISH) rather than concentric or eccentric left ventricular (LV) hypertrophy, limited data are available on cardiac structure, function, and arrhythmias in hypertensive patients with ISH. Clinical features, hemodynamics, M-mode echocardiograms, and 24-hour electrocardiographic recordings were evaluated in 21 healthy normotensive subjects, 23 hypertensive patients without LV hypertrophy, 31 hypertensive patients with concentric LV hypertrophy, and 23 hypertensive patients with ISH to determine the prevalence and complexity of cardiac arrhythmias and diastolic LV filling abnormalities. Age, sex, race, obesity indexes, preload, ejection fraction, and LV contractility were similar in all 4 groups, and arterial pressure and afterload were statistically similar in the 3 hypertensive groups. Left atrial emptying index (p < 0.01) and peak LV filling rate (p < 0.01), 2 indexes of diastolic LV filling, were significantly reduced in the 3 hypertensive groups compared with the normotensive group. The duration of rapid LV filling, however, was significantly prolonged only in hypertensive patients with concentric LV hypertrophy and ISH (p < 0.05) but not in hypertensive patients without LV hypertrophy. The prevalence (p < 0.001) and complexity (p < 0.001) of ventricular ectopic activity was also significantly increased to a similar degree in hypertensive patients with concentric LV hypertrophy and in those with ISH compared with normotensive subjects or hypertensive patients without LV hypertrophy. The prevalence and complexity of atrial ectopic activity was only increased significantly (p < 0.001) in those with ISH.

Angiotensin converting enzyme inhibitors. Disparities in the mechanism of their antihypertensive effect.

Systemic and renal hemodynamics were studied by invasive and noninvasive techniques in 30 patients with mild to moderate essential hypertension before and after antihypertensive therapy with captopril (12 patients), enalapril (8 patients), and lisinopril (10 patients). All three angiotensin-converting enzyme (ACE) inhibitors reduced arterial pressure to about the same extent: captopril by 14%, enalapril by 18%, and lisinopril by 13%. However, lisinopril produced a significant fall (14%, P less than 0.001) in cardiac output that was not seen with captopril or enalapril therapy. Moreover, lisinopril elicited an increase in renal blood flow (22%, P less than 0.05) that was more marked than that with enalapril (12%) or captopril (4%). Although left ventricular mass was reduced (P less than 0.05) with all three agents, enalapril induced a twofold greater reduction (29%) than captopril (14%) or lisinopril (12%). These findings suggest that systemic and renal hemodynamic effects may be drug specific and not uniform for all ACE inhibitors.

Antihypertensive therapy and cardiovascular reactivity during isometric stress.

The cardiovascular reactivity to isometric stress test before and after antihypertensive therapy was evaluated by invasive haemodynamic techniques in 23 patients with mild to moderate essential hypertension. A beta-blocking agent (atenolol 50 to 100 mg daily) was given to 11 patients; 12 patients received calcium entry blockers (diltiazem 240 to 360 mg daily or verapamil 240 to 480 mg per day). The pressor response to isometric stress before therapy consisted of an increase in systolic, diastolic, and mean arterial pressure (all P less than 0.01) that was similar in both treatment groups. The rise in arterial pressure was mainly due to an increase in cardiac output (P less than 0.01), as total peripheral resistance did not change significantly. After treatment with the beta-blocker, the increase in total peripheral resistance during isometric stress was exaggerated (P less than 0.01), and, conversely, the increase in cardiac output was attenuated (P less than 0.01). In contrast, treatment with calcium entry blockers preserved the haemodynamic reactivity pattern of the untreated state: arterial pressure increased during isometric stress through an increase in cardiac output, while total peripheral resistance remained unchanged. Since the haemodynamic culprit of essential hypertension is an elevated peripheral resistance, a drug that numerically increases this culprit under conditions of resting and isometric stress becomes less attractive than one that lowers peripheral resistance and preserves the physiologic response pattern.

Serum uric acid in renovascular hypertension: reduction following surgical correction.

Mild hyperuricemia in patients with essential hypertension reflects early renal vascular involvement. This report describes a retrospective analysis of 28 patients with unilateral renal arterial disease and hypertension who underwent surgical treatment. Following surgical repair of the arterial lesion: systolic pressure decreased from 188 +/- 25 to 146 +/- 21 mm Hg (p less than 0.001); diastolic pressure decreased from 108 +/- 4 to 87 +/- 6 mm Hg (p less than 0.001), and serum uric acid and creatinine concentrations decreased from 7.0 +/- 1.1 to 6.1 +/- 1.4 mg/dL and from 1.3 +/- 0.3 to 1.0 +/- 0.3 (p less than 0.02 and p less than 0.03, respectively). The reduced serum potassium levels, reflecting hyperaldosteronism, increased after surgical treatment (p less than 0.003). The 28 patients were classified in three groups according to previous therapy: group I (14 patients) had been treated with a centrally active adrenergic agonist or a beta adrenergic receptor blocking agent; group II (7 patients) had been treated with a diuretic, and group III (7 patients) had never received antihypertensive therapy. Serum uric acid concentrations were similar in each of the three groups and decreased significantly in each group after correction of the renal artery stenosis. These data strengthen our previous observations and further suggest that serum uric acid concentration may be useful as an index of renal vascular involvement in hypertension.

Systemic and regional hemodynamic and humoral effects of nitrendipine in essential hypertension.

The hemodynamic effects of 3 months of nitrendipine therapy were evaluated in 14 patients with mild to moderate essential hypertension. Nitrendipine reduced systolic and diastolic pressures from 145 +/- 4/95 +/- 3 to 119 +/- 3/78 +/- 2 mm Hg, respectively, (p less than 0.001) through a fall in total peripheral resistance index (46 +/- 4 to 34 +/- 3 units/m2, p less than 0.001) without associated reflex cardiac stimulation. This antihypertensive effect was related directly to the height of pretreatment arterial pressure (r = -0.67, p = 0.006) but not to age or pretreatment plasma renin activity. Renal and forearm blood flow increased, vascular resistance decreased, and glomerular filtration rate remained stable. In addition, nitrendipine reduced left ventricular mass index (133 +/- 7 to 116 +/- 5 g/m2, p = 0.003) and wall thickness, changes that were accompanied by improvement in diastolic as well as systolic (ejection fraction and fractional fiber shortening rate) left ventricular functions. Intravascular volume did not expand with reduction in pressure. This study provides new information concerning the long-term hemodynamic effects and associated echocardiographic changes with nitrendipine. It also provides the first regional hemodynamic data in essential hypertensive patients detailing forearm and splanchnic changes and renal blood flow increase during prolonged treatment.

Hypertensive concentric left ventricular hypertrophy: when is ventricular ectopic activity increased?

The Framingham Study has indicated that patients with left ventricular hypertrophy (LVH) have a greater risk of cardiovascular complications and sudden death than subjects with a normal heart. We have previously demonstrated that ventricular ectopy was more prevalent and complex in hypertensive patients with LVH by electrocardiographic (ECG) criteria than in those without ECG evidence of LVH. The present study was designed to detect and quantify ventricular dysrhythmias in hypertensive patients with early concentric LVH by echocardiography but without LVH by ECG criteria. Continuous ambulatory ECG tracings were recorded for 24 hours in 94 patients with essential hypertension: 37 without LVH, 26 with concentric LVH by echocardiographic but not ECG criteria, and 31 with LVH on both echocardiography and ECG. Patients with LVH by ECG criteria had significantly more premature ventricular contractions (P less than .001) and more complex (higher Lown's class) ventricular ectopy (P less than .001) than hypertensives without LVH or with LVH only by echocardiographic criteria. Prevalence and complexity of ventricular ectopic activity, however, was not affected by mild to moderate concentric cardiac hypertrophy detected echocardiographically. We conclude that unlike LVH shown by ECG, early hypertensive concentric LVH detected echocardiographically is not associated with increased electrical irritability of the myocardium.

Dietary salt intake. A determinant of cardiac involvement in essential hypertension.

Because a given increase in afterload does not consistently produce the same degree of left ventricular hypertrophy, we evaluated several clinical, hemodynamic, and endocrine factors that are prone to modify the adaptation of left ventricular structure in patients with mild essential hypertension (World Health Organization stages I or II). Dietary salt intake assessed by sodium excretion over 24 hours was a powerful determinant of posterior wall thickness (r = 0.64, p less than 0.001), relative wall thickness (r = 0.67, p less than 0.001), and left ventricular mass (r = 0.37, p less than 0.05). In contrast, diastolic pressure, body mass index, hematocrit, and epinephrine were found to be weaker determinants of left ventricular structure (r = 0.31-0.40, p less than 0.05). A stepwise multiple regression analysis revealed that sodium excretion was the strongest predictor for posterior wall thickness (p less than 0.02) and relative wall thickness (p less than 0.05) independent of the other examined variables. These results identify dietary salt intake as a strong determinant of cardiac structural adaptation to a persistent increase in arterial pressure. Consequently, a high salt intake might aggravate and, conversely, dietary salt restriction might prevent (or at least mitigate) the development of left ventricular hypertrophy in patients with essential hypertension.

Cardiovascular effects of verapamil in patients with essential hypertension.

The cardiovascular effects of intravenous verapamil and 3 months of oral administration of a slow-release form of verapamil (verapamil-SR) were studied in 10 patients with mild-to-moderate essential hypertension. Intravenous verapamil reduced arterial pressure by 15% (p less than .01) through a fall in total peripheral resistance of 29% (p less than .01); provoked a reflexive rise in heart rate (by 19%, p less than .02), cardiac output (by 74%, p less than .01), and plasma catecholamines; and shifted intravascular volume toward the cardiopulmonary circulation indicating peripheral venoconstriction. Quite in contrast to the immediate effects of the intravenous drug, oral therapy with verapamil-SR for 2 to 3 months lowered arterial pressure effectively (by 15%, p less than .01) by inducing vasodilation of 15% (p less than .02), but without causing reflex tachycardia, activation of the sympathetic-adrenergic or renin-angiotensin systems, or volume expansion. Oral therapy with verapamil-SR preserved systemic and renal blood flow and slightly reduced cardiac mass (by 6%, p less than .05) and renal vascular resistance (by 25%, p less than .05). Whereas intravenous verapamil tended to depress myocardial contractility, oral verapamil-SR did not at all affect myocardial contractility or left ventricular function. These cardiovascular effects make verapamil-SR an excellent agent for long-term antihypertensive therapy.

Sex differences in cardiac adaptation to essential hypertension.

Left ventricular functional and structural adaptations to mild essential hypertension were assessed by 2D-guided M-mode echocardiography in a population of premenopausal and postmenopausal women (n = 29) who were matched with the same number of men with regard to mean arterial pressure, age and race. Premenopausal women had a thinner posterial wall (P less than 0.05), a smaller left ventricular systolic and diastolic diameter, and a smaller left ventricular mass than men with the same level of arterial pressure. Left ventricular performance indices, ejection fraction, velocity of circumferential fibre shortening, and the ratio of the end-systolic wall stress to the end-systolic volume index (a load-insensitive contractility index) were higher in women than in men. These sex differences were most pronounced before the menopause and tended to disappear thereafter. We conclude that in the presence of the same level of arterial pressure, women have smaller left ventricular dimensions and enhanced ventricular performance compared with men. These differences in cardiac adaptations between the genders may account for the lower risk of cardiovascular morbidity and mortality in premenopausal women with essential hypertension.

Disparate cardiovascular findings in men and women with essential hypertension.

We measured systemic hemodynamic, volume, and endocrine findings in 100 hypertensive women matched to 100 men by mean arterial pressure, age, race, and body surface area. Women had a higher resting heart rate, cardiac index, and pulse pressure and lower total peripheral resistance (all p less than 0.01) than men with the same pressure level. Isometric stress caused an increase in arterial pressure that was almost 50% higher in men than in women. The sexual difference in cardiovascular findings was significant before but not after menopause. For any level of arterial pressure, total peripheral resistance (and therefore the risk of hypertensive cardiovascular disease) was lower in women than in men. We conclude that premenopausal women are hemodynamically younger than men of the same chronologic age. Our study identifies a pathophysiologic mechanism for the clinical and epidemiologic finding that essential hypertension is less lethal in women than in men.

Biventricular cardiac hypertrophy in essential hypertension.

Left ventricular hypertrophy (LVH) is the major adaptation of the heart to a prolonged increase in the left ventricular afterload in hypertension. However, the structure and function of the right ventricle have received little attention. The present study was designed to assess right ventricular structural changes in patients with established essential hypertension. To accomplish this, M-mode echocardiograms were obtained from 15 healthy normotensive subjects and 35 patients with essential hypertension-15 with normal left ventricles and 20 with clear-cut echocardiographic evidence of LVH. In comparison with the normotensive subjects, right ventricular wall thickness was increased almost twofold in the hypertensive patients with LVH (7.0 +/- 2.1 mm vs 3.7 +/- 0.8 mm; p less than 0.001); there was a significant, direct correlation between right and left ventricular wall thickness in the entire patient population (r = 0.65; p less than 0.001). Furthermore, the left atrial emptying index was significantly reduced in all patients with hypertension regardless of whether LVH was present (p less than 0.001) and suggests early diastolic functional involvement of the left ventricle in hypertension. We therefore conclude that right ventricular hypertrophy is associated with LVH in patients with hypertension, although the changes of LVH are frequently more obvious to the clinician.