Amlodipine: effective for treatment of mild to moderate essential hypertension and left ventricular hypertrophy

This was a 20-week, open-label, uncontrolled clinical investigation of the long-acting calcium antagonist amlodipine in 33 male or female patients with essential hypertension and left ventricular hypertrophy (LVH). A once-daily dose (5-10 mg/day) of amlodipine provided a consistent antihypertensive effect, reducing the sitting diastolic (-13.8% change) and systolic (-13.0% change) blood pressures by clinically meaningful and statistically significant (p = 0.0001, n = 33) amounts. Amlodipine had no effect on heart rate. A significant regression in LVH was seen (left ventricular mass index reduced from 169.0 [SD 30.7] g/m(2) to 140.6 [SD 19.6] g/m(2), p < 0.01, n = 12). There was also a significant reduction in total peripheral resistance and improvement in left ventricular diastolic filling (E/A ratio increased from 0.86 pre-treatment to 1.03 post-treatment, p = 0.038, n = 12). These results are consistent with other studies in showing that a relatively short treatment regimen with amlodipine is associated with a significant reduction in left ventricular mass index.     

Determinants of left ventricular hypertrophy in arterial hypertension

A long term study (2-7 years, mean 3.6 years) monitoring 112 clinical and echocardiographic pattern in 593 hypertensives and 156 normotensives was performed in order to find associations to left ventricular hypertrophy (LVH) developing later. 49% of the hypertensives developed echocardiographic signs of LVH (wall thickness of 12 mm and more), in contrast to 5.1% of normotensive persons. Multivariate analysis revealed the following parameters examined at entry were associated with LVH on follow-up: male sex, prolonged hypertensive history, higher diastolic blood pressure, frequent lipid-metabolism disturbances, uncharacteristic chest pain and less effective antihypertensive treatment. Thus, LVH development can be regarded as a multifactorial process.     

Atrial natriuretic peptide, left ventricular mass and renin-angiotensin-aldosterone system in essential arterial hypertension of a mild or moderate degree]

OBJECTIVE. The relationship between plasma atrial natriuretic peptide (ANP), renin-angiotensin-aldosterone system and left ventricular mass in essential hypertension was assessed. PATIENTS AND METHODS. Immunoreactive ANP in 10 normal subjects and 20 untreated patients with mild to moderate essential hypertension was compared with echocardiographic measurement of cardiac size, function and blood pressure. Venous plasma concentrations of ANP were also studied in relation to urinary sodium and potassium excretion, as well as the renin-angiotensin-aldosterone system. RESULTS. Plasma ANP was higher in hypertensive patients (25.3 +/- 13.3 pg/ml; p = 0.003) than normotensive subjects (11.1 +/- 2.7 pg/ml). In hypertensive patients, plasma ANP was inversely related to plasma renin activity (PRA) (r = -0.6; p = 0.009). No relationship was found between ANP and blood pressure, nor between the indices of left ventricular mass and function or urinary electrolytes. CONCLUSIONS. This study showed that circulating ANP is, in average, significantly increased in hypertensive patients, consistent with previous reports. Our data do not support a direct link between left ventricular mass and increased plasma ANP levels in hypertensive patients. Whether the inverse relationship between ANP and PRA in this pathologic state is a direct one or merely a secondary association has not been clearly established.     

Influence of the arterial blood pressure and nonhemodynamic factors on left ventricular hypertrophy in moderate essential hypertension.

In a group of 36 untreated patients with mild to moderate essential hypertension (office systolic and diastolic blood pressures (BPs) 160 +/- 3.4 and 102 +/- 1.5 mm Hg, respectively), a 24-hour ambulatory BP monitoring and determination of left ventricular (LV) mass index according to the formula of Devereux were performed. After an overnight fast, blood samples were taken for the determination of serum aldosterone, plasma renin activity and serum parathyroid hormone. Urinary catecholamines were sampled for 24 hours. LV mass index (143.7 +/- 8 g/m2) did not correlate significantly either with office systolic or diastolic BP. The correlation of LV mass index with mean 24-hour systolic BP (145 +/- 3 mm Hg) was statistically significant: r = 0.395, p = 0.026. However, the best correlation was obtained with mean 24-hour diastolic BP (90 +/- 3 mm Hg) with r = 0.500 (p = 0.004). Urinary catecholamines were not correlated with LV mass index. LV mass index correlated significantly with plasma renin activity (r = 0.346, p = 0.050), and aldosterone (r = 0.559, p = 0.001). There was a very significant correlation between LV mass index and parathyroid hormone (r = 0.719, p = 0.00001) even after adjustment for mean 24-hour systolic and diastolic BPs. These results clearly demonstrate that ambulatory BP determinants but not office BP parameters are well correlated with LV hypertrophy in essential hypertension. Nonhemodynamic factors are important determinants of LV mass as well. Besides the renin-angiotensin-aldosterone system, parathyroid hormone appears to play an important role in cardiac hypertrophy.     

Arterial hypertension, left ventricular hypertrophy and arrhythmias]

Arterial hypertension is the most common cause of chronic pressure overload of the left ventricle. Electrocardiographic and echocardiographic signs of left ventricular hypertrophy in hypertensive patients are associated with an increased cardiovascular mortality and incidence of sudden death habitually due to ventricular arrhythmias. The significance of a normal increase in systolic blood pressure during exercise in persons without evident resting hypertension is uncertain. M-mode and 2D echocardiography, 24-hour continuous ambulatory electrocardiographic (Holter), exercise testing and 24-hour ambulatory blood pressure monitoring (ABPM) were performed on 22 normotensive patients (group I); 25 normotensives with exaggerated blood pressure response to exercise (greater than 220 mmHg) (group II) and 33 hypertensive patients (group III). None was taking cardioactive drugs. Left ventricular hypertrophy (LVH) was found on one patient of group I (4.5%), 13 of group II (52%) and 20 of group III (61%). Left ventricular mass index (LVMI) was linearly correlated with maximum exercise blood pressure (group I: r2 = 0.518, p less than 0.0002; group II: r2 = 0.098, NS; group III: r2 = 0.407, p less than 0.0001) with 24-hour systolic pressure overload (ABPM) (group I: r2 = 0.848, p less than 0.0001; group II: r2 = 0.705, p less than 0.0001; group III: r2 = 0.839, p less than 0.0001) and 24-hour diastolic pressure overload (ABPM) (group I: r2 = 0.612, p less than 0.0001; group II: r2 = 0.815, p less than 0.0001; group III: r2 = 0.807, p less than 0.0001) within each group but not between different groups. The hypertensive subjects (group III) had a higher average heart rate (p less than 0.0001) more supraventricular premature (p less than 0.0001) and ventricular premature (p less than 0.0001) beats than the normotensive (group I) and normotensive patients with abnormal increases in systolic blood pressure response to exercise (group II) (p less than 0.0001) (NS) and (p less than 0.0002), respectively. LVMI was linearly correlated with ventricular premature beats (group I: r2 = 0.072, NS; group II: r2 = 0.823, p less than 0.0001; group III: r2 = 0.691, p less than 0.0001). Frequent and complex ventricular arrhythmias were more common in patients with LVH normotensives or hypertensives than without LVI (p less than 0.0001) and the age increases their severity. We conclude that normotensives with hypertensive response to exercise have similar incidence of LVI; if those patients develop sustained hypertension, LVI was previous to arterial hypertension. There are two types of hypertrophy: secondary hypertrophy is linked to the high afterload and vasoconstriction typical in hypertension.(ABSTRACT TRUNCATED AT 400 WORDS)     

Ambulatory pulse pressure, left ventricular hypertrophy and function in arterial hypertension

BACKGROUND: A wide pulse pressure (PP) can provide important risk assessment information about myocardial infarction, carotid artery atherosclerosis, and global cardiovascular risk. Ambulatory pulse pressure (APP) does not have a well-known prognostic value in hypertensive patients. METHODS:To evaluate the relationship among high APP, atrial volumes, and cardiac function, an observational study was performed on 108 untreated non-elderly hypertensive patients (mean age 54.23 +/- 7.12). Twenty-four-hour ambulatory blood pressure monitoring, Doppler and echocardiographic measurements of systolic, diastolic function, left and right atrial volumes, left ventricular mass index and dimensions, were performed in subjects with both clinic and APP > 60 mmHg (APP1 Group). A control group of hypertensive selected subjects with both clinic and APP < 60 mmHg was chosen (APP 2 Group). RESULTS: The APP1 group showed left atrial volume enlargement, high left ventricular mass index, and impaired diastolic function. A positive correlation was found in the APP1 group results among left ventricular end diastolic diameter (r = 0.39, P < 0.01), left atrial volume (0.38, P < 0.05), and left ventricular mass index (r = 0.33, P < 0.05); clinic PP showed a statistically significant correlation with left atrial volume, left ventricular end diastolic diameter, and left ventricular mass index only in the APP1 group. CONCLUSIONS: These results suggest that elevated APP can be considered an effective predictor of cardiovascular risk in hypertensive subjects. In these patients echocardiographic evaluation of left ventricular function and morphology can increase the prognostic value of PP.     

Effect of diltiazem on left ventricular mass and diastolic filling in mild to moderate hypertension

It is still uncertain whether antihypertensive therapy with calcium antagonists in general, and diltiazem in particular, can reduce left ventricular (LV) mass index and improve LV diastolic filling in hypertension. Therefore, 24 patients with mild to moderate hypertension (diastolic blood pressure 95 to 114 mm Hg before therapy) were randomly assigned to receive either a sustained-release preparation of diltiazem (n = 13) or placebo (n = 11) for 16 weeks in a double-blind, parallel-group protocol. M-mode and pulsed Doppler echocardiograms were performed at baseline and at the end of monotherapy. Echocardiograms were read blindly by 2 independent observers. The patients who received placebo exhibited no change in blood pressure, cardiac dimensions or LV function. Diltiazem significantly reduced both systolic pressure (151 +/- 14 to 139 +/- 12 mm Hg) and diastolic pressure (101 +/- 4 to 90 +/- 7 mm Hg, both p less than 0.05). Posterior wall and septal wall thicknesses decreased, but the changes were not statistically significant. End-diastolic dimension was reduced by diltiazem from 53 +/- 5 to 51 +/- 5 mm (p less than 0.05). LV mass index decreased significantly with diltiazem by 10%, from 125 +/- 21 to 113 +/- 23 g/m2 (p less than 0.05). The LV wall thickness to radius ratio remained unchanged during both diltiazem and placebo treatments. Changes in LV mass index and blood pressure did not correlate, suggesting that this response is influenced by factors other than pressure reduction alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

The usefulness of the electrocardiogram in the diagnosis of left ventricular hypertrophy in essential arterial hypertension]

The aim of the study is to analyse the usefulness of electrocardiographic criteria of left ventricular hypertrophy in essential hypertension. Seventy four patients (27 males, 47 females), 49 +/- 11 years--old with mild--moderate systemic hypertension (blood pressure greater than or equal to 140/90 mmHg) have been prospectively studied. A 12-lead electrocardiogram and an echocardiogram (M and 2D mode) have been performed after the basic clinical study. A left ventricular mass index (Devereux's method) greater than 131 g/square meters (males) or greater than 110 g/square meters (females) has been considered as left ventricular hypertrophy. Sensitivity, specificity and accuracy of 11 current electrocardiographic criteria of left ventricular hypertrophy have been determined. Sensitivity of these criteria was very low (0-0.35), while specificity was high (0.71-1). Total QRS voltage showed the best accuracy (0.51), while V5 or V6 R wave amplitude greater than 26 mm showed the best sensitivity (0.35). Current electrocardiographic criteria of left ventricular hypertrophy are not very useful in the diagnosis of left ventricular hypertrophy in essential hypertension.     

Coronary reserve in treated hypertension with persistent left ventricular hypertrophy]

It has been demonstrated that coronary reserve (CR) is impaired in hypertensive patients with left ventricular hypertrophy and normal epicardial coronary arteries. The present study was undertaken in order to determine if CR returns to normal level after antihypertensive therapy in patients with persistent left ventricular hypertrophy, when the decrease of arterial blood pressure induces a reduction of LV wall stress (LVWS). In 26 patients with normal coronary arteriography, end-diastolic wall thickness (EDWT), LV mass (LVM) and peak systolic LVWS were determined on 30 degrees right anterior oblique LV angiography with simultaneous recording of LV pressure (micromanometer). Coronary flow velocity was measured with a coronary doppler catheter before and after a maximally vasodilating dose of intracoronary papaverine (12 mg). The study group included 6 untreated (G1) and 7 treated (G2) hypertensive patients with LV hypertrophy, and 13 control subjects (C). The peak-to-resting coronary flow velocity ratio (P/R) and a minimal coronary vascular resistance index (MCVRI) calculated as the quotient of mean aortic pressure at peak flow velocity to peak flow velocity and mean aortic pressure at resting flow velocity to resting flow velocity were assessed. Results evidenced that in hypertensive patients with LV hypertrophy, levels of P/R and MCVRI were similar in treated and untreated groups. Thus, in treated patients P/R remained lower and MCVRI remained higher than in control subjects despite the normalization of arterial pressure that resulted in a low peak systolic LVWS. [table: see text] Conclusion: this study demonstrates that anti-hypertensive therapy does not restore a normal coronary vascular reserve in patients with persistent LV hypertrophy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Left ventricular performance in patients with left ventricular hypertrophy caused by systemic arterial hypertension.

To assess the adaptation of the left ventricle to a chronic pressure overload we used echocardiography to study 18 patients with left ventricular hypertrophy caused by systemic arterial hypertension. Increased values for either posterior wall or interventricular septal thickness or both confirmed the presence of left ventricular hypertrophy in all patients and an increase in the average wall thickness to radius ratio was consistent with the development of concentric hypertrophy. No patient had clinical evidence of ischaemic heart disease. Ejection phase indices of left ventricular performance (mean Vcf, fractional per cent of shortening, normalised posterior wall velocity, and ejection fraction) were within the normal range in the basal state in 16 of the 18 patients. The hypothesis is advanced that patients with concentric left ventricular hypertrophy resulting from systemic arterial hypertension usually have normal left ventricular performance in the basal state because values for wall stress remain within the normal range. We conclude that the hypertrophic response to a chronic increase in systemic arterial pressure does not per se result in depression of the basal inotropic state of the left ventricle.     

Left ventricular performance in patients with left ventricular hypertrophy caused by systemic arterial hypertension.

To assess the adaptation of the left ventricle to a chronic pressure overload we used echocardiography to study 18 patients with left ventricular hypertrophy caused by systemic arterial hypertension. Increased values for either posterior wall or interventricular septal thickness or both confirmed the presence of left ventricular hypertrophy in all patients and an increase in the average wall thickness to radius ratio was consistent with the development of concentric hypertrophy. No patient had clinical evidence of ischaemic heart disease. Ejection phase indices of left ventricular performance (mean Vcf, fractional per cent of shortening, normalised posterior wall velocity, and ejection fraction) were within the normal range in the basal state in 16 of the 18 patients. The hypothesis is advanced that patients with concentric left ventricular hypertrophy resulting from systemic arterial hypertension usually have normal left ventricular performance in the basal state because values for wall stress remain within the normal range. We conclude that the hypertrophic response to a chronic increase in systemic arterial pressure does not per se result in depression of the basal inotropic state of the left ventricle.     

Index of left ventricular hypertrophy in adolescents genetically predisposed to the development of arterial hypertension

Experimental studies on strains of normotensive rats genetically prone to hypertension and investigations on humans with borderline hypertension have shown an early involvement of the heart, mainly consisting in a trend to ventricular hypertrophy. To assess whether such alterations may preceed or follow the elevation of blood pressure, subjects who will develop hypertension, but whose blood pressure is currently normal must be studied. For this reason, we studied by means of M-mode echocardiography 51 normotensive males aged 14-19 years with family history for hypertension (at least one hypertensive parent; SHT). Fifty-five normotensive subjects with both normotensive parents (SNT), matched for sex and age, were the controls. Average values of the following parameters were significantly higher in SHT than in SNT subjects: interventricular septum (5.4 +/- 0.8 versus 4.9 +/- 0.9 mm/m2; p less than 0.01) and posterior wall (5.4 +/- 1.1 versus 5.0 +/- 0.8 mm/m2; p less than 0.05) thickness, left ventricular mass (125.0 +/- 29.1 versus 109.2 +/- 25.4 g/m2; p less than 0.005) and cross sectional area (10.0 +/- 1.8 versus 8.9 +/- 1.6 cm2/m2; p less than 0.005). No significant difference between the two groups was observed in the indexes of left ventricular function. The existence of alterations of cardiac morphology in normotensive adolescents with genetic risk of hypertension shows that the cardiac involvement may preceed the development of high blood pressure.     

Human chymase expression in a mice induces mild hypertension with left ventricular hypertrophy.

A number of in vitro studies have suggested potential pathophysiological roles of human (h-) chymase. However, the lack of an appropriate animal model has left the in vivo roles of chymase unclear. To approach this problem, a transgenic mouse (TGM) model carrying the h-chymase gene was established. The h-chymase cDNA transgene was constructed with the chicken beta actin promoter and cytomegalovirus immediate early gene enhancer, and injected into mouse oocytes. Homozygous mice with a high copy number of the h-chymase gene suffered from intrauterine death. In three heterozygous TGM lines, h-chymase transgene expression was detected in entire organs, including the heart, vessels, skin, liver, lung, and brain. The h-chymase immunoreactivity was localized in the extracellular matrices of each organ, especially on the basement membranes of vessels. Aortic and hepatic chymase-dependent angiotensin II formations were significantly higher than those in the wild-type littermates. Three independent TGM lines showed the same phenotypic changes: elevation of blood pressure, left ventricular hypertrophy, emaciation with reduction in the lipid tissue, leukocytosis, and oligotrichia. The angiotensin II subtype 1 (AT1) receptor antagonist valsartan suppressed the elevated blood pressure completely and left ventricular hypertrophy incompletely, but did not affect the other phenotypes. These data suggested that in vivo expression of h-chymase caused mild hypertension (AT1 receptor-dependent) with left ventricular hypertrophy (partially AT1 receptor-dependent), and also chronic inflammatory changes (AT1 receptor-independent).     

Restoring normal coronary reserve in treated hypertension without left ventricular hypertrophy]

It has been previously demonstrated that coronary vascular reserve (CVR) was severely impaired in hypertensive patients with left ventricular hypertrophy (LVH), even after anti-hypertensive therapy. To assess if CVR was similarly depressed in hypertensive patients without LVH, peak-to-resting coronary flow velocity ratio (P/R) and a minimal coronary vascular resistance index (MCVRI) were determined with a coronary Doppler catheter placed into the left anterior descending coronary artery and maximally vasodilating dose of intracoronary papaverine (12 mg) in 16 control subjects (C), 7 untreated hypertensives without LVH (G1), and 7 hypertensives without LVH treated for at least one year (G2). All subjects and patients had normal left ventricular angiography and coronary arteriography. Left ventricular and aortic pressures, rate-pressure-product (RPP) were significantly elevated in G1 and were similar to those of control subjects in G2. Results evidenced that P/R was reduced and that MCVRI was increased in G1. However, these alterations were moderate. In G2, these two indices were similar to those of control subjects: [table: see text] Conclusions: These results suggest: 1) that alterations of coronary microcirculation occur before left ventricular hypertrophy in hypertensive patients; 2) that anti-hypertensive therapy may restore a normal coronary vascular reserve in hypertensive patients without LVH, when coronary vascular reserve remained severely impaired despite normalization of arterial pressure in patients with persistent LVH.     

Relationship between the force of left atrial ejection to left ventricular function in arterial hypertension]

The left atrial ejection force (LAEF), defined as that force exerted by the left atrium (LA) to accelerate the blood into the left ventricle during atrial systole, is well accepted for the evaluation of LA systolic function. The aim of this study is to determine whether LAEF is a precursor of the impairement of LV systolic function in patients with arterial hypertension (HTN). For that purpose we studied LAEF in 36 patients with HTN (av. age 58 +/- 8 years) with LV hypertrophy (Lvmi > 134 g/m2 for men and > 110 g/m2 for women). LV systolic function estimated by the fractional shortening (FSh) was 35 +/- 4% (28 to 44); 32 normal subjects (NS) were also analyzed. All subjects were submitted to echo and doppler examinations. METHODS: LAEF was obtained by the formula: 1/3 x MVA x (A-vel)2, where MVA is mitral valve area measured by 2D echo while A-vel. is the late diastolic (atrial) mitral velocity. RESULTS: 1. LAEF increased significantly with age in NS (r = 0.78) p < 0.05). Age corrected LEAF was calculated as % LEAF = (actual LAEF/normal LAEF x 100. 2. Compared to NS. % LAEF was lower in HTN (78 + 25%). 3. There was a significant inverse correlation between LAEF and LV wall thickness (r = -0.46) (p < 0.05). 4. % LAEF was 66 +/- 31% in patients with FSh < 33% and 79 +/- 25% in those with FSh > 33% (p < 0.05). 5. In HTN with the duration > 15 years, % LAEF was lower than in patients with < 15 years (62 +/- 25 vs 76 +/- 24) (p < 0.05). CONCLUSIONS: 1. LAEF is decreased in more advance stages of HTN. 2. This impairment is related to LV hypertrophy and to the duration of the disease. 3. LAEF is a sensitive precursor for LV systolic deterioration in patients with hypertension.     

Left ventricular morphology and function in mild to moderate essential hypertension

150 males with mild to moderate essential hypertension [EH] were examined echocardiographically and the findings in the left ventricle [LV] were compared with those in 20 normotensive men. Increased LV wall thickness and LV mass was found in 81% and 67% of hypertensives respectively in contrast with a complete absence of LV hypertrophy in normotensives. The former showed also a tendency to the concentric type hypertrophy, which can be considered a characteristic feature of the 2nd stage [WHO] EH. There was an almost uniform incidence of asymmetric septal hypertrophy in the two groups [12 vs. 10%]. Decreased LV end-systolic wall stress in EH was a sign of compensatory myocardial hypertrophy without LV dilatation. The hypertensives exhibited a normal or slightly elevated systolic LV function. On the other hand, some indirect indices of LV properties [peak rate of LV relaxation and left atrial dimension] were indicative of diastolic function impairment. A slight but significant correlation between the degree of LV hypertrophy and systemic blood pressure at rest was found in a part of hypertensive patients. The study indicates that mild to moderate EH leads to some changes in LV morphology and function, which can be easily recognized by echocardiography.