Lorena Sampieri

High prevalence of cardiac and extracardiac target organ damage in refractory hypertension

Objective Target organ damage (TOD) in chronically treated hypertensives is related to effective blood pressure (BP) control. The aim of this study was to evaluate the prevalence of cardiac and extracardiac TOD in patients with refractory hypertension (RH) compared with well-controlled treated hypertensives (C). Methods Fifty-four consecutive patients with RH (57 ± 10 years), selected according to WHO/ISH guidelines definition, and 51 essential hypertensives (55 ± 10 years) with satisfactory BP control obtained by association therapy, underwent the following procedures: (1) clinic BP measurement; (2) blood sampling for routine chemistry examinations; (3) 24 h urine collection for microalbuminuria; (4) non-mydriatic retinography; (5) echocardiogram; (6) carotid ultrasonogram. In order to exclude ‘office resistance’ (defined as clinic BP > 140/90 mmHg and average 24 h BP ⩽ 125/79 mmHg), all patients with RH were subjected to 24-hour ambulatory BP monitoring. Results Both groups were similar for age, gender, body surface area, smoking habit and duration of hypertension, glucose, creatinine and lipid levels. By definition, clinic BP was significantly higher in RH than C (161 ± 19/96 ± 9 versus 127 ± 6/80 ± 5 mmHg, respectively, P < 0.01). The increased prevalence of left ventricular hypertrophy (LVH) and carotid intima–media (IM) thickening (40 versus 12%, P < 0.01, according to a non-gender-specific partition value of 125 g/m2 ; and 36 versus 14%, P < 0.01, according to IM thickness ⩾1.0 mm, respectively); a higher prevalence of carotid plaques (65 versus 32%, P < 0.05), a more advanced retinal involvement (grade II and III, 73 and 5% versus 38 and 0%, P < 0.01) and a greater albumin urinary excretion (22 ± 32 mg/24 h versus 11 ± 13 mg/24 h, P < 0.01) were found in RH compared to C. Conclusions Our study suggests that RH is a clinical condition associated with a high prevalence of TOD at cardiac, macro- and microvascular level and consequently with high absolute cardiovascular risk, which needs a particularly intensive therapeutic approach aimed to normalize BP levels and to induce TOD regression.

Comparison of cardiovascular, renal, and humoral effects of acute administration of two calcium channel blockers in normotensive and hypertensive subjects

The acute effects of two calcium channel blockers, nifedipine and verapamil, were compared in eight normotensive subjects and eight patients with essential hypertension. Nifedipine 10 mg and verapamil 160 mg orally had no effect on blood pressure of normal subjects, but reduced systolic and diastolic pressures of hypertensive patients to the same extent. The blood pressure reduction caused by nifedipine was more prompt and of lesser duration than that caused by verapamil. In both normal subjects and hypertensive patients nifedipine caused a transient rise in heart rate and plasma renin activity, and plasma catecholamines showed a tendency to increase; verapamil did not affect these variables. Nifedipine induced a marked increase in urine volume and renal sodium excretion in hypertensive patients, with a much smaller change in normotensives. Verapamil did not influence water and sodium excretion in either direction. Thus, this study shows similarities and differences between the effects induced by acute oral administration of the most-used vasodilating calcium antagonists.

Target organ damage and non-dipping pattern defined by two sessions of ambulatory blood pressure monitoring in recently diagnosed essential hypertensive patients.

Objective To evaluate in a selected population of patients with a recent diagnosis of hypertension whether a reduced nocturnal fall in blood pressure, confirmed by two 24 h ambulatory blood pressure monitoring (ABPM) sessions is associated with more prominent target organ damage (TOD). Methods The study was structured in two phases: in the first, 141 consecutive, recently diagnosed, never-treated essential hypertensives underwent 24 h ABPM twice within 3 weeks; in the second phase, 118 of these patients showing reproducible dipping or non-dipping patterns underwent the following procedures: (1) routine blood chemistry, (2) 24 h urinary collection for microalbuminuria, (3) amydriatic photography of ocular fundi, (4) echocardiography and (5) carotid ultrasonography. Results The 92 patients with (>10%) night-time fall in systolic blood pressure (SBP) and diastolic blood pressure (DBP) (dippers) in both monitoring sessions were similar for age, gender, body surface area, smoking habit, clinic BP, 24 h and 48 h BP to the 26 patients with a ⩽10% nocturnal fall (non-dippers) in both sessions. The prevalence of left ventricular hypertrophy (LVH) (defined by two criteria: (1) LV mass index ⩾ 125 g/m2 in both genders; (2) LV mass index ⩾ 120 and 100 g/m2 in men and women, respectively) and that of carotid intima–media (IM) thickening (IM thickness ⩾ 0.8 mm) were significantly higher in non-dippers than in dippers (23 versus 5%, P < 0.01; 50 versus 22%, P < 0.05; and 38 versus 18%, P < 0.05, respectively). There were no differences among the two groups in the prevalence of retinal changes and microalbuminuria. The strength of the association of LV mass index with night-time BP was slightly but significantly greater than that with daytime BP. Conclusions This study suggests that a blunted reduction in nocturnal BP, persisting over time, may play a pivotal role in the development of some expressions of TOD, such as LVH and IM thickening, during the early phase of essential hypertension, despite similar clinic BP, 24 h and 48 h BP levels observed in non-dippers and dippers.

Different effects of antihypertensive regimens based on fosinopril or hydrochlorothiazide with or without lipid lowering by pravastatin on progression of asymptomatic carotid atherosclerosis: Principal results of PHYLLIS - A randomized double-blind trial

Background and Purpose— The Plaque Hypertension Lipid-Lowering Italian Study (PHYLLIS) tested whether (1) the angiotensin-converting enzyme (ACE) inhibitor fosinopril (20 mg per day) was more effective on carotid atherosclerosis progression than the diuretic hydrochlorothiazide (25 mg per day), (2) pravastatin (40 mg per day) was more effective than placebo when added to either hydrochlorothiazide or fosinopril, and (3) there were additive effects of ACE inhibitor and lipid-lowering therapies. Methods— A total of 508 hypertensive, hypercholesterolemic patients with asymptomatic carotid atherosclerosis were randomized to: (A) hydrochlorothiazide; (B) fosinopril; (C) hydrochlorothiazide plus pravastatin; and (D) fosinopril plus pravastatin, and followed up blindly for 2.6 years. B-Mode carotid scans were performed yearly by certified sonographers in 13 hospitals and read centrally. Corrections for drift were calculated from readings repeated at study end. Primary outcome was change in mean maximum intima-media thickness of far and near walls of common carotids and bifurcations bilaterally (CBMmax). Results— CBMmax significantly progressed (0.010±0.004 mm per year; P=0.01) in group A (hydrochlorothiazide alone) but not in groups B, C, and D. CBMmax changes in groups B, C, and D were significantly different from changes in group A. Changes in group A were concentrated at the bifurcations. “Clinic” and “ambulatory” blood pressure reductions were not significantly different between groups, but total and low-density lipoprotein cholesterol decreased by ≈1 mmol/L in groups C and D. Conclusions— Progression of carotid atherosclerosis occurred with hydrochlorothiazide but not with fosinopril. Progression could also be avoided by associating pravastatin with hydrochlorothiazide.

Cardiopulmonary reflex before and after regression of left ventricular hypertrophy in essential hypertension.

Studies that have examined the cardiopulmonary receptor control of circulation in hypertension have produced conflicting results. In 10 normotensive subjects and in age-matched essential hypertensive subjects without (n = 10) or with left ventricular hypertrophy (n = 12), as well as in seven subjects of the latter group restudied after 1 year of treatment that induced regression of cardiac hypertrophy, we examined the cardiopulmonary reflex by increasing central venous pressure and stimulating cardiopulmonary receptors through passive leg raising and by reducing central venous pressure and deactivating cardiopulmonary receptors through nonhypotensive lower body negative pressure. Reflex responses were measured as changes in forearm vascular resistance (mean blood pressure divided by plethysmographically measured blood flow), plasma norepinephrine concentration, and plasma renin activity. In hypertensive subjects without left ventricular hypertrophy, stimulation and deactivation of cardiopulmonary receptors caused changes in forearm vascular resistance, norepinephrine concentration, and plasma renin activity that were modestly reduced as compared with those in normotensive subjects. However, all these changes were markedly reduced in hypertensive subjects with left ventricular hypertrophy. Following regression of left ventricular hypertrophy, the changes in vascular resistance, plasma norepinephrine, and plasma renin activity induced by cardiopulmonary receptor manipulation all unproved markedly. These results demonstrate that cardiopulmonary receptor regulation of peripheral vascular resistance and of neurohumoral variables is impaired in essential hypertension and that the impairment is much more pronounced when this condition is associated with cardiac structural alterations. Therapeutic regression of these alterations, however, leads to a marked improvement of this reflex, with consequent favorable effects on circulatory homeostasis.

Systolic and pulse blood pressures (but not diastolic blood pressure and serum cholesterol) are associated with alterations in carotid intima-media thickness in the moderately hypercholesterolaemic hypertensive patients of the Plaque Hypertension Lipid Lowering Italian Study

Objective The Plaque Hypertension Lipid Lowering Italian Study (PHYLLIS), is the first study in patients with hypertension (diastolic blood pressure (DBP) 95–115 mmHg; systolic blood pressure (SBP) 150–210 mmHg), moderate hypercholesterolaemia (LDL-cholesterol 4.14–5.17 mmol/l (160–200 mg/dl) and initial carotid artery alterations (maximum intima–media thickness (IMT) Tmax ⩾ 1.3 mm). The primary objective of PHYLLIS is investigating whether in these patients administration of an angiotensin converting enzyme inhibitor, fosinopril, and a statin, pravastatin, is more effective than administration of a diuretic and a lipid-lowering diet in retarding or regressing alterations in carotid IMT. While the study is in progress, baseline data are here reported to clarify the association of various risk factors with carotid IMT in these medium–high risk hypertensive patients. Methods Patients numbering 508 have been randomized to PHYLLIS by 13 peripheral units, in Italy. Age was (mean ± SD) 58.4 ± 6.7 years, males were 40.2%, current smokers 16.5%, means ± SD of serum total, low-density lipoprotein (LDL), high-density lipoprotein (HDL) cholesterol and triglycerides concentrations were 6.79 ± 0.67, 4.69 ± 0.51, 1.37 ± 0.38, 1.59 ± 0.64 mmol/l (262.4 ± 25.8, 181.3 ± 19.8, 53.0 ± 14.6, 141.0 ± 56.7 mg/dl). Means ± SD of clinic sitting SBP/DBP were 159.8 ± 9.0/98.3 ± 4.2 mmHg. 483 of the 508 patients also had 24 h ambulatory BP monitoring, edited and read at a centralized unit (mean ± SD 24 h SBP/DBP averages 136.3 ± 14.1/84.0 ± 10.0 mmHg). Quantitative B-mode ultrasound (Biosound 2000 II 5A, Biosound, Indianapolis, Indiana, USA) recordings of carotid arteries were taken by certified sonographers in the peripheral units and tracings were all read at a central unit. CBMmax (mean IMT of eight sites at common carotids and bifurcations) was 1.21 ± 0.17; Mmax (mean of 12 sites also including internal carotids) 1.16 ± 0.17, and Tmax (single maximum) 1.85 ± 0.48 mm. Results Ambulatory SBP and pulse pressure (PP) (24 h, daytime, night-time averages) and their variability indices (24 h SD) were always significantly correlated with CBMmax and Mmax (P 0.01–0.001), and the correlations remained significant after adjustment for age, gender and smoking. No measurement of DBP was ever associated with any IMT measurement. Likewise, no lipid variable was found associated with any IMT measurement. Conclusions Baseline data from PHYLLIS indicate that in this population of hypertensive patients with moderate hypercholesterolaemia, SBP and PP are with age among the most significant factors associated with carotid artery alterations. However, the narrow range of inclusion LDL-cholesterol and DBP values may have obscured an additional role of these variables.

Midwall Mechanics Are Improved After Regression of Hypertensive Left Ventricular Hypertrophy and Normalization of Chamber Geometry

Background —It is still unclear whether substantial regression of hypertensive left ventricular hypertrophy (LVH) and normalization of chamber geometry are associated with improved left ventricular (LV) myocardial function. Methods and Results —Midwall mechanics were evaluated in 152 patients undergoing 1 year of effective antihypertensive treatment. Two-dimensionally directed M-mode echocardiography was performed as follows: (1) after a 4-week placebo “run-in” period, (2) after 1 year of treatment with 20 mg/d lisinopril (alone or associated with 12.5 to 25 mg/d hydrochlorothiazide), and (3) after a final 1-month placebo period to allow blood pressure (24-hour average ambulatory monitoring) to return to pretreatment levels. Treatment-induced reductions in blood pressure (from 149±16/95±11 to 131±12/83±10 mm Hg, P <0.05) and circumferential end-systolic wall stress (from 84±22 to 72±19 g/cm2, P <0.05) were associated with a marked reduction in LV mass index (from 159±30 to 133±26 g/m2, P <0.05). LVH regression was accompanied by an increase in midwall fractional shortening (from 19.7±2.7% to 20.9±2.7%, P <0.05) and by a decrease in relative wall thickness (from 48.2±7.7% to 44.1±6.7%, P <0.05). The improvement in midwall function associated with afterload reduction and substantial LVH regression persisted after antihypertensive therapy withdrawal and restoration of the hypertensive state. Despite a significant increase in end-systolic wall stress, further LV chamber remodeling did not occur. The preservation of relative wall thickness was associated with a persistent improvement in midwall systolic function. Conclusions —Regression of concentric LVH is associated with an improvement of midwall systolic function, which is more dependent on the normalization of LV geometry than on the reduction in LV systolic stress.

Cardiac and carotid structure in patients with established hypertension and white-coat hypertension

Aim The introduction of ambulatory blood pressure monitoring in the clinical practice has defined a new subgroup of hypertensive patients called white-coat hypertensives. It has been reported that white-coat hypertensives have less cardiac involvement than established hypertensive patients. This study was designed to examine the extent of cardiac and vascular involvement in patients with white-coat hypertension and established hypertension. Patients and methods We studied 82 patients with mild essential hypertension, never previously treated, using 24-h ambulatory blood pressure monitoring and an echocardiographic and vascular ultrasonographic study. Left ventricular dimensions and mass were obtained according to the Penn convention. The intima–media thickness of the posterior wall of both common carotid arteries was measured 5, 10 and 20 mm caudally to the flow-divider and the average value was used for analysis. Results Of the 82 patients, 31 (mean ± SD age 35 ± 10 years) had average, 24-h systolic/diastolic blood pressure values of below 132/85 mmHg white-coat hypertensives) and 51 (aged 42 ± 2. years) had a consistently elevated diastolic blood pressure. Both groups had similar body surface area (1.82 ± 0.22 versus 1.81 ± 0.22 m2), sex distribution (20 males and 11 females versus 32 males and 19 females), duration of hypertension, metabolic parameters and smoking habit. The 24-h ambulatory blood pressure monitoring values were, by definition, significantly higher in established hypertensives than in white-coat hypertensives (142 ± 10/94 ± 6 versus 127 ± 6/79 ± 4 mmHg, P < 0.001). The left ventricular mass index and intima–media thickness were significantly higher in the established hypertensives (112 ± 17 g/m2, 0.67 ± 0.11 mm, respectively) than in the white-coat hypertensives (98 ± 18g/m2, 0.58 ± 0.09 mm; P < 0.001 for both). Conclusions The prevalence of left ventricular hypertrophy and cardiac remodeling was significantly more frequent in established hypertensives (51%) compared to white-coat hypertensives (19%). These confirm that structural changes in the left ventricle in white-coat hypertensives are more limited than in established hypertensives and show that in white-coat hypertensives there is significantly less involvement of the conductance vessels than in established hypertensives.

Left ventricular concentric remodelling and carotid structural changes in essential hypertension

Aim Left ventricular concentric remodelling defines a modified left ventricular geometry in the presence of a normal left ventricular mass; it is an early and frequent adaptation in arterial hypertension. The present study was designed to evaluate the extent of carotid structural changes in essential hypertensives with left ventricular remodelling. Patients and methods Two groups of hypertensive patients, who had never previously received anti-hypertensive treatment, 14 with left ventricular concentric remodelling (group I, relative wall thickness 0.48 ± 0.02) and 48 with normal left ventricular geometry (group II, relative wall thickness 0.37 + 0.04) underwent clinical and laboratory examination, echocardiography, carotid artery ultrasonography and 24 h ambulatory blood pressure monitoring (ABPM). The left ventricular dimensions and mass were obtained according to the Penn convention. The intima—media thickness (IMT) of the posterior wall of both common carotid arteries was measured 5, 10 and 20 mm caudally to the bulb and the average value was used for analysis. Results In both groups age (group I 44 + 9 years; group II 40 + 9 years), body surface area (group I 1.85 ± 0.2 m2; group Il 1.80 +0.2 m2), duration of hypertension (group I 4.4 + 4; group II 3.8 + 3.9 years), metabolic parameters and smoking habits were similar. Both clinic and 24 h ABPM values were higher in group I (clinic 157 + 12/102 + 5; 24 h ABPM 145 ± 10/95 + 7 mmHg) than they were in group II (clinic 146 ± 11/97 ±5; 24 h ABPM=134 + 10/87 ± 8 mmHg, P<0.01). The left ventricular mass index (LVMI) and IMT were found to be slightly but significantly greater in group I than they were in group II (LVMI 106 + 7 versus 98 ± 12g/m2, P<0.05; IMT 0.68 ± 0.13 versus 0.61 ± 0.10 mm, P<0.05). A significant correlation was found between LVMI and common carotid IMT in the whole group of hypertensive patients (r=0.43, P<0.01). Conclusions Our results indicate that left ventricular concentric remodelling does not represent the only early cardiovascular change in arterial hypertension but rather is associated often with carotid intima—media thickening.

Cardiopulmonary receptor modulation of plasma renin activity in normotensive and hypertensive subjects.

Cardiopulmonary receptors modulate renin release in several animals species. However, their involvement in reflex control of this humoral substance in humans is controversial. Furthermore, no information is available on the alteration of this control in hypertension. We studied the modulation of plasma renin activity (radioimmunoassay) in 12 normotensive subjects and in 12 age-matched subjects with untreated hypertension of mild or moderate degree. Cardiopulmonary receptors were stimulated by increasing central venous pressure (right atrial catheter) and cardiac volume (echocardiographic measurement) through passive leg raising and deactivated by reducing central venous pressure and cardiac volume through lower body negative pressure. The stimuli were maintained for 20 to 30 minutes, and their degree was set to avoid changes in blood pressure (indirect or direct measurements) and heart rate, thus avoiding involvement of arterial baroreceptors. In normotensive subjects, deactivation of cardiopulmonary receptors induced a progressive rise in plasma renin activity and stimulation of cardiopulmonary receptors induced a progressive fall. The reflex gain (ratio between plasma renin activity and central venous pressure or cardiac volume changes) was similar for deactivation and stimulation. During cardiopulmonary receptor deactivation, the gain corresponded to that obtained by dividing the increase in plasma renin by the reduction in central venous pressure induced by tilting. Cardiopulmonary receptor deactivation and stimulation also induced clear-cut changes in plasma renin activity in hypertensive subjects, but the percent magnitude of the reflex plasma renin activity excursion was less than that in normotensive subjects. These observations indicate that cardiopulmonary receptors modulate plasma renin activity in humans.(ABSTRACT TRUNCATED AT 250 WORDS)