Cesare Cuspidi

Prognostic value of 24-hour blood pressure variability

Objectives: Evaluation of the prognostic value of 24-h blood pressure averages and 24-h blood pressure variability. Design: After an initial thorough clinical and laboratory evaluation which included 24-h continuous ambulatory blood pressure monitoring, a group of hypertensive patients were re-examined after an average of 7.4 years. End-organ damage at the follow-up visit was related to different measures of blood pressure levels and variability obtained at the initial or the follow-up visit or both. Methods: Seventy-three patients with essential hypertension of variable severity, in whom ambulatory blood pressure was monitored intra-arterially for 24 h (Oxford technique) were re-examined at a follow-up visit (including echocardiographic assessment of left ventricular mass index) 4-13 years later (mean 7.4 years). The severity of end-organ damage was quantified by a score and related to clinic blood pressure at follow-up and to (1) clinic blood pressure, (2) 24-h blood pressure mean, (3) 24-h short-term and long-term blood pressure variability, and (4) end-organ damage, all assessed at the initial visit (multiple regression analysis). Results: The set of independent variables considered was significantly related to end-organ damage at follow-up (R = 0.51). The individual variables most important in determining end-organ damage at follow-up were clinic blood pressure at the follow-up visit (P < 0.01), the initial level of end-organ damage (P < 0.05) and long-term blood pressure variability (among half-hour standard deviation of 24-h mean blood pressure) at the initial evaluation (P < 0.05). The prognostic individual weight of the other haemodynamic parameters considered was less and not statistically significant. Conclusions: The results confirm that the level of blood pressure achieved by treatment and the degree of end-organ damage at the time of initial evaluation are important determinants of future end-organ damage related to hypertension. They also constitute the first longitudinal evidence that the cardiovascular complications of hypertension may depend on the degree of 24-h blood pressure variability.

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.

Reproducibility and clinical value of nocturnal hypotension: Prospective evidence from the SAMPLE study

Objective To assess whether modifications in the night-time blood pressure fall caused by antihypertensive treatment predict the regression of end-organ damage of hypertension. Methods The analysis was performed in patients with essential hypertension and echocardiographically detected left ventricular hypertrophy involved in the SAMPLE study. For each patient, ambulatory blood pressure monitoring and echocardiographic determination of left ventricular mass index were performed at the end of a 4-week wash-out pretreatment period, after 3 and 12 months of treatment with lisinopril or with lisinopril plus hydrochlorothiazide and after a final 4-week placebo period. For each ambulatory blood pressure monitoring the 24 h average, daytime average (0600–2400 h), night-time average (2400–0600 h) and day–night difference was computed. The percentages of dipper and non-dipper patients (i.e. the patients with night blood pressure falls greater and less than 10% of the daytime average, respectively) were also computed. Results The reproducibility of the day–night difference was low, both for comparison of the pretreatment and final placebo periods (n = 170) and for comparison of the third and the 12th month of treatment (n = 180). The reproducibility of the dipper–non-dipper dichotomy was also low, 35–40% of patients becoming non-dippers if they were dippers and vice versa, both with and without treatment. The changes in left ventricular mass index after 12 months of treatment were significantly (P < 0.01) related to the changes in 24 h, daytime and night-time blood pressure (r always > 0.33), but this was not the case for the treatment-induced modification of the day–night difference (r = −0.03 and −0.008 for systolic and diastolic blood pressures, respectively). Conclusions Our results show that day–night blood pressure changes and the classification of patients into dippers and non-dippers are poorly reproducible over time. It also provides the first prospective evidence that treatment-induced changes in day–night blood pressure difference are not related to treatment-induced regression of left ventricular mass index, thus having a limited clinical significance.

Role of echocardiography and carotid ultrasonography in stratifying risk in patients with essential hypertension: the Assessment of Prognostic Risk Observational Survey

Background Echocardiography and carotid ultrasonography, by providing a more accurate assessment of cardiac and vascular damage related to hypertension, may lead to a more precise stratification of the global cardiovascular risk. However, current guidelines do not recommend systematic use of ultrasound examination of heart and large arteries in evaluating the cardiovascular risk in patients with hypertension. Objective To assess the impact of echocardiography and carotid ultrasonography on global risk stratification in hypertensive patients classified as being at low or medium risk according to routine clinical work-up as suggested by current hypertension guidelines. Methods Among 8502 consecutive patients screened at 44 outpatient hypertension hospital clinics in different parts of Italy, 1074 untreated individuals with low-to-medium risk essential hypertension were identified on the basis of the diagnostic routine procedures suggested by 1999 World Health Organization/International Society of Hypertension guidelines: medical history, physical examination and clinic blood pressure measurement; routine blood chemistry and urine analysis; electrocardiogram. The extent of risk for the 1074 individuals was reassessed by adding the results of ultrasound examinations of heart and carotid arteries: left ventricular hypertrophy (defined as left ventricular mass index > 120 g/m2 in men and > 100 g/m2 in women), carotid intima–media thickening (defined as diffuse thickening if ⩾ 0.8 mm), and presence of plaque (defined as focal thickening > 1.3 mm). Results According to routine classification, 18.7% (n = 201) of the 1074 patients were considered at low risk and 81.3% (n = 873) at medium risk. A marked change in risk stratification was obtained when ultrasound markers of target-organ damage were taken into consideration: the proportion of low-risk patients decreased to 11.1%, and that of medium risk patients to 35.7%, whereas more than 50% of the patients previously classified at low-medium risk were found to be at high absolute risk. According to a multivariate analysis, age, grade of hypertension, male sex, and serum cholesterol concentration were the variables with the greatest impact on risk class change. Conclusions Ultrasound assessment of the heart and carotid wall helps to obtain a more valid assessment of global cardiovascular risk in hypertensive patients without evidence of target-organ damage after routine examination.

Metabolic syndrome and target organ damage in untreated essential hypertensives

Background The prevalence and the relationship between metabolic syndrome, and target organ damage (TOD) in essential hypertensive patients has not been fully explored to date. Objective To investigate the association between metabolic syndrome, as defined by the ATP III report, and cardiac and extracardiac TOD, as defined by the 2003 ESH–ESC guidelines for management of hypertension, in a large population of never-treated essential hypertensives. Methods A total of 447 grade 1 and 2 hypertensive patients (mean age 46 ± 12 years) who were attending a hypertension hospital outpatient clinic for the first time underwent the following procedures: (i) physical examination and repeated clinic blood pressure measurements; (ii) routine examinations; (iii) 24-h urine collection for microalbuminuria; (iv) 24-h ambulatory blood pressure monitoring; (v) echocardiography; and (vi) carotid ultrasonography. Metabolic syndrome was defined as involving at least three of the following alterations: increased waist circumference, increased triglycerides, decreased high-density lipoprotein cholesterol, increased blood pressure, or high fasting glucose. Left ventricular hypertrophy (LVH) was defined according to two different criteria: (i) 125 g/m2 in men and 110 g/m2 in women; (ii) 51 g/h2.7 in men and 47 g/h2.7 in women. Results The 135 patients with metabolic syndrome (group I) were similar for age, sex distribution, known duration of hypertension and average 24-h, daytime and night-time ambulatory blood pressure to the 312 patients without it (group II).The prevalence of altered left ventricular patterns (LVH and left ventricular concentric remodelling) was significantly higher in group I (criterion a = 30%, criterion b = 42%) than in group II (criterion a = 23%, criterion b = 30%, P < 0.05 and P < 0.01, respectively). A greater urinary albumin excretion (17 ± 35 versus 11 ± 23 mg/24 h, P = 0.04) was also found in group I compared to group II. There were no significant differences between the two groups in the prevalence of carotid intima–media thickening and plaques. Conclusions These results from a representative sample of untreated middle-aged hypertensives show that: (i) the metabolic syndrome is highly prevalent in this setting and (ii) despite similar ambulatory blood pressure values, patients with metabolic syndrome have a more pronounced cardiac and extracardiac involvement than those without it.

Cardiovascular target organ damage in essential hypertensives with or without reproducible nocturnal fall in blood pressure

Objective The clinical significance of classifying patients as dippers and non-dippers on the basis of a single period of ambulatory blood pressure monitoring (ABPM) has been questioned. The aim of this study was to evaluate the relationship between nocturnal dipping status, defined on the basis of two periods of ABPM, and cardiac and extracardiac target organ damage in essential hypertension. Methods A total of 375 never-treated essential hypertensive patients [mean 24-h blood pressure (BP) ⩾ 125/80 mmHg; mean ± SD age 45.9 ± 11.9 years] referred for the first time to our outpatient clinic underwent the following procedures: (i) repeated clinic BP measurements; (ii) blood sampling for routine chemistry examinations; (iii) 24-h urine collection for microalbuminuria; (iv) ABPM over two 24-h periods within 4 weeks; (v) echocardiography; and (vi) carotid ultrasonography. Results A reproducible nocturnal dipping (decrease in BP > 10% from mean daytime BP in both ABPM periods) and non-dipping profile (decrease in BP ⩽ 10% in both ABPM periods) was found in 199 (group I) and 79 patients (group II), respectively; 97 patients (group III) had a variable dipping profile. The three groups did not differ with regard to age, gender, body mass index, clinic BP, 48-h BP and heart rate. Left ventricular mass index, interventricular septum thickness, left atrium and aortic root diameters were significantly higher in group II compared with group I (mean ± SD 108.5 ± 19.5 versus 99.7 ± 19.6 g/m2, P < 0.05; 9.3 ± 0.9 versus 9.1 ± 0.9 mm, P < 0.05; 33.6 ± 3.6 versus 32.2 ± 3.7 mm, P < 0.01; 36.9 ± 4.6 mm versus 35.5 ± 4.6, P < 0.05, respectively). The smaller differences seen between groups II and III and between groups I and III were not statistically significant. The prevalence of left ventricular hypertrophy (defined as a left ventricular mass index > 134 g/m2 in men and > 110 g/m2 in women) was greater in group II (19%) than in group I (6%) (P < 0.05), whereas the differences between groups II and III and between groups I and III did not reach statistical significance. Differences among the three groups in the prevalence of carotid structural alterations (such as carotid plaques or intima–media thickening) were not statistically significant, and microalbuminuria had a similar prevalence in all three groups. Conclusions Despite similar clinic and 48-h BP values, never-treated hypertensive patients with a persistent non-dipper pattern showed a significantly greater extent of cardiac structural alterations compared with subjects with a reproducible dipping pattern, but not those with a variable BP nocturnal profile. A non-dipping pattern diagnosed on two concordant ABPM periods instead of a single monitoring therefore represents a clinical trait associated with more pronounced cardiac abnormalities. Finally, in non-dipping middle-aged hypertensives, echocardiography appears to provide a more accurate risk stratification than carotid ultrasonography or microalbuminuria.

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.

Adrenergic, Metabolic, and Reflex Abnormalities in Reverse and Extreme Dipper Hypertensives

Limited information is available on whether and to what extent the different patterns of the nocturnal blood pressure profile reported in hypertension are characterized by differences in sympathetic drive that may relate to, and account for, the different day-night blood pressure changes. In 34 untreated middle-aged essential hypertensive dippers, 17 extreme dippers, 18 nondippers, and 10 reverse dippers, we assessed muscle sympathetic nerve traffic, heart rate, and beat-to-beat arterial blood pressure at rest and during baroreceptor deactivation and stimulation. Measurements were also performed in 17 age-matched dipper normotensives. All patients displayed reproducible blood pressure patterns at 2 different monitoring sessions. The 4 hypertensive groups did not differ by gender or 24-hour or daytime blood pressure. Muscle sympathetic nerve traffic was significantly higher in nondipper, dipper, and extreme dipper hypertensives than in normotensive controls (58.6±1.8, 55.6±0.9, and 53.3±0.8 versus 43.5±1.4 bursts/100 heartbeats, respectively; P<0.01 for all), a further significant increase being detected in reverse dippers (76.8±3.1 bursts/100 heartbeats; P<0.05). Compared with normotensives, baroreflex–heart rate control was similarly impaired in all the 4 hypertensive states, whereas baroreflex-sympathetic control was preserved. The day-night blood pressure difference correlated inversely with sympathetic nerve traffic (r=−0.76; P<0.0001) and homeostasis model assessment index (r=−0.32; P<0.005). Thus, the reverse dipping state is characterized by a sympathetic activation greater for magnitude than that seen in the other conditions displaying abnormalities in nighttime blood pressure pattern. The present data suggest that in hypertension, sympathetic activation represents a mechanism potentially responsible for the day-night blood pressure difference.

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.