Michele Bombelli

Prognostic Value of Ambulatory and Home Blood Pressures Compared With Office Blood Pressure in the General Population Follow-Up Results From the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) Study

Background—Studies in hypertensive patients suggest that ambulatory blood pressure (BP) is prognostically superior to office BP. Much less information is available in the general population, however. Obtaining this information was the purpose of the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study. Methods and Results—Office, home, and 24-hour ambulatory BP values were obtained in 2051 subjects between 25 and 74 years of age who were representative of the general population of Monza (Milan, Italy). Subjects were followed up for an average of 131 months, during which time cardiovascular and noncardiovascular fatal events were recorded (n=186). Office, home, and ambulatory BP values showed a significant exponential direct relationship with risk of cardiovascular or all-cause death. The goodness of fit of the relationship was greater for systolic than for diastolic BP and for night than for day BP, but its overall value was not better for home or ambulatory than for office BP. The slope of the relationship, however, was progressively greater from office to home and ambulatory BP. Home and night BP modestly improved the goodness of fit of the risk model when added to office BP. Conclusions—In the PAMELA population, risk of death increased more with a given increase in home or ambulatory than in office BP. The overall ability to predict death, however, was not greater for home and ambulatory than for office BP, although it was somewhat increased by the combination of office and outside-of-office values. Systolic BP was almost invariably superior to diastolic BP, and night BP was superior to day BP.

Long-Term Risk of Mortality Associated With Selective and Combined Elevation in Office, Home, and Ambulatory Blood Pressure

In the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study, office, home, and ambulatory blood pressure (BP) values were measured contemporaneously between 1990 and 1993 in a large population sample (n=2051). Cardiovascular (CV) and non-CV death certificates were collected over the next 148 months, which allowed us to assess the prognostic value of selective and combined elevation in these 3 BPs over a long follow-up. There were 69 CV and 233 all-cause deaths. Compared with subjects with normal office and 24-hour BP, the hazard ratio for CV death showed a progressive increase in those with a selective office BP elevation (white-coat hypertension), a selective 24-hour BP elevation (masked hypertension), and elevation in both office and 24-hour BP. This was the case also when the above conditions were identified by office versus home BP values. Selective elevation in home versus ambulatory BP or vice versa also carried an increased risk. There was indeed a progressive increase in both CV and all-cause mortality risk from subjects in whom office, home, and ambulatory BP were all normal to those in whom 1, 2, or all 3 BPs were elevated, regardless of which BP was considered. The trends remained significant after adjustment for age and gender, as well as, in most instances, after further adjustment for other cardiovascular risk factors. Thus, white-coat hypertension and masked hypertension, both when identified by office and ambulatory or by office and home BPs, are not prognostically innocent. Indeed, each BP elevation (office, home, or ambulatory) carries an increase in risk mortality that adds to that of the other BP elevations.

Long-Term Prognostic Value of Blood Pressure Variability in the General Population. Results of the Pressioni Arteriose Monitorate e Loro Associazioni Study

The hypothesis has been advanced that cardiovascular prognosis is related not only to 24-hour mean blood pressure but also to blood pressure variability. Data, however, are inconsistent, and no long-term prognostic study is available. In 2012 individuals randomly selected from the population of Monza (Milan), 24-hour ambulatory blood pressure (Spacelabs 90207) was measured via readings spaced by 20 minutes. Systolic and diastolic blood pressure variability was obtained by calculating the following: (1) the SD of 24-hour, day, and night mean values; (2) the day–night blood pressure difference; and (3) the residual or erratic blood pressure variability (Fourier spectral analysis). Fatal cardiovascular and noncardiovascular events were registered for 148 months. When adjusted for age, sex, 24-hour mean blood pressure, and other risk factors, there was no relationship between the risk of death and 24-hour, day, and night blood pressure SDs. In contrast, the adjusted risk of cardiovascular death was inversely related to day–night diastolic BP difference (&bgr; coefficient=−0.040; P<0.02) and showed a significant positive relationship with residual diastolic blood pressure variability (&bgr; coefficient=0.175; P<0.002). Twenty-four–hour mean blood pressure attenuation of nocturnal hypotension and erratic diastolic blood pressure variability all independently predicted the mortality risk, with the erratic variability being the most important factor. Our data show that the relationship of blood pressure to prognosis is complex and that phenomena other than 24-hour mean values are involved. They also provide the first evidence that short-term erratic components of blood pressure variability play a prognostic role, with their increase being accompanied by an increased cardiovascular risk.

Comparative effects of candesartan and hydrochlorothiazide on blood pressure, insulin sensitivity, and sympathetic drive in obese hypertensive individuals: Results of the CROSS study

Objective The increase in blood pressure that accompanies the obese state is almost invariably associated with alterations in metabolism (insulin resistance and dyslipidaemia) and the neurohumoral profile (activation of the renin–angiotensin system, sympathetic overactivity), which potentiate the cardiovascular risk associated with hypertension. However, debate remains as to the antihypertensive drug on which treatment of obesity-related hypertension should be based. The CROSS (Candesartan Role on Obesity and on Sympathetic System) study was undertaken to examine the antihypertensive, neuroadrenergic, and metabolic effects of an angiotensin II receptor blocker in comparison with a diuretic in obese hypertensive individuals. Methods In 127 obese hypertensive individuals aged 50.7 ± 5.1 years (mean ± SD), we measured clinic blood pressure, heart rate, plasma glucose, and insulin at rest and during an oral glucose load before and 12 weeks after treatment with either candesartan cilexetil (8–16 mg once daily) or hydrochlorothiazide (HCTZ, 25–50 mg once daily), administered orally in accordance with a double-blind, randomized, placebo-controlled, two-parallel-groups study design. Insulin sensitivity was expressed as insulin resistance index (IRI), calculated as the ratio of the area under the curve (AUC) for glucose to that for insulin. In a subgroup of patients, measurements also included direct microneurographic recording of muscle sympathetic nerve activity (MSNA) in the peroneal nerve. Results Candesartan cilexetil caused a significant (P < 0.01) reduction in both mean blood pressure (from 114.2 ± 5.1 to 99.6 ± 6.0 mmHg) and MSNA (from 51.0 ± 12.3 to 40.4 ± 12.5 bursts per 100 heart beats), and a significant (P < 0.02) increase in insulin sensitivity (AUC IRI: from −23.2 ± 22.1 to −17.6 ± 12.2). In contrast, HCTZ did not significantly affect MSNA and worsened insulin sensitivity, while achieving blood pressure reductions similar to those produced by candesartan cilexetil. Conclusions These data provide evidence that, in obese hypertensive individuals, treatment with candesartan cilexetil has an antihypertensive effect similar to that of HCTZ. Unlike diuretic treatment, however, treatment with candesartan cilexetil improves insulin sensitivity and exerts sympathoinhibitory effects.

Metabolic Syndrome in the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) Study: Daily Life Blood Pressure, Cardiac Damage, and Prognosis

The prevalence of the metabolic syndrome (National Cholesterol Education Program Adult Treatment Panel III criteria) and its relationships with daily life blood pressures, cardiac damage, and prognosis were determined in 2013 subjects from a Northern Italian population aged 25 to 74 years. Home blood pressure, 24-hour blood pressure, and left ventricular mass index (echocardiography) were also measured. Cardiovascular and noncardiovascular deaths were registered over 148 months. Metabolic syndrome was found in 16.2% of the sample, an office blood pressure elevation being the most frequent (95.4%) and the blood glucose abnormality the least frequent (31.5%) component. There was in metabolic syndrome a frequent elevation in home and/or 24-hour average blood pressure, as well as a greater left ventricular mass index and prevalence of left ventricular hypertrophy, which was manifest even when data were adjusted for between-group differences, including blood pressure. The adjusted risk of cardiovascular and all-cause mortality was greater in metabolic syndrome subjects (+71.0% and +37.0%; P<0.05), a further marked increase being observed with left ventricular hypertrophy or “in-office” and “out-of-office” blood pressure elevations. The increased risk was related to the blood pressure and the blood glucose component of metabolic syndrome, with no contribution of the remaining components. Thus, metabolic syndrome is common in a Mediterranean population in which it significantly increases the long-term risk of death. Cardiac abnormalities and increases in home and 24-hour blood pressure are common in metabolic syndrome, and their occurrence further enhances the risk. The contribution of metabolic syndrome components to the risk, however, is unbalanced and mainly related to blood pressure and glucose abnormalities.

Long-Term Risk of Sustained Hypertension in White-Coat or Masked Hypertension

It is debated whether white-coat (WCHT) and masked hypertension (MHT) are at greater risk of developing a sustained hypertensive state (SHT). In 1412 subjects of the Pressioni Arteriose Monitorate e Loro Associazioni Study, we measured office blood pressure (BP), 24-hour ambulatory BP, and home BP. The condition of WCHT was identified as office BP >140/90 mm Hg and 24-hour BP mean <125/79 mm Hg or home BP <132/82 mm Hg. Corresponding values for MHT diagnosis were office BP <140/90 mm Hg, 24-hour BP ≥125/79 mm Hg, and home BP ≥132/82 mm Hg. SHT was identified when both office and 24-hour BP means or home BP were over threshold values and normotension was under the threshold value. Subjects were reassessed 10 years later to evaluate the BP status of the various conditions defined previously. At the first examination, 758 (54.1%), 225 (16.1%), 124 (8.9%), and 293 (20.9%) subjects were normotensive, WCHT, MHT, and SHT subjects, respectively. At the second examination, 136 normotensives (18.2%), 95 WCHT (42.6%), and 56 MHT (47.1%) subjects became SHT. As compared with normotensives, adjusting for age and sex, the risk of becoming SHT was significantly higher for WCHT and MHT subjects (odds ratio: 2.51 and 1.78, respectively; P<0.0001). Similar results were obtained when the definition of the various conditions was based on home BP. Independent contributors of worsening of hypertension status were not only baseline BP, but also, although to a lesser extent, metabolic variables and age. Subjects with WCHT and MHT are at increased risk of developing SHT. This may contribute to their prognosis that appears to be worse as compared with that of normotensive subjects.

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.

Left ventricular hypertrophy increases cardiovascular risk independently of in-office and out-of-office blood pressure values

Objectives Previous studies have shown that left ventricular hypertrophy (LVH) represents a cardiovascular risk factor independently of clinic blood pressure (BP). The present study was aimed at determining the impact of LVH on the incidence of cardiovascular morbid and fatal events taking into account not only classical risk factors but also home and ambulatory BP values, which have been shown to have an important independent prognostic impact. Methods In 1716 patients belonging to the ‘Pressioni Arteriose Monitorate E Loro Associazioni’ population of Monza, we quantified left ventricular mass index and identified LVH by standard cutoff values. We also measured clinic, home and 24-h ambulatory BPs together with serum glucose and lipids. Results During a follow-up of 148 months, the rate of fatal and nonfatal (hospitalizations) cardiovascular events as well as of all-cause death was markedly greater (four-fold to five-fold) in patients as compared with those without LVH. In LVH individuals, the increased risk remained significant even when data were adjusted for a large number of other confounding factors including home BP, 24-h mean BP and ambulatory BP. Results were similar when left ventricular mass was indexed by height and body surface area. A 10% increase in left ventricular mass index was associated with a significant increase in cardiovascular risk or all-cause deaths. In multivariate analysis, left ventricular mass index was always an independent predictor of cardiovascular events and death for any cause. Conclusion Our data provide evidence that LVH is an important risk factor even when the contribution of different BPs to risk is fully taken into account.

HIV and metabolic syndrome - A comparison with the general population

Objective:To compare the prevalence of metabolic syndrome (MS) in HIV-positive patients with that from a sample of a general Italian population. Design:Cross-sectional study. Methods:A total of 1263 HIV-infected patients 18 years of age or older were recruited in 18 centers for infectious diseases in northern and central Italy. Controls were 2051 subjects aged 25 to 74 years representative of the residents of Monza, a town in Milan province, who were enrolled in the Pressioni Arteriose Monitorate E Loro Associazioni study. Results:The prevalence of MS in the HIV group was 20.8%, whereas in the control group, it was only 15.8%, with the difference being statistically significant. The age- and gender-adjusted risk of having MS in HIV-infected patients was twice as great as that in controls. Compared with controls, HIV-infected patients had a greater prevalence of the impaired fasting glucose, increased plasma triglycerides, and reduced high-density lipoprotein cholesterol components. MS prevalence was similar in treated and never-treated HIV-infected patients, and so were the various MS components. Conclusions:The risk of MS is greater in HIV-infected patients compared with the general population because of a greater prevalence of lipid and glucose abnormalities. The prevalence of MS and its components is similar in treated and untreated HIV-positive patients.

Relationship of Office, Home, and Ambulatory Blood Pressure to Blood Glucose and Lipid Variables in the PAMELA Population

Alterations in blood glucose and cholesterol are more frequently detectable in hypertensive than in normotensive conditions. However, no information exists as to whether this phenomenon involves only office or also home and 24-hour ambulatory blood pressure (ie, when values are representative of daily life). In 2045 subjects enrolled in the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study, we measured home, 24-hour, and office blood pressure. Measurements also included fasting blood glucose and serum total and HDL cholesterol values. Prevalence of diabetes (≥126 mg/dL or use of antidiabetic drugs), impaired fasting blood glucose (≥110 to <126 mg/dL), and hypercholesterolemia (serum total cholesterol ≥240 mg/dL or 200 mg/dL) increased progressively from “optimal” to “normal,” “ high-normal,” and “elevated” office systolic or diastolic blood pressure. Fasting blood glucose and total serum cholesterol also increased progressively from the first to the fourth group, with HDL cholesterol values showing a concomitant progressive decrease. This was also the case for quartiles of office, home, and 24-hour blood pressure. In the whole population, there was a positive correlation between serum cholesterol or blood glucose and all blood pressure values (P always <0.0001), with a much smaller and less consistent relationship with heart rate. In a multivariate analysis that included gender, body mass index, age, and antihypertensive treatment, all blood pressure values remained highly significantly related to values of either metabolic variables. Thus, in the PAMELA population, glucose and lipid values are independently related to blood pressure. This is also the case when daily life blood pressure values are considered.