Dr. Giuseppe Mancia
Prof. Guido Grassi
PAMELA's important study results in the field of hypertension confirms the importance of epidemiological studies which are capable of providing dynamic information on a given disease, its complications and interactions with other pathological states or risk factors.
The Pressioni Arteriose Monitorate E Loro Associazioni, known worldwide as PAMELA Study, was planned and initiated almost twenty years ago. This research project was designed to collect information from a sample of the general population geographically located in Monza (a town located in the north-east of Milan, Italy) and surroundings. The PAMELA study allowed important new insights to be achieved in the following areas:
The study started in 1990 with, as first goal to define the values of normality of blood pressure as self-measured at home - home blood pressure - and ambulatory blood pressure - 24-hour blood pressure - as measured outside the clinic environment. Until then, these normality values had mostly only been based on measurements collected in subjects referred for hypertension to specialists’ clinics, thus introducing an important selection bias. PAMELA solved this issue for the first time (1), by obtaining several types of blood pressure measurements, i.e. clinic blood pressure with a mercury sphygmomanometer, home blood pressure with a semiautomatic oscillometric validated device, and 24-hour blood pressure with an automatic and validated device. All were taken from a large sample randomly selected from the population of Monza, stratified only for gender and age ranging from 25 to 74 years. In addition, study protocol included collection of medical history, echocardiograhic determination of left ventricular mass as well as metabolic data. Out of 3200 subjects selected, 64% agreed to take part in the study. This portion of subjects underwent the same measurements 10 years later -participation rate was approximately 70%-, and were followed from randomisation for 148 months altogether a time during which all causes of deaths and cardiovascular events were recorded.
Results of the survey provided evidence that:
It was found that the determination of normality values for home and 24-hour blood pressure allowed for a more comprehensive assessment of blood pressure control in treated hypertensives. Indeed, treated hypertensives’ blood pressure values are much higher than normotensives’, and are similar to that of hypertensives not taking antihypertensive therapy: this holds true for clinic and for home and 24-hour blood pressure measurements. The percentage of treated hypertensives with clinic blood pressure lower than 140/90 mmHg was approximately 20%, however blood pressure control improved further when going from clinic to home and 24-hour values (3).
PAMELA explored the clinical importance of home and 24-hour blood pressure in the general population, making use of a long follow-up -around 12 years-, and supplying results that were quite different to those from other population-based studies (1-4). In PAMELA, Clinic, home and 24-hour blood pressure were all found predictive of cardiovascular events, with no superiority of “out of office” blood pressures (home and 24-hour) over the clinic blood pressures.
The new availability of these various types of blood pressure assessments allowed recognising that in an individual subject, the normality or abnormality of various measurements may be heterogeneously associated: if we consider clinic and 24-hour blood pressure, one can identify various groups of subjects:
In the PAMELA study, the last two conditions showed a non-negligible prevalence, being - approximatively 12% and 9% respectively, while studies addressing the problem of prognosis in white-coat and masked hypertension have reported different results. PAMELA indicated that the prevalence of left ventricular hypertrophy is clearly lower in subjects characterised by a true normotension than in subjects with white coat or masked hypertension, and cardiac organ damage, on the other hand was less frequent in white coat or masked hypertension than in true hypertensives (4). Results also show that white-coat and masked hypertension increase the 10-year risk of developing an impairment of glucose tolerance (impaired fasting glucose and diabetes mellitus) and sustained hypertension (5,6). PAMELA emphasised the evidence that white-coat and masked hypertension are not clinically innocent conditions, they are pathological states associated with increased cardiovascular risk, at a level between that of normotensives and hypertensives.
PAMELA’s methodology included evaluation of left ventricular mass and geometry by echocardiography. Thus, new, major findings relating to cardiac organ damage resulted:
A first aspect of this substudy was the description of the long-term aspect of blood pressure variability, i.e. seasonal variation of systo-diastolic values (8). PAMELA showed that blood pressure is highest in winter and lowest in summer, with intermediate values during other two seasons, not only for clinic but also for home and 24-hour measurements, a finding further supported by the fact that these modifications were evident during both day and night-time, with conditions during each period engendering widely different factors controlling the cardiovascular system. We found that a component of systolic and diastolic blood pressure variability, the so called non-erratic pressure, residual pressure, was directly and independently associated with left ventricular mass index (9). In addition, cardiovascular and all-cause mortality were independently predicted by residual diastolic 24-hour variability and by attenuation of the major cyclic component of circadian blood pressure variability (10).
Several studies had shown that hypertensives display alterations in glucose and lipid metabolism more frequently than age-matched normotensives do. Data collected, however, were mainly based on clinic blood pressure and no information was available until a few years ago as regarding the relationship between metabolic variables and out-of-office blood pressure. PAMELA addressed this issue by assessing serum total cholesterol, high density lipoprotein cholesterol (HDL-C), fasting blood glucose, and calculating the incidence proportion of hypercholesterolemia, impaired fasting glucose and diabetes mellitus in its study population (11). The cohort was subdivided in four categories according to the presence of optimal (<120/80 mmHg), normal (120-129/80-84 mmHg), high normal (130-139/85-89 mmHg) and elevated blood pressure (=140/90 mmHg)(classification of European Society of Hypertension/European Society of Cardiology) (12). Similarly, subjects were subdivided in categories of home blood pressure and quartiles of 24-hour blood pressure. Results showed that, with increasing clinic blood pressure,
PAMELA also contributed to expanding the information available on the metabolic syndrome (11). The metabolic syndrome:
The results of the PAMELA study as reviewed in this paper confirm the importance of epidemiological studies which are capable of providing dynamic information on a given disease, its complications and interactions with other pathological states or risk factors. In the next years new data will hopefully be collected in the context of a new PAMELA study, whose detailed planning is currently ongoing.
1. Mancia G, Sega R, Bravi C, De vito G, Valagussa F, Cesana G, Zanchetti A. Ambulatory blood pressure normality: results from the PAMELA study. J Hypertens 1995;13:1377-1390 2. Mancia G, Sega R, Grassi G, Cesana G, Zanchetti A. Defining ambulatory and home blood pressure normality: further considerations based on data from the PAMELA study. J Hypertens 2001;19:995-999 3. Mancia G, Bombelli M, Lanzarotti A, Grassi G, Cesana G, Zanchetti A, Sega R. Systolic vs diastolic blood pressure control in the hypertensive patients of the PAMELA population. Pressioni Arteriose Monitorate E Loro Associazioni. Arch Intern Med 2002;162:582-586. 4. Sega R, Trocino G, Lanzarotti A, Carugo S, Cesana G, Schiavina R, Valagussa F, Bombelli M, Giannattasio C, Zanchetti A, Mancia G. Alterations of Cardiac Structure in Patients With Isolated Office, Ambulatory, or Home Hypertension: Data From the General Population (Pressione Arteriose Monitorate E Loro Associazioni [PAMELA] Study). Circulation 2001;104:1385-1392. 5. Mancia G, Facchetti R, Bombelli M, Madotto F, Quarti-Trevano F, Grassi G, Sega R. Increased long-term risk of new-onset diabetes mellitus in white-coat and masked hypertension. J Hypertens 2009;27:1672-1678 6. Mancia G, Bombelli M, Facchetti R, Madotto F, Quarti-Trevano F, Polo Friz H, Grassi G, Sega R. Long-term risk of sustained hypertension in white-coat or masked hypertension. Hypertension 2009;54:226-232. 7. Mancia G, Carugo S, Grassi G, Lanzarotti A, Schiavina R, Cesana G, Sega R. Prevalence of left ventricular hypertrophy in hypertensive patients without and with blood pressure control: data from the PAMELA population. Hypertension 2002;39:744-749. 8. Sega R, Cesana GC, Bombelli M, Grassi G, Stella ML, Zanchetti A, Mancia G. Seasonal variations in home and ambulatory blood pressure in the PAMELA population. J Hypertens 1998;16:1585-1592 9. Sega R, Corrao G, Bombelli M, Beltrame L, Facchetti R, Grassi G, Ferrario M, Mancia G. Blood pressure variability end organ damage in a general population: results from the PAMELA study. Hypertension 2002;39:710-714 10. Mancia G, Bombelli M, Facchetti R, Madotto F, Corrao G, Quarti-Trevano F, Grassi G, Sega R. Long-term prognostic value of blood pressure variability in the general population. Results of the Pressioni Arteriose Monitorate E Loro Associazioni Study. Hypertension 2007;49:1265-1270. 11. Mancia G, Bombelli M, Corrao G, Facchetti R, Madotto F, Giannattasio C, Quarti-Trevano F, Grassi G, Zanchetti A, Sega R. Metabolic syndrome in the Pressioni Arteriose Monitorate E Loro Associazioni study: daily life blood pressure, cardiac damage, and prognosis. Hypertension 2007;49:40-47. 12. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, Grassi G, Heagerty AM, Kjeldsen SE, Laurent S, Narkiewicz K, Ruilope L, Rynkiewicz A, Schmieder RE, Boudier HA, Zanchetti A. 2007 Guidelines for the management of arterial hypertension: the Task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).Eur Heart J. 2007 Jun;28(12):1462-536. Epub 2007 Jun 11.
Guido Grassi, Giuseppe Mancia Clinica Medica, Dipartimento di Medicina Clinica e Prevenzione, Ospedale San Gerardo,Monza and Università Milano-Bicocca, Milan, Italy.
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