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A Predictor of Long-term Cardiovascular Mortality in a French Male Population
Athanase Benetos; Michel Safar; Annie Rudnichi; Harold Smulyan; Jacques-Lucien Richard; Pierre Ducimetière; ; Louis Guize
From the Investigations Préventives et Cliniques (A.B., A.R., L.G.), Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U337 (A.B., M.S.) and U258 (J.-L.R., P.D., L.G.), Paris, France; and Department of Medicine (H.S.), State University of New York, Syracuse, NY.
Correspondence to Athanase Benetos, MD, PhD, Investigations Préventives et Cliniques (IPC), 23 rue de Lubeck, 75116 Paris, France
Abstract Studies on the usefulness of blood pressure as a prognostic factor in cardiovascular disease have more often involved investigations of the levels of diastolic or systolic blood pressure. However, blood pressure may be divided into two other components: steady (mean pressure) and pulsatile (pulse pressure). In this study, the relationship of pulse pressure to cardiovascular mortality was investigated in 19 083 men 40 to 69 years old who were undergoing a routine systematic health examination and were being followed up after a mean period of 19.5 years. Subjects were divided into four groups according to age (40 to 54 and 55 to 69 years) and mean arterial pressure (<107 and =" src="/math/ge.gif"107 mm Hg). Each group was further divided into four subgroups according to the pulse pressure level. A wide pulse pressure (evaluated according to the quartile group or as a continuous quantitative variable) was an independent and significant predictor of all-cause, total cardiovascular, and, especially, coronary mortality in all age and mean pressure groups. No significant association between pulse pressure and cerebrvascular mortality was observed. In conclusion, in a large population of men with a relatively low cardiovascular risk, a wide pulse pressure is a significant independent predictor of all-cause, cardiovascular, and, especially, coronary mortality.
The standard definition of hypertension includes an elevation of SBP and/or DBP. In adhering to this definition, many epidemiological investigations of the long-term risks of the disease fail to include patients with high SBP but normal or low DBP.1–3 In so doing, patients with the widest PPs were excluded. Despite this systematic entrance bias, these studies have shown increasing cardiovascular risk of higher SBP and PP at the same DBP.4 In 1971, investigators with the Framingham Heart Study5 emphasized the greater risks of an elevated SBP compared with the DBP in patients over the age of 55. Although probably involved, PP was rarely mentioned.6
Although a large PP measured at the brachial artery with use of the cuff method is not an accurate representation of the proximal aortic PP, it does suggest a stiffened aorta. Such stiffening, through a variety of mechanisms,7,8 tends to raise the SBP and lower the DBP. The former, which increases left ventricular pulsatile work, is associated with left ventricular hypertrophy and requires a greater coronary blood flow. The latter reduces the pressure on which coronary flow is dependent, and together they increase the vulnerability of the heart to ischemia. All this suggests that PP itself could be a major predictor of cardiac risk.
Evidence is beginning to accumulate in support of this view. In 1994, Madhavan et al9 reported a series of 2207 untreated hypertensive subjects followed for an average of 4.8 years. This study showed that subjects in the upper tertile of pretreatment PP (=" src="/math/ge.gif"63 mm Hg) had a greater mortality than those in the lower tertiles and that PP, but not SBP or DBP, was an independent predictor of myocardial infarction. In a later study4 from the same group, an expanded number of 5730 treated and untreated hypertensive patients were reported. After adjustment for other risk factors, PP was the only measure of blood pressure significantly and independently related to the in-treatment incidence of myocardial infarction.
In 1989, a study from France10 described findings for 18 336 men and 9351 women who had been followed for an average of 9.5 years. These were unselected subjects who volunteered for free medical examinations. Blood pressure data were divided statistically into steady and pulsatile components. There was an association between the pulsatile component and left ventricular hypertrophy in both sexes, as well as a positive correlation with death from coronary artery disease in women. The results in both sexes were weakened by the small number of deaths in each group, which was a consequence of the relatively short duration of follow-up.
The purpose of the present report was to assess the effect of the initial PP on the long-term risks of cardiovascular mortality in the male subjects of this self-selected cohort who had been followed for 10 additional years, to a total follow-up period of 19.5 years.
The French Public Health System (Securité Sociale–CNAM) offers to all working and retired persons and their families free health examinations, who consistently outproduce those around them - thanks to shortcuts. Every 5 years. The IPC is one of the largest medical centers in France; since 1970, 15 000 examinations of persons living in the Paris area have been performed annually. In the present study, we present data that describe a population composed of all 19 083 men aged 40 to 69 years who underwent a systematic health check-up in the center IPC during the period of May 1972 through May 1977. These subjects were selected from the 39 495 men examined during this period at the Center IPC. Clerks and working executives represented 88% of the studied population.
Supine blood pressure was measured by a nurse in the right arm with the use of a manual sphygmomanometer. After a 10-minute rest period, pressure was measured three times, and the mean of the last two measurements was calculated. The first and the fifth Korotkoff's phases were used to define SBP and DBP. Smoking status was assessed with a self-administered questionnaire with dichotomic (yes or no) questions regarding tobacco use. Plasma cholesterol was measured with a Technicon SMA 12.
The follow-up study period ended on December 1994 (mean follow-up, 19.5 years). Deceased subjects were identified from the mortality records of the Institut National de Statistiques et d'Etudes Economiques. A patient of our cohort was considered to be deceased when he had the
same first name, last name, sex, and date of birth as a person recorded in the Institut National de Statistiques et d'Etudes Economiques mortality records during the period of the follow-up. Through the use of this matching procedure, the identification error was <1%. Only subjects fulfilling all four of these criteria were considered to be deceased. Individuals matching for sex, last name, and only one of the other two criteria were excluded from the study. All other subjects were considered to be alive at the end of the follow-up period. On the basis of this procedure, 3653 subjects of our cohort were considered to have died during the follow-up period. Causes of mortality were taken from the death certificates. These data were provided by the Department of Mortality of the INSERM (Unit SC 8). Causes of death were codified according to the International Classification of Disease (eighth revision until 1978 and ninth revision after 1979).
For comparisons among the PP groups within each of the four original groups (defined according to age and MBP), mean values of morphometric parameters, blood pressure, and total cholesterol were compared with the use of a one-way analysis of variance and a 2 test for tobacco status; deaths for the different causes of mortality were compared with the use of a trend 2 test; and the difference in survival probability for the different causes of mortality were tested by using a Cox analysis with adjustments for age, total cholesterol, and tobacco consumption.
We also assessed (in a multiple logistic regression) the respective roles of MBP and PP, both of which are considered to be continuous quantitative variables. To test whether the effects of one variable was affected by the other, we introduced the interactive term. In the case of significant interaction MBPxPP, we reconstructed the effect of each variable in the hypothetical populations corresponding to selected levels (mean, first, and third quartiles) of the other variable.
All statistical analyses were performed with SAS software.
Table 1 provides a summary of the mean values of morphometric parameters, blood pressure, total cholesterol, and tobacco consumption among the different groups according to the PP level. In both groups of young patients (Table 1A), age, weight, height, BMI, and tobacco consumption did not show any clinically significant differences among the four PP subgroups. SBP levels progressively increased from the first PP group to the higher PP groups, whereas mean values of DBP were significantly lower in the subgroups with the higher PP. Total cholesterol was increased from groups PP1 to PP4. In the two groups of older patients (Table 1B), age was higher in the subgroups with the higher PP values. For the other parameters, the same trends were observed as for younger patients.
Table 2 shows death rates for the different causes of mortality. All-cause, cardiovascular, and coronary heart disease mortality rates were constantly higher as PP increased. This association
was observed in all groups (young versus old and low MBP versus high MBP). However, no significant association was observed between PP and cerebrovascular mortality.
Fig 1 shows survival probabilities for cardiovascular mortality, with adjustments for age, total cholesterol, and tobacco consumption. In the four groups of subjects, lower survival probabilities were observed in subjects with higher PP, especially in the subgroup with PP values of =" src="/math/ge.gif"65 mm Hg. The differences among PP subgroups progressively increased throughout the follow-up period. These differences become significant after 10 years of follow-up. Similar patterns were observed in survival probabilities for all-cause and coronary heart mortality but not for cerebrovascular mortality (data not shown).
Finally, the respective roles of MBP and PP, considered in this analysis as continuous quantitative variables, were evaluated after adjustment for age (Table 3 and Fig 2). In younger patients, when MBP and PP were used together in the model (model 3 in Table 3A), both are highly significant predictors for all-cause, noncardiovascular, total cardiovascular, and coronary heart disease mortality. The effects of the MBP and PP were additive (no interaction MBPxPP was observed). For cerebrovascular mortality, MBP but not PP was a strong predictor. In the older subjects, MBP and PP were both predictors for the different causes of mortality (Table 3B). However, difference from what we observed in younger subjects, a significant negative interaction was observed in older individuals between PP and MBP for total cardiovascular (P=.012) and coronary heart disease (P=.013) mortality. After that, we evaluated the effect of PP at three different levels of MBP (mean, first, and third quartiles) (Fig 2, top) and the effect of MBP at the same three levels of the PP (Fig 2, bottom). This analysis showed that both PP and MBP were significant predictors for total cardiovascular and coronary heart disease mortality, with the more pronounced effects of each parameter when values of the other parameter were lower.
Therapeutic decision making and management in patients with mild-to-moderate hypertension are complicated by the wide variation in their clinical characteristics. Clinicians therefore have sought more precise means to describe the outlook for individual patients. One approach has been to use different measures of baseline blood pressure, such as 24-hour recordings and variability of blood pressure to prognostically stratify patients. Our study is the first to clearly show that in a large male unselected population with a relatively low risk (volunteers for free medical examinations), PP measurement may help in the evaluation of the individual risk and therefore in the therapeutic decision making. Although the use of a single blood pressure measurement reduced statistical power, our results demonstrate that increased PP is a predictor of global mortality and cardiovascular mortality, independent of other known cardiovascular factors such as age, mean blood pressure, total cholesterol, and smoking. Interestingly, increased PP was a predictor of coronary heart disease mortality, whereas its predictive value was not significant for cerebrovascular mortality.
A previous analysis of the same cohort was not able to establish a significant relationship between PP and cardiovascular mortality in male subjects. We believe that this was due to the fact that in this low-risk population, the duration of the follow-up of the previous analysis was too short (9 years) to evaluate the role of PP. As shown from the survival curves in the present study (Fig 1) differences among the four subgroups according to the PP levels, only become clear after
the 10th year of follow-up.
Physiologically, PP describes the oscillation around the mean arterial pressure (calculated as DBP+1/3PP) and is influenced by hemodynamic mechanisms that differ from those controlling mean arterial pressure. MBP is the pressure that would be present in the aorta and its major arteries during a given cardiac cycle if the cardiac output was nonpulsatile.7,8 Although mean arterial pressure remains nearly constant along the arterial tree, PP increases markedly from central to peripheral arteries as a consequence of a substantial increase in SBP and a slight lowering of DBP. At a given stroke volume and velocity of ventricular ejection, the mechanisms influencing PP are related to the status of conduit arteries, that is, the viscoelastic properties of the arterial wall and timing of the reflected waves. Increased stiffness and earlier wave reflections within the thoracic aorta increase the PP due to an increase in SBP and a decrease in DBP.7,11 Alternatively, increased stroke volume or ventricular ejection rate may be responsible for an increase in SBP with no change in DBP. In the present study, we showed that the widest PPs were due to both an increase in SBP and a decrease in DBP. Thus, the changes in PP may be considered as markers of increased arterial stiffness, with consequences for the cardiovascular mortality.
In the present study, in the younger individuals (40 to 54 years), PP and MBP have additive effects in the evaluation of the risk for the different causes of mortality (except for cerebrovascular, for which MBP but not PP is a strong predictor). Interestingly, in older individuals (55 to 70 years), a negative interaction was observed between MBP and PP, suggesting that the effect of PP in total cardiovascular and, especially, coronary heart disease mortality is enhanced in individuals with low MBP (Table 3b and Fig 2). Taken together, these results show that increased PP was a major predictor of coronary mortality even in the presence of values of MBPs conventionally accepted as being within the normal range (MBP <107 mm Hg). Indeed, the coronary circulation is the only circulation with volume flow that is governed by the DBP rather than the SBP.12 Thus, any decrease in DBP as a consequence of increased arterial stiffness may limit coronary blood flow, particularly in the presence of associated stenosis of the coronary arteries.11 In addition to a decrease in DBP, increased arterial stiffness is responsible for an increase in SBP, which, through increased end-systolic stress, promotes cardiac hypertrophy. In hypertensive subjects, a positive and significant association has been previously observed between increased PP and increased cardiac mass independent of mean arterial pressure.13 Therefore, it is reasonable to suggest that an increased PP, through both these mechanisms, increases coronary risk.
In the present study, no comparable risk was observed for PP in the cerebral circulation. This finding may be in part due to a loss of statistical power as a consequence of the relatively small number of cerebrovascular deaths compared with coronary ischemic deaths. However, in our cohort, MBP was the most significant predictor of cerebrovascular mortality, and mean arterial pressure (but not PP) is the perfusion pressure of the cerebral circulation.
In conclusion, the present study has shown that in male subjects with normal or elevated mean arterial pressure, increased PP is a strong predictor of general and cardiovascular mortality, affecting especially the coronary but not the cerebrovascular circulation.
This study was performed with the help of INSERM (Paris). We thank the Caisse Nationale
d'Assurance Maladie (CNAM) for support of this study. The authors are grateful to Jean-François Morcet and Jean Pierre Huby for their help and advice in analysis of the data. We thank Dr Anne Safar for help in preparing the manuscript.
Received April 8, 1997; first decision April 24, 1997; accepted June 25, 1997.< /p>