Pulse hypertension: a new component of the metabolic syndrome in elderly women?

Abstract

The classification of arterial hypertension (HT) to define metabolic syndrome (MS) is unclear in that different cutoffs of blood pressure (BP) have been proposed. We evaluated the categorization of HT most qualified to define MS in relationship with coronary heart disease (CHD) mortality at a population level. A total of 3257 subjects aged 65 years were followed up for 12 years. MS was defined according to the criteria of the National Education Cholesterol Program using three different categories of HT: MS-1 (systolic blood pressure (SBP) 130 and diastolic blood pressure (DBP) 85 mm Hg), MS-2 (SBP 130 or DBP 85 mm Hg) and MS-3 (pulse pressure (PP) 75 mm Hg in men and 80 mm Hg in women). Gender-specific adjusted hazard ratio (HR) with 95% confidence intervals (CI) for CHD mortality was derived from Cox analysis in the three MS groups, both including and excluding antihypertensive treatment. In women with MS untreated for HT, the risk of CHD mortality was always significantly higher than in those without MS, independent of categorization; the HR of MS was 1.73 (CI 1.12–2.67) using MS-1, 1.75 (CI 1.10–2.83) using MS-2 and 2.39 (CI 3.71–1.31) using MS-3. In women with MS treated for HT, the HR of CHD mortality was significantly increased only in the MS-3 group (1.92, CI 1.1–2.88). MS did not predict CHD in men. In conclusion, MS can predict CHD mortality in elderly women with untreated HT but not in those with treated HT; in the latter, PP is the most predictive BP value.

Introduction

Metabolic syndrome (MS), also referred as to insulin resistance syndrome, is defined by the clustering of several cardiovascular risk factors,1, 2, 3 namely impaired glucose tolerance, abdominal obesity, dyslipidemia and arterial hypertension (HT). Epidemiological studies have shown that MS is quite common in men and in younger adults,4, 5, 6, 7, 8, 9, 10 while poorly investigated in the age class over 64 years, where >90% of coronary events occur.11

Furthermore, some criteria used for defining MS are ambiguous or incomplete. This is particularly true in defining HT. Different cutoff values of HT have been proposed, and antihypertensive treatment has from time to time been considered3 or not considered12 as a criterion to define HT. Furthermore, the criteria to define HT derive from middle-aged people, particularly men,2 while very few data are available about the elderly and particularly about elderly women.3

The aim of this study was to evaluate at a population level the definition of HT most able to predict the risk of coronary mortality in elderly subjects with MS defined according to the criteria of the National Education Cholesterol Program Adult Treatment Panel III (NCEP-ATP III). For this purpose, 3282 elderly subjects aged 65 years, taking part of the CArdiovascular STudy in the ELderly (CASTEL), were investigated.

Materials and methods

The CASTEL is a longitudinal epidemiological study involving 3282 elderly subjects aged 65 years from the general population of Northern Italy. The study was approved by the CASTEL ethics committee and all the procedures were in accordance with the Helsinky declaration and with institutional guidelines. Each subject gave informed consent to the study.

Data collection

Details on recruitment and procedures for baseline examination and follow-up have been described elsewhere.13 Briefly, the survey included the gathering of demographic information, medical and social questionnaires, blood tests, anthropometrics, spirometry, electrocardiogram and blood pressure (BP) measurement. All-cause 12-year mortality was assessed yearly through the Register Office, hospital discharge records and death certificates. Causes of death were collected from hospital files and by questioning general practitioners. All records were coded according to ICD-9-CM by a trained research worker. The codes for coronary mortality were 410–414. Mortality was defined as cardiovascular when deriving from coronary disease (code 410–414), stroke, 436 heart failure, (398.91, 402.11, 404.11, 404.13, 404.91, 404.93, 428.0–428.11), arrhythmias (427) or pulmonary embolism (415.1), and as non-cardiovascular when as a result of other causes. No cause of death was missed.

Measurement of variables and definition of diseases

Body mass index (BMI, in kg/m2) was defined as weight/squared height. According to World Health Organisation, subjects having BMI 30 kg/m2 were labelled as obese.

Fasting lipid concentrations were enzymatically measured in the Laboratory of the Department of Clinical and Experimental Medicine of the University of Padova. Subjects with triglyceride (TG) values 1.7 mmol/l or high-density lipoprotein cholesterol (HDL-C) <1.0 mmol/l in men or <1.3 mmol/l in women were defined as having dyslipidemia. Subjects with known diabetes (fasting blood glucose repeatedly 7.0 mmol/l, active treatment with glucose-lowering medication or history of diabetes) were excluded from the analysis concerning the predictive value of the MS; those with fasting serum glucose 6.1 mmol/l were considered as people with glucose intolerance.

BP was measured eight times in a 3-month period (three times at the first impact with the patient, three times 1 month later and twice another month later); in order to avoid any white coat/alert reaction, only the average of the last two measurements was considered for data analysis. Pulse pressure (PP) was the difference between systolic blood pressure (SBP) and diastolic blood pressure (DBP).

HT was diagnosed at the initial screening using three different criteria:

  1. 1)

    systolic 130 mm Hg and diastolic 85 mm Hg (HT-1)

  2. 2)

    systolic ≥130 mm Hg or diastolic 85 mm Hg (HT-2) according to NCEP-ATP III,3 and

  3. 3)

    PP 75 in men or 80 mm Hg in women (HT-3) according to definition of ‘pulse HT’ derived from our direct experience in elderly people.14, 15 Antihypertensive treatment at the initial screening was not included as a criterion of HT, but its role was tested in the multivariate analysis of coronary risk.

Creatinine clearance (Crcl, in ml/min) was calculated from serum creatinine using the Cockroft and Gault formula:16, 17

Daily alcohol consumption was recorded by means of a questionnaire; intake of wine, beer and spirits was reported separately. Most of the alcohol consumed was represented by wine, one drink corresponding to 10–12 g ethanol.

Subjects with at least one of the following items at baseline: Minnesota code equal to 1.1 or 1.2 or 1.3 (if absent 6.4.1) or 4.1 or 4.4 (if absent 6.4.1, 7.1.1 and 7.2.1) or 5.1 or 5.2 or 5.3 or 5.4 (if absent 6.4.1, 7.1.1, 7.2.1 and 7.4), positive myocardial scintigraphy, positive stress test, history of myocardial infarction confirmed by hospital files, history of angina pectoris confirmed by hospital or physician's files, appropriate antianginal chronic treatment, were labelled as having historical coronary disease. Left ventricular hypertrophy diagnosis required Minnesota code 3-1 or 3-3.

Diagnosis of proteinuria required 200 mg/l urinary proteins.

According to the NCEP-ATP III,3 subjects with obesity, glucose intolerance, dyslipidemia and HT were labelled as having MS. HT was defined using the three above-mentioned categorizations and MS was named MS-1, MS-2 or MS-3 when HT-1, HT-2 or HT-3 were used. As recently suggest by the International Diabetes Federation,18 a modified ATP III definition of obesity in MS was used, replacing waist circumference with BMI 30 kg/m2. No particular cardioprotective agents were taken either by MS1 and MS2 subjects.

Statistical analysis

Only 3257 subjects out of the 3282 evaluated at baseline were included in the statistical analysis, as 25 of them had incomplete data. Continuous variables were averaged, expressed as mean and standard deviation, and compared with analysis of covariance and the Bonferroni's post hoc test. Categorical variables were expressed as percentage rates and compared with the Pearson's χ2 test.

Annual mortality rates were compared with the Kaplan–Meier approach after generating cumulative survival curves.

Multivariate stepwise proportional hazard Cox regression was used to identify the variables having a prognostic role on coronary heart disease (CHD) mortality. Hazard ratio (HR) of CHD mortality with 95% confidence intervals was calculated for each item and adjusted for confounders. Covariates were selected because of their potential relation with MS or CHD mortality. The proportionality assumption of the Cox model was previously tested by adding a time-dependent covariate for each variable, so that the conditional hazard at each point in time was a function of the covariate and time and the effect of the covariate on survival was dependent on time. MS, gender, age, historical CHD, creatinine clearance, serum total cholesterol (TC), low-density lipoprotein serum cholesterol (LDL-C), serum uric acid, smoking, alcohol consumption, proteinuria and antihypertensive treatment were included as covariates in the analysis of CHD mortality. As gender was accepted in the Cox models for CHD mortality (see below), the analysis was performed separately in each gender.

A Cox analysis was separately performed by gender using the combinations MS-1, MS-2 and MS-3.

Results

General characteristics of study population are summarized in Table 1, which also shows gender stratification. Women were older and had, in comparison to men, significantly higher heart rate, TC, LDL-C, HDL-C and TG, and higher prevalence of MS, diabetes, obesity and HT. Men had higher serum creatinine levels, and higher prevalence of smoking habits, alcohol consumption and chronic obstructive pulmonary disease. General characteristics of subjects and the distribution of different components of MS, divided into the three models (MS-1, MS-2 and MS-3) stratified by gender, were shown in Table 2. SBP and DBP were not different between treated and untreated women (data not shown).

Table 1 General characteristics of the study population
Table 2 General characteristics of subjects into the three models of metabolic syndrome (MS-1, MS-2, MS-3) by gender

During the 12 years of follow-up, there were 1532 deaths (848 in men and 684 in women); 834 of them were cardiovascular (507 in men, 327 in women) and more precisely 155 were due to CHD (91 in men, 64 in women).

As in a preliminary Cox analysis performed on the whole population, an interaction between gender and CHD mortality was detected (HR of male gender 1.31 (1.17–1.48)), multivariate analysis was carried out separately in men and in women.

In men, CHD mortality was directly predicted by age, historical CHD, creatinine clearance, TC and LDL-C, and in women by age, historical CHD, uric acid and MS (Table 3).

Table 3 Multivariate Cox analysis of CHD mortality in men and women both including and excluding antihypertensive treatment

More precisely, among women not taking any antihypertensive treatment, CHD mortality rate was significantly higher in those having MS than in those who did not have it. This was true for any classification of MS: 6.9 vs 4.3% (P<0.0001) when using MS-1 criterion, 6.5 vs 4.1% (P<0.0001) when using MS-2 and 8.5 vs 4.3% (P<0.0001) when using MS-3 criteria (Figure 1). On the contrary, among those women who were taking antihypertensive treatment, CHD mortality was higher in those with than in those without MS-3 (7.3 vs 4.3%, P<0.02), while no effect of MS was detected when using MS-1 (5.6 vs 4.4%) or MS-2 (5.4 vs 4.3%) (Figure 2). Cumulative survival in relation to MS defined using the NECP criteria by gender is shown in Figure 3.

Figure 1
figure1

Adjusted hazard ratio (HR) for coronary (CHD) mortality in untreated women with () and without (•) metabolic syndrome (MS-1, MS-2, MS-3). *P<0.05, **P<0.01 vs reference. CHD, coronary heart disease.

Figure 2
figure2

Adjusted hazard ratio (HR) for coronary (CHD) mortality in treated women with (•) and without () metabolic syndrome (MS-1, MS-2, MS-3). **P<0.01 vs reference. CHD, coronary heart disease.

Figure 3
figure3

Coronary (CHD) mortality survival in men (•) and women (▪) according to the three models of metabolic syndrome (MS-1, MS-2, MS-3). *P<0.05, **P<0.01 vs reference. CHD, coronary heart disease.

Discussion

Arterial HT is one of the components of MS, but the BP levels proposed to classify HT2, 3 have changed many times in the last decades.19 The first attempt to furnish clear cutoff values for defining HT in subjects with MS was made in 1999 by the WHO Diabetes Group, labelling as hypertensive those having BP >140/90 mm Hg independent of antihypertensive treatment.2 At the same time, the European Group for the Study of Insulin Resistance, while maintaining the same BP levels, included antihypertensive treatment in the definition of HT.20 Finally, in 2001, the NECP-ATP III labelled as HT the condition characterized by BP levels 135/80 mm Hg or by current antihypertensive treatment.3 This classification was also used 2 years later by the American College of Endocrinology (ACE).21 Nevertheless, both in NCEP and ACE definitions, it is unclear whether HT has to be diagnosed for SBP values 130 mm Hg and DBP values 85 mm Hg rather than SBP 130 mm Hg or DBP85 mm Hg.2 This could be a very important difference; as in our experience collected from 11 598 subjects from the Italian general population, the use of the boolean operator or rather than and (that is use of systo-diastolic rather than isolated systolic HT criteria) increases prevalence of HT by 50.2% (data not shown).22

The role of HT as a factor influencing CHD risk in subjects with MS is under debate, particularly in the elderly.23 Saad et al.24 stated that the higher prevalence of HT observed in European than in African/Asian people is one of the possible reasons influencing higher CHD mortality observed in subjects with MS. Shen et al.25 suggested that HT is related to MS only secondary to other mechanisms activated by insulin resistance and hyperinsulinemia, that is increased renal sodium and water retention, plasma noradrenaline and sympathetic nervous system activity.26, 27, 28 Grundy et al.29 believe that HT is ‘less metabolic’ than other metabolic-syndrome components, being multifactorial in nature. Another potential confounder about the role of HT in MS is aging, because both HT and MS increase in prevalence with age.30

In our experience, the classification of HT proposed by the NCEP did not modify CHD profile. In fact, for an old person with MS, a systolic 130 and/or a diastolic 85 mm Hg did not increase the risk of dying for a CHD event when antihypertensive treatment was present; and on the other hand, untreated elderly hypertensives were at increased risk of CHD mortality independent of systolic or diastolic category. This observation outlines the role of the antihypertensive treatment as a protective factor and confirms the importance to treat HT patients as suggested by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.31

Nevertheless, in our experience, the application of a new classification of HT as a criterion of inclusion in MS – namely pulse HT – was able to define the risk of CHD mortality more efficiently. PP is probably a more accurate way to define HT in the elderly than those used by the NCEP. In the elderly, PP is a marker of increased arterial stiffness, a condition able per se to increase coronary risk.14 In fact high PP (namely >80 mm Hg) may derive from rise of systolic (usual in the elderly), decrease of diastolic or both. In our population, the systolic component was prominent, as diastolic BP was the same in the three different classifications of MS. MS is independently associated to increased arterial stiffness. In this perspective, MS can be perceived as accelerating vascular aging. In the present analysis, the prognostic effect of pulse HT is so evident and plausible that we are obliged to ask whether the predictive value of MS is entirely due to high PP. Although the general belief is that the MS is a well-defined nosographic entity, in the last few years, it has been suggested that it could be nothing more than a constellation of risk factors, whose overall prognostic effect is not higher than that of the single components.32, 33 The results of the analysis described here are partially in agreement with this opinion, showing that the predictive value of MS-3 largely coincides with that of pulse HT. It might be worthwhile to underline this possibility in elderly subjects too.

The question on why in our experience MS was more soundly related to survival in women than in men is difficult to answer. A potential explanation is the different impact of arterial stiffness on coronary mortality in men and women. Arterial degenerative changes due to increasing age appear later in women,34, 35 and stiffening does not occur in women until menopause.36 Another possibility is the higher prevalence of glucose intolerance in our female population, a condition preceding frank diabetes.37 Increasing evidence shows that the gender-specific difference in CHD mortality decreases with age, and women with MS experience the greater risk.38

Of course, we have observed a population in which a natural selection has occurred in the previous decades, a selection that is notoriously more important in men, more prone to succumb to MS. This may have subtracted men from observation.39 The experience of the CASTEL is, to our knowledge, the second prospective cohort study; Hillier et al.40, 41 previously found increased coronary mortality in elderly women with MS.

In conclusion MS – namely a constellation of obesity, glucose intolerance, dyslipidemia and arterial HT – MS (1) has no role in predicting CHD mortality in elderly men, (2) can predict CHD disease in elderly women with untreated HT and (3) shows no predictive power in elderly women with treated HT, where PP is particularly active in predicting CHD disease. In this view, MS seems to have the same predictive role as high PP. Nevertheless, as a ‘MS world’ will still continue to exist for a long time yet, in the meantime, it might be advisable to employ PP as the BP criterion for defining HT in MS.

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Acknowledgements

We thank miss Jillian Walton for kindly revising the paper.

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Correspondence to E Casiglia.

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Mazza, A., Zamboni, S., Tikhonoff, V. et al. Pulse hypertension: a new component of the metabolic syndrome in elderly women?. J Hum Hypertens 21, 934–941 (2007). https://doi.org/10.1038/sj.jhh.1002245

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Keywords

  • arterial hypertension
  • coronary
  • elderly
  • epidemiology
  • metabolic syndrome
  • pulse pressure

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