Is obesity-related hypertension less of a cardiovascular risk? The Framingham Study

PROGRESS IN CARDIOLOGY

Is obesity-related hypertension cardiovascular risk? The Framingham Study William

B. Kannel,

Boston,

Mass.,

MD:

Tingjie

and Bethesda,

Zhang, MD, and Robert J. Garrison,

METHODOLOGY

The Framingham Study has observed a cohort of 5209 men and women initially aged 30 to 62 years in From sthe Section of Preventive Medicine and Epidemiology, Boston University School of Medicine, Evans Memorial Department of Clinical Research, University Hospital at Boston University Medical Center; and bField Studies and Biometry Branch, Epidemiology and Biometry Program, Division of Epidemiology and Clinical Applications, National Heart, Lung and Blood Institute. Supported by National Heart, Lung, and Blood Institute grant numbers NIH-NOl-HV-92922, NIH-NOl-HV-52971 and by contract number NOlHC-38038, by The Charles A. Dana Foundation; and by Merck Sharp and Dohme, West Point, Pa. for publication

April

2, 1990;

accepted

Reprint requests: William B. Kannel, MD, 720 Harrison Ave., Boston, MA 02118.

4/l/23607

MS.b

Md.

Hypertension and obesity have been frequently noted to coexist.‘-7 In fact, obesity and weight gain have been found prospectively to predispose to the development of elevated blood pressure.3-5 Both obesity and hypertension predispose to the occurrence of cardiovascular disease, including coronary disease, stroke, and cardiac failure.4s7-14 Since obesity and weight gain have also been shown to promote other risk factors such as glucose intolerance, hypercholesterolemia, hyperuricemia, reduced high-density lipoprotein (HDL)-cholesterol, and hyperinsulinemia, it would seem that hypertension accompanied by obesity should be more dangerous than hypertension that is not accompanied by obesity. However, controversy exists as to whether hypertension accompanied by obesity is more15-18 or less1g-26 hazardous. Thus it is not clear whether hypertension has a different prognostic importance in the obese than in the lean. The purpose of this report is to examine this issue in a prospective study that utilizes 34 years of cardiovascular disease information on 5209 subjects biennially characterized by their blood pressure and weight status.

Received

less of a

Doctors

May

25, 1990.

Office

Bldg.,

Suite

1105,

1948 to 1952 for a period of 34 years for the development of cardiovascular disease by means of biennial clinic examinations, surveillance of hospital admissions, death certification, and medical examiner reports. Sampling, response rates, clinical criteria for cardiovascular end points, and laboratory methods employed have been reported in detail elsewhere.27T 28 Blood pressures were measured to the nearest 2 mm Hg, using a mercury sphygmomanometer with cuffs of variable widths, depending on the arm circumference, in the left arm with the patient seated. A participant was designated hypertensive if either of the two systolic blood pressure measurements were >160 mm Hg and either of two diastolic pressure measurements was >95 mm Hg, or if the examining physician determined that the subject was taking an antihypertensive agent. Mild hypertension was defined as pressure in the range of 140 to 159 mm Hg systolic and/or diastolic pressures between 90 and 94 mm Hg. Height and weight were determined on each biennial examination throughout the follow-up. Subjects were weighed on a clinical beam scale, wearing an examination gown. The obesity index chosen for this analysis was the body mass index (BMI) calculated from the ratio of weight (kilograms) to height (meters) squared. The 34-year follow-up period was divided into four segments of 8 years to permit reclassification of individuals at each of four baseline examinations. In this report, the final 2 years of follow-up information is ignored. Biennial examination number 1,5,9, and 13 were used as the baseline examinations at which an individual’s risk factor values and his or her age were “updated.” Unless otherwise specified, only study participants who were free of cardiovascular disease (CVD) as defined below were entered at the baseline examinations, and the time of occurrence of death or the first occurrence of CVD over the subsequent 8 years was noted. All 8-year segments were pooled for analyses, 1195

1 I 96

Kannel,

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November 1990 Heart Journal

I. Eight-year cardiovascular diseaseincidence rates per 100 participants by sex, age, and baselineexamination number: Framingham Study, 34-year follow-up Table

Men

Women

Rasrline exam No. * Age (.vri 30-39 40-49 50-59 60-69

1

5

3.0 (823j 8.9 (766) 18.2 (600) 20.0

(60) 70+

-

9

Baseline exam No. * 1 :I

Total rL~rnt.s/No.

18.8 (309) 22.9 (407) 32.9 (243)

(911) 160 (I 743) 385 (2093) 273 (1193) 13’1 (398) ”

2.3

2:

(88) 8.6 (752) 19.4 (583) 19.8 (329) -

12.0 (22.5) 17.5 (601) 26.0 (396) 34.0 (153)

Number of subjects is shown in parentheses. *Subjects with prevalent cardiovascular disease

at

each baseline are

II. Prevalence of hypertension by relative weight* excluding subjects with prevalent cardiovascular disease

Tertile of BMI Lowest Middle Highest *All trends statistically gression analysis.

Women

Age (yr)

Age fyr)

S-64

659d

X5-64

65-94

11 17

19 32

9 15

44 39

27

30

30

53

significant

(p < 0.001 I by age-adjusted

1.0 (1040) 2.9 (944) 10.2 (773) 16.4

(611

,5 0.0 (111) 2.8 (960) 9.7 1785) 15.9 (484)

9

13 -~

Total events/No. 1 (1151)

x.2 (292) 10.5

(846) 17.5 (560) 28.7 (265)

(2lt) 11.5 (399) 14.1 (661 t 25.2 (445)

290 (2803) 278 (1766) 189 (714)

excluded

Table

Men

I

logistic re-

which included multivariate logistic regression analysis2g for testing the relationship between hypertension prevalence and other attributes. The Cox proportional hazards mode13’ was used to model the time to CVD as a function of hypertension, BMI, and the other CVD risk factors. The coefficients from the model provide point estimates of relative risks of CVD for contrasting levels of the independent variables in the regression analysis. The likelihood ratio test was used to test the significance of the regression coefficients. The appropriateness of the proportional hazards model-i.e., the constancy of the ratio of hazards for various risk factor levels over time-was tested by evaluating the association between model residuals and the rank order of the time to CVD.31 Cardiovascular events included in the analysis were coronary heart disease, stroke, cardiac failure, and occlusive peripheral arterial disease, which were defined using previously published criteria.27* 28,32 When study participants who had prevalent CVD

at the first examination are excluded, there were 978 men and 845 women who suffered an incident CVD event. The age-, sex-, and baseline-specific CVD incidence rates are displayed in Table I. The remarkable uniformity of the age-specific rates across the four baseline examinations justifies pooling of 8-year observations from the 32-year period. OBSERVATIONS

Under age 65 years, the prevalence of hypertension in both sexes increased three-fold from the lowest to the highest tertile of BMI (Table II). Over age 65 years, the upward trend is less striking in men but is statistically significant. The risk of cardiovascular events is increased in both borderline and definite hypertensive individuals at all ages and in both men and women (Table III). The risk of cardiovascular events also increased progressively with relative weight in men (Table IV). This relationship is statistically significant at all ages. On adjustment for other risk factors promoted by obesity, including hypertension, the association remains statistically significant in men. In women, a significant relationship, age- and risk factor-adjusted, is noted under age 65 with borderline statistical significance noted above age 65. The $-year relative risk of an initial cardiovascular event associated with hypertension (compared to non-hypertensive individuals) was estimated from the multivariate proportional hazards regression coefficient. In addition to hypertension status, the model included age in years and cigarette smoking, since the relation of cardiovascular disease to weight may be confounded by the tendency of smokers to be leaner. There is no hint of a diminishing impact of

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hypertension with increasing BMI in either sex at any age (Table V). For cardiovascular mortality, there is also no indication of a diminishing impact of hypertension with increasing BMI, and the lean subjects under age 65 appear to have the lowest relative risk (Table VI). There is a suggestion of a lesser impact in those overweight individuals who are over age 65 that is not statistically significant. For coronary events in particular, there is if anything an increased impact of hypertension in the obese (Table VII). However, a formal statistical test of this hypothesis failed to reject the null hypothesis of no interaction. For coronary heart disease mortality, the trend is not seen and at no age in either sex does the impact of hypertension wane with increasing weight (Table VIII). A graphic display of the data cross-classifying ageadjusted incidence rates of cardiovascular disease by tertiles of BMI and systolic blood pressure indicates no diminishing impact of hypertension with increasing relative weight (Fig. 1). In fact, the risk at any level of blood pressure seems to increase with BMI. Extending the analysis to include the important cardiovascular end points of myocardial infarction and stroke adjusted for age and cigarette smoking, no interaction of BMI and hypertension in any age-sex subgroup as indicated. The net effect of hypertension on cardiovascular disease incidence shows no tendency to diminish with increasing BMI in either sex (Table IX). COMMENTS

Obesity and hypertension have evoked widespread concern because of their high prevalence and influence on public health. In the United States it has been recently noted that 26% of the population between 1976 and 1980 were overweight, and no less than 12.4 million of these 34 million adult Americans were severely overweight. g* 33 Childhood and adolescent obesity has increased dramatically over the past two decades. It is estimated that about one fourth of all American children are overweight, and these children tend to become obese adults?, 34 This situation is not unique to the United States, as it is also a problem in Europe.l’t 23,35 Hypertension is also a ubiquitous major problem in North America, in Europe, and in Asia.36* 37 In the Framingham Study, it has been recently noted that 60% of all 70-year-old individuals are now receiving hypertensive treatment. 35 The Tecumseh Study found that 27 % of men and 37 % of women aged 40 to 59 years were hypertensive.4 A recent epidemiologic study in China (1979 to 1980), sampling more

Obesity-related hypertension

1197

III. Risk of cardiovascular events by hypertensive status; &year age-adjustedrate per 100study participants: Framingham Study, 34-year follow-up Table

Hypertensive status Normal Mild Definite All trends significant

Men

Women

Age (yr)

Age (.vr)

35-64

65-94

35-64

65-94

9.0 15.2 21.7

17.4 30.4 43.0

4.5 7.1 13.3

13.5 21.3 28.2

at p < 0.001.

IV. Risk of cardiovascular events by relative weight; 8-year age-adjusted rates per 100 study participants: Framingham Study, 34-year follow-up Table

BMI

quintile

First Second Third Fourth Fifth Significant

Men

Women

Age lyr)

Age (yr)

35-64

65-94

35-64

65-94

11.1 11.5 13.6 14.9 15.5

20.9 30.7 26.2 31.4 34.0

6.5 6.4 5.7 7.6 9.8

21.7 20.0 17.6 26.0 26.0

pValue

trend

Age-adjusted Risk factor-adjusted


<0.05

0.13 0.07

V. Estimated relative risk of cardiovascular disease in men and womenwith hypertension (versus those without hypertension) by obesity status Table

Age group <65 yr Relative tertile Lowest Middle Highest

weight (BMI)

Men

*

1.97 (191) 1.84 (249) 2.21

(282) Number *Subjects

of incidence cases is shown with prevalent cardiovascular

65+ ,yr

Women

*

Men*

M70men

(246)

1.80 (68) 1.70 (84) 2.96 (90)

2.01 (102) 1.58 (95) 1.51 (119)

2.49 (135) 2.34 (135) 2.43

*

in parentheses.

disease are excluded

than four million persons aged 15 and over, found that by age 65, 40% were hypertensive.37 Both hypertension and obesity have been shown to be associated with an increased risk of cardiovascular disease.4, ’ Also, obesity has been shown to predispose to impaired glucose tolerance, to hyperurice-

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Table VI. Estimated relative risk of cardiovasculardeath in

Table VII. Estimated relative risk of coronary heart disease

men and women with hypertension (versusthose without hypertension) by obesity status

in men and women with hypertension (versusthose without hypertension) by obesity status Age group

Age group <65 yr

Relative weight tertile (BMI) Lowest Middle

yr

Men*

Women *

Men *

Women *

2.97 (54) 4.12

1.64 (31) 2.68 (21) 3.49 (44)

2.94 (27) 1.93 (36) 2.03 (31)

2.66 (44) 2.88 (23) 2.21

(60) Highest

6.5+

3.22

(64)

(46)

<65 yr

Relative weight tertile (BMI) Lowest Middle Highest

65+ yr

Men*

Women *

Men *

Women *

1.78 (130) 1.51 (192) 2.08 (272)

1.89

1.26 (40) 1.85

1.75 (53) 1.22 (57) 2.19 (66)

(78) 2.41 (91) 2.28

(160)

(48) 2.11 (63)

Number of incidence caaea is shown in parentheses. *Subjects with prevalent cardiovascular disease are excluded.

Number of incidence cases is shown in parentheses. *Subjects with prevalent cardiovascular disease are excluded.

mia, elevated triglyceride, reduced HDL-cholesterol, and left ventricular hypertrophy.7‘11 All these have been shown to increase the risk of cardiovascular disease. Thus it seems unlikely that the obese individual more burdened with these additional risk factors would be less vulnerable to the presence of hypertension. Despite this, it has been claimed that hypertension accompanied by obesity is less hazardous than hypertension associated with a lean habitus.lgp 20,23-25It would seem that this would be possible only if obesity-induced major risk factors are of no consequence, a rather unlikely possibility, or if lean hypertensive individuals have elevated pressures caused by some different mechanism such as renal disease. There is considerable evidence linking obesity to hypertension. Both frequently coexist in the same person, and weight gain and loss have been shown, on average, to be mirrored by corresponding changes in blood pressure. l-7 Estimates from the Framingham Study suggest that about 70% of newly developing hypertension can be attributed to obesity or to excessive weight gain. 38 If hypertension acquired in this way were innocuous, this would be a less serious problem than it appears to be. Published reports on the prognostic implications of obesity-related hypertension have been inconsistent, some claiming it to be more dangerous,15-l7 some claiming it is less dangerous,1g-26, 31and others claiming it is inconsequential.22, 35 Most studies have shown that obese hypertensive individuals experience a greater amount of cardiovascular disease.4-10s~9 3g,40 Others20 have claimed that in the presence of obesity, hypertension does not increase risk and indeed appears to be protective. Cambien et a1.23 reported in two studies that there is a negative interaction between blood pressure and BMI in rela-

tion to cardiovascular mortality.

Goldbourt et al.,lg

reporting on the Israeli Ischemic Heart Disease Study, suggested that excess coronary heart disease mortality associated with hypertension is more pronounced in lean than in overweight men. Bloom et a1.,17 on the other hand, found that the relationship of blood pressure to cardiovascular disease incidence does not vary with the level of BMI. The Evans County Study found a higher relative risk in lean hypertensive individuals.31 Messerli et a1.15q18.3g,41-43 have reflected on the problem based on clinical and pathologic data, concluding that obesity has a dual effect on cardiovascular pathology in hypertension. They note that in the obese hypertensive individual, cardiac output is higher and vascular resistance is lower, imposing a burden on the left ventricle. On the other hand, obesity tends to mitigate the harmful effects of a chronically increased peripheral and renal vascular resistance, which could reduce end-organ damage such as nephrosclerosis. The results of the current Framingham Study investigation provide no evidence for a protective effect of obesity in persons with hypertension. Hypertension is dangerous at all weights and it should be noted that the leaner hypertensive individual has a lower absolute risk (Fig. 1). The conclusion from this report

is that the relatiue risk of cardiovascular disease in hypertension is no different in persons with high or low BMIs. It is difficult to explain the discordant results of the various studies. To a degree this could derive from arbitrary dichotomization into “lean” and “obese” at various BMIs in the different studies. The discordant results could also be due to different age groups being examined. Also, most studies of the problem are confined to men. Obesity appears to have a stronger

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Obesity-related

hypertension

1199

CVD RATE

CVD RATE

6

6

SUI TERTILE G

0 KM0l.E SSP TERTILE

lDwEST

HmlEsT

MIOOLE SBP TEATILE

l.owEST

Fig. 1. Cardiovascular diseaserates by body massindex (B&U) and systolic blood pressure@BP) tertiles. Shown are eight-year age-adjustedrates for each 100 study participants in personsfree of cardiovascular disease(CVD) at baselineexaminations.

independent influence on coronary heart disease (CHD) in men than in women, and in younger than in older men.35 It is also possible that the pattern of adiposity has varied in the different samples, and abdominal obesity has been noted to be more hazardous.4’, 44-48Phillips and Shaper4g recently examined the issue in the British Regional Heart Study and found that for both hypertensive and normotensive men the rate of major coronary events rose with increasing BMI. They present a review of 11 prospective studies, including the British Regional Heart Study, which suggest that lean hypertensive men are not at higher risk of major CHD events than obese hypertensive men. In consideration of the known and consistently demonstrated atherogenic accompaniments of obesity, it is unlikely that hypertension in the obese should be less dangerous than hypertension in the lean. This prospective study of the Framingham cohort does not confirm these illogical claims. As a large proportion of the incidence of hypertension appears to be directly attributable to obesity, weight control would appear to be an important public health measure against hypertension. Also, although direct controlled trial evidence is lacking, weight reduction should improve the cardiovascular risk of the hypertensive individual by helping reduce the blood pressure, blood sugar, uric acid, and triglycerides while raising the HDL-cholesterol level.

Table VIII. Estimated relative risk of cardiovasculardisease

death in men and women with hypertension (versusthose without hypertension) by obesity status Age

group 65-b yr

<65 yr Relative tertile

weight fBM1)

Lowest Middle Highest

Men*

Women*

Men*

Women*

2.21 (37) 3.72 (331 3.19 (50)

1.06 (14) 3.49 (11) 2.46

1.69 02) 2.25 (21) 2.06

2.44 1.95 (14) 2.25

(23)

(18)

(23)

(20)

Proportion with hypertension in parentheses (“C). Number of incidence cases is shown in parentheses. *Subjects with prevalent cardiovascular disease are excluded.

IX. Net effect of hypertension on incidence of cardiovascular disease by BMI quintile:Framingham Study, 34-year follow-up

Table

Multivariate Cox Regression coefficients BMI

quintile

First Second Third Fourth Fifth

*

Men

Women

0.655 0.589 0.925 1.020 0.774

1.033 0.900 0.673 0.664 0.853

SUMMARY

*Controlled

The hypothesis that obesity-related hypertension is relatively innocuous was explored by an examination of cardiovascular events over 34 years of followup when related to biennially measured weights and blood pressures using time-dependent covariate proportional hazards analysis. The 5209 participants were also classified by age, cigarette smoking, and

antihypertensive treatment at each of four baseline examinations with B-year follow-up periods. Over the period of follow-up, there were 978 cardiovascular events in men and 836 in women. Risk of cardiovascular morbidity and mortality in general and of CHD

for age and cigarette

smoking

by sex.

1200

Kannel, Zhng, and Garrison

in particular was as strongly related to hypertension at all levels of body mass index. This was also found to apply when adjustment was made for possible confounding by cigarette smoking. Age and smokingadjusted absolute risks of cardiovascular events were found to be higher in hypertensive individuals with high than with low BMIs. Furthermore, the relative risk of cardiovascular disease did not vary significantly with BMI. Thus hypertension is at least as dangerous in obese as in lean persons at all ages in either sex, providing no support for the hypothesis that hypertension in the obese is more benign. This is important, since obesity predisposes to hypertension and most who have hypertension are obese. This report examines the hypothesis for CVD outcomes considered by previous reports and also the subcategories of CVD disease such as myocardial infarction and stroke, and includes data on both men and women and on young and old. REFERENCES

1.

2.

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14. 15. 16.

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45. Larsson B, Svardsudd K, Welin L, et al. Abdominal adipose tissue distribution, obesity and risk of cardiovascular disease and death: a 13-year follow-up of participants in the study of men born in 1913. Br Med J 1984;288:1041-4. 46. Stern MP, Haffiner SM. Body fat distribution and hyperinsulinemia as a risk factor for diabetes and cardiovascular disease (Review). Atherosclerosis 1986;6:123-30. 47. Blair D, Habicht JP, Sims EAH, et al. Evidence for an increased risk for hypertension with centrally located body fat

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