Low Risk-Factor Profile and Long-term Cardiovascular and Noncardiovascular Mortality and Life Expectancy: Findings for 5 Large Cohorts of Young Adult and Middle-Aged Men and Women

Context Three major coronary risk factors—serum cholesterol level, blood pressure, and smoking—increase incidence of coronary heart disease (CHD) and related end points. In previous investigations, risks for low-risk reference groups were estimated statistically because samples contained too few such people to measure risk.

Objective To measure long-term mortality rates for individuals with favorable levels for all 3 major risk factors, compared with others.

Design Two prospective studies, involving 5 cohorts based on age and sex, that enrolled persons with a range of risk factors. Low risk was defined as serum cholesterol level less than 5.17 mmol/L (<200 mg/dL), blood pressure less than or equal to120/80 mm Hg, and no current cigarette smoking. All persons with a history of diabetes, myocardial infarction (MI), or, in 3 of 5 cohorts, electrocardiogram (ECG) abnormalities, were excluded.

Setting and Participants In 18 US cities, a total of 72,144 men aged 35 through 39 years and 270,671 men aged 40 through 57 years screened (1973-1975) for the Multiple Risk Factor Intervention Trial (MRFIT); in Chicago, a total of 10,025 men aged 18 through 39 years, 7490 men aged 40 through 59 years, and 6229 women aged 40 through 59 years screened (1967-1973) for the Chicago Heart Association Detection Project in Industry (CHA) (N = 366,559).

Main Outcome Measures Cause-specific mortality during 16 (MRFIT) and 22 (CHA) years, relative risks (RRs) of death, and estimated greater life expectancy, comparing low-risk subcohorts vs others by age strata.

Results Low-risk persons comprised only 4.8% to 9.9% of the cohorts. All 5 low-risk groups experienced significantly and markedly lower CHD and cardiovascular disease death rates than those who had elevated cholesterol level, or blood pressure, or smoked. For example, age-adjusted RRs of CHD mortality ranged from 0.08 for CHA men aged 18 to 39 years to 0.23 for CHA men aged 40 through 59 years. The age-adjusted relative risks (RRs) for all cardiovascular disease mortality ranged from 0.15 for MRFIT men aged 35 through 39 years to 0.28 for CHA men aged 40 through 59 years. The age-adjusted RR for all-cause mortality rate ranged from 0.42 for CHA men aged 40 through 59 years to 0.60 for CHA women aged 40 through 59 years. Estimated greater life expectancy for low-risk groups ranged from 5.8 years for CHA women aged 40 through 59 years to 9.5 years for CHA men aged 18 through 39 years.

Conclusions Based on these very large cohort studies, for individuals with favorable levels of cholesterol and blood pressure who do not smoke and do not have diabetes, MI, or ECG abnormalities, long-term mortality is much lower and longevity is much greater. A substantial increase in the proportion of the population at lifetime low risk could contribute decisively to ending the CHD epidemic.

Long-term, population-based, prospective studies have amassed extensive data on relationships of major coronary-cardiovascular risk factors—particularly serum cholesterol level, blood pressure, and cigarette smoking—with incidence of coronary heart disease (CHD), stroke, and cardiovascular disease (CVD), to mortality from these causes and all causes and longevity.^1-7 These relationships have been well summarized as " . . . strong, continuous, graded, consistent, independent, predictive, and etiologically significant for those with and without coronary heart disease."⁷ The judgment on etiologic significance is based on the consistent results of many epidemiological studies and on concordant findings from clinical and postmortem investigations and animal experimentation. This judgment is reinforced by data from randomized controlled trials demonstrating that sustained lowering of high blood pressure or elevated serum cholesterol level produces sizable reductions in CHD-CVD incidence and in cause-specific and all-cause mortality.^7-14 These positive results have been obtained repeatedly, even though trials have been undertaken in middle-aged and older people after decades of exposure to these adverse traits. Extensive data also document that smoking cessation has similar favorable effects.^15,16

Most epidemiologic research on the impact of major risk factors deals with the predictive value of higher levels of such factors. In assessments of their combined impact, risks of those with favorable status for all 3 major risk factors have been estimated statistically, for example, by extrapolation down multiple logistic smoothed curves.³ This was necessary because in the population samples studied, numbering in the hundreds or thousands, too few people had low levels of all major risk factors—hence too few CVD events—to permit direct measurement of risk.

Large, long-term studies permit measured estimates based on actual observed mortality. In this article, we use data on 5 cohorts from 2 studies, the Multiple Risk Factor Intervention Trial (MRFIT) and the Chicago Heart Association Detection Project in Industry (CHA): 2 cohorts of young adult men, 2 cohorts of middle-aged men, and 1 cohort of middle-aged women—366,559 people all together.

Published reports on the MRFIT and CHA cohorts detail their baseline screening methods.^5,6,17-19 We provide a summary of these here.

All together, 361,662 men aged 35 through 57 years were screened in 1973-1975 at 22 centers in 18 US cities for recruitment for MRFIT. The 342,815 men with complete baseline risk factor data are the focus here, stratified into 2 cohorts: those aged 35 through 39 years (n = 72,144) and 40 through 57 years (n = 270,671). Trial eligibility was based on a man's major risk factor profile; therefore, initial screening included measurements only of blood pressure and serum cholesterol level; current smoking (by questionnaire), including number of cigarettes per day; and conditions for exclusion, ie, drug treatment for diabetes and previous hospitalization for myocardial infarction (MI). Blood pressure was measured according to a standardized protocol by trained certified staff, using a mercury sphygmomanometer, with the man seated. Diastolic blood pressure (DBP) was measured at the fifth Korotkoff sound. Three readings per individual were taken; the average of the second and third systolic blood pressure (SBP) measurements was used for analyses. Serum total cholesterol level was determined, in 15 standardized local laboratories, by the Lieberman-Burchard color reaction and use of serum calibrators to yield values equivalent to Abell-Kendall reference values.^17-19

Vital status of the men is ascertained periodically through the US National Death Index. Prior to 1979, Social Security Administration records were used. With a mean follow-up of 16 years, 38,265 deaths have been identified; cause of death is known for 98.9% of decedents. Underlying cause of death was coded by a nosologist using the International Classification of Diseases, Ninth Revision (ICD-9).²⁰

Employees of 84 Chicago-area companies and organizations, about 75,000 people, were invited to participate. The response rate was 55%. Screening was done by 2 trained and standardized 4-person field teams who collected demographic information, medical history, and medical treatment data; information on past and present smoking status; 1 measurement of height, weight, heart rate, and supine blood pressure; resting electrocardiogram (ECG); and venipuncture for blood chemistry measurements. Serum total cholesterol level was determined by the Levine and Zak method.^6,17 The criteria of the Pooling Project³ were used to code ECG abnormalities. Three cohorts are the focus here: men aged 18 through 39 years, men aged 40 through 59 years, and women aged 40 through 59 years.

Methods of follow-up to ascertain vital status include local procedures and use of Social Security Administration and National Death Index records. With a mean follow-up of 22 years, vital status has been determined for more than 99% of the cohorts. For each decedent, underlying cause of death was coded by a trained staff professional, using the International Classification of Diseases, Eighth Revision (ICD-8 ).²¹

Criteria for defining a person as low risk were all of the following at baseline: serum cholesterol level less than 5.17 mmol/L (<200 mg/dL), SBP/DBP of 120/80 mm Hg or lower; not a current smoker; no history of diabetes or MI; and, for the 3 CHA cohorts, no ECG abnormalities.

Deaths from all CHDs were defined for MRFIT cohorts as ICD-9 codes 410 through 414 and 429.9, for CHA cohorts as ICD-8 codes 410 through 414; MI, code 410; stroke, codes 430 through 438; all CVD, codes 390 through 459; all cancers, codes 140 through 209; violence, for MRFIT cohorts ICD-9 codes 800 through 999, for CHA cohorts ICD-8 codes E800 through E999 exclusive of codes E930 through E936. Coders were blinded to baseline data.

To focus on risk for persons with favorable levels of serum cholesterol, blood pressure, and no tobacco use (all 3 combined), compared with persons with adverse levels of 1 or more of these, persons with histories of diabetes or MI were excluded (all 5 cohorts), as were persons with ECG abnormalities (the 3 CHA cohorts). Mortality rates for low-risk and other persons were age-adjusted by the direct method to the age distribution of all persons in an age stratum. Cox proportional hazards regression was used to calculate age-adjusted relative risks (RRs) and their 95% confidence intervals (CIs) for low-risk compared with other persons.

Cox multivariate proportional hazards regression was used to calculate coefficients for the relation of baseline major risk factors to all-cause mortality for each cohort. Coefficients were used to estimate number of years of greater life expectancy for each low-risk subcohort compared with other persons of the same cohort.¹⁷ Thus, the coefficient for the relationship of SBP to all-cause mortality in the Cox multivariate analyses for CHA men aged 18 through 39 years is 0.0116. Average SBP for the 942 low-risk men was 116.0 mm Hg; for the 9083 other men, 136.0 mm Hg; by exponentiation, estimated RR of death is e^{−0.0116×20} = e^−0.232 = 0.793. To estimate impact of this lower SBP on life expectancy, we used the concomitant Cox coefficient for the relationship of age to all-cause mortality, 0.0703. The product for SBP exponentiation, 0.0116 × 20 = 0.232, is also obtained when the coefficient for age, 0.0703, is multiplied by 3.3, which indicates that SBP of 116 mm Hg vs 136 mm Hg is equivalent to being, on average, 3.3 years younger: eg, age 26.7 years rather than age 30 years. From US life tables,²² male expectation of life at age 30 years is 44.1 years; at age 26.7 years, 47.2 years: ie, 3.1 years estimated greater life expectancy is attributable to SBP 116 mm Hg vs SBP 136 mm Hg. Similar calculations yield data on impact on life expectancy of favorable status of the low-risk subcohort for serum cholesterol level and smoking compared with the other subcohort. These 3 estimates are summed to give the overall estimate presented here.

The proportion of persons meeting low-risk criteria was small: for young adult men, 9.9% (MRFIT) and 9.4% (CHA); for middle-aged men, 6.0% (MRFIT) and 4.8% (CHA); and for middle-aged women, 6.8% (CHA) (Table 1 and Table 2). In accordance with low-risk criteria, average blood pressure and serum cholesterol levels were much lower for low-risk subcohorts compared with other persons. Body mass index was lower for CHA low-risk subcohorts compared with others (Table 2).

The CHD mortality rate was much lower for low-risk subcohorts than for others, by 86% to 92% for low-risk young adult men (<40 years) and 77% to 79% for low-risk middle-aged subcohorts (Table 3). Findings were similar for death attributed to acute MI.

For low-risk subcohorts, CHD death accounted for a much smaller proportion of all death than for others (Table 3). This finding was especially prominent for low-risk young adult men, with CHD mortality only 6% to 8% of all mortality vs 25% to 29% for others.

All CVD mortality was much lower for low-risk subcohorts than for others by 72% to 85% (Table 3).

There were no stroke deaths in the 2 young adult low-risk subcohorts. For the 2 middle-aged, male low-risk subcohorts, stroke mortality was lower than for others by 52% to 76%. Mortality from cancers was consistently lower for low-risk subcohorts compared with others: by 44% to 56% for the 4 male low-risk subcohorts and 17% for the female low-risk subcohort. No results significantly supported the hypothesis that low serum cholesterol level is associated with greater risk of violent death. For the 2 young adult cohorts, mortality from all other causes was similar for low-risk men and others. For the 3 middle-aged cohorts, RR was lower for low-risk groups than others by 36% to 86%(Table 4).

Mortality from all causes was consistently and markedly lower for low-risk groups vs others: by 50% to 58% for men and 40% for women (Table 5). Estimated greater life expectancy for low-risk subcohorts vs others ranged from 5.8 years to 9.5 years.

Large sample sizes and long follow-up of the 5 MRFIT and CHA cohorts enabled measurement of actual cause-specific and all-cause mortality experience of adults assessed to be low risk at baseline. Results were consistent qualitatively and quantitatively for all 5 cohorts, young adult and middle-aged, male and female, free at baseline of a history of diabetes and MI, and of ECG abnormalities (CHA cohorts). Only a small minority (<10%) met all criteria for low risk—serum cholesterol level under 5.17 mmol/L (<200 mg/dL), SBP/DBP of 120/80 mm Hg or less, and no cigarette smoking. During long-term follow-up, low-risk subcohorts, compared with others, consistently experienced significantly and markedly lower CHD death rates by 77% to 92%, and CHD mortality was a much smaller proportion of all-cause mortality. Findings for stroke and for all CVD paralleled those for CHD. There was no evidence of significant countervailing non-CVD mortality for low-risk subcohorts; rather, their cancer mortality was consistently lower. Consequently, compared with others, all-cause mortality was markedly lower for low-risk persons (by 40% to 58%), and their estimated longevity was much greater (by 5.8 to 9.5 years).

These findings directly confirm earlier statistical estimates of the benefits of low-risk status. For example, in the national cooperative Pooling Project, risk of a first major coronary event was estimated by multiple logistic regression to be lower by 70% for middle-aged men in the lowest quintile of risk, compared with all other men.³ Concordantly, recent data from the Framingham Study estimate CHD risk to be considerably reduced for low-risk men and women compared with all men and women.²³ Results for the 5 MRFIT and CHA cohorts go beyond such estimates in several respects: (1) they are actual observations, not extrapolations from regression analyses; (2) they are not only for middle-aged men and women, but also young adult men; (3) they demonstrate the favorable impact of low-risk status not only on CHD incidence, but also CHD mortality, risk of fatal stroke, all CVD, all cancers, and all causes, without any significant evidence of countervailing mortality risks; (4) they indicate that low-risk status is associated with greater life expectancy by several years; and (5) additional analyses (reported previously) on the CHA cohorts show further that low risk in middle age is associated with lower average annual costs for medical care in older age.²⁴

These data on the benefits of low risk are almost certainly underestimates due to both misclassification of individuals with a single measurement of the 3 major risk factors²⁵ and lack of data on the fourth independent major risk factor, adverse dietary pattern.^{1,2,5,6,8,17,19,26} Data on participant exercise habits were also missing. In this regard, the 2 diet-dependent major risk factors (serum cholesterol level and blood pressure) may be viewed not only as etiologically significant traits, but also as markers of other lifestyle characteristics contributing to favorable outcomes for low-risk subcohorts. This inference is supported by the CHA data showing lower average body mass index for low-risk individuals vs others.

The data here challenge the view that the major risk factors " . . . explain at most half of all myocardial infarctions." ²⁷ Despite underestimation, favorable status for all 3 major risk factors consistently predicted long-term CHD and MI mortality rates that are lower by much more than 50%: by 86% to 92% for young adult men and 77% to 79% for middle-aged persons compared with others. Consequently, for low-risk subcohorts, in contrast to others, MI and CHD mortality rates were not at epidemic levels, were not main causes of death, and did not account for a large proportion of all deaths. Available data indicate that this favorable status for low-risk persons holds for both African Americans and whites, and for those of lower and higher socioeconomic status.²⁸

These findings are relevant for the national effort to end the CHD-CVD epidemic. They lend strong support to the concept² that a strategy based on identifying, evaluating, and treating people with risk factors is not enough. A population-wide strategy is critical to prevent and reduce the magnitude of all the major risk factors, first and foremost by safe nutritional-hygienic means, so that a substantial increase is achieved in the proportion of people in the population who, throughout life, have favorable levels for all the major risk factors and so are at low risk. For upcoming generations, this means encouraging favorable behaviors beginning in early childhood in regard to eating, drinking, exercising, and smoking. For others (particularly older children, teenagers, and young adults), this strategy emphasizes efforts to preserve favorable risk factor status for those who still have none of the major risk factors.

Genetic makeup undoubtedly influenced propensity to fall into low-risk categories. However, as shown by multiple data sets on groups such as American Seventh Day Adventists, Chinese, Greeks, Italians, Japanese, and South Africans, adult population average serum cholesterol level lower than 5.17 mmol/L (<200 mg/dL) is widely prevalent.^1,2 For the US population as a whole in the 1990s, mean serum cholesterol level has fallen almost to the national health goal for the year 2000 of no more than 5.17 mmol/L (200 mg/dL).²⁹ Similarly, extensive data are available on isolated populations around the world with average adult SBP/DBP of 120/80 mm Hg or less, with little or no blood pressure rise during adulthood, and with little or no hypertension³⁰: favorable blood pressure patterns that are not due to unusual genetic makeup, since with migration and adoption of modern lifestyles these populations too develop adverse blood pressure levels.

Therefore, lifestyle also clearly influences who will fall into the low risk-factor group. Since the 1960s, nutritional recommendations have been available for prevention of dyslipidemia in the form of advice to decrease intake of dietary total fat, saturated fat, cholesterol; partially replace saturated fat with monounsaturated and polyunsaturated fat; increase intake of dietary fiber, especially water-soluble fiber; and prevent or reduce overweight.^{1,2,8,19,26,29,31} Average serum cholesterol levels of the adult population have decreased from approximately 6.21 mmol/L (240 mg/dL) to less than 5.30 mmol/L (205 mg/dL).²⁹ More recently, lifestyle recommendations have been set down for prevention of adverse blood pressure levels. These initially involved avoidance of high salt intake, inadequate potassium intake, excess alcohol use, overweight, and sedentary habits,^30-32 and have been expanded to include high intake of fruits and vegetables, fat-free and low-fat protein sources, and low intake of lipid-rich foods (ie, reduced dietary total fat, saturated fat, and cholesterol).^7,33,34 National survey data indicate that average blood pressure levels of Americans and rates of high blood pressure are lower as a result of improved lifestyles, independent of effects of antihypertensive drug treatment.³⁵ All these data support the concept that lifestyles, particularly nutritional habits, interdigitate with polygenic propensities (widespread in the population) to influence average serum lipid and blood pressure levels of both individuals and the overall population. Adverse levels are not fixed consequences of the genome; they are widely amenable to prevention by safe nutritional-hygienic means, with resultant sizable increases in the proportion of the population at low risk.

In summary, data from large, population-based, prospective studies indicate that lifetime favorable status in regard to all 3 major CHD-CVD risk factors (serum cholesterol level, blood pressure, and smoking) leads to low mortality rates from CHD, CVD, and all causes and increased life expectancy. The extensive findings support a strategic emphasis on population-wide primary prevention of all major risk factors as a key component of the effort to end the CHD-CVD epidemic. Research advances have supplied the scientific information to make implementation of this strategic component widely feasible. The challenge is to mobilize the societal will and resources to realize these goals in all population strata to help end the CHD-CVD epidemic early in the next century.