Historical data on human life span: The French National Institute of Demographic Studies has collected comprehensive data on life span in France from 1750, at 50 year intervals.13 Data on heart rate was not available here, we assumed that mean heart rate was 80 throughout this period.
Paris Prospective Study I: This study is based on 7976 participants, aged 42 to 53 years, recruited to the study from 1967 to 1972 with a 93.4% response rate.14,15 Briefly, oral informed consent was given by each participant, and the research protocol was approved by the institutional board, Commission Nationale Informatique et Liberté. Clinical examination consisted of electrocardiograms, physical examination, and collection of blood samples for laboratory tests; participants also responded to a questionnaire administered by trained interviewers. Resting heart rate was determined by measurement of the radial pulse during a one-minute recording, after a five-minute rest in supine position. The covariates assessed were age, smoking (mean consumption g/days over the 5 last years), diabetes (self-report of history of diabetes, whether treated), body mass index, current sport, systolic blood pressure, total cholesterol. Participants were invited back for a clinical examination each year for the following 4 years using the same procedure; a total of 5589 provided a heart rate at the final follow-up (five years from the baseline follow-up).
Mortality data were collected from medical records in hospital departments or general practitioners and death certificates. The end of the follow-up period was 1st January, 1994. The vital status could not be determined for 355 subjects (4.6%). The baseline characteristics of those 355 subjects lost to follow up and of those who did not complete the final follow-up examinations (five years from the baseline follow-up) were not different from the remaining 5589 men studied in the present analysis. Vital status was followed on all subjects until the last recorded survey in 1994 (25 years of average follow up), through the administrative department in charge of the study population until retirement age and then thereafter via the French national death registry.
Whitehall I Study: Data were collected from 19,019 male London-based government employees aged 40 to 69 at screening between 1967 and 1970, with a 77% response rate. Participants provided informed written consent and research ethics approval was obtained from the National Health Service London - Harrow Research Ethics Committee. Screening involved the completion of a study questionnaire and participation in a medical examination, both of which have been described in detail elsewhere.16 Heart rate was measured in a random subset of 1263 men (mean age 52, SD 7 years) in whom radiologic heart volume was calculated.17 The covariates assessed in this age, smoking, diabetes, body mass index, current sport, systolic blood pressure, total cholesterol.
All cohort participants were traced using the National Health Service Central Registry for mortality for 40 years until 31st October 2008 by which time 977 men had died.
Framingham Heart Study: The final sample size for the current investigation consisted of 7300 participants (3299 men and 4001 women) from the Original (Examination 12, 1971–1974) and Offspring (Examination 1, 1971–1975) cohorts in the Framingham Heart Study after exclusion of participants < 20 years of age (n = 245), with prevalent cardiovascular disease (n = 698), or a systolic blood pressure > 180 mm Hg (n = 198). Heart rate was measured by echocardiogram and data on covariates (age, sex, systolic blood pressure, current smoking, diabetes status, body mass index, physical activity index, and total cholesterol level) were drawn from the same wave. Written informed consent was provided by all participants and the study protocol was approved by the Boston University Medical Center Institutional Review Board.
Death were confirmed from death certificates and supporting information was obtained from hospital records.18 Participants were followed until 31st December 2017, an average follow-up of 30.9 years for men and 32.8 for women.
Life span in all three cohorts was defined by age at death among participants who died over the follow-up period. For participants in the Paris Prospective and Whitehall studies who were alive at the end of the follow-up, life span was estimated based on national age and sex in the corresponding country.
Aim 1 and 2: As the sample size and number of deaths were larger in the Paris Prospective Study I and Framingham Study, heart rate was categorized into 5 groups: ≤60, 60–70, 70–80, 80–90, > 90 bpm. In the Whitehall I study smaller numbers led us to use 4 categories: ≤60, 60–70, 70–80, > 80 bpm. Participants with known or suspected cardiovascular disease or with any of the following conditions were excluded from the study: resting systolic blood pressure > 180 mm Hg, resting 12-lead standard electrocardiogram abnormality (Minnesota code). A linear regression was used to examine the association between resting heart rate and life span in each cohort study, first unadjusted and then adjusted for age, baseline body mass index, smoking, physical activity, diabetes, systolic blood pressure, and total cholesterol level.
Aim 3: The inverse linear relationship between logarithmic transformed heart rate and life span in mammalian species and humans was derived by Levine.1 We used data from the French National Institute of Demographic Studies to plot the point estimate every 50 years, for the period from 1750 (when earliest reliable records were available) until 2000.13
Aim 4: In the Paris Prospective Study I and Framingham Heart Study, multivariable Cox proportional hazards regression models were used to assess the change in heart rate (over a 5-year period in the Paris Prospective Study I and 8-years period in the Framingham Study) and risk of mortality. These analyses were adjusted for the covariates used in aim 2 along with resting heart rate at baseline. In the Paris Prospective Study, I, change in heart rate was defined as resting heart rate at the last follow-up visit minus resting heart rate at baseline. In the Framingham Heart Study, heart rate change (increase or decrease) was defined as resting heart rate at examination 16 (1979–1982) minus resting heart rate at examination 12 (1971–1974) for the Original cohort, and examination 2 (1979–1983) minus examination 1 for the Offspring cohort (1971–1975). A positive difference in heart rate indicated an increase in heart rate at the subsequent examination, while a negative difference indicated a decrease in heart rate.
SAS, Version 9.2 and 9.4 (Statistical Analysis System, Cary, N.C.) was used for analysis. P-values were 2-sided.