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Higher Fitness Is Strongly Protective in Patients with Family History of Heart Disease: The FIT Project

Published:October 14, 2016DOI:https://doi.org/10.1016/j.amjmed.2016.09.026

      Abstract

      Background

      Cardiorespiratory fitness protects against mortality; however, little is known about the benefits of improved fitness in individuals with a family history of coronary heart disease. We studied the association between cardiorespiratory fitness and risk of incident coronary heart disease and all-cause mortality, hypothesizing an inverse relationship similar to individuals without a family history of coronary heart disease.

      Methods

      We included 57,999 patients (aged 53 ± 13 years; 49% were female; 29% were black) from the Henry Ford Exercise Testing (FIT) Project. Cardiorespiratory fitness was expressed in metabolic equivalents of task based on exercise stress testing. Family history was determined as self-reported coronary heart disease in a first-degree relative at any age. We used Cox proportional hazards models adjusted for demographics and cardiovascular disease risk factors to examine the association between cardiorespiratory fitness and risk of incident coronary heart disease and mortality over a median (interquartile range) follow-up of 5.5 (5.6) and 10.4 (6.8) years, respectively.

      Results

      Overall, 51% reported a positive family history. Each 1-unit metabolic equivalent increase was associated with lower incident coronary heart disease and mortality risk regardless of family history status. The hazard ratio and 95% confidence interval for a negative family history and a positive family history were 0.87 (0.84-0.89) and 0.87 (0.85-0.89) for incident coronary heart disease and 0.83 (0.82-0.84) and 0.83 (0.82-0.85) for mortality, respectively. There was no significant interaction between family history and categoric cardiorespiratory fitness, sex, or age (P >.05 for all).

      Conclusions

      Higher cardiorespiratory fitness is strongly protective in all patients regardless of family history status, supporting recommendations for regular exercise in those with a family history.

      Keywords

      Clinical Significance
      • Increasing exercise capacity is protective against cardiovascular disease and mortality among those with and without a family history of coronary heart disease.
      • Each metabolic equivalent increase in cardiorespiratory fitness is associated with a 13% and 17% decrease in incident coronary heart disease and all-cause mortality, respectively.
      • Patients with a family history of coronary heart disease should be encouraged to engage in guideline-recommended exercise regimens to improve fitness and thus prognosis.
      A family history of coronary heart disease is an independent risk factor for incident coronary heart disease and cardiovascular mortality.
      • Lloyd-Jones D.M.
      • Nam B.-H.
      • D'Agostino R.B.
      • et al.
      Parental cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults: a prospective study of parents and offspring.
      Preventive efforts aimed at addressing traditional, modifiable risk factors in this group have been shown to reduce cardiovascular disease risk.
      • Khaw K.T.
      • Barrett-Connor E.
      Family history of heart attack: a modifiable risk factor?.
      Cardiorespiratory fitness is known to be a central determinant of survival in both healthy individuals and those with comorbidities.
      • Kodama S.
      • Saito K.
      • Tanaka S.
      • et al.
      Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women.
      • Hung R.K.
      • Al-Mallah M.H.
      • McEvoy J.W.
      • et al.
      Prognostic value of exercise capacity in patients with coronary artery disease: the FIT (Henry Ford ExercIse Testing) project.
      Low fitness has been proposed as a novel, modifiable marker to improve risk stratification.
      • Kodama S.
      • Saito K.
      • Tanaka S.
      • et al.
      Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women.
      However, the extent to which cardiorespiratory fitness can provide clinically meaningful risk stratification beyond traditional risk factors based on family history of coronary heart disease status remains to be studied.
      We aimed to study the association of cardiorespiratory fitness and risk of incident coronary heart disease and all-cause mortality among individuals with and without a family history of coronary heart disease. We hypothesized that cardiorespiratory fitness is inversely associated with incident coronary heart disease and mortality independently of family history status.

      Materials and Methods

      The Henry Ford Exercise Testing (FIT) Project is a retrospective cohort study consisting of 69,885 consecutive patients who underwent a physician-referred exercise stress test at Henry Ford Health System–affiliated hospitals and ambulatory cares centers in Detroit, Michigan, between 1991 and 2009. The Henry Ford Health System institutional review board approved the FIT Project, and the methods have been published.
      • Al-Mallah M.H.
      • Keteyian S.J.
      • Brawner C.A.
      • et al.
      Rationale and design of the Henry Ford Exercise Testing Project (the FIT project).
      Patients with a history of coronary heart disease or heart failure (n = 10,948) and any missing stress test data (n = 938) were excluded, resulting in a final cohort of 57,999 patients. Family history was determined by self-report as the presence of coronary heart disease at any age in a first-degree relative (ie, father, mother, or sibling). Patients were stratified by family history status: those with a family history (family history positive) (n = 29,745) and those without (family history negative) (n = 28,254).
      Incident coronary heart disease (including myocardial infarction and coronary revascularization) was ascertained through linkage with administrative claims files.
      • Al-Mallah M.H.
      • Keteyian S.J.
      • Brawner C.A.
      • et al.
      Rationale and design of the Henry Ford Exercise Testing Project (the FIT project).
      All-cause mortality was ascertained through an algorithmic search of the Social Security Death Index Death Master File. Cardiorespiratory fitness, expressed in metabolic equivalents, was based on the workload derived from the maximal speed and grade achieved during the total treadmill time, categorized into 4 groups: <6, 6 to 9, 10 to 11, and ≥12 metabolic equivalents.
      • Al-Mallah M.H.
      • Keteyian S.J.
      • Brawner C.A.
      • et al.
      Rationale and design of the Henry Ford Exercise Testing Project (the FIT project).
      Baseline characteristics between the family history groups were compared using analysis of variance or chi-square test as appropriate. Incident event rates were reported per 1000 patient-years. We used Cox proportional hazards models to calculate hazard ratios (HRs) (95% confidence interval [CI]) of incident events for each family history group. The proportionality assumption was tested using complementary log-log plots. Models were adjusted for age (years); sex; race; body mass (kilograms); cigarette smoking; hypertension; hyperlipidemia; diabetes; obesity; and medication use for chronic obstructive pulmonary disease, hyperlipidemia, hypertension, and cardiorespiratory fitness. We also tested for multiplicative interaction between family history status and each of categoric cardiorespiratory fitness, sex, and age (<60 vs ≥60 years) in the association with incident events.
      A 2-sided P value of <.05 was considered statistically significant. All analyses were performed using Stata/IC version 13.1 (StataCorp LP, College Station, Tex).

      Results

      Baseline characteristics are shown in Table 1. The mean (standard deviation) age was 53 (13) years (49% were female; 29% were black), and 51% (n = 29,745) were family history positive. Compared with family history negative, patients with a positive family history were more likely to be female, to be white, and to have dyslipidemia (P <.001 for all).
      Table 1Baseline Characteristics of the Study Population by Family History Status
      Total Cohort (n = 57,999)FH− (n = 28,254)FH+ (n = 29,745)P Value
      P value calculated using analysis of variance for continuous variables and chi-square test for categoric variables.
      Age (y)53 (13)54 (13)53 (12)<.001
      Female, %28,151 (49)12,395 (44)15,756 (53)<.001
      Race, %<.001
       White37,152 (64)16,958 (60)20,194 (68)
       Black16,724 (29)9096 (32)7628 (26)
       Other4123 (7)2200 (8)1923 (6)<.001
      Weight (kg)85 (19)85 (19)84 (19)<.001
      BMI, kg/m229.5 (6.1)29.6 (6.2)29.4 (6.0).03
      History of obesity, %13,308 (23)6324 (22)6984 (23).002
      Cigarette smoking, %23,972 (41)11,372 (40)12,600 (42)<.001
      Hypertension, %35,640 (61)17,483 (62)18,157 (61).04
      Dyslipidemia, %24,806 (43)11,427 (40)13,379 (45)<.001
      Diabetes mellitus, %10,445 (18)5514 (20)4931 (17)<.001
      METs of task9.2 (3.0)9.1 (3.1)9.3 (2.9)<.001
       <67626 (13)4159 (15)3467 (12)
       6-1015,627 (27)7694 (27)7933 (27)
       10-1221,323 (37)10,022 (35)11,301 (38)
       ≥1213,423 (23)6379 (23)7044 (24)
      Continuous variables presented as mean (standard deviation); categoric variables presented as number (percentage).
      BMI = body mass index; FH = family history of any coronary heart disease; MET = metabolic equivalent.
      P value calculated using analysis of variance for continuous variables and chi-square test for categoric variables.
      After a median (interquartile range) of 5.5 (5.6) years and 10.4 (6.8) years follow-up, a total of 1699 coronary heart disease events and 6600 mortality events were recorded, respectively. The unadjusted incidence rates for coronary heart disease and mortality (per 1000 person-years) were 4.74 and 10.34, respectively. Family history was not associated with outcomes in univariate analyses or in models adjusted for cardiovascular risk factors and cardiorespiratory fitness (HR, 1.01; 95% CI, 0.92-1.12 and HR, 0.97; 95% CI, 0.92-1.02 for coronary heart disease and mortality, respectively). The occurrence of incident events in the follow-up period decreased with higher metabolic equivalents in patients with and without family history (Figure A and B).
      Figure thumbnail gr1
      Figure(A and B) Unadjusted incidence rates for coronary heart disease and all-cause mortality stratified by family history status. family history of any coronary heart disease; MET = metabolic equivalent.
      In fully-adjusted models, the HRs (95% CI) of events per unit metabolic equivalents increase for family history negative and family history positive were as follows: 0.87 (0.84-0.89) and 0.87 (0.85-0.89) for incident coronary heart disease and 0.83 (0.82-0.84) and 0.83 (0.82-0.85) for mortality, respectively. Similar results were obtained in categoric metabolic equivalents analyses (Table 2). There was no significant interaction between family history and categories of metabolic equivalents, sex, or age in the association with either event (all P >.05).
      Table 2Hazard Ratios (95% Confidence Interval) for the Association Between Metabolic Equivalents and Incident Coronary Heart Disease and All-Cause Mortality, Stratified by Baseline Family History Status
      METsFH− (n = 28,254)FH+ (n = 29,745)
      METs <6METs 6-10METs 10-12METs ≥12METs <6METs 6-10METs 10-12METs ≥12
      N4159769410,02263793467793311,3017044
      CHD
       Events (n)3373052096523826319587
       Unadjusted IR
      Incident rate reported per 1000 person-years.
      14.136.963.451.4412.095.712.791.77
       Unadjusted HR1 (ref)0.51 (0.44-0.59)0.25 (0.21-0.30)0.10 (0.07-0.12)1 (ref)0.48 (0.41-0.58)0.23 (0.19-0.28)0.14 (0.11-0.18)
       Model 11 (ref)0.63 (0.54-0.74)0.38 (0.31-0.46)0.18 (0.13-0.24)1 (ref)0.61 (0.51-0.73)0.35 (0.28-0.43)0.22 (0.17-0.30)
       Model 21 (ref)0.64 (0.54-0.76)0.45 (0.37-0.55)0.24 (0.18-0.33)1 (ref)0.63 (0.52-0.76)0.38 (0.30-0.47)0.28 (0.21-0.38)
      All-Cause Mortality
       Deaths (n)161312076782231105913623238
       Crude IR
      Incident rate reported per 1000 person-years.
      38.7815.146.232.9031.1710.804.962.79
       Unadjusted HR1 (ref)0.40 (0.37-0.43)0.16 (0.15-0.17)0.07 (0.06-0.08)1 (ref)0.35 (0.32-0.38)0.16 (0.14-0.17)0.08 (0.07-0.10)
       Model 11 (ref)0.52 (0.48-0.57)0.28 (0.26-0.31)0.17 (0.14-0.20)1 (ref)0.48 (0.44-0.52)0.28 (0.25-0.31)0.17 (0.15-0.20)
       Model 21 (ref)0.55 (0.51-0.60)0.30 (0.27-0.33)0.18 (0.15-0.21)1 (ref)0.51 (0.46-0.56)0.30 (0.27-0.34)0.19 (0.16-0.23)
      Model 1 adjusted for age (years), sex, and race. Model 2 adjusted for Model 1 + weight (kg), cigarette smoking, hypertension, hyperlipidemia, diabetes, history of obesity, chronic obstructive pulmonary disease medication use, statin use, and antihypertensive medication use.
      CHD = coronary heart disease; CI = confidence interval; FH = family history of any coronary heart disease; HR = hazard ratio; IR = incidence rate; MET = metabolic equivalent.
      Incident rate reported per 1000 person-years.

      Discussion

      In this large, demographically diverse cohort free of known coronary heart disease or heart failure at baseline, we found that higher fitness was inversely associated with incident coronary heart disease and mortality in all patients, irrespective of family history status. Each metabolic equivalent increase in cardiorespiratory fitness was associated with a 13% and 17% reduction in incident coronary heart disease and mortality risk, respectively. Our results are consistent with the current literature on the importance of cardiorespiratory fitness, with benefits from higher fitness likely mediated through reductions in coronary heart disease risk factor burden and severity of acute cardiovascular events.
      • Mora S.
      • Cook N.
      • Buring J.E.
      • et al.
      Physical activity and reduced risk of cardiovascular events: potential mediating mechanisms.
      The association between family history and coronary heart disease risk is well studied; however, relatively limited data are available on the association of improved fitness and hard events in individuals with a family history of coronary heart disease. Similar to prior studies, our study did not find a significant association between family history and outcomes, even after adjustment for cardiorespiratory fitness.
      • Bachmann J.M.
      • Willis B.L.
      • Ayers C.R.
      • et al.
      Association between family history and coronary heart disease death across long-term follow-up in men: the Cooper Center Longitudinal Study.
      Indeed, the presence of family history influences decision making regarding risk factor management in a positive fashion,
      • Safarova M.S.
      • Bailey K.R.
      • Kullo I.J.
      Association of a family history of coronary heart disease with initiation of statin therapy in individuals at intermediate risk: post hoc analysis of a randomized clinical trial.
      which may balance out the risk imparted by the interaction of genetic risk factors and environmental exposures. In addition, individuals with a strong family history may die prematurely, resulting in a survivorship bias with less extreme forms of family history.
      • Williamson C.
      • Jeemon P.
      • Hastie C.E.
      • et al.
      Family history of premature cardiovascular disease: blood pressure control and long-term mortality outcomes in hypertensive patients.

      Study Limitations

      Data for family history were based on medical records, suggesting that the definition for family history may not have been applied consistently, introducing misclassification bias. Accurate family history assessment may be limited by reporting errors, resulting in underestimation of the true risk associated with family history.
      • Khoury M.J.
      • Flanders W.D.
      Bias in using family history as a risk factor in case-control studies of disease.
      However, we believe our definition of family history is justified for the following reasons: (1) Family history is generally fixed (shared genetic risk factors), such that family history of any coronary heart disease in a first-degree relative is significantly associated with early- and late-onset coronary heart disease
      • Scheuner M.T.
      • Whitworth W.C.
      • McGruder H.
      • et al.
      Expanding the definition of a positive family history for early-onset coronary heart disease.
      ; and (2) similar rates of coronary heart disease events are seen when comparing premature family history with any family history of coronary heart disease in a first-degree relative.
      • Patel J.
      • Al Rifai M.
      • Blaha M.J.
      • et al.
      Coronary artery calcium improves risk assessment in adults with a family history of premature coronary heart disease: results from multiethnic study of atherosclerosis.
      This was a retrospective study, and analysis was based on administrative claims files; thus, some data may not have been available, and misclassification may have been introduced because of coding errors.

      Conclusions

      Higher cardiorespiratory fitness was associated with a lower risk for incident coronary heart disease and mortality in all patients, regardless of family history status. Family history did not modify the association between cardiorespiratory fitness and incident events. Our results add to the growing body of evidence regarding the benefits of fitness by extending it to include individuals with a family history of coronary heart disease.

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