title: The association between cardiorespiratory fitness and cardiovascular risk may be modulated by known cardiovascular risk factors.
abstract: BACKGROUND
  We aimed to evaluate whether reduced cardiovascular fitness has a direct or indirect effect for the development of cardiovascular disease.
  
  
  METHODS
  We investigated 15,595 men and women who were annually screened in a tertiary medical center. All subjects were free of ischemic heart disease and had completed maximal exercise stress test according to the Bruce protocol at their first visit. Fitness was categorized into age- and sex-specific quintiles (Q) according to Bruce protocol treadmill time with Q1 as lowest fitness. Subjects were categorized at baseline into 3 groups: low fitness (Q1), moderate fitness (Q2-Q4), and high fitness (Q5). The primary end point of the current analysis was the development of a first cardiovascular event during follow-up.
  
  
  RESULTS
  Mean age of study patients was 48 ± 10 years, and 73% were men. A total of 679 events occurred during 92,092 person-years of follow-up. Kaplan-Meier survival analysis showed that the cumulative probability of cardiovascular events at 6 years was significantly higher among subjects with low fitness (P < .001). Low fitness was associated with known cardiovascular risk factors, including hypercholesterolemia (odds ratio [OR] 1.58, 95% CI 1.31-1.89), diabetes mellitus (OR 2.32, 95% CI 1.58-3.41), and obesity (OR 10.46, 95% CI 8.43-12.98). The effect of low fitness on cardiovascular events was no longer significant when including diabetes mellitus, hypercholesterolemia, and obesity as mediators (hazard ratio 0.99, 95% CI 0.82-1.19).
  
  
  CONCLUSIONS
  The association between cardiovascular fitness and adverse cardiovascular outcomes may be modulated through traditional cardiovascular risk factors. These findings need to be further validated in prospective clinical trials.
authors.affiliation: Leviev Heart Center, Chaim Sheba Medical Center, Ramat Gan, Israel. Electronic address: aharon.erez@sheba.health.gov.il.
authors.forename: Aharon
authors.initials: A
authors.lastname: Erez
authors.affiliation: Department of Internal Medicine C, Chaim Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Shaye
authors.initials: S
authors.lastname: Kivity
authors.affiliation: Leviev Heart Center, Chaim Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Berkovitch
authors.affiliation: Leviev Heart Center, Chaim Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Assi
authors.initials: A
authors.lastname: Milwidsky
authors.affiliation: Leviev Heart Center, Chaim Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Robert
authors.initials: R
authors.lastname: Klempfner
authors.affiliation: Institute for Medical Screening, Chaim Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Shlomo
authors.initials: S
authors.lastname: Segev
authors.affiliation: Leviev Heart Center, Chaim Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ilan
authors.initials: I
authors.lastname: Goldenberg
authors.affiliation: Leviev Heart Center, Chaim Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Yechezkel
authors.initials: Y
authors.lastname: Sidi
authors.affiliation: Leviev Heart Center, Chaim Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Elad
authors.initials: E
authors.lastname: Maor
mesh_terms: D000328:Adult; D002318:Cardiovascular Diseases / Q000453:epidemiology* / Q000209:etiology; D002320:Cardiovascular Physiological Phenomena; D015897:Comorbidity; D048909:Diabetes Complications; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications; D007557:Israel / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications; D010809:Physical Fitness; D011446:Prospective Studies; D012143:Respiratory Physiological Phenomena; D012307:Risk Factors