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

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.

Effect of Beta-Blocker Therapy, Maximal Heart Rate, and Exercise Capacity During Stress Testing on Long-Term Survival (from The Henry Ford Exercise Testing Project).

Whether lower heart rate thresholds (defined as the percentage of age-predicted maximal heart rate achieved, or ppMHR) should be used to determine chronotropic incompetence in patients on beta-blocker therapy (BBT) remains unclear. In this retrospective cohort study, we analyzed 64,549 adults without congestive heart failure or atrial fibrillation (54 ± 13 years old, 46% women, 29% black) who underwent clinician-referred exercise stress testing at a single health care system in Detroit, Michigan from 1991 to 2009, with median follow-up of 10.6 years for all-cause mortality (interquartile range 7.7 to 14.7 years). Using Cox regression models, we assessed the effect of BBT, ppMHR, and estimated exercise capacity on mortality, with adjustment for demographic data, medical history, pertinent medications, and propensity to be on BBT. There were 9,259 deaths during follow-up. BBT was associated with an 8% lower adjusted achieved ppMHR (91% in no BBT vs 83% in BBT). ppMHR was inversely associated with all-cause mortality but with significant attenuation by BBT (per 10% ppMHR HR: no BBT: 0.80 [0.78 to 0.82] vs BBT: 0.89 [0.87 to 0.92]). Patients on BBT who achieved 65% ppMHR had a similar adjusted mortality rate as those not on BBT who achieved 85% ppMHR (p >0.05). Estimated exercise capacity further attenuated the prognostic value of ppMHR (per-10%-ppMHR HR: no BBT: 0.88 [0.86 to 0.90] vs BBT: 0.95 [0.93 to 0.98]). In conclusion, the prognostic value of ppMHR was significantly attenuated by BBT. For patients on BBT, a lower threshold of 65% ppMHR may be considered for determining worsened prognosis. Estimated exercise capacity further diminished the prognostic value of ppMHR particularly in patients on BBT.

High Exercise Capacity Attenuates the Risk of Early Mortality After a First Myocardial Infarction: The Henry Ford Exercise Testing (FIT) Project.

OBJECTIVE: To examine the effect of objectively measured exercise capacity (EC) on early mortality (EM) after a first myocardial infarction (MI). PATIENTS AND METHODS: This retrospective cohort study included 2061 patients without a history of MI (mean age, 62±12 years; 38% [n=790] women; 56% [n=1153] white) who underwent clinical treadmill stress testing in the Henry Ford Health System from January 1, 1991, through May 31, 2009, and suffered MI during follow-up (MI event proportion, 3.4%; mean time from the exercise test to MI, 6.1±4.3 years). Exercise capacity was categorized on the basis of peak metabolic equivalents (METs) achieved: less than 6, 6 to 9, 10 to 11, and 12 or more METs. Early mortality was defined as all-cause mortality within 28, 90, or 365 days of MI. Multivariable logistic regression models were used to assess the effect of EC on the risk of mortality at each time point post-MI adjusting for baseline demographic characteristics, cardiovascular risk factors, medication use, indication for stress testing, and year of MI. RESULTS: The 28-day EM rate was 10.6% overall, and 13.9%, 10.7%, 6.9%, and 6.0% in the less than 6, 6 to 9, 10 to 11, and 12 or more METs categories, respectively (P<.001). Patients who died were more likely to be older, be less fit, be nonobese, have treated hypertension, and have a longer duration from baseline to incident MI (P<.05). Adjusted regression analyses revealed a decreased risk of EM with increasing EC categories. A 1-MET higher EC was associated with an 8% to 10% lower risk of mortality across all time points (28 days: odds ratio [OR], 0.92; 95% CI, 0.87-0.98; P=.006; 90 days: OR, 0.90; 95% CI, 0.86-0.95; P<.001; 365 days: OR, 0.91; 95% CI, 0.87-0.94; P<.001). CONCLUSION: Higher baseline EC was independently associated with a lower risk of early death after a first MI.

Age-dependent prognostic value of exercise capacity and derivation of fitness-associated biologic age.

OBJECTIVE: Given the aging population and prevalence of sedentary behaviour in the USA, we investigated the impact of differences in exercise capacity associated with age on long-term outcomes. We derived fitness-associated 'biologic age' as a tool to encourage positive lifestyle changes. METHODS: This retrospective cohort study included 57085 patients without established coronary artery disease or heart failure (median age 53 years, 49% women, 29% black) who underwent clinically-referred treadmill stress testing at the Henry Ford Health System from 1991 to 2009. Patients were followed for 10.4±5 and 5.4±4 years for all-cause mortality and myocardial infarction (MI), respectively. We calculated hazard ratios associated with exercise capacity by age deciles using Cox regression models, adjusting for demographic and haemodynamic data, medical history, and medication use. Fitness-associated 'biologic age' was derived as the chronologic age with equivalent mortality or MI risk. RESULTS: There were 6356 deaths and 1646 MIs during follow-up. Exercise capacity declined with increasing age. Higher exercise capacity was strongly associated with greater survival, with per-MET HR ranging from 0.82 (95% CI 0.78 to 0.86) in patients under 40 years of age, to 0.88 (95% CI 0.87 to 0.90) in those over 70 years of age. Biologic age varied markedly-up to three decades-within each age decile, and was a stronger predictor of mortality (C-statistic 0.81 vs 0.77) and MI (C-statistic 0.72 vs 0.68) than chronologic age. CONCLUSIONS: Higher exercise capacity remained a powerful predictor of survival despite lower average exercise capacity at older ages, reinforcing its importance in patients of all ages. Fitness-associated biologic age was a stronger predictor of survival than chronologic age, and may be a useful clinical tool for facilitating patient discussions regarding the impact of exercise capacity on long-term risk.

Cardiorespiratory fitness attenuates risk for major adverse cardiac events in hyperlipidemic men and women independent of statin therapy: The Henry Ford ExercIse Testing Project.

AIMS: We sought to evaluate the effect of cardiorespiratory fitness (CRF) in predicting mortality, myocardial infarction (MI), and revascularization in patients with hyperlipidemia after stratification by gender and statin therapy. METHODS AND RESULTS: This retrospective cohort study included 33,204 patients with hyperlipidemia (57 ± 12 years old, 56% men, 25% black) who underwent physician-referred treadmill stress testing at the Henry Ford Health System from 1991 to 2009. Patients were stratified by gender, baseline statin therapy, and estimated metabolic equivalents from stress testing. We computed hazard ratios using Cox regression models after adjusting for demographics, cardiac risk factors, comorbidities, pertinent medications, interaction terms, and indication for stress testing. RESULTS: There were 4,851 deaths, 1,962 MIs, and 2,686 revascularizations over a median follow-up of 10.3 years. In men and women not on statin therapy and men and women on statin therapy, each 1-metabolic equivalent increment in CRF was associated with hazard ratios of 0.86 (95% CI 0.85-0.88), 0.83 (95% CI 0.81-0.85), 0.85 (95% CI 0.83-0.87), and 0.84 (95% CI 0.81-0.87) for mortality; 0.93 (95% CI 0.90-0.96), 0.87 (95% CI 0.83-0.91), 0.89 (95% CI 0.86-0.92), and 0.90 (95% CI 0.86-0.95) for MI; and 0.91 (95% CI 0.88-0.93), 0.87 (95% CI 0.83-0.91), 0.89 (95% CI 0.87-0.92), and 0.90 (95% CI 0.86-0.94) for revascularization, respectively. No significant interactions were observed between CRF and statin therapy (P > .23). CONCLUSION: Higher CRF attenuated risk for mortality, MI, and revascularization independent of gender and statin therapy in patients with hyperlipidemia. These results reinforce the prognostic value of CRF and support greater promotion of CRF in this patient population.

Prognostic value of exercise capacity in patients with coronary artery disease: the FIT (Henry Ford ExercIse Testing) project.

OBJECTIVE: To examine the prognostic value of exercise capacity in patients with nonrevascularized and revascularized coronary artery disease (CAD) seen in routine clinical practice. PATIENTS AND METHODS: We analyzed 9852 adults with known CAD (mean ± SD age, 61±12 years; 69% men [n=6836], 31% black race [n=3005]) from The Henry Ford ExercIse Testing (FIT) Project, a retrospective cohort study of patients who underwent physician-referred stress testing at a single health care system between January 1, 1991, and May 31, 2009. Patients were categorized by revascularization status (nonrevascularized, percutaneous coronary intervention [PCI], or coronary artery bypass graft [CABG] surgery) and by metabolic equivalents (METs) achieved on stress testing. Using Cox regression models, hazard ratios for mortality, myocardial infarction (MI), and downstream revascularizations were calculated after adjusting for potential confounders, including cardiac risk factors, pertinent medications, and stress testing indication. RESULTS: There were 3824 all-cause deaths during median follow-up of 11.5 years. In addition, 1880 MIs, and 1930 revascularizations were ascertained. Each 1-MET increment in exercise capacity was associated with a hazard ratio (95% CI) of 0.87 (0.85-0.89), 0.87 (0.85-0.90), and 0.86 (0.84-0.89) for mortality; 0.98 (0.96-1.01), 0.88 (0.84-0.92), and 0.93 (0.90-0.97) for MI; and 0.94 (0.92-0.96), 0.91 (0.88-0.95), and 0.96 (0.92-0.99) for downstream revascularizations in the nonrevascularized, PCI, and CABG groups, respectively. In each MET category, the nonrevascularized group had similar mortality risk as and higher MI and downstream revascularization risk than the PCI and CABG surgery groups (P<.05). CONCLUSION: Exercise capacity was a strong predictor of mortality, MI, and downstream revascularizations in this cohort. Furthermore, patients with similar exercise capacities had an equivalent mortality risk, irrespective of baseline revascularization status.

Vav2 protein overexpression marks and may predict the aggressive subtype of ductal carcinoma in situ.

BACKGROUND: A subset of patients with ductal carcinoma in situ (DCIS) will develop invasive breast cancer (IBC). To date, there are no effective predictive biomarkers for identifying this subset with worse prognosis whose lesions are essentially indistinguishable histologically from those with favorable outcomes. We hypothesized that measurable parameters that discriminate DCIS from DCIS with concurrent invasion may serve as diagnostic biomarkers (BM) of progressive cancer in situ (CIS). RESULTS: Using a novel imaging-based method of tissue testing, we measured the relative expression levels of three candidate BM proteins specifically implicated in IBC progression - the insulin-like growth factor I receptor (IGF-IR), Ras-related protein 1 (Rap1), and Vav2 oncoprotein. Protein profiles were compared in 42 histologically normal mammary epithelial samples, 71 CIS (35 without/36 with invasion either on diagnostic biopsy or final surgical excision), and 98 IBC of known estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status. The levels of the IGF-IR and Rap1 protein expression were significantly elevated in ER-positive (ER+/PR+/-/HER2 -) DCIS relative to normal epithelium (P <0.0001). The IGF-IR protein expression was also significantly up regulated in HER2-positive (ER+/-/PR+/-/HER2+) DCIS relative to normal epithelium (P = 0.0002). IGF-IR and Rap1 protein expression levels were similar among DCIS patients without or with concurrent invasion. Vav2 upregulation in DCIS relative to normal group was not associated with steroid hormone receptor and HER2 status, but was associated with the presence of concurrent invasion, including microinvasion (invasive foci of less than 1 mm). DCIS with high Vav2 were more than twice as likely to progress to invasive cancers as DCIS with low Vav2 (odds ratio, 2.42; 95% CI, 1.26-4-65; P =0.008). Furthermore, a receiver operating characteristic curve analysis revealed moderate ability of Vav2 protein expression measurements in DCIS to predict the existence of invasion concurrent with DCIS (area under the curve, 0.71; 95% CI, 0.59- 0.84). CONCLUSIONS: Our novel findings hold promise for utilizing Vav2 protein as a predictive BM for differentiating progressive from non-progressive DCIS.