Background Low aerobic fitness and obesity are associated with atherosclerosis, and thereforegreatly increase the risk of cardiovascular disease (CVD) and early death. It has long been known that atherosclerosis my begin early in life. Despite this fact, it remains unknown how obesity and aerobic fitness early in life influence the risks of atherosclerosis, CVD and death. Furthermore, it is unknown whether high aerobic fitness can compensate for the risks associated with obesity, and how genetic confounding affects the relationshipsof aerobic fitness with CVD and all-cause mortality. Thus, the main aims of this thesis were to investigate the associations of aerobic fitness in late adolescence with myocardial infarction (Study I), stroke (Study II) and all-cause mortality (Study III), and how genetic confounding influences the relationshipsof aerobic fitness with CVD, diabetes and death (Study IV). Methods The study population comprised up to1.3 million men who participated in mandatory Swedish military conscription. During conscription, all conscripts underwent highly standardized tests to assess aerobic fitness, body mass index, blood pressure and cognitive function. A physician also examined all conscripts. Data on subjects’ diagnoses, death and socioeconomic status during follow-up were retrieved using record linkage. Subjects were subsequently followed until the study endpoint, date of death or date of any outcome of interest. Associations between baseline variables and the risks of adverse outcomes were assessed using Cox’s proportional hazard models. Genetic confounding of the relationships between aerobic fitness and diabetes, CVD and death was assessed using a twin population and a paired logistic regression model. Results In Study I, low aerobic fitness at conscription was associated with an increased risk of myocardial infarction (MI) during follow-up (hazard ratio [HR] 0.82 per standard deviation increase). Similarly, in Study II, high aerobic fitness reduced the risk of stroke (HR 0.84 for ischemic stroke, HR 0.82 for hemorrhagic stroke; P < 0.001 for all), and obesity was associated with an increased risk of stroke (HR 1.15 for ischemic stroke, HR 1.18 for hemorrhagic stroke; P < 0.001 for all). In Study III, high aerobic fitness was also associated with reduced all-cause mortality later in life (HR 0.49, P < 0.001). High aerobic fitness exerted the strongest protection against death from substance and alcohol abuse, suicide and trauma (HRs 0.20, 0.41 and 0.52, respectively; P < 0.001 for all). Obese individuals with aerobic fitness were at higher risk of MI and all-cause mortality than were normal-weight individuals with low fitness (Studies I and III). In Study IV, fit twins had no reduced risk of CVD or death during follow-up compared with their unfit twin siblings (odds ratio 1.11, 95% confidence interval 0.88–1.40), regardless of how large the difference in fitness was. However, the fitter twins were protected against diabetes during follow-up. Conclusions Already early in life, aerobic fitness is a strong predictor of CVD and all-cause mortality later in life. In contrast to the “fat but fit” hypothesis, it seems that high aerobic fitness cannot fully compensate for the risks associated with obesity. The associationsof aerobic fitness with CVD and all-cause mortality appear to be mediated by genetic factors. Together, these findings have implications for the view of aerobic fitness as a causal risk factor for CVD and early death.

The primary objective of this study was to assess the relationship between dietary patterns with diabetes and mortality risk from all-cause and cardiovascular disease while controlling for the confounding effects of fitness. The secondary objective was to examine the combined effects of dietary patterns and fitness on chronic disease and mortality risk. Participants consisted of 13,621 men and women from the Aerobics Center Longitudinal Study who completed a standardized medical examination and 3-day diet record between 1987 and 1999. Reduced rank regression was used to identify dietary patterns that were predictive of unfavorable profiles of cholesterol, white blood cell count, glucose, mean arterial pressure, HDL-cholesterol, uric acid, triglycerides, and body mass index. One primary dietary pattern emerged, which was labeled the “Unhealthy Eating Index”. This pattern was characterized by a large consumption of processed meat, red meat, white potato products, non-whole grains, added fat, and a small consumption of non-citrus fruits. After adjustment for covariates, the odds ratio for diabetes and the hazard ratio for all-cause mortality were 2.55 (95% confidence interval: 1.81-3.58) and 1.40 (1.02-1.91) in the highest quintile of the Unhealthy Eating Index when compared to the lowest quintile, respectively. After controlling for fitness, these risk estimates were reduced by 51.6% and 55.0%. The Unhealthy Eating Index was not a significant predictor of cardiovascular disease mortality before or after controlling for fitness. Examining the combined effects of dietary patterns and fitness revealed that both variables were independent predictors of diabetes (Ptrend <0.0001), while fitness (Ptrend <0.0001) but not unhealthy eating (Ptrend=0.071) significantly predicted all-cause mortality risk. These results suggest that both diet and fitness must be considered when studying disease. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2009-07-08 07:11:06.809

Background: Patients with left ventricular ejection fractions between 40% and 49% either discovered de novo, having declined from ≥50%, or improved from <40% have been described as heart failure (HF) with mid-range ejection fraction (HFmrEF). Though clinical signs and symptoms are similar to other phenotypes, possible prognostic differences and therapeutic responses reinforce the need for further understanding of patients’ characteristics especially in a rural community based population. The purpose of this study is to evaluate the clinical characteristics, comorbidities and prognosis of a rural patient population with HFmrEF. Materials and Methods: We queried the electronic medical record from a community based university practice for all patients with a HF diagnosis. We included only those patients with >3 months follow-up and interpretable Doppler echocardiograms. We recorded demographic, Doppler-echo, and outcome variables (up to 2,083 days). Results: There were 633 HF patients: 42.4% with preserved ejection fraction (HFpEF, EF ≥50%), 36.4% with HFmrEF, and 21.0% with reduced ejection fraction (HFrEF, EF <40%). HFmrEF patients were older, had greater coronary disease prevalence, lower systolic blood pressure, elevated brain natriuretic peptide, lower hemoglobin, and higher creatinine than HFpEF. All-cause mortality was intermediate between HFrEF and HFpEF but was not significantly different. Landmark analysis revealed a trend toward greater second readmission in HFmrEF as compared to HFpEF (hazard ratio: 1.43 [0.96-2.14],P = 0.0767). Conclusions: Rural patients with HFmrEF without an ambulatory HF clinic represent a higher percentage of HF patients than previously reported with greater coronary disease prevalence with comparable readmission rates and nonsignificantly different all-cause mortality.

The worldwide population of patients with chronic kidney disease (CKD) is growing, with estimated prevalence at 12-15% of adults. Of particular concern are those with late stage CKD, defined as an estimated glomerular filtration rate (eGFR)of less than 30 ml/min/1.73m2, as they are susceptible to the highest risk of adverse outcomes such as progression to end stage kidney disease (ESKD), cardiovascular disease and all-cause mortality (1, 2). As such, late stage CKD patients are often managed in specialized clinics with set clinical targets, standardized education and multi-disciplinary care(3). A key clinical target for therapeutic intervention and prevention of the progression of CKD is blood pressure (BP) reduction(4). Yet, multiple relevant questions remain regarding the strength and nature of association of BP with clinical outcomes in late stage CKD. As the risks of hypotension-related complications are high in late stage CKD, it remains unclear whether strict BP control delays CKD progression in a real world clinic population(5). Furthermore, it is unclear how to appropriately specify the nature of the longitudinal association between BP and clinical outcomes of ESKD and mortality. The overall objective of this thesis is to examine the longitudinal association of BP and adverse clinical outcomes in a cohort of 1203 patients (mean eGFR 17.8 ml/min/1.73m2; mean of 6.7 BP measures per patient) with late stage CKD. In our first paper we examined the association of repeat measures of BP with CKD progression, defined as a decline in eGFR. When modeling eGFR using longitudinal linear regression, we found that its over-time trajectory was non-linear and that this trajectory was modified by BP; thus, we found a significant time-dependant association between BP and eGFR. When modeling time to eGFR decline ≥ 30% using Cox proportional hazards regression with categorized BP specified as a time-dependent exposure, BP was significantly associated with risk of eGFR decline; in particular, extremes of low and high systolic blood pressure (SBP) and high diastolic blood pressure (DBP) significantly increased the risk of eGFR decline. In our second paper, we examined different methods of modelling longitudinal BP and its association with time to mortality and ESKD. We found that elevations in SBP and DBP, in particular, when expressed as current (most recent visit), lag (previous visit), and cumulative exposure were significantly associated with increased risk of ESKD while low SBP (current, lag and cumulative exposure) was significantly associated with increased risk of mortality. Baseline BP measures were not statistically significantly associated with any outcomes. In patients with more moderate ranges of SBP (121-140) or DBP (60-85) at baseline, a subsequent rise to >160 or > 85 respectively, was associated with an increased risk of ESKD. Thus, longitudinal BP measures in late-stage CKD are significantly associated with adverse outcomes and convey important information beyond baseline BP measures.

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