Probing Evidence of Cerebral White Matter Microstructural Disruptions in Ischemic Heart Disease Before and Following Cardiac Rehabilitation: A Diffusion Tensor MR Imaging Study.

BACKGROUND: Ischemic heart disease (IHD) is linked to brain white matter (WM) breakdown but how age or disease effects WM integrity, and whether it is reversible using cardiac rehabilitation (CR), remains unclear. PURPOSE: To assess the effects of brain aging, cardiovascular disease, and CR on WM microstructure in brains of IHD patients following a cardiac event. STUDY TYPE: Retrospective. POPULATION: Thirty-five IHD patients (9 females; mean age = 59 ± 8 years), 21 age-matched healthy controls (10 females; mean age = 59 ± 8 years), and 25 younger controls (14 females; mean age = 26 ± 4 years). FIELD STRENGTH/SEQUENCE: 3 T diffusion-weighted imaging with single-shot echo planar imaging acquired at 3 months and 9 months post-cardiac event. ASSESSMENT: Tract-based spatial statistics (TBSS) and tractometry were used to compare fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) in cerebral WM between: 1) older and younger controls to distinguish age-related from disease-related WM changes; 2) IHD patients at baseline (pre-CR) and age-matched controls to investigate if cardiovascular disease exacerbates age-related WM changes; and 3) IHD patients pre-CR and post-CR to investigate the neuroplastic effect of CR on WM microstructure. STATISTICAL TESTS: Two-sample unpaired t-test (age: older vs. younger controls; IHD: IHD pre-CR vs. age-matched controls). One-sample paired t-test (CR: IHD pre- vs. post-CR). Statistical threshold: P \u3c 0.05 (FWE-corrected). RESULTS: TBSS and tractometry revealed widespread WM changes in older controls compared to younger controls while WM clusters of decreased FA in the fornix and increased MD in body of corpus callosum were observed in IHD patients pre-CR compared to age-matched controls. Robust WM improvements (increased FA, increased AD) were observed in IHD patients post-CR. DATA CONCLUSION: In IHD, both brain aging and cardiovascular disease may contribute to WM disruptions. IHD-related WM disruptions may be favorably modified by CR. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2

Clinical and pharmacogenetic predictors of circulating atorvastatin and rosuvastatin concentrations in routine clinical care

Background-A barrier to statin therapy is myopathy associated with elevated systemic drug exposure. Our objective was to examine the association between clinical and pharmacogenetic variables and statin concentrations in patients. Methods and Results-In total, 299 patients taking atorvastatin or rosuvastatin were prospectively recruited at an outpatient referral center. The contribution of clinical variables and transporter gene polymorphisms to statin concentration was assessed using multiple linear regression. We observed 45-fold variation in statin concentration among patients taking the same dose. After adjustment for sex, age, body mass index, ethnicity, dose, and time from last dose, SLCO1B1 c.521T\u3eC (P\u3c0.001) and ABCG2 c.421C\u3eA (P\u3c0.01) were important to rosuvastatin concentration (adjusted R2=0.56 for the final model). Atorvastatin concentration was associated with SLCO1B1 c.388A\u3eG (P\u3c0.01) and c.521T\u3eC (P\u3c0.05) and 4β-hydroxycholesterol, a CYP3A activity marker (adjusted R2=0.47). A second cohort of 579 patients from primary and specialty care databases were retrospectively genotyped. In this cohort, genotypes associated with statin concentration were not differently distributed among dosing groups, implying providers had not yet optimized each patient\u27s risk-benefit ratio. Nearly 50% of patients in routine practice taking the highest doses were predicted to have statin concentrations greater than the 90th percentile. Conclusions-Interindividual variability in statin exposure in patients is associated with uptake and efflux transporter polymorphisms. An algorithm incorporating genomic and clinical variables to avoid high atorvastatin and rosuvastatin levels is described; further study will determine whether this approach reduces incidence of statin myopathy. © 2013 American Heart Association, Inc

Relative risk for cardiovascular atherosclerotic events after smoking cessation: 6–9 years excess risk in individuals with familial hypercholesterolemia

BACKGROUND: Smoking history is often di- or trichotomized into for example "never, ever or current smoking". However, smoking must be treated as a time-dependent covariate when lifetime data is available. In particular, individuals do not smoke at birth, there is usually a wide variation with respect to smoking history, and smoking cessation must also be considered. METHODS: Therefore we analyzed smoking as a time-dependent risk factor for cardiovascular atherosclerotic events in a cohort of 2400 individuals with familial hypercholesterolemia who were followed from birth until 2004. Excess risk after smoking-cessation was modelled in a Cox regression model with linear and exponential decaying trends. The model with the highest likelihood value was used to estimate the decay of the excess risk of smoking. RESULTS: Atherosclerotic events were observed in 779 patients with familial hypercholesterolemia and 1569 individuals had a smoking history. In the model with the highest likelihood value the risk reduction of smoking after cessation follows a linear pattern with time and it appears to take 6 to 9 years before the excess risk is reduced to zero. The risk of atherosclerotic events due to smoking was estimated as 2.1 (95% confidence interval 1.5; 2.9). CONCLUSION: It was concluded that excess risk due to smoking declined linearly after cessation in at least six to nine years

Importance of Completing Hybrid Cardiac Rehabilitation for Long-Term Outcomes: A Real-World Evaluation

Community-based hybrid cardiac rehabilitation (CR) programs offer a viable alternative to conventional centre-based CR, however their long-term benefits are unknown. We conducted a secondary analysis of the CR Participation Study conducted in London, Ontario, between 2003 and 2006. CR eligible patients hospitalized for a major cardiac event, who resided within 60 min, were referred to a hybrid CR program; 381 of 544 (64%) referred patients initiated CR; an additional 1,498 CR eligible patients were not referred due to distance. For the present study, CR participants were matched using propensity scores to CR eligible non-participants who resided beyond 60 min, yielding 214 matched pairs. Subjects were followed for a mean (standard deviation, SD) of 8.56 (3.38) years for the outcomes of mortality or re-hospitalization for a major cardiac event. Hybrid CR participation was associated with a non-significant 16% lower event rate (Hazard Ratio [HR]: 0.84, 95% CI: 0.59–1.17). When restricting to pairs where CR participants achieved a greater than 0.5 metabolic equivalent exercise capacity increase (123 pairs), CR completion was associated with a 51% lower event rate (HR: 0.49, 95% CI: 0.29–0.81). Successful completion of a community-based hybrid CR program may be associated with decreased long-term mortality or recurrent cardiac events

Coronary artery disease affects cortical circuitry associated with brain-heart integration during volitional exercise

© 2015 the American Physiological Society. This study tested the hypothesis that coronary artery disease (CAD) alters the cortical circuitry associated with exercise. Observations of changes in heart rate (HR) and in cortical blood oxygenation level-dependent (BOLD) images were made in 23 control subjects [control; 8 women; 63 ± 11 yr; mean arterial pressure (MAP): 90 ± 9 mmHg] (mean ± SD) and 17 similarly aged CAD patients (4 women; 59 ± 9 yr; MAP: 87 ± 10 mmHg). Four repeated bouts each of 30%, 40%, and 50% of maximal voluntary contraction (MVC) force (LAB session), and seven repeated bouts of isometric handgrip (IHG) at 40% MVC force (fMRI session), were performed, with each contraction lasting 20 s and separated by 40 s of rest. There was a main effect of group (P = 0.03) on HR responses across all IHG intensities. Compared with control, CAD demonstrated less task-dependent deactivation in the posterior cingulated cortex and medial prefrontal cortex, and reduced activation in the right anterior insula, bilateral precentral cortex, and occipital lobe (P \u3c 0.05). When correlated with HR, CAD demonstrated reduced activation in the bilateral insula and posterior cingulate cortex, and reduced deactivation in the dorsal anterior cingulate cortex, and bilateral precentral cortex (P \u3c 0.05). The increased variability in expected autonomic regions and decrease in total cortical activation in response to the IHG task are associated with a diminished HR response to volitional effort in CAD. Therefore, relative to similarly aged and healthy individuals, CAD impairs the heart rate response and modifies the cortical patterns associated with cardiovascular control during IHG