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AIMS: For the primary prevention of cardiovascular disease, the Framingham Risk Score (FRS) is the most well-known risk prediction method. However, there are limited data regarding physicians' method of risk assessment and guideline adherence in clinical practice. METHODS AND RESULTS: In the PARADIGM (Primary cARe AuDIt of Global risk Management) study (March 2009-10), 105 primary care physicians across Canada prospectively collected data for 3015 patients (mean age 56 years, 59% men) without known cardiovascular disease, diabetes, or lipid-lowering medications at baseline. For each patient, the treating physician determined their cardiovascular risk, and reported the risk stratification method and subsequent treatment decisions. Kappa statistics assessed the agreement between the study-calculated FRS and the treating physician's reported risk assessment. The FRS was the most commonly reported risk assessment method, but was used in only 34.0% of patients. Regardless of the method used (even if the FRS was reportedly used), there was only fair agreement between the risk stratification as reported by the physician and the study-calculated FRS. Moreover, physicians recommended statin initiation in 92% of all patients that they identified as high risk; however, according to the study-calculated FRS, only 56% of the truly high-risk patients were recommended statin therapy. CONCLUSION: For the primary prevention of cardiovascular disease, these findings indicate a need to improve risk assessment and stratification, as misclassification directly contributes to suboptimal risk factor management in real-world clinical practice. Future studies should establish the optimal risk stratification method with quality improvement strategies for its subsequent implementation. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov/ct2/show/NCT00950703; NCT00950703.
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The tumour suppressor BRCA1 is mutated in familial breast and ovarian cancer but its role in protecting other tissues from DNA damage has not been explored. Here we show a new role for BRCA1 as a gatekeeper of cardiac function and survival. In mice, loss of BRCA1 in cardiomyocytes results in adverse cardiac remodelling, poor ventricular function and higher mortality in response to ischaemic or genotoxic stress. Mechanistically, loss of cardiomyocyte BRCA1 results in impaired DNA double-strand break repair and activated p53-mediated pro-apoptotic signalling culminating in increased cardiomyocyte apoptosis, whereas deletion of the p53 gene rescues BRCA1-deficient mice from cardiac failure. In human adult and fetal cardiac tissues, ischaemia induces double-strand breaks and upregulates BRCA1 expression. These data reveal BRCA1 as a novel and essential adaptive response molecule shielding cardiomyocytes from DNA damage, apoptosis and heart dysfunction. BRCA1 mutation carriers, in addition to risk of breast and ovarian cancer, may be at a previously unrecognized risk of cardiac failure.