Reprogramming of human fibroblasts toward a cardiac fate.

Reprogramming of mouse fibroblasts toward a myocardial cell fate by forced expression of cardiac transcription factors or microRNAs has recently been demonstrated. The potential clinical applicability of these findings is based on the minimal regenerative potential of the adult human heart and the limited availability of human heart tissue. An initial but mandatory step toward clinical application of this approach is to establish conditions for conversion of adult human fibroblasts to a cardiac phenotype. Toward this goal, we sought to determine the optimal combination of factors necessary and sufficient for direct myocardial reprogramming of human fibroblasts. Here we show that four human cardiac transcription factors, including GATA binding protein 4, Hand2, T-box5, and myocardin, and two microRNAs, miR-1 and miR-133, activated cardiac marker expression in neonatal and adult human fibroblasts. After maintenance in culture for 4-11 wk, human fibroblasts reprogrammed with these proteins and microRNAs displayed sarcomere-like structures and calcium transients, and a small subset of such cells exhibited spontaneous contractility. These phenotypic changes were accompanied by expression of a broad range of cardiac genes and suppression of nonmyocyte genes. These findings indicate that human fibroblasts can be reprogrammed to cardiac-like myocytes by forced expression of cardiac transcription factors with muscle-specific microRNAs and represent a step toward possible therapeutic application of this reprogramming approach.

Risk Stratification in Patients Who Underwent Percutaneous Left Atrial Appendage Occlusion.

Left atrial appendage occlusion (LAAO) is effective in preventing thromboembolism. Risk stratification tools could help identify patients at risk for early mortality after LAAO. In this study, we validated and recalibrated a clinical risk score (CRS) to predict risk of all-cause mortality after LAAO. This study used data from patients who underwent LAAO in a single-center, tertiary hospital. A previously developed CRS using 5 variables (age, body mass index [BMI], diabetes, heart failure, and estimated glomerular filtration rate) was applied to each patient to assess risk of all-cause mortality at 1 and 2 years. The CRS was recalibrated to the present study cohort and compared with established atrial fibrillation-specific (CHA2DS2-VASc and HAS-BLED) and generalized (Walter index) risk scores. Cox proportional hazard models were used to assess the risk of mortality and discrimination was assessed by Harrel C-index. Among 223 patients, the 1- and 2-year mortality rates were 6.7% and 11.2%, respectively. With the original CRS, only low BMI (<23 kg/m2) was a significant predictor of all-cause mortality (hazard ratio [HR] [95% CI] 2.76 [1.03 to 7.35]; p = 0.04). With recalibration, BMI <29 kg/m2 and estimated glomerular filtration rate <60 ml/min/1.73 m2 were significantly associated with an increased risk of death (HR [95% CI] 3.24 [1.29 to 8.13] and 2.48 [1.07 to 5.74], respectively), with a trend toward significance noted for history of heart failure (HR [95% CI] 2.13 [0.97 to 4.67], p = 0.06). Recalibration improved the discriminative ability of the CRS from 0.65 to 0.70 and significantly outperformed established risk scores (CHA2DS2-VASc = 0.58, HAS-BLED = 0.55, Walter index = 0.62). In this single-center, observational study, the recalibrated CRS accurately risk stratified patients who underwent LAAO and significantly outperformed established atrial fibrillation-specific and generalized risk scores. In conclusion, clinical risk scores should be considered as an adjunct to standard of care when evaluating a patient's candidacy for LAAO.

Contextualizing National Policies Regulating Access to Low-Dose Aspirin in America and Europe Using the Full Report of a Transatlantic Patient Survey of Aspirin in Preventive Cardiology.

Background Aspirin is widely administered to prevent cardiovascular disease (CVD). However, appropriate use of aspirin depends on patient understanding of its risks, benefits, and indications, especially where aspirin is available over the counter (OTC). Methods and Results We did a survey of patient-reported 10-year cardiovascular risk; aspirin therapy status; form of aspirin access (OTC versus prescription); and knowledge of the risks, benefits, and role of aspirin in CVD prevention. Consecutive adults aged ≥50 years with ≥1 cardiovascular risk factor attending outpatient clinics in America and Europe were recruited. We also systematically reviewed national policies regulating access to low-dose aspirin for CVD prevention. At each site, 150 responses were obtained (300 total). Mean±SD age was 65±10 years, 40% were women, and 41% were secondary prevention patients. More than half of the participants at both sites did not know (1) their own level of 10-year CVD risk, (2) the expected magnitude of reduction in CVD risk with aspirin, or (3) aspirin's bleeding risks. Only 62% of all participants reported that aspirin was routinely indicated for secondary prevention, whereas 47% believed it was routinely indicated for primary prevention (P=0.048). In America, 83.5% participants obtained aspirin OTC compared with 2.5% in Europe (P<0.001). Finally, our review of European national policies found only 2 countries where low-dose aspirin was available OTC. Conclusions Many patients have poor insight into their objectively calculated 10-year cardiovascular risk and do not know the risks, benefits, and role of aspirin in CVD prevention. Aspirin is mainly obtained OTC in America in contrast to Europe, where most countries restrict access to low-dose aspirin.