Cyclin A2 (Ccna2), normally silenced after birth in the mammalian heart, can induce cardiac repair in small-animal models of myocardial infarction. We report that delivery of the Ccna2 gene to infarcted porcine hearts invokes a regenerative response. We used a catheter-based approach to occlude the left anterior descending artery in swine, which resulted in substantial myocardial infarction. A week later, we performed left lateral thoracotomy and injected adenovirus carrying complementary DNA encoding CCNA2 or null adenovirus into peri-infarct myocardium. Six weeks after treatment, we assessed cardiac contractile function using multimodality imaging including magnetic resonance imaging, which demonstrated ~18% increase in ejection fraction of Ccna2-treated pigs and ~4% decrease in control pigs. Histologic studies demonstrate in vivo evidence of increased cardiomyocyte mitoses, increased cardiomyocyte number, and decreased fibrosis in the experimental pigs. Using time-lapse microscopic imaging of cultured adult porcine cardiomyocytes, we also show that Ccna2 elicits cytokinesis of adult porcine cardiomyocytes with preservation of sarcomeric structure. These data provide a compelling framework for the design and development of cardiac regenerative therapies based on cardiomyocyte cell cycle regulation.

Objective: To evaluate segmental right ventricular (RV) dysfunction in pulmonary hypertension (PH) using cardiac magnetic resonance (CMR). Design: Cross-sectional analysis in a retrospective cohort of consecutive adult patients. Setting: Mount Sinai Hospital in New York. Patients: 192 patients with known or suspected PH undergoing right heart catheterisation and CMR. PH was defined as mean pulmonary artery pressure ≥25 mm Hg. Abnormal RV ejection fraction (RVEF) was defined as <50%. Patients were classified into: group 1 (no PH, normal RVEF; n=40), group 2 (PH, normal RVEF; n=41) or group 3 (PH, abnormal RVEF; n=111). Interventions: CMR and right heart catheterisation within a 2-week interval. Main outcome measures: On cine CMR images, the stack of RV short-axis views was divided into two equal halves. Basal and apical RVEF were calculated using Simpson's method, and a ratio of basal-to-apical RVEF (RVEF_ratio) was derived. Results: Basal RVEF did not differ between groups 1 and 2 (63±8% vs 64±8%; p=1); however, patients in group 2 had significantly lower apical RVEF (46±13% vs 58±10%; p<0.01) and higher RVEF_ratio (median 1.4 vs 1.1; p<0.01). Both apical and basal RVEF were reduced in group 3 compared with groups 1 and 2 (p<0.01), and the RVEF_ratio increased with increasing PH severity (p<0.01 for trend). An apical RVEF <50% was more sensitive than global RV dysfunction for the detection of PH. Conclusions: Apical dysfunction appears to occur before global RVEF decreases in chronic PH, potentially constituting an early and sensitive marker of RV dysfunction in this setting.

Stress echocardiography (SE) is dependent on subjective interpretations. As a prelude to the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) Trial, potential sites were required to submit two SE, one with moderate or severe left ventricular (LV) myocardial ischemia and one with mild ischemia. We evaluated the concordance of site and core lab interpretations. Eighty-one SE were submitted from 41 international sites. Ischemia was classified by the number of new or worsening segmental LV wall motion abnormalities (WMA): none, mild (1 or 2) or moderate or severe (3 or more) by the sites and the core lab. Core lab classified 6 SE as no ischemia, 35 mild and 40 moderate or greater. There was agreement between the site and core in 66 of 81 total cases (81 %, weighted kappa coefficient [K] =0.635). Agreement was similar for SE type - 24 of 30 exercise (80 %, K = 0.571) vs. 41 of 49 pharmacologic (84 %, K = 0.685). The agreement between poor or fair image quality (27 of 36 cases, 75 %, K = 0.492) was not as good as for the good or excellent image quality cases (39 of 45 cases, 87 %, K = 0.755). Differences in concordance were noted for degree of ischemia with the majority of discordant interpretations (87 %) occurring in patients with no or mild LV myocardial ischemia. While site SE interpretations are largely concordant with core lab interpretations, this appears dependent on image quality and the extent of WMA. Thus core lab interpretations remain important in clinical trials where consistency of interpretation across a range of cases is critical. ClinicalTrials.gov NCT01471522