Control of the adaptive response of the heart to stress via the Notch1 receptor pathway.

In the damaged heart, cardiac adaptation relies primarily on cardiomyocyte hypertrophy. The recent discovery of cardiac stem cells in the postnatal heart, however, suggests that these cells could participate in the response to stress via their capacity to regenerate cardiac tissues. Using models of cardiac hypertrophy and failure, we demonstrate that components of the Notch pathway are up-regulated in the hypertrophic heart. The Notch pathway is an evolutionarily conserved cell-to-cell communication system, which is crucial in many developmental processes. Notch also plays key roles in the regenerative capacity of self-renewing organs. In the heart, Notch1 signaling takes place in cardiomyocytes and in mesenchymal cardiac precursors and is activated secondary to stimulated Jagged1 expression on the surface of cardiomyocytes. Using mice lacking Notch1 expression specifically in the heart, we show that the Notch1 pathway controls pathophysiological cardiac remodeling. In the absence of Notch1, cardiac hypertrophy is exacerbated, fibrosis develops, function is altered, and the mortality rate increases. Therefore, in cardiomyocytes, Notch controls maturation, limits the extent of the hypertrophic response, and may thereby contribute to cell survival. In cardiac precursors, Notch prevents cardiogenic differentiation, favors proliferation, and may facilitate the expansion of a transient amplifying cell compartment.

Outcomes and reoperations after total correction of complete atrio-ventricular septal defect

BACKGROUND: Surgical correction of complete atrio-ventricular septal defect (AVSD) achieves satisfactory results with low morbidity and mortality, but may require reoperation. Our recent operative results at mid-term were followed-up. METHODS: From June 2000 to December 2007, 81 patients (Down syndrome; n=60), median age 4.0 months (range 0.7-118.6) and weight 4.7kg (range 2.2-33), underwent complete AVSD correction. Patch closure for the ventricular septal defect (VSD; n=69) and atrial septal defect (ASD; n=42) was performed with left atrio-ventricular valve (LAVV) cleft closure (n=76) and right atrio-ventricular valve (RAVV) repair (n=57). Mortality, morbidity, and indications for reoperation were retrospectively studied; the end point 'time to reoperation' was analyzed using Kaplan-Meier curves. Follow-up was complete except in two patients and spanned a median of 28 months (range 0.4-6.1 years). RESULTS: In-hospital mortality was 3.7% (n=3) and one late death occurred. Reoperation was required in 7/79 patients (8.9%) for LAVV insufficiency (n=4), for a residual ASD (n=1), for right atrio-ventricular valve insufficiency (n=1), and for subaortic stenosis (n=1). At last follow-up, no or only mild LAVV and RAVV insufficiency was present in 81.3% and 92.1% of patients, respectively, and 2/3 of patients were medication-free. Risk factors for reoperation were younger age (<3 months; p=0.001) and lower weight (<4kg; p=0.003), and a trend towards less and later reoperations in Down syndrome (p<0.2). CONCLUSIONS: Surgical correction of AVSD can be achieved with low mortality and need for reoperation, regardless of Down syndrome or not. Immediate postoperative moderate or more residual atrio-ventricular valve insufficiency will eventually require a reoperation, and could be anticipated in patients younger than 3 months and weighing <4kg.

Radio-frequency ablation as primary management of well-tolerated sustained monomorphic ventricular tachycardia in patients with structural heart disease and left ventricular ejection fraction over 30%.

AIMS: Patients with well-tolerated sustained monomorphic ventricular tachycardia (SMVT) and left ventricular ejection fraction (LVEF) over 30% may benefit from a primary strategy of VT ablation without immediate need for a 'back-up' implantable cardioverter-defibrillator (ICD). METHODS AND RESULTS: One hundred and sixty-six patients with structural heart disease (SHD), LVEF over 30%, and well-tolerated SMVT (no syncope) underwent primary radiofrequency ablation without ICD implantation at eight European centres. There were 139 men (84%) with mean age 62 ± 15 years and mean LVEF of 50 ± 10%. Fifty-five percent had ischaemic heart disease, 19% non-ischaemic cardiomyopathy, and 12% arrhythmogenic right ventricular cardiomyopathy. Three hundred seventy-eight similar patients were implanted with an ICD during the same period and serve as a control group. All-cause mortality was 12% (20 patients) over a mean follow-up of 32 ± 27 months. Eight patients (40%) died from non-cardiovascular causes, 8 (40%) died from non-arrhythmic cardiovascular causes, and 4 (20%) died suddenly (SD) (2.4% of the population). All-cause mortality in the control group was 12%. Twenty-seven patients (16%) had a non-fatal recurrence at a median time of 5 months, while 20 patients (12%) required an ICD, of whom 4 died (20%). CONCLUSION: Patients with well-tolerated SMVT, SHD, and LVEF > 30% undergoing primary VT ablation without a back-up ICD had a very low rate of arrhythmic death and recurrences were generally non-fatal. These data would support a randomized clinical trial comparing this approach with others incorporating implantation of an ICD as a primary strategy.

Reversibility of muscle and heart lesions in chronic Trypanosoma cruzi infected mice after late trypanomicidal treatment

The effect of trypanomicidal treatment upon established histopathological Trypanosoma cruzi induced lesions was studied in Swiss mice. The animals were inoculated with 50 trypomastigotes and infection was allowed to progress without treatment for 99 days. After this period, the animals were divided in three groups, treated for 30 days with either placebo, benznidazole (200 mg/kg/day) or nifurtimox (100 mg/kg/day). These treatments induced 94 and 100 (per cent) cure rates respectively as detected by xenodiagnosis and reduction of antibody levels. Autopsies and histopathological studies of heart, urinary bladderand skeletal muscle performed on day 312 after infection showed almost complete healing without residual lesions. As long periods were allowed between infection, treatment and autopsy, the results indicate that tissue lesions depend, up to advances stages, on the continuous presence of the parasite.