Midterm results of surgical box line ablation for atrial fibrillation by bipolar radiofrequency.

OBJECTIVES: The surgical box lesion isolation of pulmonary veins and left atrium is recently reported to be superior to the conventional Cox maze IV procedure. The aim of this study is to investigate the midterm results of surgical box lesion ablation with the use of the bipolar radiofrequency energy performed at our institution. METHODS: From April 2004 to December 2008, 35 patients underwent the surgical box lesion ablation using bipolar radiofrequency and were followed for mean 31 months ranging from 3 to 58 months. RESULTS: There was no operative mortality. One patient (2.86%) needed electric cardioversion before discharge. One patient (2.86%) needed pacemaker implantation. At discharge, all patients were in normal sinus rhythm. During the follow-up period, the rate of sinus rhythm maintenance was 100%, the rate of freedom from antiarrhythmic medication was 42.9%, and the rate of freedom from thromboembolic episodes was 100%. CONCLUSIONS: The surgical box lesion ablation was a safe and effective procedure to terminate atrial fibrillation and restore sinus rhythm.

Adaptive and maladptive effects of SMAD3 signaling in the adult heart after hemodynamic pressure overloading.

BACKGROUND: Previous studies suggest that transforming growth factor-beta provokes cardiac hypertrophy and myocardial fibrosis; however, it is unclear whether the deleterious effects of transforming growth factor-beta signaling are conveyed through SMAD-dependent or SMAD-independent signaling pathways. METHODS AND RESULTS: To determine the contribution of SMAD-dependent signaling to cardiac remodeling, we performed transaortic constriction in SMAD3 null (SMAD3(-/-)) and littermate control mice (age, 10 to 12 weeks). Cumulative survival 20 days after transaortic constriction was significantly less in the SMAD3(-/-) mice when compared with littermate controls (43.6% versus 90.9%, P<0.01). Transaortic constriction resulted in a significant increase in cardiac hypertrophy in the SMAD3(-/-) mice, denoted by an increase in the heart weight to tibial length ratio and increased myocyte cross-sectional area. Loss of SMAD3 signaling also resulted in a significant 60% decrease in myocardial fibrosis (P<0.05). A microRNA microarray showed that 55 microRNAs were differentially expressed in littermate and SMAD3(-/-) mice and that 10 of these microRNAs were predicted to bind to genes that regulate the extracellular matrix. Of these 10 candidate microRNAs, both miR-25 and miR-29a were sufficient to decrease collagen gene expression when transfected into isolated cardiac fibroblasts in vitro. CONCLUSIONS: The results suggest that SMAD3 signaling plays dual roles in the heart: one beneficial role by delimiting hypertrophic growth and the other deleterious by modulating myocardial fibrosis, possibly through a pathway that entails accumulation of microRNAs that decrease collagen gene expression.

Clinical results of staged repair with complete unifocalization for pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries.

OBJECTIVE: Our treatment strategy for pulmonary atresia with ventricular septal defect (VSD) and major aortopulmonary collateral arteries is a staged repair that comprises the first complete unifocalization (UF) with 'unification' of intrapulmonary arteries and then the definitive repair. The purpose of this study is to evaluate the outcome of our staged repair strategy with complete UF and to determine the results of our current management strategy. METHODS: From 1982 to 2004, 113 consecutive patients were treated with staged repair at our institute. We evaluated the risk of definitive repair failure or death in the 3 years after definitive repair using logistic regression. Furthermore, we compared the early group (patients who underwent UF before December 1995) and the late group (patients who underwent UF after January 1996). RESULTS: The mean follow-up interval was 8.8 years (0.8 months to 23.3 years), and Kaplan-Meier-estimated overall survival rates after first UF were 80.9, 73.8, and 69.9% at 5, 10, and 15 years, respectively. Survival in patients with an absent central pulmonary artery (PA) was significantly lower than in those with a central PA (p<0.05), and the factor that was significantly associated with definitive repair failure or death in the 3 years after definitive repair was central PA morphology (p<0.05). Higher mean PA pressure after UF was detected in patients with hypoplastic central PA, compared with those without hypoplastic PA (30.9 mmHg vs 23.3 mmHg, p<0.05). In the late group, age (in years) at first UF (3.9 vs 8.4, p<0.01), second UF (4.3 vs 9.2, p<0.01), and definitive repair (5.8 vs 9.1, p<0.01) was significantly younger than in early group, and the survival rate after first UF in the late group was 96.2 and 91.3% at 3 and 7 years, respectively. Systolic right ventricular pressure and the pressure ratio between the right and the left ventricles after definitive repair in the late group were significantly lower than in the early group (53.6 mmHg vs 75.0 mmHg, p<0.01; 61.7% vs 75.9%, p<0.05). CONCLUSIONS: Hypoplastic central PA was a significant risk factor in this disease. The overall survival was improved by our current management strategy. Improved RV pressure after definitive repair appears to affect the long-term outcome.

Outcomes of definitive surgical repair for congenitally corrected transposition of the great arteries or double outlet right ventricle with discordant atrioventricular connections: risk analyses in 189 patients.

OBJECTIVE: This study was undertaken to compare long-term results of various types of surgical repairs for either congenitally corrected transposition of the great arteries or double outlet right ventricle with discordant atrioventricular connections, and to analyze the risk factors that affect early and late mortality and reintervention. METHODS: Between January 1972 and September 2005, a total of 189 patients (median age 8.3 years, range 2 months to 47 years old) with congenitally corrected transposition of the great arteries or double outlet right ventricle with discordant atrioventricular connections underwent definitive repairs. The definitive repairs comprised a conventional repair (atrial septal defect, or ventricular septal defect closure with or without pulmonary stenosis release, or isolated tricuspid valve surgery) in 36 patients (group I), conventional Rastelli in 31 patients (group II), double-switch operation (atrial switch plus arterial switch) in 15 patients (group III), atrial switch plus intraventricular rerouting (with or without extracardiac conduits) in 69 patients (group IV), and a Fontan-type repair in 38 patients (group V). The mean follow-up period was 10.1 years. Hospitalization and late mortality and reoperation were indicated as events. Risk factors for these events were analyzed by logistic regression for hospital death and a Cox proportional hazards model for late events. RESULTS: The Kaplan-Meier survival including hospital and late mortality was 62.4% at 32 years in group I, 78.5% at 27 years in group II, 74.5% at 15 years in group III, 80% at 16 years in group IV, and 79.3% at 22 years in group V. The reoperation-free ratio was 64.2% in group I, 76.6% in group II, 84.4% in group III, 89.6% in group IV, and 91.3% in group V. Risk analyses showed that the risk for hospital death was preoperative in patients with more than moderate tricuspid regurgitation and a cardiopulmonary bypass time of more than 240 minutes. A risk for late mortality was the presence of tricuspid regurgitation. Risks for reoperation were preoperative cardiomegaly, preoperative tricuspid regurgitation of more than grade II, ventricular septal defect enlargement, and body weight less than 10 kg. Risks for pacemaker implantation, as indicated by multivariate analysis, were ventricular septal defect enlargement during operation and age less than 3 years. CONCLUSIONS: There were no statistical differences between long-term survival rates of patients who underwent conventional surgical repair versus those of patients who underwent anatomic surgical repair. Results of conventional repair were satisfactory except in patients with significant tricuspid regurgitation. Results of anatomic repair were also satisfactory even for patients with significant tricuspid regurgitation, and therefore, anatomic repair should be the procedure of choice for those patients.

Double-outlet right ventricle with left malposition of the great arteries and total anomalous pulmonary venous connection.

The patient was diagnosed with double-outlet right ventricle with left malposition of the great arteries, total anomalous pulmonary venous connection, and pulmonary stenosis at 2 months of age. Because the progression of pulmonary venous obstruction was suspected at 2 years of age, the patient was catheterized and underwent a definitive repair. The patient had a right aortic arch and left juxtaposition of the atrial appendages; the intraventricular anatomy exhibits malalignment between the conal septum and the muscular intraventricular septum, and the conal septum is well developed and dextroposed, resulting in pulmonary obstruction and multiple ventricular septal defects (VSDs). Because a supracardiac type (Darling's type Ib) of total anomalous pulmonary venous connection was also combined with such an anomaly, total correction consisted of an anastomosis of the left atrium and the common pulmonary vein, creation of an intraventricular tunnel, direct closures of muscular VSDs, pulmonary valvotomy, and infundibular resection. To our knowledge, this is the first description of the successful surgical correction of this type of anomaly in one stage.

Inhibition of PPAR-alpha activity in mice with cardiac-restricted expression of tumor necrosis factor: potential role of TGF-beta/Smad3.

A shift in energy substrate utilization from fatty acids to glucose has been reported in failing hearts, resulting in improved oxygen efficiency yet perhaps also contributing to a state of energy deficiency. Peroxisome proliferator-activated receptor (PPAR)-alpha, the principal transcriptional regulator of cardiac fatty acid beta-oxidation (FAO) genes, is downregulated in heart failure, and this may contribute to reduced fatty acid utilization. Cardiomyopathic states are also accompanied by elevated levels of circulating cytokines, such as tumor necrosis factor (TNF), as well as increased local production of cytokines and profibrotic factors, such as transforming growth factor (TGF)-beta. However, whether these molecular pathways directly modulate cardiac energy metabolism and PPAR-alpha activity is not known. Therefore, FAO capacity and FAO gene expression were determined in mice with cardiac-restricted overexpression of TNF (MHCsTNF(3)). MHCsTNF(3) hearts had significantly lower FAO capacity and decreased expression of PPAR-alpha and FAO target genes compared with control hearts. Surprisingly, TNF had little effect on PPAR-alpha activity and FAO rates in cultured ventricular myocytes, suggesting that TNF acts indirectly on myocyte FAO in vivo. We found that TGF-beta expression was upregulated in MHCsTNF(3) hearts and that treatment of cultured myocytes with TGF-beta significantly suppressed FAO rates and directly impaired PPAR-alpha activity, a result reproduced by Smad3 overexpression. This work demonstrates that TGF-beta signaling pathways directly suppress PPAR-alpha activity and reduce FAO in cardiac myocytes, perhaps in response to locally elevated TNF. Although speculative, TGF-beta-driven repair mechanisms may also include the additional benefit of limiting FAO in injured myocardium.

Functional significance of inflammatory mediators in a murine model of resuscitated hemorrhagic shock.

The mechanisms that underlie the development of myocardial dysfunction after resuscitated hemorrhagic shock (HS) are not known. Recent studies suggest that systemic activation of inflammatory mediators may contribute to cellular dysfunction and/or cell death in various organs, including the heart. However, the precise role that inflammatory mediators play in the heart in the setting of resuscitated HS is not known. Accordingly, the purpose of the present study was to use a well-defined murine model of resuscitated HS to characterize the functional significance of inflammatory mediators in the heart in vivo. Mice were subjected to sham operation or resuscitated HS. Left ventricular (LV) function was assessed by two-dimensional echocardiography 6 h after resuscitation. Myocardial TNF, IL-1beta, and IL-6 proteins were measured 1 and 6 h after resuscitation. To determine the role of TNF in HS-induced LV dysfunction, mice were treated with a soluble TNF receptor antagonist (etanercept) before HS or at the time of resuscitation. LV fractional shortening was significantly depressed (P < 0.05) in resuscitated HS mice (28 +/- 1.5%) compared with sham controls (35.8 +/- 1.0%). TNF and IL-1beta levels were significantly increased (P < 0.05) in resuscitated HS mice. Pretreatment with etanercept abrogated resuscitated HS-induced LV dysfunction, whereas treatment at the time of resuscitation significantly attenuated, but did not abrogate, LV dysfunction. Together, these data suggest that TNF plays a critical upstream role in resuscitated HS-induced LV dysfunction; however, once the deleterious consequences of reperfusion injury are initiated, TNF contributes to, but is not necessary for, the development of LV dysfunction.

PPAR-gamma agonist rosiglitazone ameliorates ventricular dysfunction in experimental chronic mitral regurgitation.

Previously we reported that the beneficial effects of beta-adrenergic blockade in chronic mitral regurgitation (MR) were in part due to induction of bradycardia, which obviously affects myocardial energy requirements. From this observation we hypothesized that part of the pathophysiology of MR may involve faulty energy substrate utilization, which in turn might lead to potentially harmful lipid accumulation as observed in other models of heart failure. To explore this hypothesis, we measured triglyceride accumulation in the myocardia of dogs with chronic MR and then attempted to enhance myocardial metabolism by chronic administration of the peroxisome proliferator-activated receptor (PPAR)-gamma agonist rosiglitazone. Cardiac tissues were obtained from three groups of dogs that included control animals, dogs with MR for 3 mo without treatment, and dogs with MR for 6 mo that were treated with rosiglitazone (8 mg/day) for the last 3 mo of observation. Hemodynamics and contractile function (end-systolic stress-strain relationship, as measured by K index) were assessed at baseline, 3 mo of MR, and 6 mo of MR (3 mo of the treatment). Lipid accumulation in MR (as indicated by oil red O staining score and TLC analysis) was marked and showed an inverse correlation with the left ventricular (LV) contractility. LV contractility was significantly restored after PPAR therapy (K index: therapy, 3.01 +/- 0.11*; 3 mo MR, 2.12 +/- 0.34; baseline, 4.01 +/- 0.29; ANOVA, P = 0.038; *P < 0.05 vs. 3 mo of MR). At the same time, therapy resulted in a marked reduction of intramyocyte lipid. We conclude that 1) chronic MR leads to intramyocyte myocardial lipid accumulation and contractile dysfunction, and 2) administration of the PPAR-gamma agonist rosiglitazone ameliorates MR-induced LV dysfunction accompanied by a decline in lipid content.