Nestor Villamizar

Thoracoscopic lobectomy is associated with lower morbidity compared with thoracotomy

OBJECTIVES Advantages of thoracoscopic lobectomy include less postoperative pain, shorter hospitalization, and improved delivery of adjuvant chemotherapy. The incidence of postoperative complications has not been thoroughly assessed. This study analyzes morbidity after lobectomy to compare the thoracoscopic approach and thoracotomy. METHODS By using a prospective database, the outcomes of patients who underwent lobectomy from 1999-2009 were analyzed with respect to postoperative complications. Propensity-matched groups were analyzed based on preoperative variables and stage. RESULTS Of the 1079 patients in the study, 697 underwent thoracoscopic lobectomy, and 382 underwent lobectomy by means of thoracotomy. In the overall analysis thoracoscopic lobectomy was associated with a lower incidence of atrial fibrillation (P = .01), atelectasis (P = .0001), prolonged air leak (P = .0004), transfusion (P = .0001), pneumonia (P = .001), sepsis (P = .008), renal failure (P = .003), and death (P = .003). In the propensity-matched analysis based on preoperative variables, when comparing 284 patients in each group, 196 (69%) patients who underwent thoracoscopic lobectomy had no complications versus 144 (51%) patients who underwent thoracotomy (P = .0001). In addition, thoracoscopic lobectomy was associated with a lower incidence of atrial fibrillation (13% vs 21%, P = .01), less atelectasis (5% vs 12%, P = .006), fewer prolonged air leaks (13% vs 19%, P = .05), fewer transfusions (4% vs 13%, P = .002), less pneumonia (5% vs 10%, P = .05), less renal failure (1.4% vs 5%, P = .02), shorter chest tube duration (median of 3 vs 4 days, P < .0001), and shorter length of hospital stay (median of 4 vs 5 days, P < .0001). CONCLUSIONS Thoracoscopic lobectomy is associated with a lower incidence of major complications, including atrial fibrillation, compared with lobectomy by means of thoracotomy. The underlying factors responsible for this advantage should be analyzed to improve the safety and outcomes of other thoracic procedures.

Endogenous S-nitrosothiols protect against myocardial injury

Despite substantial evidence that nitric oxide (NO) and/or endogenous S-nitrosothiols (SNOs) exert protective effects in a variety of cardiovascular diseases, the molecular details are largely unknown. Here we show that following left coronary artery ligation, mice with a targeted deletion of the S-nitrosoglutathione reductase gene (GSNOR−/−) have reduced myocardial infarct size, preserved ventricular systolic and diastolic function, and maintained tissue oxygenation. These profound physiological effects are associated with increases in myocardial capillary density and S-nitrosylation of the transcription factor hypoxia inducible factor-1α (HIF-1α) under normoxic conditions. We further show that S-nitrosylated HIF-1α binds to the vascular endothelial growth factor (VEGF) gene, thus identifying a role for GSNO in angiogenesis and myocardial protection. These results suggest innovative approaches to modulate angiogenesis and preserve cardiac function.

Dynamic Regulation of Phosphoinositide 3-Kinase-γ Activity and β-Adrenergic Receptor Trafficking in End-Stage Human Heart Failure

Background— Downregulation of &bgr;-adrenergic receptors (&bgr;ARs) under conditions of heart failure requires receptor targeting of phosphoinositide 3-kinase (PI3K)–&ggr; and redistribution of &bgr;ARs into endosomal compartments. Because support with a left ventricular assist device (LVAD) results in significant improvement of cardiac function in humans, we investigated the effects of mechanical unloading on regulation of PI3K&ggr; activity and intracellular distribution of &bgr;ARs. Additionally, we tested whether displacement of PI3K&ggr; from activated &bgr;ARs would restore agonist responsiveness in failing human cardiomyocytes. Methods and Results— To test the role of PI3K on &bgr;AR endocytosis in failing human hearts, we assayed for PI3K activity in human left ventricular samples before and after mechanical unloading (LVAD). Before LVAD, failing human hearts displayed a marked increase in &bgr;AR kinase 1 (&bgr;ARK1)–associated PI3K activity that was attributed exclusively to enhanced activity of the PI3K&ggr; isoform. Increased &bgr;ARK1-coupled PI3K activity in the failing hearts was associated with downregulation of &bgr;ARs from the plasma membrane and enhanced sequestration into early and late endosomes compared with unmatched nonfailing controls. Importantly, LVAD support reversed PI3K&ggr; activation, normalized the levels of agonist-responsive &bgr;ARs at the plasma membrane, and depleted the &bgr;ARs from the endosomal compartments without changing the total number of receptors (sum of plasma membrane and early and late endosome receptors). To test whether the competitive displacement of PI3K from the &bgr;AR complex restored receptor responsiveness, we overexpressed the phosphoinositide kinase domain of PI3K (which disrupts &bgr;ARK1/PI3K interaction) in primary cultures of failing human cardiomyocytes. Adenoviral-mediated phosphoinositide kinase overexpression significantly increased basal contractility and rapidly reconstituted responsiveness to &bgr;-agonist. Conclusions— These results suggest a novel paradigm in which human &bgr;ARs undergo a process of intracellular sequestration that is dynamically reversed after LVAD support. Importantly, mechanical unloading leads to complete reversal in PI3K&ggr; and &bgr;ARK1-associated PI3K activation. Furthermore, displacement of active PI3K from &bgr;ARK1 restores &bgr;AR responsiveness in failing myocytes.

A cost-minimisation analysis of lobectomy: thoracoscopic versus posterolateral thoracotomy.

OBJECTIVE Recent evidence suggests that lobectomy performed either through thoracoscopy (TL) or via a posterolateral thoracotomy (PLT) produces equivalent oncologic outcomes in appropriately selected patients. Advantages of thoracoscopic lobectomy include decreased postoperative pain, shorter length of stay, fewer postoperative complications and better compliance with adjuvant chemotherapy. This study evaluates the costs associated with lobectomy performed thoracoscopically or via thoracotomy. METHODS This is a retrospective analysis of actual costing and prospectively collected health-related quality of life (QOL) outcomes. Between 2002 and 2004, 113 patients underwent lobectomy (PLT: n=37; TL: n=76) and completed QOL assessments both preoperatively and 1-year postoperatively. Actual fixed and variable direct costs from the preoperative, hospitalisation and 30-day postoperative phases were captured using a T1 cost accounting system and were combined with actual professional collections. Cost-utility analysis was performed by transforming a global QOL measurement to an estimate of utility and calculating a quality-adjusted life year (QALY) for each patient. RESULTS Baseline characteristics were similar in the two groups. Total costs (USD) were significantly greater for the strategy of PLT (USD 12,119) than for TL (USD 10,084; p=0.0012). Even when only stage I and II lung cancers were included (n=32 PLT, n=69 TL), total costs for PLT were still higher than that for TL (USD 11,998 vs USD 10,120; p=0.005). The mean QALY for the PLT group was 0.74+/-0.22 and for the TL group was 0.72+/-0.18 (p=0.68). CONCLUSIONS In this retrospective analysis, TL was significantly less expensive than PLT from the preoperative evaluation through 30 days postoperatively, with overall savings of approximately USD 2000 per patient. In light of equivalent QALY outcomes, this cost-utility analysis supports increased adoption of TL as a cost-minimisation strategy. The use of TL for the 50,000 lobectomies performed in the United States each year would represent a savings of approximately USD 100 million.

Impact of T status and N status on perioperative outcomes after thoracoscopic lobectomy for lung cancer

OBJECTIVE We sought to evaluate the effect of tumor size, location, and clinical nodal status on outcomes after thoracoscopic lobectomy for lung cancer. METHODS All patients who underwent attempted thoracoscopic lobectomy for lung cancer between June 1999 and October 2010 at a single institution were reviewed. A model for morbidity including published risk factors as well as tumor size, location, and clinical N status was developed by multivariable logistic regression. RESULTS During the study period, 916 thoracoscopic lobectomies met study criteria: 329 for peripheral, clinical N0 tumors ≤ 3 cm and 504 for tumors that were central, clinical node positive, or >3 cm. Tumor location could not be documented for 83 patients. Conversions to thoracotomy occurred in 36 patients (4%); patients with clinically node-positive disease had higher conversion rates (11 conversions in 153 clinical N1 to N3 patients [7.2%] vs 25 in 763 clinical N0 patients [3.3%, P = .03]. Overall operative mortality was 1.6% (14 patients) and morbidity was 32% (296 patients). Although patients with larger tumors (P = .006) and central tumors (P = .01) had increased complications by univariate analysis, tumor size >3 cm (P = .17) and central location (P = .5) did not predict significantly overall morbidity in multivariate analysis. Clinical node status did not predict increased complications by univariate or multivariate analysis. Significant predictors of morbidity in multivariable analysis were increasing age, decreasing forced expiratory volume in 1 second, prior chemotherapy, and congestive heart failure. CONCLUSIONS Thoracoscopic lobectomy for lung cancers that are central, clinically node positive, or >3 cm does not confer increased morbidity compared with peripheral, clinical N0 cancers that are <3 cm.

Right ventricular hypertrophy with early dysfunction: A proteomics study in a neonatal model

OBJECTIVE Right ventricular hypertrophy and subsequent dysfunction is common in patients with congenital heart defects, but the molecular mechanisms underlying change from adaptive hypertrophy to dysfunction remain elusive. We used the novel technique of proteomics to characterize protein changes in right ventricular myocardium in a neonatal model of right ventricular hypertrophy and early dysfunction. METHODS Twelve neonatal piglets were equally randomized to pulmonary artery banding (PAB group), or sham operation (thoracotomy without banding). After 4 weeks, right ventricular morphology and function were assessed in vivo using magnetic resonance imaging. Animals were humanely killed. Proteomics of right ventricular myocardium was performed. Purified right ventricular proteins were separated by 2-dimensional difference gel electrophoresis using fluorescent cyanine dyes. After gel imaging, software analysis revealed protein spots differentially expressed between the 2 groups; these spots were excised and identified by mass spectrometry. RESULTS On magnetic resonance imaging, animals with pulmonary artery banding demonstrated significant right ventricular hypertrophy, cavity dilatation, and mild systolic impairment (right ventricular ejection fraction 39.8% +/- 15% vs 56.7% +/- 10% controls; P < .05). Right ventricular free wall mass on harvest confirmed right ventricular hypertrophy. Proteomic analysis revealed 18 proteins that were significantly differentially expressed: 5 structural proteins, 6 metabolic enzymes, 2 stress proteins, and 5 miscellaneous proteins. Expression of calsarcin-1 and vinculin was increased, as were certain metabolic enzymes, although F(1)-ATPase beta-chain and heat shock protein 70 decreased. CONCLUSIONS This is the first study characterizing right ventricular protein changes in a large animal model specifically capturing the change from compensated to maladaptive hypertrophy. These findings can guide future work at elucidating the mechanisms in the pathophysiology of neonatal right ventricular hypertrophy and dysfunction.

Reproducibility of left atrial ablation with high-intensity focused ultrasound energy in a calf model.

OBJECTIVE Achieving transmural tissue ablation might be necessary for successful treatment of atrial fibrillation. The purpose of this study was to evaluate the reproducibility of transmural left atrial ablation using a high-intensity focused ultrasound energy system in a calf model. METHODS Nine heparinized bovines underwent a beating-heart left atrial ablation with a single application of the high-intensity focused ultrasound device. All animals were acutely killed, and the left atrium was fixed in formalin. Protocolized histological sections (5 μm) were obtained throughout each lesion and prepared with Masson trichrome and hematoxylin and eosin staining. Measurements were performed on a total of 359 slides from the 9 lesions. In addition, fresh left atrial tissues from 18 unused human donor hearts that did not meet the criteria for cardiac transplantation were measured at the site where the high-intensity focused ultrasound device is normally applied. RESULTS Calf left atrial thickness ranged between 2.5 and 20.1 mm, with a mean of 9.10 mm. High-intensity focused ultrasound ablation consistently produced a 100% transmural lesion in left atrial thickness up to 6 mm. In addition, a transmural lesion was observed in 91% of tissues that were up to 10 mm thick and in 85% that were up to 15 mm thick. Human left atrial thickness ranged between 1.2 to 6 mm, with a mean of 3.7 mm. CONCLUSIONS Calf left atrial thickness in this study was greater than human left atrial thickness. Human left atrial thickness is generally less than 6 mm, and in this range high-intensity focused ultrasound ablation achieved 100% transmurality. These histological results might correlate with a high success rate of atrial fibrillation ablation by using the high-intensity focused ultrasound system.

Adeno-associated viral vectors based on serotype 3b use components of the fibroblast growth factor receptor signaling complex for efficient transduction.

Adeno-associated virus type 3b (AAV3b) has been largely ignored by gene therapists because of the inability of vectors based on this serotype to transduce target tissues efficiently. Here we describe a phenomenon unique to AAV3b in that vectors based on this serotype mediate enhanced transduction in the presence of heparin. Among the many biological functions attributed to heparin, its interaction with, and ability to regulate, several growth factors (GFs) and growth factor receptors (GFRs) has been well characterized. Using GFR-overexpressing cell lines, soluble GFs and heparins, as well as specific GFR inhibitors, we have demonstrated a requirement for fibroblast growth factor receptor-2 (FGFR2) and FGF1 in the heparin-mediated augmentation of AAV3b vector transduction. In contrast to AAV2, we establish that heparin can be used as an adjunct with AAV3b to further increase transduction in a variety of cells and target tissues, additionally suggesting that AAV3b may be an attractive viral vector for clinical use during procedures in which heparin is used. In summary, AAV3b exhibits FGFR2-dependent, markedly enhanced transduction efficiency in the presence of heparin and FGFs, which could make it a useful vector for gene therapy in a variety of human diseases.