Mauro Cassese

Clinical and hemodynamic outcomes of ''all-comers'' undergoing transapical aortic valve implantation: Results from the Italian Registry of Trans-Apical Aortic Valve Implantation (I-TA)

OBJECTIVE The aim of this study was to assess clinical and hemodynamic outcomes of transapical aortic valve implantation (TA-TAVI) in patients enrolled in the Italian Registry of Trans-Apical Aortic Valve Implantation (I-TA). METHODS From April 2008 until November 2010, 504 patients from 20 Italian centers were enrolled in the I-TA registry. Mean logistic EuroSCORE and Society of Thoracic Surgeons score were 24% ± 16% and 11% ± 4%, respectively. Mean follow-up was 9.2 ± 6.5 months (range, 1-26 months). Outcomes were analyzed according to intraoperative complications, procedural volume (high-volume centers, >20 cases; low-volume centers, < 20 cases) and learning curve (first 50% cases vs second 50% cases of each center). RESULTS All-cause overall mortality was 8.3% (42 patients). Device success was 99% (500/504 patients). Intraoperative severe complications occurred in 24 (4.8%) patients. Overall 2-year survival was 71.5% ± 6.2%. At discharge, peak and mean gradients were 16.4 ± 11.2 and 8.7 ± 4.1 mm Hg, respectively, and effective orifice area was 1.67 cm(2). These values remained stable at 3, 6, and 12 months after surgery. Independent risk factors for mortality after TA-TAVI were as follows: New York Heart Association class III and IV (odds ratio [OR], 4.43; 95% confidence intervals [CI], 1.28-15.40; P = .02); logistic EuroSCORE greater than 20 (OR, 1.83; 95% CI, 1.02-3.29; P = .04); creatinine concentration greater than 200 μmol/L (OR, 2.56; 95% CI, 1.07-6.15; P = .03), and intraoperative complications (OR, 5.80; 95% CI, 2.68-12.55; P < .001). There were no significant differences in outcomes between high- and low-volume centers and between the first and the second 50% of cases. CONCLUSIONS TA-TAVI represents a safe and effective alternative treatment for patients who are inoperable or at high risk for surgery. The occurrence of an intraoperative complication significantly affects survival. Procedural volume and learning curve have no impact on patient survival.

Medium Term Outcomes of Transapical Aortic Valve Implantation: Results From the Italian Registry of Trans-Apical Aortic Valve Implantation

BACKGROUND Transcatheter aortic valve implantation (TAVI) has been proposed as a therapeutic option for high-risk or inoperable patients with severe symptomatic aortic valve stenosis. The aim of this multicenter study was to assess early and medium term outcomes of transapical aortic valve implantation (TA-TAVI). METHODS From April 2008 through June 2012, a total of 774 patients were enrolled in the Italian Registry of Trans-Apical Aortic Valve Implantation (I-TA). Twenty-one centers were included in the I-TA registry. Outcomes were also analyzed according to the impact of the learning curve (first 50% cases versus second 50% cases of each center) and of the procedural volume (high-volume versus low-volume centers). RESULTS Mean age was 81.0±6.7 years, mean logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) I, EuroSCORE II, and The Society of Thoracic Surgeons risk score were 25.6%±16.3%, 9.4%±11.0%, and 10.6%±8.5%, respectively. Median follow-up was 12 months (range, 1 to 44). Thirty-day mortality was 9.9% (77 patients). Overall 1-, 2-, and 3-year survival was 81.7%±1.5%, 76.1%±1.9%, and 67.6%±3.2%, respectively. Thirty-day mortality of the first 50% patients of each center was higher when compared with the second half (p=0.04) but 3-year survival was not different (p=0.64). Conversely, 30-day mortality at low-volume centers versus high-volume centers was similar (p=0.22). At discharge, peak and mean transprosthetic gradients were 21.0±10.3 mm Hg and 10.2±4.1 mm Hg, respectively. These values remained stable 12 and 24 months after surgery. CONCLUSIONS Transapical TAVI provides good results in terms of early and midterm clinical and hemodynamic outcomes. Thus it appears to be a safe and effective alternative treatment for patients who are inoperable or have high surgical risk.

Risk stratification for in-hospital mortality after cardiac surgery: external validation of EuroSCORE II in a prospective regional registry

OBJECTIVES To evaluate performance of the European System for Cardiac Operation Risk Evaluation (EuroSCORE II), to assess the influence of model updating and to derive a hierarchical tree for modelling the relationship between EuroSCORE II risk factors and hospital mortality after cardiac surgery in a large prospective contemporary cohort of consecutive adult patients. METHODS Data on consecutive patients, who underwent on-pump cardiac surgery or off-pump coronary artery bypass graft intervention, were retrieved from Puglia Adult Cardiac Surgery Registry. Discrimination, calibration, re-estimation of EuroSCORE II coefficients and hierarchical tree analysis of risk factors were assessed. RESULTS Out 6293 procedures, 6191 (98.4%) had complete data for EuroSCORE II assessment with a hospital mortality rate of 4.85% and EuroSCORE II of 4.40 ± 7.04%. The area under the receiver operator characteristic curve (0.830) showed good discriminative ability of EuroSCORE II in distinguishing patients who died and those who survived. Calibration of EuroSCORE II was preserved with lower predicted than observed risk in the highest EuroSCORE II deciles. At logistic regression analysis, the complete revision of the model had most of re-estimated regression coefficients not statistically different from those in the original EuroSCORE II model. When missing values were replaced with the mean EuroSCORE II value according to urgency and weight of intervention, the risk score confirmed discrimination and calibration obtained over the entire sample. A recursive tree-building algorithm of EuroSCORE II variables identified three large groups (55.1, 17.1 and 18.1% of procedures) with low-to-moderate risk (observed mortality of 1.5, 3.2 and 6.4%) and two groups (3.8 and 5.9% of procedures) at high risk (mortality of 14.6 and 32.2%). Patients with low-to-moderate risk had good agreement between observed events and predicted frequencies by EuroSCORE II, whereas those at greater risk showed an underestimation of expected mortality. CONCLUSIONS This study demonstrates that EuroSCORE II is a good predictor of hospital mortality after cardiac surgery in an external validation cohort of contemporary patients from a multicentre prospective regional registry. The EuroSCORE II predicts hospital mortality with a slight underestimation in high-risk patients that should be further and better evaluated. The EuroSCORE II variables as a risk tree provides clinicians and surgeons a practical bedside tool for mortality risk stratification of patients at low, intermediate and high risk for hospital mortality after cardiac surgery.

iNOS induction and PARP-1 activation in human atherosclerotic lesions: an immunohistochemical and ultrastructural approach.

BACKGROUND Several lines of clinical and experimental evidence have demonstrated that reactive oxygen species and nitrogen species are generated in unregulated amounts during diverse cardiovascular disorders. It has been previously reported by our group and others that augmented expression of nitric oxide synthase isoforms is associated with human atherogenesis and that the activity of the enzymes in an atherosclerotic environment may promote the formation of peroxynitrite. Among the downstream mechanisms triggered by oxidants, poly(ADP-ribose) polymerase-1 activation has recently been implicated in the pathogenesis of acute and chronic myocardial dysfunction, diabetes, hypertension, aging, and various forms of shock. METHODS Based on these observations, we performed immunohistochemical and immunogold labeling analyses to evaluate the expression profile and the subcellular localization of inducible nitric oxide synthase and poly(ADP-ribose) polymerase-1 in healthy and atherosclerotic human aortae. RESULTS We have demonstrated that inducible nitric oxide synthase colocalizes with poly(ADP-ribose) polymerase-1 within vascular cells of atherosclerotic human aortae. We have reported for the first time, to our knowledge, the ultrastructural localization of poly(ADP-ribose) polymerase-1 within the nuclei of lesional smooth muscle cells. Finally, we have evidenced that poly(ADP-ribose) polymerase-1 induction within cells of the diseased aorta strongly correlates with alterations in mitochondrial morphology. CONCLUSIONS Our data imply the possibility of a significant role for cross-talk between inducible nitric oxide synthase and poly(ADP-ribose) polymerase-1 in human atherosclerotic lesions. We conclude that the prooxidant milieu of the plaque might exert damaging effects on mitochondria via a poly(ADP-ribose) polymerase-1-mediated mechanism since the absence of the enzyme results in a corresponding lack of changes in mitochondrial morphology. The present report may open avenues for further researches that could have important therapeutic consequences for the treatment of atherosclerosis and its clinical sequelae.

Incremental Value of Anemia in Cardiac Surgical Risk Prediction With the European System for Cardiac Operative Risk Evaluation (EuroSCORE) II Model

BACKGROUND Anemia is a risk factor for adverse events after cardiac operations. We evaluated the incremental value of preoperative anemia over the European System for Cardiac Operative Risk Evaluation (EuroSCORE) II to predict hospital death after cardiac operations. METHODS Data for 4,594 consecutive adults (1,548 women [33.7%]), aged 67 ± 11 years, who underwent cardiac operations from January 2011 to July 2013 were extracted from the Regional Cardiac Surgery Registry of Puglia. The last preoperative hemoglobin value was used, according to World Health Organization criteria, to classify anemia as mild (hemoglobin 11.0 to 12.9 g/dL in men and 11.0 to 11.9 g/dL in women) in 1,021 patients (22.2%) and as moderate to severe (hemoglobin <11.0 g/dL) in 593 patients (12.9%). The EuroSCORE II was used to evaluate predicted hospital death after operations. Logistic regression analysis for in-hospital death was performed including EuroSCORE II risk factors and anemia, with model discrimination quantified by C statistic and risk classification by the use of net reclassification improvement (NRI). RESULTS Overall expected and observed mortality rates were 4.4% and 5.9%. Anemia was significantly associated with a mortality rate of 3.4% in patients without anemia, 7.7% in mild anemia, and 15.7% in moderate to severe anemia (p < 0.001) and also at multivariate analysis correcting for EuroSCORE II (p < 0.001). When anemia was analyzed with EuroSCORE II, the model improved in discrimination (C statistic = 0.852 vs 0.860; p = 0.007) and reclassification (category free-NRI, 0.592; p < 0.001), preserving the calibration with good concordance between predicted probabilities and outcome. CONCLUSIONS Preoperative anemia has strong association with operative death in cardiac surgical patients. Anemia provides significant incremental value over the EuroSCORE II and should be considered for assessment of cardiac surgical risk.

Inducible and endothelial nitric oxide synthase expression in human atherogenesis: an immunohistochemical and ultrastructural study

BACKGROUND Nitric oxide has been proven to play an important role in the maintenance of vascular tone and structure. Impairment of nitric oxide production is an early indicator of atherosclerosis, but not much is known about the real mechanisms underlying this phenomenon. METHODS In the present study, immunocytochemical methods have been used to analyze the patterns of expression of endothelial nitric oxide synthase and inducible nitric oxide synthase proteins in healthy and atherosclerotic human aortae using both confocal laser scanning microscopy and electron microscopy. RESULTS Induction of the expression of endothelial nitric oxide synthase and inducible nitric oxide synthase proteins was observed in smooth muscle cells of atherosclerotic human aortae. Altered nitric oxide synthase expression was reported in atheromatous plaques and in apparently normal vascular tissues adjacent to the lesions. CONCLUSIONS Our data confirm and extend previous findings of a direct relationship between dysregulation of nitric oxide pathway and atherosclerosis, suggesting another possible mechanism by which nitric oxide synthase system abnormalities may promote vascular dysfunction during human atherogenesis. Changes in nitric oxide production might be the primary step in the development of atheroma.

When does transapical aortic valve replacement become a futile procedure? An analysis from a national registry

OBJECTIVES Patient selection is crucial to achieve good outcomes and to avoid futile procedures in patients undergoing transcatheter aortic valve replacement. The aim of this multicenter retrospective study was to identify independent predictors of 1-year mortality in patients surviving after transapical transcatheter aortic valve replacement. METHODS We analyzed data from the Italian registry of transapical transcatheter aortic valve replacement that includes patients undergoing operation in 21 centers from 2007 to 2012. Futility was defined as mortality within 1 year after transapical transcatheter aortic valve replacement in patients surviving at 30 days. Thirty-day survivors were divided in 2 groups: futility (group F) and nonfutility (group NF). Cox proportional hazard regression analysis was performed to identify independent predictors of futility. RESULTS We analyzed data from 645 patients with survival of 30 days or more after transapical transcatheter aortic valve replacement. Groups F and NF included 60 patients (10.8%) and 585 patients (89.2%), respectively. Patients in group F were more likely to have insulin-dependent diabetes (15% vs 7.2%, P = .03), creatinine 2.0 mg/dL or greater or dialysis (18.3% vs 8.2%, P = .01), logistic European System for Cardiac Operative Risk Evaluation greater than 20% (66.7% vs 50.3%, P = .02), preoperative rhythm disorders (40% vs 25.3%, P = .03), critical preoperative state (8.3% vs 1.8%, P = .002), and left ventricular ejection fraction less than 30% (15% vs 2.9%, P < .001). The multivariate analysis identified the following as independent predictors of futility: insulin-dependent diabetes (odds ratio, 3.1; P = .003), creatinine 2.0 mg/dL or greater or dialysis (odds ratio, 2.52; P = .012), preoperative rhythm disorders (odds ratio, 1.88; P = .04), and left ventricular ejection fraction less than 30% (odds ratio, 4.34; P = .001). CONCLUSIONS According to our data, among patients undergoing transapical transcatheter aortic valve replacement, those with insulin-dependent diabetes, advanced chronic kidney disease, rhythm disorders, and low left ventricular ejection fraction have a higher risk to undergo futile procedures.

MnSOD expression in human atherosclerotic plaques: an immunohistochemical and ultrastructural study

BACKGROUND Over the last decades, the role of oxidative stress in atherosclerosis has become well established, and considerable effort has been made to understand the mechanism of action of free radicals within the cardiovascular system. Conversely, relatively little attention has been directed towards the characterization of the antioxidant status of the arterial wall under disease state. Among the antioxidant enzymes, the manganese-dependent and mitochondria-specific isoform of SOD (MnSOD) represents the first line of defense against superoxide radicals attack. To date, the pathological significance of MnSOD in atherosclerosis is still unclear with conflicting data published. METHODS In the present study, we used immunohistochemical techniques at the light and electron microscopy level in combination with biochemical assays to localize and characterize the activity and expression profiles of MnSOD in healthy and atherosclerotic human aorta. RESULTS MnSOD has been found to be highly expressed in the atherosclerotic plaques where specifically localized to the foam cells of the lipid-rich regions but not to other (nonfoamy) cell types. No ultrastructural evidence of apoptosis, such as chromatin condensation and membrane blebbing, has been observed in MnSOD-expressing cells. The up-regulation of MnSOD at the protein level has been associated with a parallel, significant increase of its catalytic activity. CONCLUSIONS Our data demonstrate that MnSOD is not negatively regulated by the prooxidative and proinflammatory environment of the plaque and evidence a regional and cellular selectivity of MnSOD protein expression under disease state. We suggest that MnSOD induction might represent a protective response against the cytotoxic effect of oxidized low-density lipoprotein.

Ultrastructural Analysis and Electron Microscopic Localization of Nox4 in Healthy and Atherosclerotic Human Aorta

During diverse pathological conditions, vascular smooth muscle cells (SMCs) characteristically change from a quiescent, contractile phenotype to a proliferative, synthetic state, migrate toward the intima, and synthesize excess extracellular matrix. Although reactive oxygen species (ROS) are generally considered to be toxic to cells, recent evidence suggests that they may also modulate multiple signaling pathways. The vascular system contains several sources of ROS, among which NADPH oxidases (NOXes) have been shown to take an important part in the regulation of cell function, with effects on growth and proliferation. In the present study, the authors investigate the ultrastructural features of SMCs and the expression profile of Nox4 in healthy and atherosclerotic human aorta to explore the possibility of a relationship between Nox4 and SMCs differentiation state. The data extend at the level of immunoelectron microscopy previous observations, demonstrating for the first time the precise distribution and the differential expression of Nox4 in the morphologically distinct SMC types of healthy and diseased human aorta.

Topical cooling for myocardial protection: the results of a prospective randomized study of the "shallow technique".

Abstract  Introduction and Background: Respiratory distress following cardiac surgery is a troublesome complication. In several cases it is associated to cool‐related phrenic nerve injury (PNI) after adoption of iced slush or hypothermic cardiopulmonary bypass. We compare two different strategies for myocardial protection: the “shallow technique” (ST) (dripping and prompt removal of cold saline solution from the epicardial surface) plus normothermic cardiopulmonary bypass, versus mild hypothermic cardiopulmonary bypass plus iced slush. Methods: Two hundred forty‐nine patients undergoing elective cardiac surgery were randomly assigned to receive either ST (Group A) or iced slush (Group B). Occurrence of postoperative PNI (abnormal diaphragmatic movement plus alteration of nerve conduction) was evaluated. Multivariate analysis was performed for identification of factors associated to PNI. Patients had a 6‐month follow‐up. Results: PNI and failure of extubation occurred more frequently in Group B (p = 0.009 and p = 0.034, respectively), but there was no statistically significant difference in mean intensive care unit stay. Diabetes and the use of iced slush were independent predictors of phrenic dysfunction, while internal thoracic artery (ITA) harvest was a significant risk factor only among Group B patients. Abnormal diaphragmatic movement was persistent at 6 months only in 30% of Group B individuals who suffered this complication in the early postoperative. Conclusions: ST likely reduces the incidence of postoperative PNI and might be protective mainly in the event of ITA harvest. It should be considered as a valuable tool for myocardial protection protocols.