Mitral Valve Replacement With a Third-Generation Porcine Valve: An Italian Multicentered Study.

BACKGROUND: Postoperative outcomes of a third-generation porcine bioprosthesis for mitral valve replacement (MVR) have been poorly addressed. The objective of this study was to perform an independent, retrospective, multicenter study on outcomes of patients undergoing MVR with a Mosaic (Medtronic Inc, Minneapolis, MN) porcine bioprosthesis. METHODS: From 1998 to 2011, 805 patients underwent MVR with a Mosaic porcine valve in 11 cardiac centers. There were 465 female patients (58%), and the overall mean age was 73.5 ± 7 years. Associated procedures included coronary artery bypass grafting (201 patients; 24.9%), aortic valve replacement (152 patients; 18.9%), tricuspid annuloplasty (187 patients; 22.3%), and other cardiac procedures (116 patients; 14.4%). RESULTS: Median follow-up was 44 months (interquartile range, 16 to 63), with a cumulative duration of 2.769 patient-years. Early mortality for isolated elective MVR was 3.8% (12 of 313), and overall early mortality was 7.8% (n = 63). The rate of late mortality was 3.4%/patient-year (95 late deaths). At 10 years, overall survival was 57.4% (95% confidence interval [CI], 48.8% to 67.5%), and cumulative rates of cardiac- and valve-related death were 7.4% (95% CI, 4.8% to 10.1%) and 1.1% (95% CI, 0.2% to 1.9%), respectively. The 10-year cumulative rates of thromboembolic and hemorrhagic events were 6.6% (95% CI, 1.4% to 11.8%) and 3.9% (95% CI, 0.1% to 8%), respectively, and the 10-year cumulative incidence of prosthetic valve endocarditis was 3% (95% CI, 1.2% to 4.9%). Finally, the 10-year cumulative incidences of structural valve degeneration and reoperations were 5.8% (95% CI, 0.2% to 11.5%) and 4.8% (95% CI, 0.7% to 10.3%), respectively. CONCLUSIONS: This independent, multicenter, retrospective study indicated that the Mosaic porcine bioprosthesis for MVR provides satisfactory results in terms of both early and long-term outcomes up to 14 years from its implantation.

Matrix Metalloproteinase-9 Expression in Calcified Human Aortic Valves: A Histopathologic, Immunohistochemical, and Ultrastructural Study.

The hallmarks of calcific aortic valve disease (CAVD) are the significant quantitative and qualitative changes that occur in the extracellular matrix (ECM), which ultimately lead to increased leaflet stiffness and obstruction of left ventricular outflow. Mounting evidence suggests that ECM remodeling not only contribute to valve cell dysfunction but also alter certain cell signaling pathways responsible for the initiation and progression of the disease state. Matrix metalloproteinases (MMPs), collectively called matrixins, are a family of enzymes known to participate in numerous ECM remodeling events during embryonic development and in disease. The aim of the present study was to evaluate whether changes in MMP-9 expression might be involved in the pathophysiology of CAVD. For this purpose, we have analyzed a total of 19 pathologic valves from patients who underwent aortic valve replacement for calcific aortic stenosis. Microscopically, the cusp tissue showed diffuse fibrosis, neovascularization, and abnormal ECM remodeling with collagen disorganization and mineralization. Western blot and immunohistochemical analyses have been performed on both the areas overlying and remote from the mineral deposits. Protein expression data evidenced a significant upregulation of MMP-9 in the calcified lesion area. Consistent with these observations, immunohistochemistry demonstrated that MMP-9 protein was almost exclusively localized near or around the mineralized nodules, whereas was generally quite weak or absent in areas devoid of any calcification. Our data suggest that MMP-9 may play a key role in CAVD probably by promoting the fibrotic and procalcific remodeling of the ECM.

HIF-1α and VEGF: Immunohistochemical Profile and Possible Function in Human Aortic Valve Stenosis.

Calcific aortic stenosis (CAS) is the most common valvular disease in Western countries. Histological findings in patients with CAS extremely resemble those of atherosclerosis and include accumulation and modification of lipoproteins, inflammation, extracellular matrix remodeling, and calcification. Angiogenesis is another prominent feature of CAS; however, there is only a limited amount of data available regarding the mechanisms behind the pathological neovascularization of a structure that is originally avascular. The present study aims to identify the molecular basis that regulates blood vessel growth in stenotic aortic valves, focusing on the role of HIF-1α and VEGF pathway. A total of 19 native degenerating aortic valves obtained at valve replacement surgery have been processed for Western blot, immunohistochemical, morphometric, and ultrastructural analyses. First, we have demonstrated the adverse ECM remodeling and the significant thickening of the leaflet also showing that HIF-1α and VEGF are significantly upregulated in the stenotic valves, are locally produced and colocalize with angiogenesis and areas of calcification. Next, we have characterized, for the first time to the best of our knowledge, the morphological features of the neovasculature evidencing the presence of intact blood vessels in close proximity to the mineralized zones. These results suggest that the complex structural remodeling of the matrix might reduce oxygen availability in the valve cusp contributing to the stabilization of HIF-1α that in turn induces a metabolic adaptation through the upregulation of VEGF and the formation of new blood vessels not only to overcome the hypoxic state but also to sustain the calcification process.

Telemedicine-guided, very low-dose international normalized ratio self-control in patients with mechanical heart valve implants.

AIM: To study in patients performing international normalized ratio (INR) self-control the efficacy and safety of an INR target range of 1.6-2.1 for aortic valve replacement (AVR) and 2.0-2.5 for mitral valve replacement (MVR) or double valve replacement (DVR). METHODS AND RESULTS: In total, 1304 patients undergoing AVR, 189 undergoing MVR and 78 undergoing DVR were randomly assigned to low-dose INR self-control (LOW group) (INR target range, AVR: 1.8-2.8; MVR/DVR: 2.5-3.5) or very low-dose INR self-control once a week (VLO group) and twice a week (VLT group) (INR target range, AVR: 1.6-2.1; MVR/DVR: 2.0-2.5), with electronically guided transfer of INR values. We compared grade III complications (major bleeding and thrombotic events; primary end-points) and overall mortality (secondary end-point) across the three treatment groups. FINDINGS: Two-year freedom from bleedings in the LOW, VLO, and VLT groups was 96.3, 98.6, and 99.1%, respectively (P = 0.008). The corresponding values for thrombotic events were 99.0, 99.8, and 98.9%, respectively (P = 0.258). The risk-adjusted composite of grade III complications was in the per-protocol population (reference: LOW-dose group) as follows: hazard ratio = 0.307 (95% CI: 0.102-0.926; P = 0.036) for the VLO group and = 0.241 (95% CI: 0.070-0.836; P = 0.025) for the VLT group. The corresponding values of 2-year mortality were = 1.685 (95% CI: 0.473-5.996; P = 0.421) for the VLO group and = 4.70 (95% CI: 1.62-13.60; P = 0.004) for the VLT group. CONCLUSION: Telemedicine-guided very low-dose INR self-control is comparable with low-dose INR in thrombotic risk, and is superior in bleeding risk. Weekly testing is sufficient. Given the small number of MVR and DVR patients, results are only valid for AVR patients.

Internal mammary artery atherosclerosis: an ultrastructural study of two cases.

Atherosclerosis of the internal mammary artery (IMA) is generally regarded as a rare (but existent) pathological entity with only a few cases reported in the most recent literature. The only study which to our knowledge has investigated the ultrastructural features of IMA atherosclerosis, demonstrate the presence of endothelial cells loss, defects of internal elastic lamina with no evidence of lipid accumulation. In the present study, we describe two cases of IMA atherosclerosis in which ultrastructural analysis revealed the presence of a typical atherosclerotic plaque morphology with infiltration of inflammatory cells, formation of intraplaque lipid pools, and accumulation of lipid-laden foam cells throughout the thickened intima, never described in this rare lesion before. Microscopically, the lesions were also characterized by intimal thickening, invagination of endothelial cells, migration of smooth muscle cells with splitting, fenestration and/or fragmentation of the elastic sheets. Our observations add new data to the scarce and contradictory literature and to this largely understudied vascular disorder.

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.

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.

Long-term mortality prediction after operations for type A ascending aortic dissection.

BACKGROUND: There are few long-term mortality prediction studies after acute aortic dissection (AAD) Type A and none were performed using new models such as neural networks (NN) or support vector machines (SVM) which may show a higher discriminatory potency than standard multivariable models. METHODS: We used 32 risk factors identified by Literature search and previously assessed in short-term outcome investigations. Models were trained (50%) and validated (50%) on 2 random samples from a consecutive 235-patient cohort. NN were run only on patients with complete data for all included variables (N = 211); SVM on the overall group. Discrimination was assessed by receiver operating characteristic area under the curve (AUC) and Gini's coefficients along with classification performance. RESULTS: There were 84 deaths (36%) occurring at 564 +/- 48 days (95%CI from 470 to 658 days). Patients with complete variables had a slightly lower death rate (60 of 211, 28%). NN classified 44 of 60 (73%) dead patients and 147 of 151 (97%) long-term survivors using 5 covariates: immediate post-operative chronic renal failure, circulatory arrest time, the type of surgery on ascending aorta plus hemi-arch, extracorporeal circulation time and the presence of Marfan habitus. Global accuracies of training and validation NN were excellent with AUC respectively 0.871 and 0.870 but classification errors were high among patients who died. Training SVM, using a larger number of covariates, showed no false negative or false positive cases among 118 randomly selected patients (error = 0%, AUC 1.0) whereas validation SVM, among 117 patients, provided 5 false negative and 11 false positive cases (error = 22%, AUC 0.821, p < 0.01 versus NN results). An html file was produced to adopt and manipulate the selected parameters for practical predictive purposes. CONCLUSIONS: Both NN and SVM accurately selected a few operative and immediate post-operative factors and the Marfan habitus as long-term mortality predictors in AAD Type A. Although these factors were not new per se, their combination may be used in practice to index death risk post-operatively with good accuracy.

Artificial neural networks versus multiple logistic regression to predict 30-day mortality after operations for type a ascending aortic dissection.

BACKGROUND: There are few comparative reports on the overall accuracy of neural networks (NN), assessed only versus multiple logistic regression (LR), to predict events in cardiovascular surgery studies and none has been performed among acute aortic dissection (AAD) Type A patients. OBJECTIVES: We aimed at investigating the predictive potential of 30-day mortality by a large series of risk factors in AAD Type A patients comparing the overall performance of NN versus LR. METHODS: We investigated 121 plus 87 AAD Type A patients consecutively operated during 7 years in two Centres. Forced and stepwise NN and LR solutions were obtained and compared, using receiver operating characteristic area under the curve (AUC) and their 95% confidence intervals (CI) and Gini's coefficients. Both NN and LR models were re-applied to data from the second Centre to adhere to a methodological imperative with NN. RESULTS: Forced LR solutions provided AUC 87.9±4.1% (CI: 80.7 to 93.2%) and 85.7±5.2% (CI: 78.5 to 91.1%) in the first and second Centre, respectively. Stepwise NN solution of the first Centre had AUC 90.5±3.7% (CI: 83.8 to 95.1%). The Gini's coefficients for LR and NN stepwise solutions of the first Centre were 0.712 and 0.816, respectively. When the LR and NN stepwise solutions were re-applied to the second Centre data, Gini's coefficients were, respectively, 0.761 and 0.850. Few predictors were selected in common by LR and NN models: the presence of pre-operative shock, intubation and neurological symptoms, immediate post-operative presence of dialysis in continuous and the quantity of post-operative bleeding in the first 24 h. The length of extracorporeal circulation, post-operative chronic renal failure and the year of surgery were specifically detected by NN. CONCLUSIONS: Different from the International Registry of AAD, operative and immediate post-operative factors were seen as potential predictors of short-term mortality. We report a higher overall predictive accuracy with NN than with LR. However, the list of potential risk factors to predict 30-day mortality after AAD Type A by NN model is not enlarged significantly.

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.

Comparative application of multivariate models developed in Italy and Europe to predict early (28 days) and late (1 year) postoperative death after on- or off-pump coronary artery bypass grafting.

OBJECTIVES: The aim of this study was to compare the risk of death predictive performances of the OP-RISK, EuroSCORE, and Italian coronary artery bypass grafting (CABG) Outcome studies' functions when applied to a southern Italian cardiac surgery center (Sant'Anna hospital in Catanzaro [SAHCZ]), which contributed data to the Italian CABG Outcome study, and to see if this predictive index may be applied to on- and off-pump interventions. METHODS: The OP-RISK study data set was used to derive Weibull and logistic functions to predict early (28 days) and late (1 year) death rates following CABG based on ejection fraction, heart rate, age, and aortic cross-clamping time. Then the data of 385 CABG patients who underwent operations in 2003 in SAHCZ were collected with 1-year follow-up data, which also included data used to obtain EuroSCORE and Italian CABG Outcome study risk indices. RESULTS: Short- and long-term observed mortality rates after CABG were 2.59% and 5.88% in the SAHCZ series, largely dependent on whether CABG was alone (1.26% and 3.55%) or associated with ventriculoplasty (4.87% and 10.81%) or valve surgery (15.38% and 28.57%). There was a significant increasing trend (P = .002) of observed death rates in equinumeric tertiles of either OP-RISK (both Weibull and logistic) or EuroSCORE in the short term, whereas the trend was not significant for the Italian CABG Outcome study index. OP-RISK functions were significantly predictive for the long term (P < .005), as well as when only ejection fraction, heart rate, and age were considered (P < .011). CONCLUSIONS: It is essential to use clinical data following CABG when outcome prediction is concerned. OP-RISK and EuroSCORE indices are equally predictive in our experience, and a statistically significant (P = 0.02) difference was observed with the Italian CABG Outcome study index, whose trend in tertiles of calculated risk was not apparent, which is unexpected and unexplained. OP-RISK functions were adequate for long-term prediction. Since aortic cross-clamping time may be absent from tested predictive functions (for both short and long term), off-pump CABG mortality may also be predicted as similar to on-pump intervention mortality.

Indexed effective orifice area after mechanical aortic valve replacement does not affect left ventricular mass regression in elderly.

OBJECTIVE: After aortic valve replacement, the effects of a small functional prosthesis on the extent and pattern of regression of left ventricular hypertrophy and on clinical outcomes may be less significant in older patients with low cardiac output requirements. The objective of this study was therefore to determine whether patient-prosthesis mismatch affects left ventricular mass regression in the elderly. METHODS: The population studied was made up of 88 patients over 65 years of age with pure aortic stenosis who underwent mechanical aortic valve replacement. The effective orifice area index was calculated for each patient on the basis of the projected prosthesis in vivo effective orifice area. It was considered a continuous variable and influence of its entire range of values on the extent of left ventricular mass regression was analyzed in a multivariate prediction model. RESULTS: Even though, in the group with prosthesis-patient mismatch there was a trend for lower postoperative left ventricular mass index (115+/-24 g/m(2) vs 102+/-27 g/m(2), p=0.24) and postoperative peak trans-prosthetic gradients (32+/-9.8 mmHg vs 28.9+/-7.79 mmHg, p=0.35) these differences were not statistically significant. The prevalence of residual left ventricular hypertrophy at follow-up was 50% in the group with patient-prosthesis mismatch and 50% in the group without patient-prosthesis mismatch (p=0.83). In multivariate analysis the only factors associated with indexed left ventricular mass were the follow-up time (p=0.015, r(2)=0.22) and preoperative indexed left ventricular mass (p=0.0012, r(2)=0.11). CONCLUSIONS: The major finding of our study is that patient-prosthesis mismatch does not affect left ventricular mass regression in patients older than 65 with pure aortic stenosis who underwent mechanical aortic valve replacement. In older patients with low cardiac output requirements, even a small change in the valve effective orifice area after aortic valve replacement with modern efficient mechanical prosthesis, will result in a marked reduction of pressure gradient and this will be associated with a significant regression of left ventricular mass.

Procalcitonin is useful whereas C-reactive protein is not, to predict complications following coronary artery bypass surgery.

BACKGROUND: The respective value of procalcitonin (PCT) and C-reactive protein (CRP) as markers of postoperative complications after coronary bypass surgery is unclear. Therefore, complications during one week after surgery were studied to evaluate the predictive role of PCT and CRP changes during the immediate postoperative period. METHODS: Thirty-two patients, in whom an uneventful immediate postoperative course was anticipated, were prospectively enrolled and followed-up to the 7th postoperative day. At the end of the follow-up, patients were divided into two groups. Group A were patients with an uncomplicated postoperative course and Group B were patients with a complicated postoperative course. RESULTS: Serum samples were drawn for PCT and CRP determination after induction of anesthesia (baseline), at the end of surgery and daily until postoperative day 2. Baseline serum PCT concentrations were 0.11 +/- 0.09 and 0.20 +/- 0.21 ng/mL in Groups A and B, respectively (NS). Serum PCT concentration increased compared with baseline in both groups during the first two days after surgery. The increase in serum PCT concentration was significantly greater in Group B than A patients (p < 0.0002). Considering a perioperative abnormal cut-off value of >0.5 ng/mL, there were none in Group A versus 57% in Group B (p < 0.0001). Baseline serum CRP concentrations were 1.44 +/- 1.30 and 1.58 +/- 1.35 ng/mL in Groups A and B, respectively (NS). After surgery, CRP increased significantly compared with baseline in both groups. When changes in time-varying variables were included in a logistic model, complications were predicted by changes (between baseline and end of surgery values) of PCT (coefficient = 9.410; t = 2.18) and heart rate (coefficient = 0.075; t = 1.57), whereas changes of CRP, white blood cells, mean blood and central venous pressures did not contribute statistically. The model constant was -4.827 (t = -2.43) and the ROC curve area was 0.8971. Thus, absolute PCT changes of 0.20, 0.40 and 0.60 ng/mL carry an approximate risk of 5, 26 and 69%, respectively, of postoperative complications in the time frame of this study. CONCLUSIONS: A postoperative serum PCT concentration of >0.5 ng/mL is highly suggestive of a postoperative complication. CRP changes do not contribute to predictive information.