Understanding the relationship between apathy, cognition and functional outcome in schizophrenia: The significance of an ecological assessment.

In recent years there has been an increasing interest in understanding the role apathy plays in mediating the relationship between cognitive impairment and functional outcome. In general, most studies measure cognition with traditional cognitive tests that give explicit instructions and guide the participants toward generating a response. However, given that apathy is defined by a decrease in self-initiated behavior, it is crucial to evaluate cognition with ecological tasks that do not explicitly direct the patient´s motivation to generate behaviors to assess the actual effect. This study investigated whether an ecological cognitive assessment (the Jansari Executive Function Assessment, JEF©) would uniquely contribute to the relationship between cognition, apathy, and functional outcome in schizophrenia. The Apathy Evaluation Scale (AES), neuropsychological tests and the JEF© were administered to 20 patients with schizophrenia. Hierarchical multiple regression and mediation analysis were performed to test the associations between the variables of interest. Results showed that JEF© explained a significant portion of the variance in AES (25%). In addition, apathy explained 36% of the variance in functional outcome. However, AES did not mediate between cognition and functional outcome. Our results highlight the importance of assessing cognition with tasks that require integration of cognitive functions needed for real life demands.

Giant Distal Anastomotic Pseudoaneurysm 35 Years after Bentall Operation Mimicking an "Elephant Trunk".

We present the case of a giant distal aortic pseudoaneurysm 35 years after a classic mechanical Bentall operation. Computed tomography and coronary angiography showed that this originated from the distal suture line. The proximal suture and coronary ostia appeared to be intact. At reoperation, we found a complete dehiscence of distal suture line: the graft was floating in the pseudoaneurysm, mimicking an "elephant trunk" procedure. This complication suggested a systematic and accurate follow-up of patients who underwent an original Bentall procedure.

[The completion Bentall procedure: aortic root and ascending aorta replacement after prior aortic valve replacement]. / "Completion Bentall": sostituzione della radice e dell'aorta ascendente in un paziente già portatore di protesi valvolare aortica.

We describe the case of a patient with an ascending aorta and aortic root aneurysm who underwent aortic valve replacement, 14 years earlier, with a mechanical prosthesis, which was normally functioning at time of reoperation. We describe the "completion Bentall" technique - a modified Bentall technique -, a procedure for prosthesis-sparing aortic root replacement. This technique simplifies the original procedure in reinterventions, reducing complication rates and aortic cross-clamping and cardiopulmonary bypass times, with a good surgical result.

Confocal Blood Flow Videomicroscopy of Thrombus Formation over Human Arteries and Local Targeting of P2X7.

Atherothrombosis exposes vascular components to blood. Currently, new antithrombotic therapies are emerging. Herein we investigated thrombogenesis of human arteries with/without atherosclerosis, and the interaction of coagulation and vascular components, we and explored the anti-thrombogenic efficacy of blockade of the P2X purinoceptor 7 (P2X7). A confocal blood flow videomicroscopy system was performed on cryosections of internal mammary artery (IMA) or carotid plaque (CPL) determining/localizing platelets and fibrin. Blood from healthy donors elicited thrombi over arterial layers. Confocal microscopy associated thrombus with tissue presence of collagen type I, laminin, fibrin(ogen) and tissue factor (TF). The addition of antibodies blocking TF (aTF) or factor XI (aFXI) to blood significantly reduced fibrin deposition, variable platelet aggregation and aTF + aFXI almost abolished thrombus formation, showing synergy between coagulation pathways. A scarce effect of aTF over sub-endothelial regions, more abundant in tissue TF and bundles of laminin and collagen type I than deep intima, may suggest tissue thrombogenicity as molecular structure-related. Consistently with TF-related vascular function and expression of P2X7, the sections from CPL but not IMA tissue cultures pre-treated with the P2X7 antagonist A740003 demonstrated poor thrombogenesis in flow experiments. These data hint to local targeting studies on P2X7 modulation for atherothrombosis prevention/therapy.

Clinicopathological Bird's-Eye View of Left Atrial Myocardial Fibrosis in 121 Patients With Persistent Atrial Fibrillation: Developing Architecture and Main Cellular Players.

BACKGROUND: Scientific research on atrial fibrosis in atrial fibrillation (AF) has mainly focused on quantitative or molecular features. The purpose of this study was to perform a clinicoarchitectural/structural investigation of fibrosis to provide one key to understanding the electrophysiological/clinical aspects of AF. METHODS: We characterized the fibrosis (amount, architecture, cellular components, and ultrastructure) in left atrial biopsies from 121 patients with persistent/long-lasting persistent AF (group 1; 59 males; 60±11 years; 91 mitral disease-related AF, 30 nonmitral disease-related AF) and from 39 patients in sinus rhythm with mitral valve regurgitation (group 2; 32 males; 59±12 years). Ten autopsy hearts served as controls. RESULTS: Qualitatively, the fibrosis exhibited the same characteristics in all cases and displayed particular architectural scenarios (which we arbitrarily subdivided into 4 stages) ranging from isolated foci to confluent sclerotic areas. The percentage of fibrosis was larger and at a more advanced stage in group 1 versus group 2 and, within group 1, in patients with rheumatic disease versus nonrheumatic cases. In patients with AF with mitral disease and no rheumatic disease, the percentage of fibrosis and the fibrosis stages correlated with both left atrial volume index and AF duration. The fibrotic areas mainly consisted of type I collagen with only a minor cellular component (especially fibroblasts/myofibroblasts; average value range 69-150 cells/mm2, depending on the areas in AF biopsies). A few fibrocytes-circulating and bone marrow-derived mesenchymal cells-were also detectable. The fibrosis-entrapped cardiomyocytes showed sarcolemmal damage and connexin 43 redistribution/internalization. CONCLUSIONS: Atrial fibrosis is an evolving and inhomogeneous histological/architectural change that progresses through different stages ranging from isolated foci to confluent sclerotic zones which-seemingly-constrain impulse conduction across restricted regions of electrotonically coupled cardiomyocytes. The fibrotic areas mainly consist of type I collagen extracellular matrix and, only to a lesser extent, mesenchymal cells.

Is myocardial revascularization really necessary in patients with ≥50% but <70% coronary stenosis undergoing valvular surgery?

OBJECTIVES: The aim of this study is to evaluate the immediate and mid-term effects of omitting coronary artery bypass grafting in patients with moderate coronary artery stenosis who have a primary indication for valvular surgery. METHODS: We included 77 consecutive patients admitted to our Institution for aortic or mitral valve surgery between June 2012 and June 2017 in whom a de novo diagnosis of ≥50%, but <70% coronary stenosis was made. In this cohort, the myocardial revascularization was omitted. All these patients were free from angina and ischaemia on echo and ECG. RESULTS: There were no in-hospital deaths. In only 1 patient, acute myocardial infarction occurred postoperatively, which was immediately treated by percutaneous coronary intervention (PCI). The 6-year overall survival was 94.7 ± 2.59%. At 6 years, no cardiac deaths were recorded. At follow-up, 4 patients underwent elective PCI after a positive stress myocardial perfusion test. Only 1 patient underwent urgent PCI due to acute coronary syndrome. At 6 years, the cumulative incidence function of PCI, with death as competing risk, was 8 ± 3.9%. CONCLUSIONS: In our experience, moderate coronary stenosis, occasionally discovered at the time of valvular heart surgery, can be safely overlooked and do not need any further treatment at follow-up in the majority of cases. Our results open up the opportunity to apply this 'intentional omission strategy' in different situations, such as minimally invasive heart surgery, percutaneous procedures and complex patients.

IL-1ß/MMP9 activation in primary human vascular smooth muscle-like cells: Exploring the role of TNFα and P2X7.

BACKGROUND: Vascular smooth muscle cells exhibit phenotypic plasticity in response to microenvironmental stimuli and contribute to vascular remodelling through mechanisms only partially understood. In atherosclerosis, P2X-purinoceptor7 (P2X7) has been related to interleukin-1ß (IL-1ß) and metalloproteinase 9 (MMP9). The hypoxia-inducible factor-1alpha (HIF1α) was associated to remodelling. Here the activation of IL-1ß and MMP9 was studied in relationship to P2X7 and HIF1α in cells exploited from human carotid plaque and internal mammary artery. METHODS AND RESULTS: Migrating cells expressed HIF1α-regulated canopy FGF-signalling regulator 2 and CD117, and led to primary cells with SMC-like phenotype (VSMC), P2X7+. We investigated in VSMC the effects of hypoxia, of treatment with tumour necrosis factor-α (TNFα) and/or with P2X7 antagonist, A740003. Quantitative RT-PCR showed that hypoxia unaffected IL-1ß and down-regulated MMP9 mRNAs, without activating HIF1α. TNFα increased IL-1ß mRNA via NLR Family Pyrin Domain-Containing 3, with production of proIL-1ß but no rise of mature IL-1ß. Zymography demonstrated that A740003 triggered MMP9 secretion from VSMC. Combination of A740003 with TNFα abrogated this effect. Combination was ineffective on IL-1ß activation elicited by TNFα, but down-regulated HIF1α mRNA. A740003 induced the intracellular P2X7 aggregation and differently perturbed lysosome and mitochondria network compared to TNFα. CONCLUSIONS: Cells migration from human arteries leads to partially differentiated VSMC analogous to neointimal cells within atherosclerotic lesions. Down-regulated HIF1α in stimulated VSMC translates in resilience in atherosclerotic lesions. P2X7-independent partial activation of IL-1ß elicited by TNFα underlines complexity of the cytokine secretion. Data also supported P2X7 as modulator of MMP9 secretion, important for atherosclerosis progression.

Surgical Techniques for Tricuspid Valve Disease.

Tricuspid valve disease affects millions of patients worldwide. It has always been considered less relevant than the left-side valves of the heart, but this "forgotten valve" still represents a great challenge for the cardiac surgeons, especially in the most difficult symptomatic scenarios. In this review we analyze the wide spectrum of surgical techniques for the treatment of a diseased tricuspid valve.

P2X7 receptor antagonism modulates IL-1ß and MMP9 in human atherosclerotic vessels.

In atherosclerosis, matrix metallopeptidases (MMPs) contribute to plaque rupture through weakening of the fibrous cap. Pleiotropic P2X purinoceptor 7 (P2X7), expressed in the carotid plaque (PL), is involved in interleukin 1 beta (IL-1ß) release that may influence MMP9 generation, thus their possible modulation through acting on P2X7 was investigated. P2X7-related machinery was characterized and the effects of P2X7 antagonists (A740003, KN62) and MMPs inhibitors (Batimastat, Ro28-2653) were studied in ex-vivo tissue cultures of human PL's vs. non-atherosclerotic internal mammary artery (IMA) by using molecular biology, immune-biochemical and microscopy methodologies. We highlighted atherosclerosis-related differences between PLs and IMAs molecular patterns, and their responsivity to P2X7 antagonism. High IL-1ß tissue content was associated with PLs morphology and instability/vulnerability. We demonstrated that A740003, but not KN62, decreased IL-1ß and MMP9 independently from NLR family pyrin domain containing 3, but in relationship with patient's smoking status. Acting downstream P2X7 by MMPs inhibitors, diminished IL-1ß mRNA without transcriptional effect at MMP9, possibly because the assumption of statin by patients. These data firstly demonstrated A740003 suitability as a specific tool to decrease inflammatory status in human vessels and might support the design of studies applying P2X7 antagonists for the local targeting and tailored therapy of atherosclerosis.

Persistent lone atrial fibrillation: clinicopathologic study of 19 cases.

BACKGROUND: The extent to which atrial myocardium is remodeled in patients with persistent lone atrial fibrillation (LAF) is largely unknown. OBJECTIVE: The purpose of this study was to perform a clinicopathologic investigation in patients with persistent LAF. METHODS: We characterized structural and molecular remodeling in atrial biopsies from 19 patients (17 males, mean age 49 years) with persistent (>7 days; n = 8) or long-lasting persistent (>1 year; n = 11) LAF who underwent surgical ablation. Atrial tissue from 15 autopsy samples without clinicopathologic evidence of heart disease served as controls. RESULTS: Morphometric analysis showed cardiomyocyte hypertrophy and greater amounts of myolytic damage and interstitial fibrosis in persistent LAF patients compared to controls (P <.0001). Atrial tissue levels of heme oxygenase-1 and 3-nitrotyrosine were increased in persistent LAF patients (P <.001), consistent with oxidative stress. Levels of superoxide dismutase-2, interleukin-8, interleukin-10, tumor necrosis factor-α, and thiobarbituric acid reactive substance were greater in controls than in persistent LAF patients. Immunoreactive signal for connexin43 was reduced more frequently in persistent LAF patients than controls. There was no correlation between features of structural or molecular remodeling and clinical parameters, including persistent LAF duration. CONCLUSION: In persistent LAF patients, the atria are modified by structural remodeling and molecular changes of oxidative stress. Tissue changes in persistent LAF appear to occur early after its onset and are qualitatively no different than those observed in patients with atrial fibrillation related to conventional risk factors. These findings suggest that different types of atrial fibrillation are associated with the same spectrum of tissue lesions. Early intervention to restore sinus rhythm in persistent LAF patients may prevent irreversible tissue change, especially interstitial fibrosis.

Mitral replacement or repair for functional mitral regurgitation in dilated and ischemic cardiomyopathy: is it really the same?

BACKGROUND: This was a study to compare the results of mitral valve (MV) repair and MV replacement for the treatment of functional mitral regurgitation (MR) in advanced dilated and ischemic cardiomyopathy (DCM). METHODS: One-hundred and thirty-two patients with severe functional MR and systolic dysfunction (mean ejection fraction 0.32 ± 0.078) underwent mitral surgery in the same time frame. The decision to replace rather than repair the MV was taken when 1 or more echocardiographic predictors of repair failure were identified at the preoperative echocardiogram. Eighty-five patients (64.4%) received MV repair and 47 patients (35.6%) received MV replacement. Preoperative characteristics were comparable between the 2 groups. Only ejection fraction was significantly lower in the MV repair group (0.308 ± 0.077 vs 0.336 ± 0.076, p = 0.04). RESULTS: Hospital mortality was 2.3% for MV repair and 12.5% for MV replacement (p = 0.03). Actuarial survival at 2.5 years was 92 ± 3.2% for MV repair and 73 ± 7.9% for MV replacement (p = 0.02). At a mean follow-up of 2.3 years (median, 1.6 years), in the MV repair group LVEF significantly increased (from 0.308 ± 0.077 to 0.382 ± 0.095, p < 0.0001) and LV dimensions significantly decreased (p = 0.0001). On the other hand, in the MV replacement group LVEF did not significantly change (from 0.336 ± 0.076 to 0.31 ± 0.11, p = 0.56) and the reduction of LV dimensions was not significant. Mitral valve replacement was identified as the only predictor of hospital (odds ratio, 6; 95% confidence interval, 1.1 to 31; p = 0.03) and overall mortality (hazard ratio, 3.1; 95% confidence interval, 1.1 to 8.9; p = 0.02). CONCLUSIONS: In patients with advanced dilated and ischemic cardiomyopathy and severe functional MR, MV replacement is associated with higher in-hospital and late mortality compared with MV repair. Therefore, mitral repair should be preferred whenever possible in this clinical setting.

Long-term results of mitral repair for functional mitral regurgitation in idiopathic dilated cardiomyopathy.

OBJECTIVES: While the results of mitral repair in ischaemic mitral regurgitation have been repeatedly reported, less data are available about the outcome of surgical repair of functional mitral regurgitation (FMR) in idiopathic dilated cardiomyopathy (iDCM) which represents the topic of this study. METHODS: Fifty-four iDCM patients (mean age 63 ± 10.5 years) underwent mitral valve repair for severe FMR. Coronary angiography confirmed the absence of coronary disease in all patients. Most of the patients (77.7%) were in New York Heart Association (NYHA) class III-IV. Pre-operative ejection fraction (EF) was 30.4 ± 8.5%, left ventricle end-diastolic diameter (LVEDD) 67.5 ± 7.8 mm, left ventricle end-systolic diameter (LVESD) diameter 53.9 ± 8.3 mm. Concomitant procedures were atrial fibrillation (AF) ablation (19 patients) and tricuspid repair (17 patients). Follow-up was 100% complete (mean 4.2 ± 2.5 years, median 4.2 years, range 3.3 months-11.1 years). RESULTS: In-hospital mortality was 5.6%. Actuarial survival at 6.5 years was 69 ± 8.8%. Patients submitted to successful AF ablation and/or cardiac resynchronization therapy (CRT) had a significantly better survival (91 ± 7.9 vs 67 ± 9.5%, P = 0.01). Freedom from MR≥3+/4+ was 89.1 ± 5.7% at 6.5 years. Follow-up echocardiography showed a reduction in LVEDD (P < 0.0001) and LVESD (P = 0.0003). Mean EF increased to 38.7 ± 12.4% (P < 0.0001). Multivariate analysis identified successful ablation of AF and/or CRT (P = 0.01) and higher preoperative EF (0.03) as predictors of overall survival. Successful ablation of AF and/or CRT (P = 0.02) and lower preoperative systolic pulmonary artery pressure (0.04) were identified as independent predictors of reverse LV remodelling at follow-up. At last follow-up, 86.2% of the patients were in NYHA II or less. CONCLUSIONS: Mitral repair for FMR in well-selected iDCM patients is associated with low hospital mortality and significant clinical benefit at late follow-up. Concomitant successful AF ablation and/or CRT provide a major symptomatic and prognostic advantage and should be associated to mitral surgery whenever indicated.

Differential structural remodeling of the left-atrial posterior wall in patients affected by mitral regurgitation with or without persistent atrial fibrillation: a morphological and molecular study.

INTRODUCTION: Atrial fibrillation (AF) in mitral regurgitation (MR) is a complex disease where multiple factors may induce left-atrial structural remodeling (SR). We explored the differential SR of the left-atrial posterior wall (LAPW) of patients affected by MR with or without persistent AF, and the expression of key proteins involved in its pathogenesis. METHODS AND RESULTS: Light microscopy of LAPW samples from 27 patients with MR and persistent AF (group 1), 33 with MR in sinus rhythm (group 2), and 15 autopsy controls (group 3) was used to measure myocyte diameter, percentage of myocytolytic myocytes, interstitial fibrosis, and capillary density; RT-PCR and Western blotting were used to assess the mRNA and protein levels of SOD-1, SOD-2, HO-1, calpain, MMP-2, MMP-9, TIMP-1, TIMP-2, and VEGF; immunofluorescence was used to locate these proteins. Myocyte diameter was similar in groups 1 and 2, but larger than controls. Compared to group 2, group 1 had more myocytolytic myocytes (20.8 ± 5.6% vs 14.7 ± 4.5%; P < 0.0001), increased interstitial fibrosis (10.4 ± 5.1% vs 7.5 ± 4.2%; P < 0.05), and decreased capillary density (923 ± 107 No/mm(2) vs 1,040 ± 100 No/mm(2); P < 0.0001). All of the proteins were more expressed in groups 1 and 2 than in controls. The protein and mRNA levels of SOD-1, SOD-2, MMP-2, and MMP-9 were higher in group 1 than in group 2. CONCLUSIONS: The LAPW of MR patients with or without AF shows considerable SR. The former has more severe histopathological changes and higher levels of proteins involved in SR, thereby reaching a threshold beyond which the sinus impulse cannot normally activate atrial myocardium.

The GeoForm annuloplasty ring for the surgical treatment of functional mitral regurgitation in advanced dilated cardiomyopathy.

OBJECTIVE: To assess the results of the three-dimensional (3D)-shaped GeoForm ring for the treatment of functional mitral regurgitation (FMR). METHODS: Seventy-four patients with severe FMR and systolic dysfunction underwent GeoForm ring implantation. Forty-six patients (62%) were in the New York Heart Association (NYHA) class III-IV. Concomitant procedures were coronary artery bypass grafting (CABG) (33 patients (pts)), tricuspid repair (23 pts), atrial fibrillation ablation (20 pts), aortic valve replacement (eight pts) and left-ventricular (LV) reconstruction (five pts). RESULTS: Hospital mortality was 9%. Three more patients died after hospital discharge. Overall survival was 81.1 ± 6.6% at 3.5 years. The 67 hospital survivors underwent clinical and echocardiographic follow-up at a mean follow-up period of 1.9 ± 1.25 years (median 1.7 years). MR was absent or mild in 83% of the patients (56/67), moderate in 7% (5/67), and moderate to severe in the remaining 9% (6/67). At 3.5 years, overall freedom from MR ≥ 3+ was 85.1 ± 8% and freedom from MR ≥ 2+ was 75.1 ± 8.6%. Statistical analysis identified preoperative asymmetric tethering with prevalent restricted motion of the posterior leaflet as the only predictor of recurrence of MR ≥ 2+ (hazard ratio (HR) 6.1, p=0.005). Reverse LV remodeling was demonstrated in 31 of the 54 patients eligible for this specific analysis (31/54, 57%): Both LV end-diastolic and end-systolic volumes indexed significantly decreased (both p=0.0001) as well as systolic pulmonary artery pressure (SPAP) (p=0.006). Ejection fraction increased from 33 ± 8% to 43 ± 8% (p<0.0001). Stress echocardiography was performed in a subgroup of eight patients. Mean mitral area at rest was 2.2 ± 0.3 cm² and did not change during stress. Cardiac output significantly increased in all patients during exercise. Although mean and peak transmitral gradients were 3.3 ± 1.3 and 8.1 ± 2.2 mmHg at rest and 6.6 ± 2.5 and 14.8 ± 3.9 mmHg under stress, respectively (both p<0.003), the increase in SPAP was not statistically significant (28 ± 3.0 vs 31 ± 7.5 mm Hg, p=0.17), revealing a preserved cardiac adaptation to exercise. CONCLUSIONS: The GeoForm ring is effective in relieving FMR in most of the patients with dilated cardiomyopathy. In presence of prevalent restricted motion of the posterior leaflet, recurrence of significant MR is more likely to occur. Clinically relevant mitral stenosis was not detected during exercise.

The clover technique for the treatment of complex tricuspid valve insufficiency: midterm clinical and echocardiographic results in 66 patients.

OBJECTIVE: This study assesses the results of the 'clover technique' (suturing together the middle point of the free edges of the tricuspid leaflets) for the treatment of tricuspid regurgitation (TR) due to severe prolapse or tethering. METHODS: From 2001, 66 patients with severe TR due to prolapsing or tethered leaflets underwent 'clover repair'. Annuloplasty was associated in 64 patients (97%). The aetiology of TR was degenerative in 52 cases (79%), post-traumatic in eight (12%) and secondary to dilated cardiomyopathy (DCM) in six (9%). The main mechanism of TR was prolapse/flail of one leaflet in 15 patients (23%), of two leaflets in 31 (47%) and of all three leaflets in 14 (21%). The remaining six patients (9%) presented with severe leaflets' tethering. RESULTS: Four deaths (6%) occurred during hospitalisation and one patient died 3.6 years after surgery. Survival was 91 + or - 4.1% at 5 years. Follow-up of the 62 hospital survivors was 100% complete (mean length 3.5 + or - 1.6 years, range 13 months-7.1 years). At the last echocardiogram, no or mild TR was detected in 55 (88.7%) patients, moderate (2+/4+) in six (9.6%) and severe (4+/4+) in one patient (1.6%). Mean tricuspid valve area and gradient were 4.3 + or - 0.6 cm(2) and 2.8 + or -1.4 mmHg. In six patients, stress echocardiography was performed and no signs of tricuspid stenosis were detected. At the multivariable analysis, the degree of TR at hospital discharge was identified as the only predictor of TR > or = 2+ at follow-up. CONCLUSIONS: Midterm clinical and echocardiographic results confirm the role of the 'clover technique' in the surgical treatment of TR due to lesions, which are unlikely to be effectively treatable by annuloplasty alone.