Tiziano Moccetti

PTX3, A Prototypical Long Pentraxin, Is an Early Indicator of Acute Myocardial Infarction in Humans

BACKGROUND Inflammation is an important component of ischemic heart disease. PTX3 is a long pentraxin whose expression is induced by cytokines in endothelial cells, mononuclear phagocytes, and myocardium. The possibility that PTX3 is altered in patients with acute myocardial infarction (AMI) has not yet been tested. METHODS AND RESULTS Blood samples were collected from 37 patients admitted to the coronary care unit (CCU) with symptoms of AMI. PTX3 plasma concentrations, as measured by ELISA, higher than the mean+2 SD of age-matched controls (2.01 ng/mL) were found in 27 patients within the first 24 hours of CCU admission. PTX3 peaked at 7.5 hours after CCU admission, and mean peak concentration was 6.94+/-11.26 ng/mL. Plasma concentrations of PTX3 returned to normal in all but 3 patients at hospital discharge and were unrelated to AMI site or extent, Killip class at entry, hours from symptom onset, and thrombolysis. C-reactive protein peaked in plasma at 24 hours after CCU admission, much later than PTX3 (P<0.001). Patients >64 years old and women had significantly higher PTX3 concentrations at 24 hours (P<0.05). PTX3 was detected by immunohistochemistry in normal but not in necrotic myocytes. CONCLUSIONS PTX3 is present in the intact myocardium, increases in the blood of patients with AMI, and disappears from damaged myocytes. We suggest that PTX3 is an early indicator of myocyte irreversible injury in ischemic cardiomyopathy.

A comparison of the early outcome of acute myocardial infarction in women and men. The Third International Study of Infarct Survival Collaborative Group.

BACKGROUND In previous studies, unadjusted comparisons of mortality and major morbidity after acute myocardial infarction have generally indicated that women have a poorer outcome than men. Much larger studies are needed, with more complete adjustment for coexisting conditions, to determine whether this difference is explained by the older age of the women studied or by the presence of other unfavorable prognostic factors, or both. METHODS As part of the Third International Study of Infarct Survival (ISIS-3), information was collected on deaths during days 0 to 35 and on major clinical events during hospitalization up to day 35 for 9600 women and 26,480 men with suspected acute myocardial infarction who were considered to have a clear indication for fibrinolytic therapy. We compared the outcome among women and men, first without adjustment, then with adjustment for age, and finally with adjustment for other recorded baseline characteristics by means of multiple logistic regression. RESULTS The unadjusted odds ratio for death among women as compared with men was 1.73 (95 percent confidence interval, 1.61 to 1.86). The women were significantly older than the men, and after adjustment for age the odds ratio was reduced markedly to 1.20 (95 percent confidence interval, 1.11 to 1.29). Adjustment for other differences in base-line clinical features further reduced the odds ratio to 1.14 (95 percent confidence interval, 1.05 to 1.23). Excesses in other major clinical events among women were generally reduced to a similar extent by adjustment. CONCLUSIONS It seems likely that there is at most only a small independent association between female sex and early mortality and morbidity after suspected acute myocardial infarction.

Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction

AIMS Recent evidence suggests that cardiac progenitor cells (CPCs) may improve cardiac function after injury. The underlying mechanisms are indirect, but their mediators remain unidentified. Exosomes and other secreted membrane vesicles, hereafter collectively referred to as extracellular vesicles (EVs), act as paracrine signalling mediators. Here, we report that EVs secreted by human CPCs are crucial cardioprotective agents. METHODS AND RESULTS CPCs were derived from atrial appendage explants from patients who underwent heart valve surgery. CPC-conditioned medium (CM) inhibited apoptosis in mouse HL-1 cardiomyocytic cells, while enhancing tube formation in human umbilical vein endothelial cells. These effects were abrogated by depleting CM of EVs. They were reproduced by EVs secreted by CPCs, but not by those secreted by human dermal fibroblasts. Transmission electron microscopy and nanoparticle tracking analysis showed most EVs to be 30-90 nm in diameter, the size of exosomes, although smaller and larger vesicles were also present. MicroRNAs most highly enriched in EVs secreted by CPCs compared with fibroblasts included miR-210, miR-132, and miR-146a-3p. miR-210 down-regulated its known targets, ephrin A3 and PTP1b, inhibiting apoptosis in cardiomyocytic cells. miR-132 down-regulated its target, RasGAP-p120, enhancing tube formation in endothelial cells. Infarcted hearts injected with EVs from CPCs, but not from fibroblasts, exhibited less cardiomyocyte apoptosis, enhanced angiogenesis, and improved LV ejection fraction (0.8 ± 6.8 vs. -21.3 ± 4.5%; P < 0.05) compared with those injected with control medium. CONCLUSION EVs are the active component of the paracrine secretion by human CPCs. As a cell-free approach, EVs could circumvent many of the limitations of cell transplantation.

Timing and Magnitude of Regional Right Ventricular Function: A Speckle Tracking-Derived Strain Study of Normal Subjects and Patients with Right Ventricular Dysfunction

BACKGROUND The aim of this study was to evaluate the timing and magnitude of global and regional right ventricular (RV) function by means of speckle tracking-derived strain in normal subjects and patients with RV dysfunction. METHODS Peak longitudinal systolic strain (PLSS) and time to PLSS in 6 RV segments (the basal, mid, and apical segments of the RV free wall and septum) were obtained in 100 healthy volunteers and 76 patients with RV dysfunction by tracking speckles inside the myocardium using grayscale images. Global PLSS and time to PLSS were based on the average of the 6 regional values. RESULTS There was a significant and close correlation between RV contractility as measured by PLSS and tricuspid annular plane systolic excursion (r = -0.83, P < .001). In normal subjects, PLSS was significantly greater in the free wall than in the septum (-28.7 + or - 4.1% vs -19.8 + or - 3.4%, P < .001), whereas time to PLSS was similar in the different regions of the right ventricle. In patients with RV dysfunction, global and regional PLSS was significantly less than in normal subjects (-13.7 + or - 3.6% vs -24.2 + or - 2.9%, P < .001), and a global PLSS cutoff value of -19% was helpful in distinguishing the two groups. Furthermore, time to PLSS in all of the RV septal segments and dispersion in RV contraction timing were significantly longer. Global PLSS in the patients with RV dysfunction was also significantly less in the presence of moderate to severe pulmonary hypertension (-12.7 + or - 3.6% vs -14.4 + or - 3.4%, P = .038). CONCLUSIONS Speckle tracking not only makes it possible to quantify global RV function but also illustrates the physiology of RV contraction and the pattern of activation at regional level. Speckle tracking-derived strain could become an important new means of assessing and following up patients with impaired RV function and increased pulmonary pressure.

Randomized Comparison of a Titanium-Nitride-Oxide–Coated Stent With a Stainless Steel Stent for Coronary Revascularization The TiNOX Trial

Background—Stent coating with titanium-nitride-oxide has been shown to reduce neointimal hyperplasia in the porcine restenosis model. We designed a prospective, randomized, clinical study to investigate the safety and efficacy of titanium-nitride-oxide–coated stents compared with stainless steel stents. Methods and Results—Ninety-two patients with de novo lesions were randomly assigned to treatment with titanium-nitride-oxide–coated stents (n=45) or stainless steel stents of otherwise identical design (n=47; control). Baseline characteristics were similar in both groups. At 30 days, no stent thromboses or other adverse events had occurred in either group. Quantitative coronary angiography at 6 months revealed lower late loss (0.55±0.63 versus 0.90±0.76 mm, P=0.03) and percent diameter stenosis (26±17% versus 36±24%, P=0.04) in lesions treated with titanium-nitride oxide–coated than in control stents. Binary restenosis was reduced from 33% in the control group to 15% in the titanium-nitride oxide–coated stent group (P=0.07). Intravascular ultrasound studies at 6 months showed smaller neointimal volume in titanium-nitride-oxide–coated stents than in control stents (18±21 versus 48±28 mm3, P<0.0001). Major adverse cardiac events at 6 months were less frequent in titanium-nitride-oxide–coated stents than in control stent–treated patients (7% versus 27%, P=0.02), largely driven by a reduced need for target-lesion revascularization (7% versus 23%, P=0.07). Conclusions—Revascularization with titanium-nitride-oxide–coated stents is safe and effective in patients with de novo native coronary artery lesions. Titanium-nitride-oxide–coated stents reduce restenosis and major adverse cardiac events compared with stainless steel stents of otherwise identical design.

Evaluation of the left atrial appendage with real-time 3-dimensional transesophageal echocardiography: implications for catheter-based left atrial appendage closure.

Background— Precise knowledge of left atrial appendage (LAA) orifice size is crucial for correct sizing of LAA closure devices. The aim of the present study was to determine the performance of real-time 3D transesophageal echocardiography (RT3DTEE) for LAA orifice size assessment, compared with 2D transesophageal echocardiography (2DTEE), and to investigate the impact of atrial fibrillation (AF) on LAA orifice size. Methods and Results— One hundred thirty-seven patients (38 control subjects, 31 with paroxysmal AF, 38 with persistent AF and 30 with permanent AF) underwent 2DTEE and RT3DTEE. Both techniques were used to measure LAA orifice area. Clinically-indicated 64-slice computed tomography (CT) was used as reference technique in 46 patients. Two-dimensional TEE underestimated LAA orifice area, compared with RT3DTEE (1.99±0.94 cm2 versus 3.05±1.27 cm2; P <0.001). RT3DTEE showed higher correlation with CT for the assessment of LAA orifice area, compared with 2DTEE ( r =0.92; 95% confidence interval, 0.85 to 0.95, versus r =0.72; 95% confidence interval, 0.54 to 0.83, respectively). At Bland–Altman analysis, RT3DTEE and 2DTEE underestimated LAA orifice area, compared with CT. However, RT3DTEE showed smaller bias (0.07 cm2 versus 0.72 cm2) and narrower limits of agreement (−0.71 to 0.85 cm2 versus −0.58 to 2.02 cm2) with CT, compared with 2DTEE. Among AF patients, a progressive increase in RT3DTEE-derived LAA orifice area was observed with increasing frequency of AF ( P <0.001). At multivariate analysis, AF and left atrial volume index ( P <0.001 for both) were independently associated with RT3DTEE-derived LAA orifice area. Conclusions— RT3DTEE is more accurate than 2DTEE for the assessment of LAA orifice size. A progressive increase in LAA orifice area is observed with increasing frequency of AF.Background— Precise knowledge of left atrial appendage (LAA) orifice size is crucial for correct sizing of LAA closure devices. The aim of the present study was to determine the performance of real-time 3D transesophageal echocardiography (RT3DTEE) for LAA orifice size assessment, compared with 2D transesophageal echocardiography (2DTEE), and to investigate the impact of atrial fibrillation (AF) on LAA orifice size. Methods and Results— One hundred thirty-seven patients (38 control subjects, 31 with paroxysmal AF, 38 with persistent AF and 30 with permanent AF) underwent 2DTEE and RT3DTEE. Both techniques were used to measure LAA orifice area. Clinically-indicated 64-slice computed tomography (CT) was used as reference technique in 46 patients. Two-dimensional TEE underestimated LAA orifice area, compared with RT3DTEE (1.99±0.94 cm2 versus 3.05±1.27 cm2; P<0.001). RT3DTEE showed higher correlation with CT for the assessment of LAA orifice area, compared with 2DTEE (r=0.92; 95% confidence interval, 0.85 to 0.95, versus r=0.72; 95% confidence interval, 0.54 to 0.83, respectively). At Bland–Altman analysis, RT3DTEE and 2DTEE underestimated LAA orifice area, compared with CT. However, RT3DTEE showed smaller bias (0.07 cm2 versus 0.72 cm2) and narrower limits of agreement (−0.71 to 0.85 cm2 versus −0.58 to 2.02 cm2) with CT, compared with 2DTEE. Among AF patients, a progressive increase in RT3DTEE-derived LAA orifice area was observed with increasing frequency of AF (P<0.001). At multivariate analysis, AF and left atrial volume index (P<0.001 for both) were independently associated with RT3DTEE-derived LAA orifice area. Conclusions— RT3DTEE is more accurate than 2DTEE for the assessment of LAA orifice size. A progressive increase in LAA orifice area is observed with increasing frequency of AF.

Predictors for efficacy of percutaneous mitral valve repair using the MitraClip system: the results of the MitraSwiss registry

Background Percutaneous mitral valve repair (MVR) using the MitraClip system has become a valid alternative for patients with severe mitral regurgitation (MR) and high operative risk. Objective To identify clinical and periprocedural factors that may have an impact on clinical outcome. Design Multi-centre longitudinal cohort study. Setting Tertiary referral centres. Patients Here we report on the first 100 consecutive patients treated with percutaneous MVR in Switzerland between March 2009 and April 2011. All of them had moderate–severe (3+) or severe (4+) MR, and 62% had functional MR. 82% of the patients were in New York Heart Association (NYHA) class III/IV, mean left ventricular ejection fraction was 48% and the median European System for Cardiac Operative Risk Evaluation was 16.9%. Interventions MitraClip implantation performed under echocardiographic and fluoroscopic guidance in general anaesthesia. Main outcome measures Clinical, echocardiographic and procedural data were prospectively collected. Results Acute procedural success (APS, defined as successful clip implantation with residual MR grade ≤2+) was achieved in 85% of patients. Overall survival at 6 and 12 months was 89.9% (95% CI 81.8 to 94.6) and 84.6% (95% CI 74.7 to 91.0), respectively. Univariate Cox regression analysis identified APS (p=0.0069) and discharge MR grade (p=0.03) as significant predictors of survival. Conclusions In our consecutive cohort of patients, APS was achieved in 85%. APS and residual discharge MR grade are important predictors of mid-term survival after percutaneous MVR.

Feasibility, safety, and short-term outcome of leadless ultrasound-based endocardial left ventricular resynchronization in heart failure patients: results of the wireless stimulation endocardially for CRT (WiSE-CRT) study.

AIMS Left ventricular (LV) endocardial pacing may address the limitations in the selection of an LV pacing site and provide improvements in cardiac resynchronization therapy (CRT) effectiveness. We report on the feasibility, the safety, and the short-term outcome of a leadless ultrasound-based technology for LV endocardial resynchronization in heart failure (HF) patients enroled into the Wireless Stimulation Endocardially for CRT (WiSE-CRT) study. METHODS AND RESULTS Seventeen HF patients were enroled and categorized as: (i) patients in whom attempted coronary sinus lead implantation for CRT had failed (n = 7); (ii) patients with a previously implanted CRT device, not responding to CRT (n = 2); and (iii) patients with previously implanted pacemakers or implantable cardioverter-defibrillator and meeting the standard indications for CRT (n = 8). System implantation was achieved in 13 patients (76.5%); mean R-wave amplitude was 5.6 ± 3.2 mV and the mean pacing threshold was 1.6 ± 1.0 V, respectively. In one patient, no sufficient pacing thresholds were found; in three patients pericardial effusion occurred. Biventricular pacing was recorded in 83% and 92% of the patients at 1 month and 6 months, respectively. QRS duration was shorter during biventricular pacing compared with right ventricular pacing at 1 month (-41 ms; P = 0.0002) and 6 months (-42 ms; P = 0.0011), respectively. At the 6-month follow-up, two-thirds of the patients had at least one functional class change. Left ventricular ejection fraction significantly increased (P < 0.01) by 6 points at the 6-month follow-up. CONCLUSION The feasibility of providing an endocardial stimulation for CRT with a leadless technology was successfully demonstrated. Despite the promising results for a novel technology, further study is required to definitively conclude the safety and the performance of the system. CLINICAL TRIAL REGISTRATION INFORMATION NCT01294527.

The effect of the gastrointestinal lipase inhibitor, orlistat, on serum lipids and lipoproteins in patients with primary hyperlipidaemia

The effect of orlistat, a nonabsorbed inhibitor of gastric and pancreatic lipases, was examined in patients with primary hyperlipidaemia (serum cholesterol ≥6.2 mmol·l−1 and triglycerides ≤5.0 mmol·l−1) not responsive to dietary change alone. In a multicentre, randomised, double-blind study, 103 men and 70 women received 30, 90, 180, or 360 mg of orlistat or placebo for 8 weeks.Total and low-density lipoprotein cholesterol levels were reduced by 4% and 5% with 30 mg orlistat, by 7% and 8% with 90 mg orlistat, by 7% and 7% with 180 mg orlistat and by 11% and 10% with 360 mg orlistat compared to placebo. High density lipoprotein cholesterol levels significantly decreased in the 360 mg orlistat group. Triglyceride levels significantly increased in the placebo group but not in the drug groups. Body weight decreased by 1.2 kg with 360 mg orlistat, despite a weight maintenance diet. Decreases in vitamin E and D levels occurred, although both vitamins remained within the normal range.Adverse effects from the gastrointestinal tract were frequent, but led to discontinuation of therapy in only seven patients. Orlistat is a new therapeutic drug for the treatment of hyperlipidaemia that may be particularly useful among overweight patients. Its potential place in therapy will await long-term studies. Vitamin supplementation should be considered during treatment.

Comparison of Brain Natriuretic Peptide Plasma Levels Versus Logistic EuroSCORE in Predicting In-Hospital and Late Postoperative Mortality in Patients Undergoing Aortic Valve Replacement for Symptomatic Aortic Stenosis

The accuracy of the logistic EuroSCORE (logES), a widely used risk prediction algorithm for cardiac surgery including aortic valve surgery, usually overestimates observed perioperative mortality. Elevated brain natriuretic peptide (BNP) in symptomatic patients with aortic stenosis (AS) is associated with a poor short-term outcome after aortic valve replacement. We aimed to compare BNP with the logES for predicting short- and long-term outcome in symptomatic patients with severe AS undergoing aortic valve replacement. We prospectively studied 144 consecutive patients referred for aortic valve replacement (42% women, 73 +/- 9 years, mean aortic gradient 51 +/- 18 mm Hg, and left ventricular ejection fraction 61 +/- 11%) undergoing either isolated aortic valve replacement (58%) or combined to bypass grafting. Both plasma BNP and logES was estimated before surgery. The median BNP plasma level and logES were 157 pg/ml (interquartile range [IQR] 61 to 440) and 6.6% (IQR 4.2 to 12.2), respectively. The perioperative mortality was 6% and the overall mortality by the end of the study was 13%. Patients with logES >10.1% (upper tertile) had a higher risk of dying over time (hazard ratio [HR] 2.86, p = 0.037), as had patients with BNP >312 pg/ml (HR 9.01, p <0.001). Discrimination (based on C statistic) and model performance (based on Akaike information criterion) were better for BNP than for logES. At the bivariable analysis, only BNP was an independent predictor of death (HR 8.2, p = 0.002). Preoperative BNP was even more accurate than logES in predicting outcome. In conclusion, in symptomatic patients with severe AS, high preoperative BNP plasma level and high logES confirm their predicting value for short- and long-term outcome.