Sodium fluorescein uptake by the tumor microenvironment in human gliomas and brain metastases.

OBJECTIVE: Intravenous sodium fluorescein (SF) is increasingly used during surgery of gliomas and brain metastases to improve tumor resection. Currently, SF is believed to permeate the brain regions where the blood-brain barrier (BBB) is damaged and to accumulate in the extracellular space but not in tumor or healthy cells, making it possible to demarcate tumor margins to guide resection. By evaluating the immune contexture of a number of freshly resected gliomas and brain metastases from patients undergoing SF-guided surgery, the authors recurrently observed fluorescence-positive cells. Therefore, the aim of this study was to determine if SF accumulates inside the cells of the tumor microenvironment (TME), and if so, in which type of cells, and whether incorporation can also be observed in the leukocytes of peripheral blood. METHODS: Freshly resected tumor specimens were dissociated to single cells and analyzed by multiparametric flow cytometry. Peripheral blood leukocytes, macrophages, and a glioma cell line were treated with SF in vitro, and their cell uptake was assessed by multiparametric and imaging flow cytometry and by confocal microscopy. RESULTS: The ex vivo and in vitro analyses revealed that SF accumulates intracellularly in leukocytes as well as in tumor cells, but with a high variability of incorporation in the different cell subsets analyzed. Myeloid cells showed the highest level of fluorescence. In vitro uptake experiments showed that SF accumulation increases over time. The imaging analyses confirmed the internalization of the compound inside the cells. CONCLUSIONS: SF is not just a marker of BBB damage, but its intracellular detection suggests that it selectively accumulates intracellularly. Future efforts should target the mechanisms of its differential uptake by the different TME cell types in depth.

Rare case of Kawasaki disease with cardiac tamponade and giant coronary artery aneurysms.

Kawasaki disease is an acute systemic vascular disease, generally self-limited and typically affecting children <5 years old, which leads to coronary artery aneurysms in about 25% of untreated cases. Cardiovascular involvement is characterised by transient pancarditis, in acute phase, while coronary illness, ranging from mild dilation to giant CAAs occurs late, rarely before the 10th day since fever onset. Here, we describe a peculiar case of KD, which occurred in a 4-month-old infant and presented with exudate cardiac tamponade and early giant aneurism of both the proximal right coronary artery) and the left circumflex coronary artery, in acute phase of the disease.

Atypical cardiac defects in patients with RASopathies: Updated data on CARNET study.

BACKGROUND: RASopathies are a set of relatively common autosomal dominant clinically and genetically heterogeneous disorders. Cardiac outcomes in terms of mortality and morbidity for common heart defects (such as pulmonary valve stenosis and hypertrophic cardiomyopathy) have been reported. Nevertheless, also Atypical Cardiac Defects (ACDs) are described. The aim of the present study was to report both prevalence and cardiac outcome of ACDs in patients with RASopathies. METHODS: A retrospective, multicentric observational study (CArdiac Rasopathy NETwork-CARNET study) was carried out. Clinical, surgical, and genetic data of the patients who were followed until December 2019 were collected. RESULTS: Forty-five patients out of 440 followed in CARNET centers had ACDs. Noonan Syndrome (NS), NS Multiple Lentigines (NSML) and CardioFacioCutaneous Syndrome (CFCS) were present in 36, 5 and 4 patients, respectively. Median age at last follow-up was 20.1 years (range 6.9-47 years). Different ACDs were reported, including mitral and aortic valve dysfunction, ascending and descending aortic arch anomalies, coronary arteries dilation, enlargement of left atrial appendage and isolated pulmonary branches diseases. Five patients (11%) underwent cardiac surgery and one of them underwent a second intervention for mitral valve replacement and severe pericardial effusion. No patients died in our cohort until December 2019. CONCLUSIONS: Patients with RASopathies present a distinct CHD spectrum. Present data suggest that also ACDs must be carefully investigated for their possible impact on the clinical outcome. A careful longitudinal follow up until the individuals reach an adult age is recommended.

A simple echocardiographic score for the diagnosis of pulmonary vascular disease in heart failure.

AIMS: A simple echocardiographic score was designed for diagnosing precapillary vs postcapillary pulmonary hypertension and for discriminating between isolated postcapillary pulmonary hypertension (Ipc-PH) and combined precapillary and postcapillary pulmonary hypertension (Cpc-PH). METHODS: The score comprised 7 points (2 for E/e' ratio ≤10, 2 for a dilated non-collapsible inferior vena cava, 1 for a left ventricular eccentricity index ≥1.2, 1 for a right-to-left heart chamber dimension ratio >1 and 1 for the right ventricle forming the heart apex) and was applied to 230 consecutive patients referred for evaluation of pulmonary hypertension. RESULTS: Precapillary pulmonary hypertension and postcapillary pulmonary hypertension were diagnosed in 160 and 70 patients, respectively. In the latter, Ipc-PH was found in 51 and Cpc-PH in 19. The echo score was higher in precapillary vs postcapillary pulmonary hypertension patients (4.2 ±â€Š1.7 vs 1.6 ±â€Š1.7, P < 0.001) and in patients with Cpc-PH vs Ipc-PH (2.7 ±â€Š2.1 vs 1.2 ±â€Š1.3, P = 0.001). The sensitivity and specificity of the echo score at least 2 for precapillary pulmonary hypertension were 99 and 54%, respectively (area under the curve 0.85). In patients with postcapillary pulmonary hypertension, the sensitivity and specificity of the echo score at least 2 for Cpc-PH were 63 and 82% (area under the curve 0.73). CONCLUSION: A simple echocardiographic score helps in the differential diagnosis between precapillary and postcapillary pulmonary hypertension, and between Ipc-PH and Cpc-PH.

Off-label use of Amplatzer Duct Occluder II additional sizes.

OBJECTIVE: To report our experience on novel, off-label use of Amplatzer Duct Occluder type II additional sizes (ADO II-AS) device (St. Jude Medical, Inc.; St. Paul, Minnesota, USA) to manage nonduct shunt lesions. METHODS AND RESULTS: Among the 114 patients submitted to ADO II-AS implantation at our institution, 12 received this device as off-label treatment of paravalvular leak (n = 5), sinus of Valsalva fissuration (n = 2), accessory atrial septal defect (n = 2), muscular ventricular septal defect (n = 1), bleeding bronchial artery aneurysm (n = 1) and reverse shunt due to abnormal origin of left subclavian artery from pulmonary artery (n = 1). Age and body weight of these patients ranged from 3 to 74 years and from 15 to 80 kg, respectively. All procedures were completed without anatomical, functional or ECG complications and without residual shunt. In one patient with mitral paravalvular leak, mild restriction of the posterior disc excursion after device deployment was recorded. CONCLUSION: In our case series, ADO II-AS was well tolerated, versatile and cost-effective in treatment of different types of nonduct shunt lesions, mainly in young children and in older patients with comorbidities.

Transcatheter treatment of Starr-Edwards paravalvular leaks.

: A 56-year-old patient was referred because of refractory heart failure and mild haemolysis caused by multiple, severe paravalvular leaks of a Starr-Edwards valve implanted in mitral position 23 years before. Owing to perceived high risk of surgical re-valving, percutaneous paravalvular leak occlusion was performed by implantation of multiple, simultaneously deployed Amplatzer Vascular Plugs.

Echocardiographic prediction of pre- versus postcapillary pulmonary hypertension.

BACKGROUND: The differential diagnosis between pre- and postcapillary pulmonary hypertension (PH) is of major therapeutic relevance and thus requires optimal clinical probability assessment with echocardiography. METHODS: We prospectively analyzed 152 consecutive patients referred to a PH center over a 1-year period undergoing quasi-simultaneous (within 1 hour) echocardiography and right heart catheterization. Echocardiography was performed as usually recommended for the assessment of PH and left heart conditions. PH was defined as a mean pulmonary artery pressure ≥ 25 mm Hg. Postcapillary PH was diagnosed on the basis of a pulmonary capillary wedge pressure >15 mm Hg. RESULTS: Ten of 152 patients (7%) had no PH, 81 of 152 (53%) had precapillary PH, and 61 of 152 (40%) had postcapillary PH. The following five echocardiographic variables were found to predict precapillary PH: right heart chamber larger than the left (P = .0018), left ventricular eccentricity index > 1.2 (P = .0039), dilated inferior vena cava without inspiratory collapse (P = .0076), E/e' ratio ≤ 10 (P = .00001), and the right ventricle forming the heart apex (P = .0144). Beta coefficients from multiple logistic regression were significant for dilated inferior vena cava without inspiratory collapse (P = .0464) and E/e' ratio ≤ 10 (P = .0002). The score based on ß coefficients, ranging from 3 to 34 points, resulted in optimal discrimination at >5, with a positive predictive value of 67.9% and a negative predictive value of 77.5% for precapillary PH. CONCLUSION: Echocardiography enables a clinically satisfactory differential diagnosis between pre- and postcapillary PH.

Patent ductus arteriosus stenting for palliation of severe pulmonary arterial hypertension in childhood.

A 4.5-year-old child with severe idiopathic pulmonary arterial hypertension underwent right-heart catheterisation, showing suprasystemic pulmonary pressure and a tiny patent ductus arteriosus with trivial right-to-left shunting. The ductus arteriosus was successfully stented with a bare metal stent. At 1-year follow-up, a remarkable improvement was observed in clinical status, functional capacity, and serology. Echocardiography confirmed a favourable cardiac remodelling.

Aortic insufficiency due to ventricular septal defect (Laubry-Pezzi syndrome).

A 15-year-old boy showed progressive aortic valve regurgitation during follow-up of supracristal ventricular septal defect. This anatomic arrangement is consistent with the Laubry-Pezzi syndrome in which prolapse of a non-coronary aortic valve cusp due to Venturi's effect results in progressive aortic valve insufficiency.

Therapy for pulmonary arterial hypertension due to congenital heart disease and Down's syndrome.

BACKGROUND: Oral bosentan is effective in pulmonary arterial hypertension (PAH) related to congenital heart disease (CHD). In patients with Down's syndrome, the effect of bosentan is largely unknown. Aim of the study was to evaluate the long-term effects of bosentan in adult patients with CHD-related PAH with and without Down's syndrome. METHODS: WHO functional class, resting oxygen saturation, 6-minute walk test (6 MWT) and hemodynamics were assessed at baseline and after 12 months of bosentan therapy in patients with CHD-related PAH with and without Down's syndrome. RESULTS: Seventy-four consecutive patients were enrolled: 18 with and 56 without Down's syndrome. After 12 months of bosentan therapy, both with and without Down's syndrome patients showed an improvement in WHO functional class (Down: 2.5 ± 0.5 vs 2.9 ± 0.6, p=0.005; controls: 2.5 ± 0.5 vs 2.9 ± 0.5, p=0.000002), 6-minute walk distance (Down: 288 ± 71 vs 239 ± 74 m, p=0.0007; controls: 389 ± 80 vs 343 ± 86 m, p=0.00003), and hemodynamics (pulmonary flow, Down: 4.0 ± 1.6 vs 3.5 ± 1.4 l/m/m(2), p=0.006; controls: 3.5 ± 1.4 vs 2.8 ± 1.0 l/m/m(2), p=0.0005; pulmonary to systemic flow ratio, Down: 1.4 ± 0.7 vs 1.0 ± 0.4, p=0.003; controls: 1.1 ± 0.7 vs 0.9 ± 0.3, p=0.012; pulmonary vascular resistance index, Down: 15 ± 9 vs 20 ± 13 WUm(2), p=0.007; controls: 2 0 ± 10 vs 26 ± 15 WUm(2), p=0.002). No differences in the efficacy of therapy were observed between the two groups. CONCLUSIONS: Bosentan was safe and well tolerated in adult patients with CHD-related PAH with and without Down's syndrome during 12 months of treatment. Clinical status, exercise tolerance, and pulmonary hemodynamics improved, regardless of the presence of Down's syndrome.

Alarm!!! A UFO inside the heart.

An 8-year-old asymptomatic child was referred for surgical repair of coronary sinus atrial septal defect resulting in significant left-to-right shunt and right chamber volume overload. The septal fenestration was located near to its drainage site into the right atrium. Due to this seemingly favourable anatomy, transcatheter closure of the septal defect was performed using an Amplatzer Septal Occluder device. The echocardiographic postprocedural evaluation imaged the occluding device almost perpendicular to the atrial septum, seemingly floating above the mitral valve orifice, like an alien spaceship inside the heart.

Association between right ventricular two-dimensional strain and exercise capacity in patients with either idiopathic or ischemic dilated cardiomyopathy.

OBJECTIVES: To detect right ventricular myocardial function in dilated cardiomyopathy (DCM) using two-dimensional strain echocardiography (2DSE) and to evaluate the relationship between right ventricular dysfunction and response to cardiopulmonary exercise test (CPET). METHODS: Seventy-five DCM patients (44 idiopathic and 31 ischemic) without clinical signs of right ventricular failure underwent standard echo, 2DSE analysis of right ventricle and bicycle CPET. RESULTS: The two groups were comparable for clinical and standard two-dimensional echocardiographic and Doppler variables, except for right ventricular diameters that were mildly increased in patients with idiopathic DCM. Right ventricular global longitudinal strain (RV GLS) and regional peak myocardial right ventricular strain were significantly impaired in patients with idiopathic DCM compared with ischemic DCM (both P<0.001). A significant correlation was detectable among RV GLS and VO2 peak percentage (r= -0.65, P<0.0001), VE/VCO2 slope (r=0.35, P<0.01), maximum work rate percentage (r= -0.55, P<0.001) and peak circulatory power (r=0.53, P<0.001). These correlations with RV GLS remained significant even in multivariate analysis. CONCLUSION: 2DSE represents a promising noninvasive technique to assess right ventricular myocardial function in patients with DCM. Reduced right ventricular myocardial deformation is related to decreased ability to perform aerobic exercise and work rate, and to impaired ventilatory response.

Dispersion of repolarization and beta-thalassemia major: the prognostic role of QT and JT dispersion for identifying the high-risk patients for sudden death.

BACKGROUND: Patients with beta-thalassemia major (ß-TM) are at increased risk for sudden cardiac death (SCD). Heterogeneity of ventricular repolarization is considered to provide an electrophysiological substrate for malignant arrhythmias. QT dispersion (QTc-D) and JT dispersion (JTc-D) are electrocardiographic parameters indicative of heterogeneity of ventricular repolarization. The aim of our study was to evaluate the heterogeneity of ventricular repolarization in patients with beta-thalassemia and to test the hypothesis that an abnormal QTc and JTc dispersion may predict SCD in this population. MATERIALS AND METHODS: The study involved 51 patients with ß-TM (age 33.9±8.4; 33M) and 51 healthy subjects used as controls, matched for age, gender, and body mass index (BMI). Among the ß-TM group, 14 patients with ß-TM (age 27±6.64; 11M) died from SCD during follow-up. For each patient, QTD and JTD intervals were calculated. RESULTS: Compared to the healthy control group, ß-TM group presented increased values of the QTc-D (65.36±33.95 vs. 37, 62±17.65; P<0.003) and JTc-D (74.64±33.27 vs. 40.32±12.45; P<0.001). In the ß-TM sudden death group, QTc-D and JTc-D were significantly greater than in survived ß-TM group (92.70±44.24 vs. 56.14±23.80, P=0.0001; 101.54±47.93 vs. 64.47±17.90, P=0.0001). A cutoff value of 70ms for QTc-D had a sensitivity and specificity of 77% in identifying patients at risk for SCD. A cutoff value of 100ms for JTc-D had a sensitivity of 65% and a specificity of 94% in identifying this category of patients. CONCLUSION: ß-TM is associated with significant changes in heterogeneity of ventricular repolarization. QTc and JTc dispersion are useful markers of risk of SCD in patients with ß-TM.