Early diagnosis and targeted approaches to pulmonary vascular disease in bronchopulmonary dysplasia.

Pulmonary hypertension has emerged as a life-threatening disease in preterm infants suffering from bronchopulmonary dysplasia (BPD). Its development is closely linked to respiratory disease, as vasculogenesis and alveologenesis are closely interconnected. Once clinically significant, BPD-associated pulmonary hypertension (BPD-PH) can be challenging to manage, due to poor reversibility and multiple comorbidities frequently associated. The pulmonary vascular disease process underlying BPD-PH is the result of multiple innate and acquired factors, and emerging evidence suggests that it progressively develops since birth and, in certain instances, may begin as early as fetal life. Therefore, early recognition and intervention are of great importance in order to improve long-term outcomes. Based on the most recent knowledge of BPD-PH pathophysiology, we review state-of-the-art screening and diagnostic imaging techniques currently available, their utility for clinicians, and their applicability and limitations in this specific population. We also discuss some biochemical markers studied in humans as a possible complement to imaging for the detection of pulmonary vascular disease at its early stages and the monitoring of its progression. In the second part, we review pharmacological agents currently available for BPD-PH treatment or under preclinical investigation, and discuss their applicability, as well as possible approaches for early-stage interventions in fetuses and neonates. IMPACT: BPD-associated PH is a complex disease involving genetic and epigenetic factors, as well as environmental exposures starting from fetal life. The value of combining multiple imaging and biochemical biomarkers is emerging, but requires larger, multicenter studies for validation and diffusion. Since "single-bullet" approaches have proven elusive so far, combined pharmacological regimen and cell-based therapies may represent important avenues for research leading to future cure and prevention.

Quality of life assessment in children before and after a successful ablation for supraventricular tachycardia.

BACKGROUND AND OBJECTIVES: Young patients suffering from rhythm disorders have a negative impact in their quality of life. In recent years, ablation has become the first-line therapy for supraventricular arrhythmias in children. In the light of the current expertise and advancement in the field, we decided to evaluate the quality of life in young patients with supraventricular arrhythmias before and after a percutaneous ablation procedure. METHODS: The prospective cohort consisted of patients <18 years with structurally normal hearts and non-pre-excited supraventricular arrhythmias, who had an ablation in our centre from 2013 to 2018. The cohort was evaluated with the PedsQL™ 4.0 Generic Core Scales self-questionnaire prior to and post-ablation. RESULTS: The final cohort included 88 patients consisted of 52 males (59%), with a mean age at ablation of 12.5 ± 3.3 years. Forty-two patients (48%) had a retrograde-only accessory pathway mediating the tachycardia, 38 (43%) had atrio-ventricular nodal re-entrant tachycardia, 7 (8%) had ectopic atrial tachycardia, and 1 (1%) had atrial flutter. The main reason for an ablation was the patient's choice in 53%. There were no severe complications. Comparison between the baseline and post-ablation assessments showed that patients reported significant improvement in the scores for physical health, emotional and social functioning, as well as in the total scores. CONCLUSIONS: The present study demonstrates that the successful treatment of supraventricular arrhythmias by means of an ablation results in a significant improvement in the quality of self-reported life scores in young patients.

Recent Experience and Follow-Up After Surgical Closure of Secundum Atrial Septal Defect in 120 Children.

While percutaneous catheter closure proves an effective treatment for secundum atrial septal defect (ASD2), some child patients require surgical closure. We assessed the risks associated with isolated surgical ASD2 closure by reviewing the outcomes of 120 children operated on between 1999 and 2011 (mean age 4.6 ± 3.9 years, mean weight 17 ± 12 kg). Direct sutures were performed in 4% and patch closures in 96%. The mean cardiopulmonary bypass duration was 38 ± 14 min, aortic cross-clamp time 19 ± 9 min, intensive care unit length of stay 1.6 ± 1.1 days, hospital stay 11.2 ± 5.1 days. There were no complications in 60 patients (50%) and major complications in 8 (6.7%), with 1 patient (0.8%) dying of pneumonia-induced sepsis, 2 (1.7%) requiring revision surgery, 3 (2.5%) requiring invasive treatment (2 pericardial drainage, 1 successful resuscitation), and 2 (1.7%) presenting thromboembolisms (1 cerebral stroke, 1 cardiac thrombus). In hospital minor complications occurred in 22 patients: 17 pericardial effusions (15%), 15 infections requiring treatment (12.5%), 1 sternal instability (0.8%), 4 anemias requiring transfusion (3.3%), 7 pulmonary atelectasis (6%), and 2 post-extubation glottis edema (1.7%). At early outpatient follow-up, complications occurred in 21 patients: 16 (13.3%) pericardial effusions, 4 (3.3%) infections requiring treatment, and 3 (2.5%) keloid scarring. No complications occurred during long-term follow-up. In line with published data, mortality was low (0.8%), yet major complications (6.7%) were more common in these cases than those following percutaneous ASD2 closure. Minor complications were frequent (43%) with no long-term sequelae.

Dnmt3a-mediated inhibition of Wnt in cardiac progenitor cells improves differentiation and remote remodeling after infarction.

Adult cardiac progenitor cells (CPCs) display a low capacity to differentiate into cardiomyocytes in injured hearts, strongly limiting the regenerative capacity of the mammalian myocardium. To identify new mechanisms regulating CPC differentiation, we used primary and clonally expanded Sca-1+ CPCs from murine adult hearts in homotypic culture or coculture with cardiomyocytes. Expression kinetics analysis during homotypic culture differentiation showed downregulation of Wnt target genes concomitant with increased expression of the Wnt antagonist, Wnt inhibitory factor 1 (Wif1), which is necessary to stimulate CPC differentiation. We show that the expression of the Wif1 gene is repressed by DNA methylation and regulated by the de novo DNA methyltransferase Dnmt3a. In addition, miR-29a is upregulated early during CPC differentiation and downregulates Dnmt3a expression, thereby decreasing Wif1 gene methylation and increasing the efficiency of differentiation of Sca-1+ CPCs in vitro. Extending these findings in vivo, transient silencing of Dnmt3a in CPCs subsequently injected in the border zone of infarcted mouse hearts improved CPC differentiation in situ and remote cardiac remodeling. In conclusion, miR-29a and Dnmt3a epigenetically regulate CPC differentiation through Wnt inhibition. Remote effects on cardiac remodeling support paracrine signaling beyond the local injection site, with potential therapeutic interest for cardiac repair.

MRI Assessment of Cardiomyopathy Induced by ß1-Adrenoreceptor Autoantibodies and Protection Through ß3-Adrenoreceptor Overexpression.

The cardiopathogenic role of autoantibodies (aabs) directed against ß1-adrenoreceptors (ß1-AR) is well established. In mouse models, they cause progressive dilated cardiomyopathy (DCM) whose characterization with echocardiography requires prolonged protocols with numerous animals, complicating the evaluation of new treatments. Here, we report on the characterization of ß1-aabs-induced DCM in mice using 11.7T MRI. C57BL/6J mice (n = 10 per group) were immunized against the ß1-AR and left ventricular (LV) systolic function was assessed at 10, 18 and 27 weeks. Increase in LV mass/tibial length ratio was detected as the first modification at 10 weeks together with dilation of cavities, thereby outperforming echocardiography. Significant impairment in diastolic index was also observed in immunized animals before the onset of systolic dysfunction. Morphometric and histological measurements confirmed these observations. The same protocol performed on ß3-AR-overexpressing mice and wild-type littermates (n = 8-12 per group) showed that transgenic animals were protected with reduced LV/TL ratio compared to wild-type animals and maintenance of the diastolic index. This study demonstrates that MRI allows a precocious detection of the subtle myocardial dysfunction induced by ß1-aabs and that ß3-AR stimulation blunts the development of ß1-aabs-induced DCM, thereby paving the way for the use of ß3AR-stimulating drugs to treat this autoimmune cardiomyopathy.

High field magnetic resonance imaging of rodents in cardiovascular research.

Transgenic and gene knockout rodent models are primordial to study pathophysiological processes in cardiovascular research. Over time, cardiac MRI has become a gold standard for in vivo evaluation of such models. Technical advances have led to the development of magnets with increasingly high field strength, allowing specific investigation of cardiac anatomy, global and regional function, viability, perfusion or vascular parameters. The aim of this report is to provide a review of the various sequences and techniques available to image mice on 7-11.7 T magnets and relevant to the clinical setting in humans. Specific technical aspects due to the rise of the magnetic field are also discussed.

Variability of Mouse Left Ventricular Function Assessment by 11.7 Tesla MRI.

We studied intraobserver (n = 24), interobserver (n = 24) and interexperiment (n = 12) reproducibility of left ventricular (LV) mass and volume measurements in mice using an 11.7 T MRI system. The LV systolic function was assessed with a short-axis FLASH-cine sequence in 29 mice, including animals having undergone transverse aortic constriction. Bland-Altman and regression analysis were used to compare the different data sets. Reproducibility was excellent for the LV mass and end-diastolic volume (coefficient of variability (CoV) between 5.4 and 11.8 %), good for end-systolic volume (CoV 15.2-19.4 %) and moderate for stroke volume and ejection fraction (CoV 14.7-20.9 %). We found an excellent correlation between LV mass determined by MRI and ex vivo morphometric data (r = 0.92). In conclusion, LV systolic function can be assessed on an 11.7 T MRI scanner with high reproducibility for most parameters, as needed in longitudinal studies. However, data should be interpreted taking into account the moderate reproducibility of small volumes.

Prospective cardiac MRI for the analysis of biventricular function in children undergoing cancer treatments.

BACKGROUND: Cardiotoxicity is one of the most serious long-term complications in childhood cancer survivors. Measurement of the left ventricular ejection and shortening fraction remains the most common screening tool for cardiac systolic dysfunction. However, M-mode echocardiography can be viewed as a crude approach as refined strategies are now available. The aim of this prospective study was to determine the role of cardiac MRI in the detection of subclinical left or right ventricular dysfunction as well as the prevalence of myocardial scaring in patients undergoing cancer treatments. PROCEDURE: Eighty-one children were enrolled in a pre-chemotherapy and then in a yearly protocol including a: (i) clinical evaluation; (ii) laboratory evaluation; (iii) electrocardiogram; (iv) echocardiogram; and (v) a cardiac magnetic resonance imaging (cMRI). RESULTS: Early left ventricular systolic dysfunction was only detected in two patients. The entire cohort presented a significant increase of the left atrial volume as measured by cMRI. This finding correlated with the total cumulative dose of anthracyclines (r = 0.34; P < 0.05) and the mean left ventricular radiation dose (r = 0.86; P < 0.05). We also observed a mild increase of myocardial scaring, similarly correlated to the radiation dose (r = 0.85; P < 0.05). CONCLUSIONS: Screening tools for late-onset cardiomyopathy secondary to cancer treatment are lacking. Our findings support the use of cMRI for the evaluation of the left atrial volume, as an early marker of diastolic dysfunction, and myocardial delayed enhancement, as a marker of myocardial fibrosis and scaring. Longer follow-up and larger studies are still needed to better define the role of cMRI in the evaluation of childhood cancer survivors.