Intramyocardial cell-based therapy with Lomecel-B during bidirectional cavopulmonary anastomosis for hypoplastic left heart syndrome: the ELPIS phase I trial.

Aims: Hypoplastic left heart syndrome (HLHS) survival relies on surgical reconstruction of the right ventricle (RV) to provide systemic circulation. This substantially increases the RV load, wall stress, maladaptive remodelling, and dysfunction, which in turn increases the risk of death or transplantation. Methods and results: We conducted a phase 1 open-label multicentre trial to assess the safety and feasibility of Lomecel-B as an adjunct to second-stage HLHS surgical palliation. Lomecel-B, an investigational cell therapy consisting of allogeneic medicinal signalling cells (MSCs), was delivered via intramyocardial injections. The primary endpoint was safety, and measures of RV function for potential efficacy were obtained. Ten patients were treated. None experienced major adverse cardiac events. All were alive and transplant-free at 1-year post-treatment, and experienced growth comparable to healthy historical data. Cardiac magnetic resonance imaging (CMR) suggested improved tricuspid regurgitant fraction (TR RF) via qualitative rater assessment, and via significant quantitative improvements from baseline at 6 and 12 months post-treatment (P < 0.05). Global longitudinal strain (GLS) and RV ejection fraction (EF) showed no declines. To understand potential mechanisms of action, circulating exosomes from intramyocardially transplanted MSCs were examined. Computational modelling identified 54 MSC-specific exosome ribonucleic acids (RNAs) corresponding to changes in TR RF, including miR-215-3p, miR-374b-3p, and RNAs related to cell metabolism and MAPK signalling. Conclusion: Intramyocardially delivered Lomecel-B appears safe in HLHS patients and may favourably affect RV performance. Circulating exosomes of transplanted MSC-specific provide novel insight into bioactivity. Conduct of a controlled phase trial is warranted and is underway.Trial registration number NCT03525418.

Autologous Cardiac Stem Cell Injection in Patients with Hypoplastic Left Heart Syndrome (CHILD Study).

Mortality in infants with hypoplastic left heart syndrome (HLHS) is strongly correlated with right ventricle (RV) dysfunction. Cell therapy has demonstrated potential improvements of RV dysfunction in animal models related to HLHS, and neonatal human derived c-kit+ cardiac-derived progenitor cells (CPCs) show superior efficacy when compared to adult human cardiac-derived CPCs (aCPCs). Neonatal CPCs (nCPCs) have yet to be investigated in humans. The CHILD trial (Autologous Cardiac Stem Cell Injection in Patients with Hypoplastic Left Heart Syndrome) is a Phase I/II trial aimed at investigating intramyocardial administration of autologous nCPCs in HLHS infants by assessing the feasibility, safety, and potential efficacy of CPC therapy. Using an open-label, multicenter design, CHILD investigates nCPC safety and feasibility in the first enrollment group (Group A/Phase I). In the second enrollment group, CHILD uses a randomized, double-blinded, multicenter design (Group B/Phase II), to assess nCPC efficacy based on RV functional and structural characteristics. The study plans to enroll 32 patients across 4 institutions: Group A will enroll 10 patients, and Group B will enroll 22 patients. CHILD will provide important insights into the therapeutic potential of nCPCs in patients with HLHS.Clinical Trial Registration https://clinicaltrials.gov/ct2/home NCT03406884, First posted January 23, 2018.

Cardiac MRI Findings of Myocarditis After COVID-19 mRNA Vaccination in Adolescents.

BACKGROUND. A possible association has been reported between COVID-19 messenger RNA (mRNA) vaccination and myocarditis. OBJECTIVE. The purpose of our study was to describe cardiac MRI findings in patients with myocarditis after COVID-19 mRNA vaccination. METHODS. This retrospective study included patients without known prior SARS-CoV-2 infection who underwent cardiac MRI between May 14, 2021, and June 14, 2021, for suspected myocarditis within 2 weeks of COVID-19 mRNA vaccination. Information regarding clinical presentation, hospital course, and events after hospital discharge were recorded. A cardiothoracic imaging fellow and cardiothoracic radiologist reviewed cardiac MRI examinations in consensus. Data were summarized descriptively. RESULTS. Of 52 patients without known prior SARS-CoV-2 infection who underwent cardiac MRI during the study period, five underwent MRI for suspected myocarditis after recent COVID-19 mRNA vaccination. All five patients were male patients ranging in age from 16 to 19 years (mean, 17.2 ± 1.0 [SD] years) who presented within 4 days of receiving the second dose of a COVID-19 mRNA vaccine. Troponin levels were elevated in all patients (mean peak troponin I value, 6.82 ± 4.13 ng/mL). Alternate possible causes of myocarditis were deemed clinically unlikely on the basis of medical history, physical examination findings, myocarditis viral panel, and toxicology screening. Cardiac MRI findings were consistent with myocarditis in all five patients on the basis of the Lake Louise criteria, including early gadolinium enhancement and late gadolinium enhancement (LGE) in all patients and corresponding myocardial edema in four patients. All five patients had a favorable hospital course and were discharged from the hospital in stable condition with improved or resolved symptoms after hospitalization (mean length of hospital stay, 4.8 days). Two patients underwent repeat cardiac MRI that showed persistent, although decreased, LGE. Three patients reported mild intermittent self-resolving chest pain after hospital discharge, and two patients had no recurrent symptoms after discharge. CONCLUSION. In this small case series, all patients with myocarditis after COVID-19 vaccination were male adolescents and had a favorable initial clinical course. All patients showed cardiac MRI findings typical of myocarditis from other causes. LGE persisted in two patients who underwent repeat MRI. These observations do not establish causality. CLINICAL IMPACT. Radiologists should be aware of a possible association of COVID-19 mRNA vaccination and myocarditis and recognize the role of cardiac MRI in the assessment of suspected myocarditis after COVID-19 vaccination.

Exosomes isolated from human cardiosphere-derived cells attenuate pressure overload-induced right ventricular dysfunction.

OBJECTIVES: Cardiosphere-derived cell (CDC) transplantation has been shown to attenuate right ventricular (RV) dysfunction in patients with hypoplastic left heart syndrome. However, live cell transplantation requires complex handling protocols that may limit its use. Exosomes are protein and nucleic acid-containing nanovesicles secreted by many cell types, including stem cells, which have been shown to exert a cardioprotective effect comparable with whole cells following myocardial injury. We therefore sought to evaluate 3 human CDC-derived exosome preparations in a juvenile porcine model of acute pressure-induced RV dysfunction. METHODS: Twenty immunocompetent juvenile Yorkshire pigs (7-10 kg) underwent pulmonary arterial banding followed by intramyocardial test agent administration: control (n = 6), XO-1 (n = 4), XO-2 (n = 5), and XO-3 (n = 5). Animals were monitored for 28 days postoperatively with periodic phlebotomy and echocardiography, followed by extensive postmortem gross and histopathologic analysis. RESULTS: All animals survived the banding operation. One died suddenly on postoperative day 1; another was excluded due to nonstandard response to banding. Of the remaining animals, there were no clinical concerns. RV fractional area change was improved in the XO-1 and XO-2 groups relative to controls at postoperative day 28. On histologic analysis, exosome-treated groups exhibited decreased cardiomyocyte hypertrophy with respect to controls. CONCLUSIONS: Human CDC-derived exosome administration was associated with significant preservation of RV systolic function in the setting of acute pressure overload. Such acellular preparations may prove superior to whole cells and may represent a novel therapeutic approach to clinical myocardial injury.

Cardiorespiratory Fitness in Youth: An Important Marker of Health: A Scientific Statement From the American Heart Association.

Cardiorespiratory fitness (CRF) refers to the capacity of the circulatory and respiratory systems to supply oxygen to skeletal muscle mitochondria for energy production needed during physical activity. CRF is an important marker of physical and mental health and academic achievement in youth. However, only 40% of US youth are currently believed to have healthy CRF. In this statement, we review the physiological principles that determine CRF, the tools that are available to assess CRF, the modifiable and nonmodifiable factors influencing CRF, the association of CRF with markers of health in otherwise healthy youth, and the temporal trends in CRF both in the United States and internationally. Development of a cost-effective CRF measurement process that could readily be incorporated into office visits and in field settings to screen all youth periodically could help identify those at increased risk.

Recommendations for exercise and screening for safe athletic participation in hypertensive youth.

Physical activity is an important component of ideal cardiovascular health. Current guidelines recommend that youth with hypertension participate in competitive sports once hypertensive target organ effects and risks have been assessed and that children with hypertension receive treatment to lower BP below stage 2 thresholds (e.g., < 140/90 mmHg or < 95th percentile + 12 mmHg) before participating in competitive sports. Despite these recommendations, pediatricians and pediatric subspecialists continue to struggle with how best to counsel their patients regarding appropriate forms of physical activity, the impact of exercise on blood pressure, and how best to screen for cardiovascular conditions that place youth at risk for sudden cardiac death. This review provides a summary of our current knowledge regarding the safety and utility of exercise in the management of high blood pressure in youth. We review determinants of blood pressure during exercise, the impact of blood pressure on cardiovascular health and structure, mechanisms for assessing cardiometabolic fitness (e.g., exercise stress test), contraindications to athletic participation, and how best to plan for athletic participation among hypertensive youth. Greater knowledge in these areas may offer clarity to providers faced with the challenge of prescribing exercise recommendations for hypertensive youth.

Stem Cell Therapy for Hypoplastic Left Heart Syndrome: Mechanism, Clinical Application, and Future Directions.

Hypoplastic left heart syndrome is a type of congenital heart disease characterized by underdevelopment of the left ventricle, outflow tract, and aorta. The condition is fatal if aggressive palliative operations are not undertaken, but even after the complete 3-staged surgical palliation, there is significant morbidity because of progressive and ultimately intractable right ventricular failure. For this reason, there is interest in developing novel therapies for the management of right ventricular dysfunction in patients with hypoplastic left heart syndrome. Stem cell therapy may represent one such innovative approach. The field has identified numerous stem cell populations from different tissues (cardiac or bone marrow or umbilical cord blood), different age groups (adult versus neonate-derived), and different donors (autologous versus allogeneic), with preclinical and clinical experience demonstrating the potential utility of each cell type. Preclinical trials in small and large animal models have elucidated several mechanisms by which stem cells affect the injured myocardium. Our current understanding of stem cell activity is undergoing a shift from a paradigm based on cellular engraftment and differentiation to one recognizing a primarily paracrine effect. Recent studies have comprehensively evaluated the individual components of the stem cells' secretomes, shedding new light on the intracellular and extracellular pathways at the center of their therapeutic effects. This research has laid the groundwork for clinical application, and there are now several trials of stem cell therapies in pediatric populations that will provide important insights into the value of this therapeutic strategy in the management of hypoplastic left heart syndrome and other forms of congenital heart disease. This article reviews the many stem cell types applied to congenital heart disease, their preclinical investigation and the mechanisms by which they might affect right ventricular dysfunction in patients with hypoplastic left heart syndrome, and finally, the completed and ongoing clinical trials of stem cell therapy in patients with congenital heart disease.

Study design and rationale for ELPIS: A phase I/IIb randomized pilot study of allogeneic human mesenchymal stem cell injection in patients with hypoplastic left heart syndrome.

Despite advances in surgical technique and postoperative care, long-term survival of children born with hypoplastic left heart syndrome (HLHS) remains limited, with cardiac transplantation as the only alternative for patients with failing single ventricle circulations. Maintenance of systemic right ventricular function is crucial for long-term survival, and interventions that improve ventricular function and avoid or defer transplantation in patients with HLHS are urgently needed. We hypothesize that the young myocardium of the HLHS patient is responsive to the biological cues delivered by bone marrow-derived mesenchymal stem cells (MSCs) to improve and preserve right ventricle function. The ELPIS trial (Allogeneic Human MEsenchymal Stem Cell Injection in Patients with Hypoplastic Left Heart Syndrome: An Open Label Pilot Study) is a phase I/IIb trial designed to test whether MSC injection will be both safe and feasible by monitoring the first 10 HLHS patients for new major adverse cardiac events. If our toxicity stopping rule is not activated, we will proceed to the phase IIb component of our study where we will test our efficacy hypothesis that MSC injection improves cardiac function compared with surgery alone. Twenty patients will be enrolled in a randomized phase II trial with a uniform allocation to MSC injection versus standard surgical care (no injection). The 2 trial arms will be compared with respect to improvement of right ventricular function, tricuspid valve annulus size, and regurgitation determined by cardiac magnetic resonance and reduced mortality, morbidity, and need for transplantation. This study will establish the safety and feasibility of allogeneic mesenchymal stem cell injection in HLHS patients and provide important insights in the emerging field of stem cell-based therapy for congenital heart disease patients.

Cardiac Progenitor Cells Enhance Neonatal Right Ventricular Function After Pulmonary Artery Banding.

BACKGROUND: C-kit+ cardiac progenitor cells (CPCs) have been shown to be safe and effective in large-animal models and in an early-phase clinical trial for adult patients with ischemic heart disease. However, CPCs have not yet been evaluated in a preclinical model of right ventricular (RV) dysfunction, which is a salient feature of many forms of congenital heart disease. METHODS: Human c-kit+ CPCs were generated from right atrial appendage biopsy specimens obtained during routine congenital cardiac operations. Immunosuppressed Yorkshire swine (6 to 9 kg) underwent pulmonary artery banding to induce RV dysfunction. Thirty minutes after banding, pigs received intramyocardial injection into the RV free wall with c-kit+ CPCs (1 million cells, n = 5) or control (phosphate-buffered saline, n = 5). Pigs were euthanized at 30 days postbanding. RESULTS: Banding was calibrated to a consistent rise in the RV-to-systemic pressure ratio across both groups (postbanding: CPCs = 0.76 ± 0.06, control = 0.75 ± 0.03). At 30 days postbanding, the CPCs group demonstrated less RV dilatation and a significantly greater RV fractional area of change than the control group (p = 0.002). In addition, measures of RV myocardial strain, including global longitudinal strain and strain rate, were significantly greater in the CPCs group at 4 weeks relative to control (p = 0.004 and p = 0.01, respectively). The RV free wall in the CPCs group demonstrated increased arteriole formation (p < 0.0001) and less myocardial fibrosis compared with the control group (p = 0.02). CONCLUSIONS: Intramyocardial injection of c-kit+ CPCs results in enhanced RV performance relative to control at 30 days postbanding in neonatal pigs. This model is important for further evaluation of c-kit+ CPCs, including long-term efficacy.

Mesenchymal stem cells preserve neonatal right ventricular function in a porcine model of pressure overload.

Limited therapies exist for patients with congenital heart disease (CHD) who develop right ventricular (RV) dysfunction. Bone marrow-derived mesenchymal stem cells (MSCs) have not been evaluated in a preclinical model of pressure overload, which simulates the pathophysiology relevant to many forms of CHD. A neonatal swine model of RV pressure overload was utilized to test the hypothesis that MSCs preserve RV function and attenuate ventricular remodeling. Immunosuppressed Yorkshire swine underwent pulmonary artery banding to induce RV dysfunction. After 30 min, human MSCs (1 million cells, n = 5) or placebo (n = 5) were injected intramyocardially into the RV free wall. Serial transthoracic echocardiography monitored RV functional indices including 2D myocardial strain analysis. Four weeks postinjection, the MSC-treated myocardium had a smaller increase in RV end-diastolic area, end-systolic area, and tricuspid vena contracta width (P < 0.01), increased RV fractional area of change, and improved myocardial strain mechanics relative to placebo (P < 0.01). The MSC-treated myocardium demonstrated enhanced neovessel formation (P < 0.0001), superior recruitment of endogenous c-kit+ cardiac stem cells to the RV (P < 0.0001) and increased proliferation of cardiomyocytes (P = 0.0009) and endothelial cells (P < 0.0001). Hypertrophic changes in the RV were more pronounced in the placebo group, as evidenced by greater wall thickness by echocardiography (P = 0.008), increased cardiomyocyte cross-sectional area (P = 0.001), and increased expression of hypertrophy-related genes, including brain natriuretic peptide, ß-myosin heavy chain and myosin light chain. Additionally, MSC-treated myocardium demonstrated increased expression of the antihypertrophy secreted factor, growth differentiation factor 15 (GDF15), and its downstream effector, SMAD 2/3, in cultured neonatal rat cardiomyocytes and in the porcine RV myocardium. This is the first report of the use of MSCs as a therapeutic strategy to preserve RV function and attenuate remodeling in the setting of pressure overload. Mechanistically, transplanted MSCs possibly stimulated GDF15 and its downstream SMAD proteins to antagonize the hypertrophy response of pressure overload. These encouraging results have implications in congenital cardiac pressure overload lesions.

Modern Outcomes of Mechanical Circulatory Support as a Bridge to Pediatric Heart Transplantation.

BACKGROUND: Pediatric patients awaiting orthotopic heart transplantation frequently require bridge to transplantation (BTT) with mechanical circulatory support. Posttransplant survival outcomes and predictors of mortality have not been thoroughly described in the modern era using a large-scale analysis. METHODS: The United Network for Organ Sharing database was reviewed to identify pediatric heart transplant recipients from 2005 through 2012. Patients were stratified into three groups: extracorporeal membrane oxygenation (ECMO), ventricular assist device (VAD), and direct transplantation (DTXP). The primary outcome was posttransplant survival. RESULTS: Two thousand seven hundred seventy-seven pediatric patients underwent orthotopic heart transplantation. There were 617 patients who required BTT with mechanical circulatory support (22.2%), of whom there were 428 VAD BTT (69.4%) and 189 ECMO BTT (30.6%). An increase in VAD use was observed during the study period (p < 0.0001). Compared with DTXP, patients in the ECMO BTT group had a lower median age (<1 versus 5 years; p < 0.0001) and were significantly smaller (8 versus 14 kg; p < 0.001), whereas patients in the VAD BTT group were older (8 versus 5 years; p = 0.0002) and larger (24 versus 14 kg; p < 0.001). Actuarial survival was greater in the DTXP group compared with ECMO BTT, but similar to VAD BTT at 30 days and 1, 3, and 5 years. However, this survival difference was lost after censoring the first 4 months after transplant. In multivariable analysis, when restricted to the first 4 months of survival, independent predictors for mortality were ECMO BTT, age, diagnosis, and functional status, whereas VAD BTT was not. CONCLUSIONS: Pediatric patients with DTXP or VAD BTT have equivalent posttransplant survival. However, those requiring ECMO BTT have inferior early posttransplant survival compared with those receiving DTXP.

The innate immune system contributes to tissue-engineered vascular graft performance.

The first clinical trial of tissue-engineered vascular grafts (TEVGs) identified stenosis as the primary cause of graft failure. In this study, we aimed to elucidate the role of the host immune response in the development of stenosis using a murine model of TEVG implantation. We found that the C.B-17 wild-type (WT) mouse (control) undergoes a dramatic stenotic response, which is nearly completely abolished in the immunodeficient SCID/beige (bg) variant. SCID mice, which lack an adaptive immune system due to the absence of T and B lymphocytes, experienced rates of stenosis comparable to WT controls (average luminal diameter, WT: 0.071 ± 0.035 mm, SCID: 0.137 ± 0.032 mm, SCID/bg: 0.804 ± 0.039 mm; P < 0.001). The bg mutation is characterized by NK cell and platelet dysfunction, and systemic treatment of WT mice with either NK cell-neutralizing (anti-NK 1.1 antibody) or antiplatelet (aspirin/Plavix [clopidogrel bisulfate]; Asp/Pla) therapy achieved nearly half the patency observed in the SCID/bg mouse (NK Ab: 0.356 ± 0.151 mm, Asp/Pla: 0.452 ± 0.130 mm). Scaffold implantation elicited a blunted immune response in SCID/bg mice, as demonstrated by macrophage number and mRNA expression of proinflammatory cytokines in TEVG explants. Implicating the initial innate immune response as a critical factor in graft stenosis may provide a strategy for prognosis and therapy of second-generation TEVGs.

Changes in speckle tracking echocardiography measures of ventricular function after percutaneous implantation of the Edwards SAPIEN transcatheter heart valve in the pulmonary position.

BACKGROUND: Patients with free pulmonary regurgitation or mixed pulmonary stenosis and regurgitation and severely dilated right ventricles (RV) show little improvement in ventricular function after pulmonary valve replacement when assessed by traditional echocardiographic markers. We evaluated changes in right and left ventricular (LV) function using speckle tracking echocardiography in patients after SAPIEN transcatheter pulmonary valve (TPV) placement. METHODS: Echocardiograms were evaluated at baseline, discharge, 1 and 6 months after TPV placement in 24 patients from 4 centers. Speckle tracking measures of function included peak longitudinal strain, strain rate, and early diastolic strain rate. RV fractional area change, tricuspid annular plane systolic excursion, and left ventricular LV ejection fraction were assessed. Routine Doppler and tissue Doppler velocities were measured. RESULTS: At baseline, all patients demonstrated moderate to severe pulmonary regurgitation; this improved following TPV placement. No significant changes were detected in conventional measures of RV or LV function at 6 months. RV longitudinal strain (-16.9% vs. -19.6%, P < 0.01), strain rate (-0.87 s(-1) vs. -1.16 s(-1) , P = 0.01), and LV longitudinal strain (-16.2% vs. -18.2%, P = 0.01) improved between baseline and 6 month follow-up. RV early diastolic strain rate, LV longitudinal strain rate and early diastolic strain rate showed no change. CONCLUSION: Improvements in RV longitudinal strain, strain rate, and LV longitudinal strain are seen at 6 months post-TPV. Diastolic function does not appear to change at 6 months. Speckle tracking echocardiography may be more sensitive than traditional measures in detecting changes in systolic function after TPV implantation.

Imaging in congenital pulmonary vein anomalies: the role of computed tomography.

Pulmonary venous anomalies comprise a wide spectrum of anatomical variations and their clinical presentations may vary from the relatively benign single partial anomalous pulmonary venous connection (PAPVC) to the critical obstructed total anomalous pulmonary venous connection (TAPVC). We briefly review the common anomalies encountered, while highlighting the utility that computed tomographic angiography (CTA) provides for this spectrum of extracardiac vascular malformations and connections. CTA has established itself as an invaluable imaging modality in these patients. A detailed knowledge of the CTA imaging findings in pulmonary venous anomalies is crucial to guide clinical decision-making in these patients.

Cardiovascular manifestations of Williams syndrome: imaging findings.

Williams syndrome is a relatively common (1 in 10,000 live births) genetic disorder caused by a deletion involving chromosome 7 that results in a variety of clinically significant abnormalities, including developmental delay, behavioral changes, hypercalcemia, and a distinct "elfin" facial appearance. Congenital cardiovascular disease that presents in childhood is responsible for most of the morbidity and mortality associated with this disorder. The purpose of this pictorial essay is to review imaging findings of some of the more common cardiovascular manifestations of Williams syndrome and to highlight some of the unique anatomic variations that can be seen in these patients.

Modified Starnes procedure in a neonate with severe tricuspid regurgitation.

We report a modification of the Starnes technique for palliating severe tricuspid regurgitation associated with a dysplastic right ventricle in a neonate, using a fenestrated pericardial patch allowing for unidirectional flow. The patient eventually underwent a successful Glenn shunt construction with a persistent reduction in right ventricle size at 1 year follow-up.

Tissue-engineered vascular grafts form neovessels that arise from regeneration of the adjacent blood vessel.

We developed a tissue-engineered vascular graft composed of biodegradable scaffold seeded with autologous bone marrow-derived mononuclear cells (BMMCs) that is currently in clinical trial and developed analogous mouse models to study mechanisms of neovessel formation. We previously reported that seeded human BMMCs were rapidly lost after implantation into immunodeficient mice as host macrophages invaded the graft. As a consequence, the resulting neovessel was entirely of host cell origin. Here, we investigate the source of neotissue cells in syngeneic BMMC-seeded grafts, implanted into immunocompetent mouse recipients. We again find that seeded BMMCs are lost, declining to 0.02% at 14 d, concomitant with host macrophage invasion. In addition, we demonstrate using sex-mismatched chimeric hosts that bone marrow is not a significant source of endothelial or smooth muscle cells that comprise the neovessel. Furthermore, using composite grafts formed from seeded scaffold anastomosed to sex-mismatched natural vessel segments, we demonstrate that the adjacent vessel wall is the principal source of these endothelial and smooth muscle cells, forming 93% of proximal neotissue. These findings have important implications regarding fundamental mechanisms underlying neotissue formation; in this setting, the tissue-engineered construct functions by mobilizing the body's innate healing capabilities to "regenerate" neotissue from preexisting committed tissue cells.