Pediatric dilated cardiomyopathy: a review of current clinical approaches and pathogenesis.

Pediatric dilated cardiomyopathy (DCM) is a rare, yet life-threatening cardiovascular condition characterized by systolic dysfunction with biventricular dilatation and reduced myocardial contractility. Therapeutic options are limited with nearly 40% of children undergoing heart transplant or death within 2 years of diagnosis. Pediatric patients are currently diagnosed based on correlating the clinical picture with echocardiographic findings. Patient age, etiology of disease, and parameters of cardiac function significantly impact prognosis. Treatments for pediatric DCM aim to ameliorate symptoms, reduce progression of disease, and prevent life-threatening arrhythmias. Many therapeutic agents with known efficacy in adults lack the same evidence in children. Unlike adult DCM, the pathogenesis of pediatric DCM is not well understood as approximately two thirds of cases are classified as idiopathic disease. Children experience unique gene expression changes and molecular pathway activation in response to DCM. Studies have pointed to a significant genetic component in pediatric DCM, with variants in genes related to sarcomere and cytoskeleton structure implicated. In this regard, pediatric DCM can be considered pediatric manifestations of inherited cardiomyopathy syndromes. Yet exciting recent studies in infantile DCM suggest that this subset has a distinct etiology involving defective postnatal cardiac maturation, such as the failure of programmed centrosome breakdown in cardiomyocytes. Improved knowledge of pathogenesis is central to developing child-specific treatment approaches. This review aims to discuss the established biological pathogenesis of pediatric DCM, current clinical guidelines, and promising therapeutic avenues, highlighting differences from adult disease. The overarching goal is to unravel the complexities surrounding this condition to facilitate the advancement of novel therapeutic interventions and improve prognosis and overall quality of life for pediatric patients affected by DCM.

Decreased erythrocyte aggregation in Glenn and Fontan: univentricular circulation as a rheologic disease model.

BACKGROUND: In the Fontan palliation for single ventricle heart disease (SVHD), pulmonary blood flow is non-pulsatile/passive, low velocity, and low shear, making viscous power loss a critical determinant of cardiac output. The rheologic properties of blood in SVHD patients are essential for understanding and modulating their limited cardiac output and they have not been systematically studied. We hypothesize that viscosity is decreased in single ventricle circulation. METHODS: We evaluated whole blood viscosity, red blood cell (RBC) aggregation, and RBC deformability to evaluate changes in healthy children and SVHD patients. We altered suspending media to understand cellular and plasma differences contributing to rheologic differences. RESULTS: Whole blood viscosity was similar between SVHD and healthy at their native hematocrits, while viscosity was lower at equivalent hematocrits for SVHD patients. RBC deformability is increased, and RBC aggregation is decreased in SVHD patients. Suspending SVHD RBCs in healthy plasma resulted in increased RBC aggregation and suspending healthy RBCs in SVHD plasma resulted in lower RBC aggregation. CONCLUSIONS: Hematocrit corrected blood viscosity is lower in SVHD vs. healthy due to decreased RBC aggregation and higher RBC deformability, a viscous adaptation of blood in patients whose cardiac output is dependent on minimizing viscous power loss. IMPACT: Patients with single ventricle circulation have decreased red blood cell aggregation and increased red blood cell deformability, both of which result in a decrease in blood viscosity across a large shear rate range. Since the unique Fontan circulation has very low-shear and low velocity flow in the pulmonary arteries, blood viscosity plays an increased role in vascular resistance, therefore this work is the first to describe a novel mechanism to target pulmonary vascular resistance as a modifiable risk factor. This is a novel, modifiable risk factor in this patient population.

Safety of Continuing Anticoagulation Prior to Cardiac Catheterization in Pediatric Patients: A Los Angeles Center Experience.

This is the first report specifically describing outcomes of pediatric patients who underwent cardiac catheterization while on uninterrupted anticoagulation. One hundred forty-four cardiac catheterizations were identified that met inclusion criteria at our institution from 11/2014 to 10/2019. The median age and weight of the patients were 6.3 [0.01-20.9] years and 19.3 [2.1-172.5] kg, respectively. Seventy-eight (54%) catheterizations involved inpatients. The most common cardiac diagnoses among the cohort were single ventricle (n = 41), conotruncal defects (n = 37), and structurally normal heart (n = 16). The most common indications for anticoagulation were arterial/venous thrombus (n = 45), Fontan physiology (n = 32), and mechanical valve thrombus prophylaxis (n = 27). The anticoagulation medications used were warfarin (n = 57), heparin (n = 52), enoxaparin (n = 25), fondaparinux (n = 5), rivaroxaban (n = 2), and both heparin and warfarin (n = 3). Interventions were performed in 96 cases (67%). The median length of the procedure was 122.5 [15-760] minutes, and the median time to achieve hemostasis was 18.0 [range: 5-76, IQR: 13-25] minutes. Adverse events were present in 11 cases (7.6%), and of those only 2 cases (1.4%) were bleeding-related complications. Our single-center data suggest that performing cardiac catheterization on pediatric patients while on uninterrupted anticoagulation is safe and does not substantially increase the risk of bleeding complications based on a cohort of patients that varied in age, size, diagnosis, medical complexity, and type of intervention performed. Patients on warfarin therapy for a mechanical valve are most likely to benefit from this practice, as the ability to continue warfarin therapy avoids the need for bridging and other interruption-related complications.

Characteristics and outcomes of acute COVID-19 infection in paediatric and young adult patients with underlying cardiac disease.

OBJECTIVE: To describe outcomes of acute coronavirus disease 2019 in paediatric and young adult patients with underlying cardiac disease and evaluate the association between cardiac risk factors and hospitalisation. STUDY DESIGN: We conducted a retrospective single-institution review of patients with known cardiac disease and positive severe acute respiratory syndrome coronavirus 2 RT-PCR from 1 March, 2020 to 30 November, 2020. Extracardiac comorbidities and cardiac risk factors were compared between those admitted for coronavirus disease 2019 illness and the rest of the cohort using univariate analysis. RESULTS: Forty-two patients with a mean age of 7.7 ± 6.7 years were identified. Six were 18 years of age or more with the oldest being 22 years of age. Seventy-six percent were Hispanic. The most common cardiac diagnoses were repaired cyanotic (n = 7, 16.6%) and palliated single ventricle (n = 7, 16.6%) congenital heart disease. Fourteen patients (33.3%) had underlying syndromes or chromosomal anomalies, nine (21%) had chronic pulmonary disease and eight (19%) were immunosuppressed. Nineteen patients (47.6%) reported no symptoms. Sixteen (38.1%) reported only mild symptoms. Six patients (14.3%) were admitted to the hospital for acute coronavirus disease 2019 illness. Noncardiac comorbidities were associated with an increased risk of hospitalisation (p = 0.02), particularly chronic pulmonary disease (p = 0.01) and baseline supplemental oxygen requirement (p = 0.007). None of the single ventricle patients who tested positive required admission. CONCLUSIONS: Hospitalisations for coronavirus disease 2019 were rare among children and young adults with underlying cardiac disease. Extracardiac comorbidities like pulmonary disease were associated with increased risk of hospitalisation while cardiac risk factors were not.

Coronary Artery Changes in Patients with Multisystem Inflammatory Syndrome in Children: Los Angeles Experience.

We compared cardiac findings in patients with multisystem inflammatory syndrome in children and Kawasaki disease in the first 6 months of the 2020 coronavirus disease pandemic to patients with Kawasaki disease during 2016-2019. We saw a high rate of coronary aneurysms in 2020, with a similar rate of coronary involvement but greater volume and incidence of cardiac dysfunction compared with previous years.

Non-invasive biomarkers of Fontan-associated liver disease.

BACKGROUND & AIMS: Fontan-associated liver disease (FALD) has emerged as an important morbidity following surgical palliation of single ventricle congenital heart disease. In this study, non-invasive biomarkers that may be associated with severity of FALD were explored. METHODS: A retrospective cohort of paediatric patients post-Fontan who underwent liver biopsy at a high volume at a paediatric congenital heart disease centre was reviewed. RESULTS: Among 106 patients, 66% were male and 69% were Hispanic. The mean age was 14.4 ± 3.5 years, and biopsy was performed 10.8 ± 3.6 years post-Fontan. The mean BMI was 20.8 ± 5 kg/m2, with 27.4% meeting obesity criteria. Bridging fibrosis was observed in 35% of patients, and 10.4% of all patients had superimposed steatosis. Bridging fibrosis was associated with lower platelet counts (168.3 ± 58.4 vs. 203.9 ± 65.8 K/µl for congestive hepatic fibrosis score [CHFS] 0-2b, p = 0.009), higher bilirubin (1.7 ± 2.2 vs. 0.9 ± 0.7 mg/dl, p = 0.0090), higher aspartate aminotransferase-to-platelet ratio index [APRI] and fibrosis-4 [FIB-4] scores (APRI: 0.5 ± 0.3 vs. 0.4 ± 0.1, p <0.01 [AUC: 0.69] and FIB-4: 0.6 ± 0.4 vs. 0.4 ± 0.2, p <0.01 [AUC: 0.69]), and worse overall survival (median 2 years follow-up post-biopsy, p = 0.027). Regression modelling of temporal changes in platelet counts before and after biopsy correlated with fibrosis severity (p = 0.005). CONCLUSIONS: In this large, relatively homogeneous adolescent population in terms of age, ethnicity, and Fontan duration, bridging fibrosis was observed in 35% of patients within the first decade post-Fontan. Bridging fibrosis was associated with worse survival. Changes in platelet counts, even years before biopsy, and APRI/FIB-4 scores had modest discriminatory power in identifying patients with advanced fibrosis. Steatosis may represent an additional risk factor for disease progression in obese patients. Further prospective studies are necessary to develop strategies to screen for FALD in the adolescent population. LAY SUMMARY: In this study, the prevalence of Fontan-associated liver disease (FALD) in the young adult population and clinical variables that may be predictive of fibrosis severity or adverse outcomes were explored. Several lab-based, non-invasive markers of bridging fibrosis in FALD were identified, suggesting that these values may be followed as a prognostic biomarker for FALD progression in the adolescent population.

Routine Surveillance Catheterization is Useful in Guiding Management of Stable Fontan Patients.

We developed a Fontan surveillance catheterization protocol as part of routine assessment of stable patients 10 years after Fontan completion. The surveillance catherization includes hemodynamic assessment with inhaled nitric oxide, angiography, liver biopsy, and transcatheter intervention if indicated. We aimed to describe hemodynamic and liver biopsy findings, response to pulmonary vasoreactivity testing, rates of transcatheter intervention, and changes in medical therapy following surveillance catheterization in stable Fontan patients. A single-center retrospective review of Fontan patients undergoing surveillance catheterization between November 2014 and May 2019 was performed. Liver biopsies were independently scored by two pathologists. Sixty-three patients underwent surveillance catheterization (mean age 14.6 ± 3.0 years). The mean Fontan pressure was 11.8 ± 2.1 mmHg. The mean cardiac index was 2.9 ± 0.6 L/min/m2. In the 51 patients who underwent pulmonary vasoreactivity testing, there was a significant decrease in median pulmonary vascular resistance (1.8 [range 0.8-4.1] vs 1.4 [range 0.7-3.0] Wood units × m2; p < 0.001). The mean cardiac index increased (3.0 ± 0.6 vs 3.2 ± 0.7 L/min/m2, p = 0.009). The Fontan pressure did not change significantly. Fifty-seven patients underwent liver biopsy, and all but one showed fibrosis. Nineteen patients (33.3%) demonstrated bridging fibrosis or cirrhosis. Twenty-five patients underwent 34 transcatheter interventions. Pulmonary artery or Fontan stent placement was performed in 19 patients. Phosphodiesterase type 5 inhibitors were initiated in nine patients following surveillance catheterization. Routine surveillance catheterization with liver biopsy in adolescent Fontan patients reveals information that can guide interventional and medical management. Further long-term follow-up and assessment are indicated to assess the benefit of these interventions.

Stent treatment of ostial branch pulmonary artery stenosis: initial and medium-term outcomes and technical considerations to avoid and minimise stent malposition.

OBJECTIVE: Stenting of ostial pulmonary artery stenosis presents several unique challenges. These include difficulty in defining anatomy and need for precise stent placement in order to avoid missing the ostial stenosis or jailing either the contralateral branch pulmonary artery or the ipsilateral upper lobe branch. DESIGN: A retrospective review of outcomes was conducted in 1.5 or 2-ventricle patients who underwent stent placement for ostial branch pulmonary artery stenosis. Specific catheterisation lab techniques were reviewed. RESULTS: Forty-seven branch pulmonary arteries underwent stent placement for ostial stenosis in 43 patients. The median age and weight were 3.7 (0.3-18.1) years and 14.2 (5.6-70.0) kg, respectively. Three (2-8) angiographic projections were needed to profile the ostial stenosis. Open-cell stents were used in 23 and stents were modified in 5 cases. Following stent implantation, the minimum diameter improved from 3.6 (0.8-10.5) to 8.1 (4.2-16.5) mm (p < 0.001). The gradient improved from 21 (0-66) to 4 (0-27) mmHg (p < 0.001). Stent malposition occurred in eight (17%) of the stents placed. Five migrated distally causing suboptimal ostial coverage necessitating placement of a second stent in four. Three migrated proximally and partially jailed the contralateral pulmonary artery. Intentional jailing of the upper lobe branch occurred in four additional cases. At a follow-up of 2.4 (0.3-4.9) years, 15 stents underwent further dilation and 1 had a second stent placed within the exiting stent. CONCLUSION: Ostial branch pulmonary artery stenosis may require additional angiography to accurately define the ostial stenosis. Treatment with stents is effective but carries high rates of stent malposition.

Unmasking the borderline coarctation: the utility of isoproterenol in the paediatric cardiac catheterisation laboratory.

BACKGROUND: One indication for intervention in coarctation of the aorta is a peak-to-peak gradient >20 mmHg. Gradients may be masked in patients under general anaesthesia and may be higher during exercise. Isoproterenol was given during cardiac catheterisation to simulate a more active physiologic state. OBJECTIVES: We aimed to describe the haemodynamic effects of isoproterenol in patients with coarctation and the impact of intervention on the elicited gradients. METHODS: A retrospective study was performed on two-ventricle patients who underwent cardiac catheterisation for coarctation with isoproterenol testing. RESULTS: 25 patients received isoproterenol before and after intervention. With isoproterenol, the mean diastolic (p=0.0015) and mean arterial (p=0.0065) blood pressures proximal to the coarctation decreased significantly. The mean systolic, diastolic, and mean arterial blood pressures distal to the coarctation decreased significantly (p20 mmHg. Post intervention, the median gradient decreased to 2 (0-29) mmHg, versus baseline, p=0.005, and with isoproterenol it decreased to 8 (0-27) mmHg, versus pre-intervention isoproterenol, p<0.0001. There were significant improvements in the gradients by Doppler (<0.0001) and by blood pressure cuff (p=0.0313). The gradients on isoproterenol best correlated with gradients by blood pressure cuff in the awake state (R2=0.76, p<0.0001). CONCLUSIONS: Isoproterenol can be a useful tool to assess the significance of a coarctation and the effectiveness of an intervention. Percutaneous interventions can effectively reduce the gradients elicited by isoproterenol.

Reduction in Radiation Dose in a Pediatric Cardiac Catheterization Lab Using the Philips AlluraClarity X-ray System.

The objective of this study was to compare radiation doses and imaging quality using Philips AlluraClarity (Philips Healthcare, Best, The Netherlands) X-ray system and an older generation reference system. AlluraClarity is a new generation fluoroscopy system designed to reduce radiation without compromising image quality, but reports of its use in pediatric patients are limited. Dose area products (DAP, mGy cm2) and DAP/kg were compared in patients catheterized using Allura Xper and AlluraClarity systems over a year of use for each. Randomly selected studies from each system were assessed for image quality. The 430 patients imaged with Clarity were larger than the 332 imaged with Xper (median BSA: 0.74 vs. 0.64 m2, p = 0.06), and median total fluoroscopic times (TFT) were similar (15.8 vs. 16.1 min, p = 0.37). Median DAPs were 8661 mGy cm2 (IQR: 18,300 mGy cm2) and 4523 mGy cm2 (IQR: 11,596 mGy cm2) with Xper and Clarity, respectively (p < 0.001). There was a reduction in median DAP in all procedure categories. After adjustment for BSA, TFT, and procedure type, using Clarity was associated with a 57.5% (95% CI 51.5-62.8%, p < 0.001) reduction in DAP for all procedures. Reductions did not significantly differ by weight (<10 kg, 10-40 kg, ≥ 40 kg). There was an adjusted percent reduction in DAP for each procedure category ranging from 39.0% (95% CI 25.6-50.1%, p < 0.001) for cardiac biopsies with or without coronary angiography to 67.6% (95% CI 61.2-72.8%, p < 0.001) for device occlusions. Mean overall imaging quality scores (4.3 ± 0.8 with Clarity vs. 4.4 ± 0.6 with Xper, p = 0.62) and scores based on specific quality parameters were similar in the two groups. Use of AlluraClarity substantially reduced radiation doses compared to the older generation reference system without compromising imaging quality in a pediatric cardiac catheterization lab.

Anomalous left coronary artery from the pulmonary artery discovered following total anomalous pulmonary venous return repair: a rare entity.

We describe a case of anomalous left coronary artery from the pulmonary artery in association with total anomalous pulmonary venous return. The infant was diagnosed with total anomalous pulmonary venous return at 6 weeks of age and underwent successful surgical repair. On routine follow-up, he was found to have an anomalous left coronary artery from the pulmonary artery without evidence of mitral regurgitation or left ventricular dysfunction. The presence of the left-to-right shunt and secondary elevation in pulmonary artery pressures likely masked the usual findings associated with this coronary anomaly.

Relationship of pulmonary artery wedge pressure to left atrial pressure and pulmonary vascular resistance in preoperative Fontan patients.

Pulmonary artery wedge pressure (PAWp) as a surrogate for left atrial pressure (LAp) has been validated in patients with fully pulsatile two-ventricle circulations. This study was to validate PAWp as an accurate estimate of LAp for calculating pulmonary vascular resistance in single-ventricle patients after the bidirectional Glenn operation. A prospective study measuring direct branch pulmonary artery pressures, ipsilateral PAWp, and direct LAp to calculate pulmonary and systemic blood flows was conducted. Pulmonary vascular resistance (PVR) was calculated for each patient using the PAWp and compared to the PVR calculated by direct LAp measurements. Twenty-eight patients were enrolled; 27 were eligible for study inclusion. Ages ranged from 21 to 60 months and weights ranged from 9.5 to 20.8 kg. Underlying congenital heart defect diagnoses varied, with all patients either functionally or anatomically univentricular. Left mPAWp measured 4.4 ± 2.6, statistically different from simultaneous direct mLAp of 2.5 ± 2.4 mmHg (P < 0.001. Right mPAWp measured 4.3 ± 3.2 mmHg, statistically different from simultaneous direct mLAp of 2.8 ± 2.6 mmHg (P < 0.001. The PVR calculated using mPAWp was 1.2 ± 0.7 W.U., statistically different to 1.8 ± 0.95 W.U. using mLAp (P < 0.001). The average PVR measurement calculated using mPAWp underestimated the PVR calculated using mLAp by 0.6 W.U. It can be extrapolated that a PVR of 2.3 W.U. calculated using wedge measurements would estimate a PVR of 3 W.U. calculated using direct LA measurements. In this study, the PVR calculated using PAWp as a surrogate for LAp either equaled or underestimated the true PVR, up to 33% different. This difference is important in patients with univentricular physiology who rely on low PVR for cardiac output. Thus, based on this study, a PVR measurement of greater than 2.3 W.U. by the mPAWp method should prompt a direct LA pressure measurement, in order to more appropriately determine true surgical risk.

Differential branch pulmonary artery growth after the Norwood procedure with right ventricle-pulmonary artery conduit versus modified Blalock-Taussig shunt in hypoplastic left heart syndrome.

OBJECTIVES: The Norwood procedure with right ventricle-pulmonary artery conduit is thought to improve postoperative hemodynamics in hypoplastic left heart syndrome, but its effects on pulmonary artery growth are unknown. This study evaluated pulmonary artery growth after the Norwood procedure in patients with a right ventricle-pulmonary artery conduit as compared with patients with a modified Blalock-Taussig shunt. METHODS: A total of 159 patients at our institution underwent the Norwood procedure between January 2000 and September 2005. Patients were divided into group A or B if they had a modified Blalock-Taussig shunt (n = 103) or a right ventricle-pulmonary artery conduit (n = 56). Angiograms from the pre-Glenn catheterizations were used to measure pulmonary artery size and assess shunt stenosis (n = 64). RESULTS: Fifty-five (53.4%) patients in group A versus 40 (71.4%) in group B underwent Glenn surgery. Group B patients often required an additional shunt (modified Blalock-Taussig) before the Glenn procedure because of hypoxemia (8/40 vs 1/55; P = .004). Branch pulmonary artery growth was better in group B patients who did not require an additional shunt (Nakata index 212 vs 169 mm(2)/m(2); P = .004) and more balanced than in group A (right pulmonary artery/left pulmonary artery ratio = 1.02 vs 1.39; P = .001) as a result of greater left pulmonary artery size (29 vs 19 mm(2); P = .001). However, group B experienced more shunt stenosis (8/32 vs 2/32; P = .001), underwent the Glenn operation earlier (192 vs 246 days; P = .03), and had central pulmonary artery hypoplasia develop more often than group A patients (25/32 vs 14/32; P = .01). CONCLUSION: The Norwood procedure with a right ventricle-pulmonary artery conduit promotes better distal left pulmonary artery growth resulting in more balanced branch pulmonary artery size, but central pulmonary artery hypoplasia occurs more often. Early right ventricle-pulmonary artery conduit stenosis also increases the need for additional shunting or early Glenn surgery.