The outcomes of pediatric ventricular assist device support in patients with diastolic heart failure have not been well described. This study reviews the North American experience with Berlin Heart ...EXCOR® ventricular assist device implants in children with such physiology. The Berlin Heart clinical database was reviewed. Patients with primary diastolic dysfunction are included in this study. Twenty pediatric patients with restrictive cardiomyopathy (n = 13), hypertrophic cardiomyopathy (n = 3), or congenital heart disease with restrictive physiology (n = 4) who were supported with EXCOR® were identified. Of these, nine (45%) were successfully bridged to transplant, one (5%) weaned from support, and 10 (50%) died after support was withdrawn. Of patients under age 3 years (n = 13), 38.5% survived, whereas those aged 3 or older (n = 7) had 71.4% survival (P = .35). Biventricular assist device (BiVAD) patients experienced a 27.3% survival, vs 77.8% for patients with left ventricular assist device only (P = .07). Primary causes of death included stroke, infection, acidosis, multisystem organ failure, and bleeding. Pediatric patients with diastolic heart failure comprise a high‐risk population for mechanical circulatory support. However, half of patients with this physiology have been successfully supported to explant with EXCOR®. The trends toward higher mortality for younger patients and those receiving BiVAD support warrant consideration.
MEK inhibitors (MEKi) have shown efficacy in pediatric low-grade glioma as well as plexiform neurofibroma. MEKi have been associated with acute cardiac dysfunction in adults. Cardiac consequences in ...children are unknown. We performed a single center retrospective cohort study evaluating cardiac function by echocardiography (echo) in children and young adults < 21 years receiving MEKi between October 2013 and May 2018. Blinded assessment of left ventricular function by fractional shortening (FS) and ejection fraction (EF) was performed on all available echocardiograms performed before, during, and following therapy, as well as after re-initiation of therapy. Twenty-six patients underwent MEKi therapy with echo follow-up during the study period. Twenty-four of these had complete echo data. Median follow-up was 12 months. Borderline EF (EF 53–57.9%) occurred in 12 (50%) patients; and 3 (12.5%) progressed to abnormal EF (EF < 53%). Cardiac dysfunction, when it occurred, was mild (lowest documented EF was 45%, and lowest FS was 24.4%). EF abnormalities typically fluctuated during therapy, resolved off therapy, and recurred with MEKi re-initiation. No clinical or demographic differences were detected between those who maintained normal cardiac function and those who developed borderline or overt cardiac dysfunction. Symptomatic heart failure did not occur. In this cohort of children and young adults, MEKi use was associated with a high (50%) incidence of borderline or mildly decreased left ventricular function. There was no evidence of permanent cardiac dysfunction. Further evaluation in larger prospective trials is needed.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most treatment refractory and lethal malignancies. The diversity of endothelial cell (EC) lineages in the tumor microenvironment (TME) impacts ...the efficacy of antineoplastic therapies, which in turn remodel EC states and distributions. Here, we present a single-cell resolution framework of diverse EC lineages in the PDAC TME in the context of neoadjuvant chemotherapy, radiotherapy, and losartan. We analyzed a custom single-nucleus RNA-seq dataset derived from 37 primary PDAC specimens (18 untreated, 14 neoadjuvant FOLFIRINOX + chemoradiotherapy, 5 neoadjuvant FOLFIRINOX + chemoradiotherapy + losartan). A single-nucleus transcriptome analysis of 15,185 EC profiles revealed two state programs (ribosomal, cycling), four lineage programs (capillary, arterial, venous, lymphatic), and one program that did not overlap significantly with prior signatures but was enriched in pathways involved in vasculogenesis, stem-like state, response to wounding and hypoxia, and endothelial-to-mesenchymal transition (reactive EndMT). A bulk transcriptome analysis of two independent cohorts (
= 269 patients) revealed that the lymphatic and reactive EndMT lineage programs were significantly associated with poor clinical outcomes. While losartan and proton therapy were associated with reduced lymphatic ECs, these therapies also correlated with an increase in reactive EndMT. Thus, the development and inclusion of EndMT-inhibiting drugs (e.g., nintedanib) to a neoadjuvant chemoradiotherapy regimen featuring losartan and/or proton therapy may be most effective in depleting both lymphatic and reactive EndMT populations and potentially improving patient outcomes.
Medical therapy for pediatric heart failure is based on a detailed mechanistic understanding of the underlying causes, which are diverse and unlike those encountered in most adult patients. Diuresis ...and improved perfusion are the immediate goals of care in the child with acute decompensated heart failure. Conversion to maintenance oral therapy for heart failure is based on the results of landmark studies in adults, as well as recent pediatric clinical trials and heart failure guidelines. There will continue to be an important role for newer drugs, some of which are in active trials in adults, and some of which are already approved for use in children. The need to plan for clinical trials in children during drug development for heart failure is emphasized.
Cancer survivors exposed to anthracycline chemotherapy are at risk for developing cardiomyopathy, which may have delayed clinical manifestation. In a retrospective cross-sectional study, we evaluated ...the utility of cardiopulmonary exercise testing (CPET) for detecting early cardiac disease in 35 pediatric cancer survivors by examining the associations between peak exercise capacity (measured via percent predicted peak VO
) and resting left ventricular (LV) function on echocardiography and cardiac magnetic resonance imaging (cMRI). We additionally assessed the relationships between LV size on resting echocardiography or cMRI and percent predicted peak VO
since LV growth arrest can occur in anthracycline-exposed patients prior to changes in LV systolic function. We found reduced exercise capacity in this cohort, with low percent predicted peak VO
(62%, IQR: 53-75%). While most patients in our pediatric cohort had normal LV systolic function, we observed associations between percent predicted peak VO
and echocardiographic and cMRI measures of LV size. These findings indicate that CPET may be more sensitive in manifesting early anthracycline-induced cardiomyopathy than echocardiography in pediatric cancer survivors. Our study also highlights the importance of assessing LV size in addition to function in pediatric cancer survivors exposed to anthracyclines.
Dilated cardiomyopathy (DCM) is an inevitable complication of Duchenne muscular dystrophy (DMD). Late gadolinium enhancement (LGE) demonstrated by cardiac MRI occurs in DMD-related DCM, indicating ...myocyte death and remodeling. We conducted a retrospective chart review identifying DMD patients in our center between January 2009 and July 2013. Subjects were cohorted by presence of LGE before age 14
.
We excluded patients in whom we could not determine LGE status prior to age 14. We reviewed comprehensive clinical data. Of the 41 subjects with complete data, 15 demonstrated LGE before age 14 (“early LGE”) and 26 had no LGE by age 14 (“controls”). Those with early LGE exhibited a more rapid decline in LV fractional shortening (
p
= 0.028). Patients with early LGE were younger at age of initiation of ACE inhibition (
p
= 0.025), mineralocorticoid receptor antagonism (
p
= 0.0024), and beta-blockade (
p
= 0.0017), suggesting aggressive clinical management in response to abnormal MRI findings. There were no significant differences in LV dilation between the two groups (
p
= 0.1547). Early LGE was not associated with obesity (
p
= 0.32), age at loss of ambulation (
p
= 0.31), or heart rate (
p-
value > 0.8). Early onset of myocardial fibrosis as indicated by LGE on cardiac MRI is associated with earlier progression of cardiomyopathic changes despite earlier medication therapy. Identifying this risk factor, observed in 34% of our cohort during preadolescence, may guide medical therapy and early counseling about cardiomyopathy progression. We advocate for obtaining at least one MRI in patients with DMD prior to age 14 to risk stratify patients.
Pulmonary hypertension (PH) is a rare yet serious complication of obstructive sleep apnea (OSA). Echocardiographic screening for PH is recommended in children with severe OSA, but the health care ...burden of universal screening is high. We sought to determine the prevalence of PH on echocardiogram among children with severe OSA and identify variables associated with a positive PH screen.
Retrospective study of 318 children with severe OSA (obstructive apnea-hypopnea index ≥ 10 events/h) and echocardiogram within 1 year of polysomnogram. PH-positive echocardiogram was defined by peak tricuspid regurgitation velocity ≥ 2.5 m/s and/or 2 or more right-heart abnormalities suggestive of elevated pulmonary artery pressure. Patient characteristics and polysomnogram data were compared to identify factors associated with PH.
Twenty-six children (8.2%; 95% confidence interval CI 5.4-11.8%) had echocardiographic evidence of PH. There was no difference in age, sex, body mass index, obstructive apnea-hypopnea index, or oxygenation indices between patients with and without PH. Sleep-related hypoventilation (end-tidal CO
> 50 mmHg for > 25% of total sleep time) was present in 25% of children with PH compared with 6.3% of children without PH (adjusted prevalence ratio = 2.73; 95% CI 1.18-6.35). Forty-six percent of children (12/26) with PH had Down syndrome vs 14% (41/292) without PH (adjusted prevalence ratio = 3.11; 95% CI 1.46-6.65).
There was a relatively high prevalence of PH on echocardiogram in our cohort of children with severe OSA. The findings of increased PH prevalence among children with sleep-related hypoventilation or Down syndrome may help inform the development of targeted screening recommendations for specific pediatric OSA populations.
Maloney MA, Davidson Ward SL, Su JA, et al. Prevalence of pulmonary hypertension on echocardiogram in children with severe obstructive sleep apnea.
. 2022;18(6):1629-1637.
Outcomes after cardiac transplantation have improved over past decades, but long-term graft survival remains limited in part because of uncertainty regarding clinical implications of donor-specific ...antibodies (DSAs). The purpose of this review is to consolidate recent advances in knowledge on the topic of DSA and their potential to impact long-term prognosis after heart transplantation.
The presence of persistent DSA increases the risk of poor outcome after heart transplantation, including development of antibody-mediated rejection (AMR), graft failure, cardiac allograft vasculopathy, and mortality. Importantly, different DSA vary in clinical significance. DSA capable of activating the complement cascade portend a higher risk of developing AMR. human leukocyte antigen class I and class II antigens are expressed differently within the heart, and so, clinical manifestations of class I and class II DSA vary accordingly. Further, compared with class I, class II DSA carry an increased risk of graft loss and mortality. When comparing preexisting DSA with formation of de-novo DSA, de-novo DSA are associated with worse outcome.
DSAs are generally associated worse long-term prognosis after heart transplantation but vary in their clinical significance. Recognition of specific risk profiles is essential for guiding posttransplant antibody management.
Pediatric HTs account for 13% of all HTs with >60% of recipients surviving at least 10 years post‐HT. The purpose of this systematic review is to synthesize the literature on exercise capacity of ...pediatric HT recipients to improve understanding of the mechanisms that may explain the decreased exercise capacity. Six databases were searched for studies that compared the exercise capacity of HT recipients ≤21 years old with a control group or normative data. Sixteen studies were included. Pediatric HT recipients, as compared to controls or normative data, exhibit significantly higher resting HR, and at peak exercise exhibit significantly decreased HR, VO2, power, work, minute ventilation, and exercise duration. Peak VO2 appears to improve within the first 2.5 years post‐HT; peak work remains constant; and there is inconclusive evidence that peak HR, HR recovery, and HR reserve improve with time since HT. These results are discussed in the context of the mechanisms that may explain the impaired exercise capacity of pediatric HT recipients, including chronotropic incompetence, graft dysfunction, side effects of immunosuppression therapy, and deconditioning. In addition, the limited literature on rehabilitation after pediatric HT is summarized.
Dilated cardiomyopathy (DCM) inevitably afflicts patients with Duchenne muscular dystrophy (DMD) as a consequence of cell death induced by unguarded calcium influx into cardiomyocytes. This mechanism ...may also inhibit muscle relaxation in early stages of cardiomyopathy. ACE inhibition (ACEi) is known to delay the onset and slow the progression of DCM in DMD. The objective of this study is to use echocardiography to assess for preclinical cardiac changes consistent with intracellular calcium dysregulation before the onset of overt ventricular dysfunction, and to evaluate how prophylactic ACEi may alter these pre-cardiomyopathic changes in the pediatric DMD population. We examined 263 echocardiograms from 70 pediatric patients with DMD. We defined abnormal tonic contraction (TC) as left ventricular internal dimension in diastole (LVIDd)
Z
-score < −1.5. In our cohort, we found that TC is detectable as early as 8 years of age, and most commonly affects patients between 11 and 15 years. This effect was independent of LV mass and systolic function. Prophylactic ACEi decreased the incidence of TC (
p
= 0.007) and preserved cardiac function (
p
< 0.0001). Left ventricular TC often precedes DCM in DMD, most commonly affecting the 11- to 15-year-old age range. TC is not related to ventricular hypertrophy, but rather may be a clinical correlate of the “calcium hypothesis” of DMD pathophysiology. LV TC is thus a promising biomarker for early detection of cardiomyopathy in DMD. ACEi prophylaxis suppresses LV TC and delays the development of DCM in DMD.
