Frameshift variants in C10orf71 cause dilated cardiomyopathy in human, mouse, and organoid models.

Research advances over the past 30 years have confirmed a critical role for genetics in the etiology of dilated cardiomyopathies (DCMs). However, full knowledge of the genetic architecture of DCM remains incomplete. We identified candidate DCM causal gene, C10orf71, in a large family with 8 patients with DCM by whole-exome sequencing. Four loss-of-function variants of C10orf71 were subsequently identified in an additional group of492 patients with sporadic DCM from 2 independent cohorts. C10orf71 was found to be an intrinsically disordered protein specifically expressed in cardiomyocytes. C10orf71-KO mice had abnormal heart morphogenesis during embryonic development and cardiac dysfunction as adults with altered expression and splicing of contractile cardiac genes. C10orf71-null cardiomyocytes exhibited impaired contractile function with unaffected sarcomere structure. Cardiomyocytes and heart organoids derived from human induced pluripotent stem cells with C10orf71 frameshift variants also had contractile defects with normal electrophysiological activity. A rescue study using a cardiac myosin activator, omecamtiv mecarbil, restored contractile function in C10orf71-KO mice. These data support C10orf71 as a causal gene for DCM by contributing to the contractile function of cardiomyocytes. Mutation-specific pathophysiology may suggest therapeutic targets and more individualized therapy.

Characteristics of Cardiac Abnormalities in Pediatric Patients With Acute COVID-19.

Introduction Coronavirus disease 2019 (COVID-19) is known to cause cardiac abnormalities in adults. Cardiac abnormalities are well-described in multisystem inflammatory syndrome in children, but effects in children with acute COVID-19 are less understood. In this multicenter study, we assessed the cardiac effects of acute COVID-19 among hospitalized children (<21 years) admitted to three large healthcare systems in New York City. Methods We performed a retrospective observational study. We examined electrocardiograms, echocardiograms, troponin, or B-type natriuretic peptides. Results Of 317 admitted patients, 131 (41%) underwent cardiac testing with 56 (43%) demonstrating cardiac abnormalities. Electrocardiogram abnormalities were the most common (46/117 patients (39%)), including repolarization abnormalities and QT prolongation. Elevated troponin occurred in 14/77 (18%) patients and B-type natriuretic peptide in 8/39 (21%) patients. Ventricular dysfunction was identified in 5/27 (19%) patients with an echocardiogram, all of whom had elevated troponin. Ventricular dysfunction resolved by first outpatient follow-up. Conclusion Electrocardiogram and troponin can assist clinicians in identifying children at risk for cardiac injury in acute COVID-19.

Fetal echocardiographic diagnosis of a triad with common embryological origins: Cervical aortic arch, retro-aortic left innominate vein and coarctation of the aorta.

Cervical aortic arch (CAA) and retro-aortic innominate vein (RAIV) are rare entities which can be associated with one another in a structurally normal heart. Less well recognized is the fact, that a third entity may often be present as well, since aortic arch abnormalities are common in a CAA. Hence, these three entities (CAA, RAIV, and an arch anomaly - in this case a post-ductal coarctation) may present as a triad. We present the first prenatal diagnosis of this rare triad which can be explained by common embryological origins which are discussed along with instructive aspects in diagnosis and management.

Association of A Dilated Coronary Sinus in the Fetus with Actual and Apparent Coarctation of the Aorta and Diminutive Left Heart Structures.

Evidence suggests an association between left heart obstructive lesions and dilated coronary sinus (DCS), but this has not been studied in fetuses. A retrospective review of fetal echocardiograms (FE) over an 8-year period was conducted, and patients with DCS were identified and confirmed postnatally. There were 5840 FE performed on 4920 women during this period. Of 49 patients with DCS, 22 had normal intracardiac anatomy and 27 patients had congenital heart disease (CHD) yielding an incidence of 4.6 % in the presence of CHD (27/584). Of 27 patients with DCS and CHD, approximately a third had either hypoplastic left ventricles and/or coarctations (10/27, 37 %). The incidence of left heart obstructive lesions was much higher in the presence of a DCS (37 % vs 45/557, 8 %, p < 0.0001). The odds ratio of left heart hypoplasia in fetuses with CHD and a DCS was 6.6 (95 % CI 2.8-15.3). Comparison of patients with postnatally confirmed coarctation with those with normal intracardiac anatomy with DCS, revealed that in the former, the right ventricle (p = 0.005), pulmonic valve annulus (p = 0.0001) and the tricuspid inflow were larger (p = 0.001) compared to corresponding left-sided structures. The size of the DCS was not significantly different between the two groups, but in the former, the DCS was more closely related to the posterior leaflet of the mitral valve and caused a significant diminution of the mitral inflow. Our study suggests a strong association, possibly causal, between left heart obstructive lesions and DCS in utero.

Relationship of ambulatory blood pressure and body mass index to left ventricular mass index in pediatric patients with casual hypertension.

Both obesity and hypertension are associated with left ventricular hypertrophy (LVH) in children. Our objective was to compare the prevalence of LVH in obese and nonobese subjects with casual hypertension who underwent ambulatory blood pressure monitoring (ABPM). Untreated children (aged 6-20 years) underwent 24-hour ABPM, and left ventricular mass index (LVMI) was measured. Subjects were classified into three groups: white coat hypertension (WCH), prehypertension (pre-HT), and hypertension (HT). The prevalence of LVH was compared between obese and nonobese subjects among the groups. Of 69 children who underwent ABPM, thirty-two patients (46%) had WCH, 13 (19%) had pre-HT, and 24 (35%) had HT. Mean age, BMI, and LVMI were similar in the groups (P = not significant [NS]). In all, 22 patients (32%) had LVH, with no difference among WCH versus pre-HT versus HT (37.5% vs. 46% vs. 16.7%, P = NS). Twenty-seven subjects (39%) were obese. The ratio of LVH in obese to nonobese was 55.5% to 16.6% (P = .001). In both pre-HT and WCH, patients with LVH had a significantly higher BMI z score (P = .02 and P = .01, respectively). LVMI correlated strongly with BMI z score (P = .0001) but not with any blood pressure parameter. Almost half of children with casual HT have WCH. LVH is prevalent in a third of children with HT, pre-HT, and WCH. In both pre-HT and WCH, patients with LVH were more likely to be obese. More than half of all the obese subjects had LVH. Obese children in all three groups may be at a greater risk for end organ damage.

Dysmorphic features, cognitive disability, chronic inflammation, and predisposition to vascular disease in two sisters: a new autosomal recessive disorder?

A 20-year-old woman presented with mental retardation and a history of stroke related to moyamoya disease at the age of 8 years. She had cognitive impairment which became more pronounced after the stroke. This patient's parents were first cousins and six close family relatives had strokes in their 60s or 70s. The patient's 16-year-old sister had learning disability, chronic muscle pain, and an ECG suggestive of previous hypoxemic heart injury. The two sisters had similar dysmorphic facial appearance including a prominent philtrum, bulbous nose, and severe acne. They both had increased subcutaneous tissue in their faces, whereas their bodies were slim. Both sisters were found to have elevated levels of rheumatoid factor, C-reactive protein, and erythrocyte sedimentation rate on repeat measurements. Partial autoimmunity screening in one of the patients was negative. Chromosome analysis and array comparative genomic hybridization analyses were also normal. Nerve conduction findings in the younger sister were consistent with distal, predominantly motor, demyelinating neuropathy localized to the lower extremities. We propose that these two sisters suffer from a new autosomal recessive syndrome. Carrier status for this condition may predispose to later onset stroke.

Unmasking of neonatal renovascular hypertension by milrinone used for cardiac dysfunction.

A neonate initially presented with heart failure, with severe cardiac dysfunction confirmed by echocardiography, at 3 days of age. Blood pressure at presentation was in the high normal range. It was not until there was a rapid improvement of left-ventricular function on intravenous milrinone that the infant was noted to be hypertensive on day of life 7. It is noteworthy that milrinone, a drug with vasodilator and inotropic properties, paradoxically unmasked hypertension by rapidly improving left-ventricular function. Subsequent work-up showed the etiology of hypertension to be left renal artery stenosis. We present this case to alert clinicians to the rarer causes of left-ventricular dysfunction and to point out that its etiology, i.e., hypertension, may not be apparent until there is improvement in the systolic function of the left ventricle.

Improvement of left ventricular mass with antihypertensive therapy in children with hypertension.

There is paucity of data on the regression of left ventricular hypertrophy (LVH) in hypertensive children. This study assessed the effects of antihypertensive therapy on left ventricular mass in children with and without LVH. Medical records of hypertensive patients who had a baseline and follow-up echocardiogram (echo 1, echo 2) were reviewed. Fifteen of 22 treated patients had LVH at echo 1. Enalapril alone or combined was used in 21/22 cases. Echo 2 was performed at a mean interval of 15 +/- 7 months. The LVH group showed significant decrease in systolic blood pressure z-score (SBPZ) (2.89 +/-1.61 to 1.40 +/- 1.19; p=0.01), diastolic blood pressure z-score (DBPZ) (1.44 +/- 0.90 to 0.26 +/- 0.82; p<0.001), and LV mass index (LVMI) (56.2 +/- 12.50 to 43.7 +/- 8.30; p=0.001), but no significant change in body mass index z-score (BMIZ) (1.79 +/- 0.75 to 1.69 +/- 0.69; p=0.74). In the no-LVH group, SBPZ (3.03 +/- 1.68 to 2.27 +/- 1.81; p=0.356), DBPZ (1.00 +/- 0.87 to 0.63 +/- 0.68; p=0.409), BMIZ (1.08 +/- 0.98 to 1.27 +/- 0.89; p=0.672), and LVMI (29.47 +/- 5.51 to 33.89 +/ -3.06;p=0.374) did not change significantly. Simple linear regression demonstrated that the change in LVMI in the combined group had a significant correlation (r=0.477; p=0.025) with the percentage change in SBPZ. This study demonstrates that LVH in hypertensive children improves with effective blood pressure control.

Relation of coarctation of the aorta to the occurrence of ascending aortic dilation in children and young adults with bicuspid aortic valves.

Children with bicuspid aortic valve (BAV) have aortic dilation that is present and progressive from birth irrespective of the functional state of the valve. There are no published data comparing aortic dilation in children with BAV with and without aortic coarctation (CoA). The objectives of this study were to (1) compare differences in aortic dimensions and rates of dilation between children with isolated BAV with those of children with BAV and CoA and (2) identify risk factors for the development of aortic dilation. Patients with BAV with CoA (group A) and without CoA (group B) were identified from our echocardiographic database (1993 to 2006). Aortic measurements at 4 levels were obtained, and z scores were compared. Criteria for exclusion were severe aortic regurgitation/stenosis, previous aortic valvuloplasty, complex left-sided cardiac disease, ventricular septal defects, and Turner, Noonan, Williams, and Marfan syndromes. There were 600 echocardiograms in 247 patients. Group A had 192 echocardiograms in 53 patients (median age 11.3 years; range 0 to 30; median follow-up 7 years), and group B had 382 in 194 patients (median age 8.7 years; range 0 to 29; median follow-up 4 years). Group B had significantly greater ascending aorta dimensions (p<0.05) and significantly faster rates of aortic dilation (p<0.0001). The ascending aorta in patients with BAV and CoA did not dilate to the same degree as in patients with isolated BAV. In conclusion, valve morphologic characteristics and function and age at CoA repair had none to minimal impact on aortic dimensions.

Electrocardiographic predictors of left ventricular hypertrophy in pediatric hypertension.

OBJECTIVE: To determine the efficacy of electrocardiography (ECG) in detecting left ventricular hypertrophy (LVH) in pediatric hypertension (HT). STUDY DESIGN: Concomitant echocardiograms and electrocardiograms in 108 children with HT were reviewed. Left ventricular mass (LVM), assessed by echocardiography, was used as a basis for a diagnosis of LVH (echo LVH) using accepted pediatric criteria. Using Wilcoxon's rank-sum test, 14 ECG variables were compared between subjects with and without echo LVH. Spearman correlations were used to examine the linear association between echo LVH and these ECG variables. The sensitivity and specificity of ECG in diagnosing LVH were computed. RESULTS: Of the 108 subjects studied, 35 (32%) met the pediatric criteria for LVH; of these, 8 (7.4%) also met the adult criteria (>51 g/m(2.7)) for LVH. Mean values for only 5 ECG criteria differed significantly among the groups: RI, SaVR, RaVL, RI+SIII, and SVI+RV6 (P < .05). Significant correlations were found for several ECG criteria and at least 1 measure of LVM, but the magnitudes were modest. Standard ECG criteria predicted LVH with high specificity (>90%) but low sensitivity (<35%). RI >10 mm was identified as demonstrating a modestly improved positive likelihood ratio of approximately 3. CONCLUSIONS: ECG is not an adequate predictor of LVH for clinical use in HT.

Frequency of aberrant subclavian artery, arch laterality, and associated intracardiac anomalies detected by echocardiography.

Tetralogy of Fallot is generally considered to be the most common congenital heart defect associated with an aberrant subclavian artery (ASA), but the prevalence of ASA in patients with other cardiac anomalies is not well described. The pediatric echocardiography database, with 15,871 initial echocardiograms, was searched for all patients with ASA. Arch laterality and associated intracardiac anomalies were documented for each patient. ASA was found in 226 patients, of whom 171 had a left aortic arch (LAA) and 55 had a right aortic arch (RAA). The occurrence of ASA was 1% in patients with LAA (171 of 15,650) and 25% in patients with RAA (55 of 221; p = 0.001). Intracardiac anatomy was normal in 32% of patients with ASA/LAA and 25% with ASA/RAA. Conotruncal anomalies occurred more frequently with ASA/RAA than ASA/LAA (36% vs 18%; p = 0.01). Atrioventricular canal defects accounted for 10% and left-sided cardiac obstructive lesions accounted for 11% of subjects with ASA/LAA. ASA was rarely associated with d-transposition of the great arteries (1 of 226) and double-outlet right ventricle (5 of 226). The prevalence of ASA was highest in patients with interrupted aortic arch (11 of 38; 29%). In patients with tetralogy of Fallot, the overall prevalence of ASA was 8% (34 of 447), but was higher with RAA (16 of 103; 16%). The highest prevalence of ASA occurred in the subgroup of patients with tetralogy of Fallot with pulmonary atresia and RAA (6 of 25; 24%). In conclusion, ASA was more common in patients with RAA, especially with conotruncal anomalies. In patients with LAA, hypoplastic left heart syndrome, aortic coarctation, and atrioventricular canal defects were commonly associated with ASA.

Left atrial appendage: variations in morphology and position causing pitfalls in pediatric echocardiographic diagnosis.

The left atrial appendage is a complex structure that exhibits great variability in structure and form. Hence, it may masquerade as several other cardiac structures by echocardiography and cause errors in diagnosis. This report critically reviews the pitfalls that result in misinterpretation of normal and abnormal anatomy in a pediatric echocardiogram, and discusses and illustrates potential misdiagnoses and methods to avoid them.

Acute myopericarditis after multiple vaccinations in an adolescent: case report and review of the literature.

We report a case of postvaccination acute myopericarditis in an adolescent. The patient presented with acute chest pain, diffuse ST-segment elevation, and elevated cardiac enzyme levels. Cardiac MRI was consistent with acute myocarditis. He recovered within a few days with nonsteroidal antiinflammatory treatment and remains clinically stable, with improvement of MRI findings at the 10-week follow-up. Postvaccination cases of myopericarditis reported in the pediatric literature are also reviewed.

Regression of left ventricular hypertrophy in children with antihypertensive therapy.

Left ventricular hypertrophy (LVH) is a complication of hypertension that has received great attention in the adult population. Large-scale randomized control studies in adults have demonstrated that LVH regresses in response to pharmacologic intervention. While it is known that LVH occurs as a complication of hypertension in the pediatric population, few studies have focused on its regression with pharmacological intervention. We report on three cases of hypertension-induced LVH in the pediatric population and its regression after treatment with antihypertensive medications. This report brings to light the need for larger, prospective studies on the incidence, natural history, and treatment of LVH associated with hypertension in the pediatric population.

Neonatal Marfan syndrome : in utero presentation with aortic and pulmonary artery dilatation and successful repair of an acute flail mitral valve leaflet in infancy.

Neonatal Marfan syndrome (nMFS) is the rare and severe form of this connective tissue disorder with poor outcome due to progressive valvular insufficiency. We describe a case of nMFS suspected in utero, by fetal echocardiography, due to marked dilatation of both great arteries, which is the first description of fetal pulmonary artery dilatation in this disorder. The patient developed a flail mitral valve leaflet during the first year of life that was successfully repaired with an excellent medium-term result. This is the first report of this type of surgery in infancy.

Ascending aortic aneurysm in a fetus due to a benign nodular myofibroblastic lesion.

A fetal echocardiogram at 20 weeks of gestation revealed a large ascending aortic aneurysm in the presence of a normal aortic root and normal intracardiac anatomy. No other abnormalities were noted in the fetus. Upon termination of pregnancy, histopathological examination revealed an isolated benign nodular myofibroblastic lesion of likely hamartomatous origin, a first description of such pathology contributing to the formation of an aneurysm in the ascending aorta.