Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency.

PURPOSE: We previously defined biallelic HYAL2 variants causing a novel disorder in 2 families, involving orofacial clefting, facial dysmorphism, congenital heart disease, and ocular abnormalities, with Hyal2 knockout mice displaying similar phenotypes. In this study, we better define the phenotype and pathologic disease mechanism. METHODS: Clinical and genomic investigations were undertaken alongside molecular studies, including immunoblotting and immunofluorescence analyses of variant/wild-type human HYAL2 expressed in mouse fibroblasts, and in silico modeling of putative pathogenic variants. RESULTS: Ten newly identified individuals with this condition were investigated, and they were associated with 9 novel pathogenic variants. Clinical studies defined genotype-phenotype correlations and confirmed a recognizable craniofacial phenotype in addition to myopia, cleft lip/palate, and congenital cardiac anomalies as the most consistent manifestations of the condition. In silico modeling of missense variants identified likely deleterious effects on protein folding. Consistent with this, functional studies indicated that these variants cause protein instability and a concomitant cell surface absence of HYAL2 protein. CONCLUSION: These studies confirm an association between HYAL2 alterations and syndromic cleft lip/palate, provide experimental evidence for the pathogenicity of missense alleles, enable further insights into the pathomolecular basis of the disease, and delineate the core and variable clinical outcomes of the condition.

Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice.

Orofacial clefting is amongst the most common of birth defects, with both genetic and environmental components. Although numerous studies have been undertaken to investigate the complexities of the genetic etiology of this heterogeneous condition, this factor remains incompletely understood. Here, we describe mutations in the HYAL2 gene as a cause of syndromic orofacial clefting. HYAL2, encoding hyaluronidase 2, degrades extracellular hyaluronan, a critical component of the developing heart and palatal shelf matrix. Transfection assays demonstrated that the gene mutations destabilize the molecule, dramatically reducing HYAL2 protein levels. Consistent with the clinical presentation in affected individuals, investigations of Hyal2-/- mice revealed craniofacial abnormalities, including submucosal cleft palate. In addition, cor triatriatum sinister and hearing loss, identified in a proportion of Hyal2-/- mice, were also found as incompletely penetrant features in affected humans. Taken together our findings identify a new genetic cause of orofacial clefting in humans and mice, and define the first molecular cause of human cor triatriatum sinister, illustrating the fundamental importance of HYAL2 and hyaluronan turnover for normal human and mouse development.

Prevalence and Progression of Late Gadolinium Enhancement in Children and Adolescents With Hypertrophic Cardiomyopathy.

BACKGROUND: Late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) is believed to represent dense replacement fibrosis. It is seen in ≈60% of adult patients with hypertrophic cardiomyopathy (HCM). However, the prevalence of LGE in children and adolescents with HCM is not well established. In addition, longitudinal studies describing the development and evolution of LGE in pediatric HCM are lacking. This study assesses the prevalence, progression, and clinical correlations of LGE in children and adolescents with, or genetically predisposed to, HCM. METHODS: CMR scans from 195 patients ≤21 years of age were analyzed in an observational, retrospective study, including 155 patients with overt HCM and 40 sarcomere mutation carriers without left ventricular (LV) hypertrophy. The extent of LGE was quantified by measuring regions with signal intensity >6 SD above nulled remote myocardium. RESULTS: Patients were 14.3±4.5 years of age at baseline and 68% were male. LGE was present in 70 (46%) patients with overt HCM (median extent, 3.3%; interquartile range, 0.8-7.1%), but absent in mutation carriers without LV hypertrophy. Thirty-one patients had >1 CMR (median interval between studies, 2.4 years; interquartile range, 1.5-3.2 years). LGE was detected in 13 patients (42%) at baseline and in 16 patients (52%) at follow-up CMR. The median extent of LGE increased by 2.4 g/y (range, 0-13.2 g/y) from 2.9% (interquartile range, 0.8-3.2%) of LV mass to 4.3% (interquartile range, 2.9-6.8%) ( P=0.02). In addition to LGE, LV mass and left atrial volume, indexed to body surface area, and z score for LV mass, as well, increased significantly from first to most recent CMR. CONCLUSIONS: LGE was present in 46% of children and adolescents with overt HCM, in contrast to ≈60% typically reported in adult HCM. In the subset of patients with serial imaging, statistically significant increases in LGE, LV mass, and left atrial size were detected over 2.5 years, indicating disease progression over time. Further prospective studies are required to confirm these findings and to better understand the clinical implications of LGE in pediatric HCM.

Arrhythmias and fasciculoventricular pathways in patients with Danon disease: A single center experience.

BACKGROUND: Danon disease is a rare X-linked storage disorder characterized by hypertrophic cardiomyopathy leading to arrhythmias and heart failure. A preexcitation pattern on electrocardiogram (ECG) has been described in these patients, however, invasive studies to distinguish between Wolff-Parkinson-White syndrome syndrome and fasciculoventricular pathways (FVP) are limited. OBJECTIVES: The purpose of this study was to delineate the electrophysiological cardiac abnormalities in patients with Danon disease and to describe the presence of FVP in this population. METHODS: We performed a retrospective study of all patients with a confirmed diagnosis of Danon disease presenting to a single center from May 2005 to May 2018. Baseline demographics, clinical characteristics, ECG findings, and electrophysiology study (EPS) results were collected. RESULTS: Ten patients with Danon disease (30% male, average age 17.4 years) were identified. Seven patients (70%) had tachyarrhythmias including five with atrial arrhythmias and six with nonsustained ventricular tachycardia. Preexcitation pattern on ECG was found in four (40%) patients. Of these, two underwent an EPS which confirmed the presence of an FVP. One patient underwent an adenosine challenge which supported a FVP. Implantable cardioverter defibrillator was placed in five patients for primary prevention with no patients receiving an appropriate discharge. Over a follow-up of 5.3 years, five underwent heart transplantation. CONCLUSIONS: This study reports a high incidence of FVP in patients with Danon disease and preexcitation. It underscores an alternate etiology of preexcitation in this population which can potentially be diagnosed without invasive EPS testing. Future multicenter studies are needed to expand this experience.

Endocardial Coronary Artery: A Rare Congenital Coronary Anomaly.

Pediatric chest pain is a common reason for cardiology referral, and evaluation of exertional chest pain requires proper delineation of coronary anatomy. Congenital coronary anomalies are rare and often benign. However, certain anomalies such as intramural coronary arteries and myocardial bridges have been associated with angina, ventricular arrhythmias, and sudden cardiac death. We present a case of a 10-year-old male with exertional chest pain whose coronary anatomy could not be defined by echocardiography and further evaluation by computed tomography angiography revealed a rare congenital coronary anomaly.

Anomalous Origin of Right Coronary Artery from the Non-coronary Cusp Demonstrated by Echocardiography and CT Angiography.

Certain coronary anomalies have been associated with sudden cardiac death. Anomalous origin of the right coronary artery (RCA) from the posterior non-coronary aortic cusp is exceedingly rare. Through multimodality imaging, we present a young female with an anomalous RCA arising from the non-coronary cusp. Given the unobstructed origin and benign course, no intervention was recommended.

Incidental finding of type A aortic dissection in a paediatric heart transplant recipient.

Aortic dissection causes significant morbidity and mortality in adults and treatment guidelines are based on well-documented risk factors. Conversely, dissection after orthotopic heart transplantation is very rare, especially in the absence of infection, hypertension, or donor-recipient aortic size mismatch. Several forms of CHD are associated with aortic dilatation, but the incidence of aortic dissection and aneurysm in children is also low, which makes use of adult guidelines in children challenging. We present a 17-year-old Amish female with a homozygous gene mutation in the MYBPC3 gene known to cause lethal, infantile hypertrophic cardiomyopathy. She underwent orthotopic heart transplantation and then developed an asymptomatic aortic dissection despite no known risk factors.

Prevalence of thoracic aortopathy in patients with juvenile Polyposis Syndrome-Hereditary Hemorrhagic Telangiectasia due to SMAD4.

Hereditary hemorrhagic telangiectasia (HHT) is characterized by abnormal vascular structures that may present as epistaxis, telangiectasias, and/or arteriovenous malformations. The genes associated with HHT (ACVRL1, ENG, and SMAD4) are members of the TGFß pathway. Other syndromes associated with abnormalities in TGFß signaling include Marfan syndrome, Loeys-Dietz syndrome and related disorders. These disorders have aortic disease as a prominent finding. While there are case reports of patients with HHT and aortopathy (dilatation/aneurysm, dissection, and rupture), this has not been systematically investigated. We conducted a retrospective chart review to determine the prevalence of aortopathy in an HHT cohort. Patients from a single institution were identified who met the Curacao Criteria for a clinical diagnosis of HHT and/or had a mutation in ACVRL1, ENG, or SMAD4 and underwent echocardiogram. Two-dimensional echocardiograms were reviewed by a single pediatric cardiologist, and data were collected on demographics, genotype, HHT features, aortic root measurements, past medical history, and family history. Z scores and nomograms were utilized to identify abnormal results. Twenty-six patients from 15 families (one ACVRL1, four ENG, eight SMAD4, and two clinical diagnoses) were included in the analysis. Aortopathy was found in 6/26 (23%) patients; all had SMAD4 mutations. In our cohort, 6/16 (38%) SMAD4 mutation carriers had evidence of aortopathy. These data suggest that aortopathy could be part of the spectrum of SMAD4-induced HHT manifestations. Routine aortic imaging, including measurements of the aorta, should be considered in patients with SMAD4 mutations to allow for appropriate medical and surgical recommendations.

Transcatheter Aortic Valve Replacement in Congenital Heart Disease.

Transcatheter aortic valve replacement is not widely used in patients with congenital heart disease. We describe our single-center experience of transcatheter aortic valve replacement in congenital heart disease, demonstrating short-term feasibility and safety, role in lifetime management of congenital aortic valve disease, and use as a bridge to recovery, future surgery, or transplantation.

Electrocardiographic QTc as a Surrogate Measure of Cardiac Risk in Children, Adolescents, and Young Adults With Eating Disorders.

The study goal was to investigate electrocardiographic findings, including corrected QT interval (QTc), in patients aged 8 to 23 with eating disorders (EDs) at presentation, compared with an age-and sex-matched control population. We retrospectively reviewed 200 ED patients, and 200 controls. Blinded electrocardiograms (ECGs) were interpreted by an expert reader, and QT intervals corrected using the Bazett formula. Eating disorder patients were 89.5% female, with mean age 16.4 years and median percent median body mass index (BMI)-for-age (%mBMI)a of 91.1%. In ED patients, QTc was significantly shorter than controls (399.6 vs 415.0msec, P < .001). After adjusting for height, %mBMI, sex, magnesium level, and bradycardia, mean QTc duration in patients with anorexia nervosa-restricting subtype (AN-R) was significantly shorter than other ED patients (P = .010). Higher %mBMI was associated with shorter QTc duration (P = .041) after adjusting for height, magnesium, bradycardia, and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis. Within the ED group, no significant association was identified between QTc and medications, electrolytes, or inpatient status.

Multifocal disease progression and subsequent intervention in patients with actin alpha-2 variants: A single-center experience.

OBJECTIVES: To describe patient characteristics and indications for surgical intervention, reoperation, and outcomes in patients with actin alpha-2 (ACTA2) variants. METHODS: A single-center retrospective cohort study with prospective follow-up was performed for 38 patients with an ACTA2 variant. RESULTS: From 1999 to 2020, 26 (70%) patients underwent surgery; 11 remain under surveillance (mean follow-up, 7.5 ± 5 years). Median age at index operation was 42 (range, 10-69) years, with 4 pediatric cases. Thoracic aortic aneurysm was present in 19 (73%) patients (mean adult max diameter, 5.2 ± 0.8 cm; pediatric z score, 10.7 ± 5.4). Aortic dissection was present in 13 (50%) patients, with 4 (15%) having type A dissection. Operations included replacement of the aortic root in 16 (17%), ascending aorta in 20 (77%), and aortic arch in 14 (54%) patients. Four (15%) patients had coronary artery disease, and 2 (7.7%) underwent concomitant coronary artery bypass grafting. There was no operative mortality, stroke, reoperation for bleeding, or dialysis-dependent renal failure; One (3.8%) patient developed acute on chronic kidney injury. Three patients (12%) required prolonged ventilation. Eleven (42%) patients underwent 26 reoperations, median time 45 (range, 4-147) months, including 5 open thoracoabdominal aneurysm repairs. CONCLUSIONS: Patients with ACTA2 variants frequently develop aortic aneurysm and are at risk of aortic dissection and coronary artery disease. However, age at diagnosis and symptoms at presentation are highly variable. Multiple operations are often required for disease management, particularly after dissection. Close monitoring and timely intervention are important in mitigating disease progression and improving outcomes.

Cardiac Remodeling in Subclinical Hypertrophic Cardiomyopathy: The VANISH Randomized Clinical Trial.

Importance: Valsartan has shown promise in attenuating cardiac remodeling in patients with early-stage sarcomeric hypertrophic cardiomyopathy (HCM). Genetic testing can identify individuals at risk of HCM in a subclinical stage who could benefit from therapies that prevent disease progression. Objective: To explore the potential for valsartan to modify disease development, and to characterize short-term phenotypic progression in subclinical HCM. Design, Setting, and Participants: The multicenter, double-blind, placebo-controlled Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) randomized clinical trial was conducted from April 2014 to July 2019 at 17 sites in 4 countries (Brazil, Canada, Denmark, and the US), with 2 years of follow-up. The prespecified exploratory VANISH cohort studied here included sarcomere variant carriers with subclinical HCM and early phenotypic manifestations (reduced E' velocity, electrocardiographic abnormalities, or an increased left ventricular [LV] wall thickness [LVWT] to cavity diameter ratio) but no LV hypertrophy (LVH). Data were analyzed between March and December 2022. Interventions: Treatment with placebo or valsartan (80 mg/d for children weighing <35 kg, 160 mg/d for children weighing ≥35 kg, or 320 mg/d for adults aged ≥18 years). Main Outcomes and Measures: The primary outcome was a composite z score incorporating changes in 9 parameters of cardiac remodeling (LV cavity volume, LVWT, and LV mass; left atrial [LA] volume; E' velocity and S' velocity; and serum troponin and N-terminal prohormone of brain natriuretic peptide levels). Results: This study included 34 participants, with a mean (SD) age of 16 (5) years (all were White). A total of 18 participants (8 female [44%] and 10 male [56%]) were randomized to valsartan and 16 (9 female [56%] and 7 male [44%]) were randomized to placebo. No statistically significant effects of valsartan on cardiac remodeling were detected (mean change in composite z score compared with placebo: -0.01 [95% CI, -0.29 to 0.26]; P = .92). Overall, 2-year phenotypic progression was modest, with only a mild increase in LA volume detected (increased by 3.5 mL/m2 [95% CI, 1.4-6.0 mL/m2]; P = .002). Nine participants (26%) had increased LVWT, including 6 (18%) who developed clinically overt HCM. Baseline LA volume index (LAVI; 35 vs 28 mL/m2; P = .01) and average interventricular septum thickness (8.5 vs 7.0 mm; P = .009) were higher in participants who developed HCM. Conclusions and Relevance: In this exploratory cohort, valsartan was not proven to slow progression of subclinical HCM. Minimal changes in markers of cardiac remodeling were observed, although nearly one-fifth of patients developed clinically overt HCM. Transition to disease was associated with greater baseline interventricular septum thickness and LAVI. These findings highlight the importance of following sarcomere variant carriers longitudinally and the critical need to improve understanding of factors that drive disease penetrance and progression. Trial Registration: ClinicalTrials.gov Identifier: NCT01912534.

Oxygen pulse kinetics in Fontan patients during treadmill ramp protocol cardiopulmonary exercise testing.

After single-ventricle palliation, patients have variable long-term functional outcomes. Cardiopulmonary exercise testing (CPET) is an assessment tool used to quantify functional outcome. Oxygen pulse kinetics during CPET, which can be an important indicator of dynamic changes in stroke volume reserve, has not been systematically studied in this population. This study aimed to analyze oxygen pulse kinetics during a treadmill ramp protocol among patients with Fontan physiology compared with that of normal subjects and to explore the ability of oxygen pulse kinetics to define functional status further. Peak oxygen pulse and change in oxygen pulse during ramp treadmill CPET were retrospectively collected and compared between 44 Fontan patients and 85 age- and sex-matched control subjects. The peak oxygen pulse was significantly lower in the Fontan group (9.80 ± 4.11 ml/beat) than in the control group (13.62 ± 4.7 ml/beat) (p ≤ 0.001). The resting oxygen pulse did not differ between the two groups (3.13 ± 1.23 vs. 3.09 ± 1.33 ml/beat; p = 0.88). The oxygen pulse was higher in the patients with chronotropic insufficiency, but the difference was not statistically significant (11.11 ± 4.97 vs. 9.25 ± 3.63 ml/beat; p = 0.17). Regression analysis showed a significant difference in the slope of the oxygen pulse-to-workload relationship. The Fontan group showed no relation between degree of reduction in the oxygen pulse from peak to end of exercise and the underlying defect, peak heart rate, peak oxygen consumption, ventilatory anaerobic threshold (VAT), expired volume (VE)/carbon dioxide output (VCO(2)) at the VAT, maximum heart rate, or minimum oxygen saturation. Analysis of oxygen pulse kinetics in Fontan patients suggests that there is an early and progressive limitation in stroke volume compared with control subjects. This limitation may be partially masked by increased oxygen extraction. In patients with chronotropic insufficiency, absolute or body surface area-indexed oxygen pulse may be higher than in those with a normal heart rate response. A composite assessment of the oxygen pulse and oxygen pulse kinetics, including the oxygen pulse slope and the percentage of reduction in oxygen pulse from peak to end of exercise, may allow a more comprehensive assessment of the degree of cardiac limitation in this group of patients.

Optimizing evaluation in pediatric and young adult patients with Marfan syndrome: Novel longitudinal metrics to track growth of aortic structures.

OBJECTIVE: Surveillance metrics in pediatric and young adult Marfan syndrome (pMFS) are challenging. We evaluated the utility of aortic root cross-sectional area/height index (CSA/Ht) on echocardiogram among pMFS patients as a risk stratification and surgical triage metric. METHODS: Genotype or phenotype positive pMFS patients aged 25 years or younger seen at our center from 2001 to 2020 were identified. Time-related transition to surgery was modeled using parametric methods. Predictive utility of CSA/Ht compared with aortic root diameter (ARd) and root Z score (ARz) were modeled using nonlinear multivariable parametric and nonparametric longitudinal regression models. RESULTS: Seventy-nine patients (43% female) presented at median age of 5.8 years (15th-85th percentile, 0.75-17 years) with median follow-up of 4.4 years (range, 0-18.5 years). Baseline echocardiography data were: CSA/Ht, 3.9 ± 1.4 cm2/m; ARd, 2.4 ± 0.89 cm; and ARz, 2.4 ± 1.7. CSA/Ht tracked ARd better compared with ARz (r = 0.91 vs 0.24). Eighteen patients underwent surgery. Surgical procedures included at least 2 components in 17 (aortic, mitral, tricuspid, aortic root, and arch procedures) and isolated mitral valve procedures in 1 patient. Time-related transition to surgery showed a prominent early phase to 1 year post presentation, followed by a slowly increasing late phase. CSA/Ht had a more linear correlation versus ARz during periods of rapid somatic growth in surgical patients. Surgical repair occurred at CSA/Ht between 5 and 7 cm2/m. CONCLUSIONS: CSA/Ht tracked ARd well over time. CSA/Ht between 5 and 7 cm2/m might be a promising metric for surgical triage in pMFS patients. CSA/Ht surgical threshold values in pMFS patients occurred at lower than current accepted "surgical" threshold values for CSA/Ht in adult Marfan syndrome patients.

Management of the ventricular septal defect during double switch operation for atrioventricular discordant connections.

Management of the ventricular septal defect at the time of the double switch operation can be challenging and deserves careful attention to the anatomic details of ventricular septal defect location, alignment with the appropriate subtended ventricles and their respective atrioventricular valves, and the disposition of the specialized conduction tissue. These anatomic details can differ considerably from hearts with concordant atrioventricular alignments, and further variations of right-left geometry and septal alignment can be exhibited. A case is described that underscores some of the particular challenges associated with management of the ventricular septal defect during double switch operation for hearts with discordant atrioventricular connections and either transposition of the great arteries or double outlet right ventricle.

Neonatal Ebstein anomaly national outcomes from 2000 to 2018 using the National Inpatient Sample.

BACKGROUND: The prevalence, morbidity, and mortality associated with Ebstein anomaly (EA) remains poorly characterized in neonates. EA is a rare form of congenital heart disease (CHD) with significant heterogeneity. OBJECTIVE: To determine the recent, 2000-2018, prevalence, mortality, outcomes, and healthcare utilization of infants admitted at ≤28 days of life with EA in comparison to other critical congenital heart defects (CCHD) in the United States using a national data set. METHODS: The National Inpatient Sample (NIS) from the Healthcare Cost and Utilization Project (HCUP) was queried for infants admitted for any reason at ≤28 days of life with a diagnosis of EA between 2000 and 2018 using ICD-9 and 10 codes in the United States. Patient characteristics, morbidity, mortality, and healthcare utilization were evaluated for EA and compared with other CCHD. RESULTS: From 2000 to 2018 a total of 68,312,952 neonatal admissions were identified, of them 4,398 neonates with isolated EA were identified, representing 7 per 100,000 neonatal admissions and 2.2% of CCHD admissions (4,398/197,881). The number of new EA cases ranged from 138 to 375 per year. In-hospital mortality was 12.3% and surgical repair occurred in 4.2% for infants with EA. There were 470 deaths without surgical repair which is 86.6% of the mortality. Arrhythmias were diagnosed in 10.6% and ECMO was used for 2.6% of neonates with EA. CONCLUSION: EA is a rare form of CHD. The prevalence has remained stable over the 19 years whereas other congenital heart defects have had an increase. The mortality in neonates with EA was significantly higher than in pooled CCHD; the burden of mortality occurred in the neonates without surgical intervention.

Left Atrial Strain and Function in Pediatric Hypertrophic Cardiomyopathy.

BACKGROUND: Left atrial (LA) strain and dysfunction are early markers of diastolic dysfunction, associated with poor exercise capacity in adults with hypertrophic cardiomyopathy (HCM). Literature on assessment of LA mechanics in pediatric HCM is lacking. The aim of this study was to assess LA strain and LA function in pediatric patients who have HCM with (phenotype positive [P+]) and without (genotype positive, phenotype negative [G+P-]) ventricular hypertrophy and evaluate their correlation with exercise stress test parameters. METHODS: Seventy-eight children (3-25 years of age) with HCM (P+, n = 46; G+P-, n = 32) and 20 healthy control subjects were retrospectively studied. LA conduit function, reservoir function, and pump function were computed using phasic LA volumetric analysis. LA reservoir strain (LASr) and LA contractile strain were measured using speckle-tracking echocardiography. Exercise test findings within 12 months of echocardiography were recorded. RESULTS: LA conduit function (36% vs 48%, P < .001) and LA reservoir function (137% vs 180%, P < .001) were lower in P+ than in G+P- patients. LA contractile function did not differ between the groups (31% vs 32%, P = .87). Compared with patients with G+P- HCM, those with P+HCM had lower four-chamber LASr (29% vs 41%, P < .001), two-chamber LASr (30% vs 41%, P < .001), average LASr (29% vs 42%, P < .001), and LA contractile strain (9% vs 12%, P = .016). In the cohort of patients with HCM who underwent stress testing (n = 35), LA conduit function weakly correlated with aerobic capacity (r = 0.42, P = .019). CONCLUSIONS: Children with P+HCM have reduced LA function, measurable by both volumetric and strain analysis. Altered LA mechanics are associated with poor exercise capacity. This study lays the foundation for the evaluation of novel LA parameters in pediatric HCM and warrants larger longitudinal studies to assess its clinical significance.

Characteristics and Longer-Term Outcomes of Contemporary Patients <18 Years of Age With Hypertrophic Cardiomyopathy.

We describe characteristics and outcomes of contemporary pediatric hypertrophic cardiomyopathy (PHC) patients. We studied 398 consecutive pediatric HC patients (<18 years, median 14 years, 65% boys) seen at our center between 2002 and 2018. Baseline clinical and pediatric echocardiographic data was collected. Left ventricular outflow tract gradient (LVOTG), LV fractional shortening and Z-score for left ventricular (LV) wall thickness were calculated. Sudden cardiac death (SCD), appropriate internal defibrillator discharge (ICD), myectomy, and orthotopic heart transplant (OHT) were composite primary endpoint. A total of 133 (33%) had symptoms (71 [18%] dyspnea, 77 [19%] angina, and 19 [5%] syncope), 109 (27%) were on beta-blockers; 179 (45%) had family history of HC. A total of 146 (37%) underwent genetic testing (of which 91 (62%) were HC-gene positive). Basal septal LV thickness, septal LV z-score and fractional shortening were 1.2 ± 0.6 cm, 4.8 ± 5.6, and 42% ± 8, whereas 23% had extreme LV hypertrophy (z-score > 6) and 8% had LVOTG >30 mm Hg (range 0 to 139 mm Hg). At a median of 5.9 years (interquartile range 2.4, 9), there were 23 (6%) ICD's placed, and 47 (12%) primary composite events (9 [2%] deaths, 3 [1%] appropriate ICD discharge, 29 [7%] myectomy, and 8 [2%] OHT). There were no in hospital deaths following myectomy/OHT. Presence of symptoms (Hazard ratio or HR 2.45), ventricular tachycardia (HR 1.52), and higher basal septal LV z-score (HR 1.10) were independently associated with primary composite outcomes. LV septal z-score >4 was independently associated with events on spline analysis. Rate of SCD/appropriate ICD discharge was 0.5%/year. In conclusion, contemporary PHC patients seen at an experienced center have excellent outcomes with presence of symptoms and higher LV septal thickness associated with primary composite events.