Publications by authors named "Samuel G Wittekind"

26 Publications

  • Page 1 of 1

Computational prediction of protein subdomain stability in MYBPC3 enables clinical risk stratification in hypertrophic cardiomyopathy and enhances variant interpretation.

Genet Med 2021 Mar 29. Epub 2021 Mar 29.

Cardiovascular Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Purpose: Variants in MYBPC3 causing loss of function are the most common cause of hypertrophic cardiomyopathy (HCM). However, a substantial number of patients carry missense variants of uncertain significance (VUS) in MYBPC3. We hypothesize that a structural-based algorithm, STRUM, which estimates the effect of missense variants on protein folding, will identify a subgroup of HCM patients with a MYBPC3 VUS associated with increased clinical risk.

Methods: Among 7,963 patients in the multicenter Sarcomeric Human Cardiomyopathy Registry (SHaRe), 120 unique missense VUS in MYBPC3 were identified. Variants were evaluated for their effect on subdomain folding and a stratified time-to-event analysis for an overall composite endpoint (first occurrence of ventricular arrhythmia, heart failure, all-cause mortality, atrial fibrillation, and stroke) was performed for patients with HCM and a MYBPC3 missense VUS.

Results: We demonstrated that patients carrying a MYBPC3 VUS predicted to cause subdomain misfolding (STRUM+, ΔΔG ≤ -1.2 kcal/mol) exhibited a higher rate of adverse events compared with those with a STRUM- VUS (hazard ratio = 2.29, P = 0.0282). In silico saturation mutagenesis of MYBPC3 identified 4,943/23,427 (21%) missense variants that were predicted to cause subdomain misfolding.

Conclusion: STRUM identifies patients with HCM and a MYBPC3 VUS who may be at higher clinical risk and provides supportive evidence for pathogenicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-021-01134-9DOI Listing
March 2021

Clinical characteristics and outcomes in childhood-onset hypertrophic cardiomyopathy.

Eur Heart J 2021 Mar 26. Epub 2021 Mar 26.

Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.

Aims: Childhood-onset hypertrophic cardiomyopathy (HCM) is far less common than adult-onset disease, thus natural history is not well characterized. We aim to describe the characteristics and outcomes of childhood-onset HCM.

Methods And Results: We performed an observational cohort study of 7677 HCM patients from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Hypertrophic cardiomyopathy patients were stratified by age at diagnosis [<1 year (infancy), 1-18 years (childhood), >18 years (adulthood)] and assessed for composite endpoints reflecting heart failure (HF), life-threatening ventricular arrhythmias, atrial fibrillation (AF), and an overall composite that also included stroke and death. Stratifying by age of diagnosis, 184 (2.4%) patients were diagnosed in infancy; 1128 (14.7%) in childhood; and 6365 (82.9%) in adulthood. Childhood-onset HCM patients had an ∼2%/year event rate for the overall composite endpoint, with ventricular arrhythmias representing the most common event in the 1st decade following baseline visit, but HF and AF becoming more common by the end of the 2nd decade. Sarcomeric variants were more common in childhood-onset HCM (63%) and carried a worse prognosis than non-sarcomeric disease, including a greater than two-fold increased risk of HF [HRadj 2.39 (1.36-4.20), P = 0.003] and 67% increased risk of the overall composite outcome [HRadj 1.67 (1.16-2.41), P = 0.006]. When compared with adult-onset HCM, childhood-onset was 36% more likely to develop life-threatening ventricular arrhythmias [HRadj 1.36 (1.03-1.80)] and twice as likely to require transplant or ventricular assist device [HRadj 1.99 (1.23-3.23)].

Conclusion: Patients with childhood-onset HCM are more likely to have sarcomeric disease, carry a higher risk of life-threatening ventricular arrythmias, and have greater need for advanced HF therapies. These findings provide insight into the natural history of disease and can help inform clinical risk stratification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehab148DOI Listing
March 2021

Antithymocyte globulin induction therapy and myocardial complement deposition in pediatric heart transplantation.

Pediatr Transplant 2021 Mar 11:e13998. Epub 2021 Mar 11.

The Heart Institute, Cincinnati Children's Medical Center, Cincinnati, OH, USA.

Background: Antithymocyte globulin (ATG) consists of polyclonal antibodies directed primarily against human T lymphocytes but may contain antibodies with affinity for other tissues in the transplanted organ, resulting in complement (C4d) deposition. This phenomenon has been demonstrated in endomyocardial biopsies (EMBs) of adult cardiac transplants. We examined the relationship of induction immunosuppression with ATG and C4d deposition in EMB of pediatric cardiac transplants.

Methods: Results of C4d immunohistochemistry were available from all EMB of patients transplanted at our center between June 2012 and April 2018 (n = 48) who received induction immunosuppression with either ATG (n = 20) or basiliximab (n = 28) as the standard of care.

Results: C4d deposition in the first year post-heart transplant was more commonly seen among patients who received ATG induction (20% of EMBs in ATG group vs 1% of EMBs in basiliximab group; p < .0001). C4d deposition related to ATG was observed early post-transplant (50% ATG vs 0% basiliximab on first EMB; p < .0001 and 35% ATG vs 0% basiliximab on the second EMB; p = .0012). While this difference waned by the third EMB (5% ATG vs 0% basiliximab; p = .41), positive C4d staining persisted to the sixth EMB in the ATG group only (6%).

Conclusion: C4d deposition is common on EMB up to 1 year post-pediatric cardiac transplant following ATG induction. This high rate of positive C4d staining in the absence of histologic AMR after ATG induction therapy must be accounted for in making clinical decisions regarding cardiac allograft rejection diagnosis and treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/petr.13998DOI Listing
March 2021

Cardiac medication management in Duchenne muscular dystrophy.

Pediatr Pulmonol 2021 Apr 1;56(4):747-752. Epub 2021 Mar 1.

The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

There have been significant improvements in the skeletal muscle and respiratory care for patients with Duchenne muscular dystrophy (DMD) over the last two decades. This has resulted in longer expected survival as many patients will live into their 20s and 30s. This timeline has resulted in a greater proportion of patients experiencing heart failure and cardiac-related mortality. Herein, we describe the current indications for medical therapy for patients with DMD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ppul.25175DOI Listing
April 2021

Landscape of Mentorship and its Effects on Success in Cardiology.

JACC Basic Transl Sci 2020 Dec 23;5(12):1181-1186. Epub 2020 Dec 23.

Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center (VUMC), Nashville, Tennessee, USA.

The effects of mentorship on measurable outcomes of success and the aspects of mentorship that are most valuable in promoting the careers of cardiologists are unclear. To address this, we conducted a large-scale survey of cardiologists in a real-world setting. We identified factors that enhance the mentorship experience, and found that mentee needs change with career stage. Importantly, satisfaction with the mentoring relationship is significantly associated with perceived satisfaction in achieving professional goals. Furthermore, we found that gender and race concordance in mentoring relationships is an important variable with the potential to increase diversity in the field of cardiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacbts.2020.09.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775959PMC
December 2020

Body Composition and Exercise Performance in Youth With a Fontan Circulation: A Bio-Impedance Based Study.

J Am Heart Assoc 2020 12 8;9(24):e018345. Epub 2020 Dec 8.

Department of Pediatrics University of Cincinnati College of Medicine Cincinnati OH.

Background Adults with a Fontan circulation tend to have myopenia and elevated adiposity when measured by dual energy x-ray absorptiometry. Bioelectrical impedance analysis is an alternative validated approach to assess body composition. We used bioelectrical impedance analysis to compare body composition between pediatric patients with a Fontan circulation and control individuals without heart disease. Methods and Results A retrospective chart review identified all patients aged <22 years with a Fontan circulation who presented for cardiopulmonary exercise testing and bioelectrical impedance analysis from April 2019 to January 2020. Data were compared with control subjects tested during the same period. We studied 47 patients with a Fontan circulation (53% boys; 15±3.1 years) and 165 controls (48% boys; 14.4±2.5 years). Fontan status was associated with shorter height, but similar age, sex, and overall body mass. Patients with Fontan had lower lean body mass (-12.0±22%, Z-score -0.5±1, =0.005), skeletal muscle mass (-13.6±1.4%; Z-score, -0.5±1; =0.004), skeletal muscle indexed to height (-10.3±13.3%; Z-score, -0.5±1; =0.005), and higher percent body fat (+13.8±18.6%; Z-score, 0.4±1.2; =0.03). Greater skeletal muscle mass was associated with higher peak oxygen consumption (=0.52, <0.0001) and oxygen pulse (=0.68, <0.0001). Patients who had suffered a late complication (ie, heart transplant referral or evidence of extracardiac organ dysfunction) of the Fontan operation (13 of 47, 27.7%) had lower skeletal muscle mass (=0.048) and higher body fat percentage (=0.003). Conclusions The Fontan circulation is associated with marked myopenia and increased adiposity. Higher muscle mass was associated with better exercise capacity. Fontan complications are associated with lower muscle mass and increased adiposity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.120.018345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955362PMC
December 2020

Left Ventricular Magnetic Resonance Imaging Strain Predicts the Onset of Duchenne Muscular Dystrophy-Associated Cardiomyopathy.

Circ Cardiovasc Imaging 2020 11 16;13(11):e011526. Epub 2020 Nov 16.

The Heart Institute (S.S., T.A., S.E.H., C.V., T.D.R., S.W., S.M.L., M.D.T.), Cincinnati Children's Hospital Medical Center, OH.

Background: Early detection of left ventricular (LV) dysfunction before the onset of overt Duchenne muscular dystrophy-associated cardiomyopathy (DMDAC) may direct clinical management to slow onset of dysfunction. We aimed to assess whether LV strain will predict those who develop DMDAC.

Methods: We performed a single center retrospective case control study of patients with Duchenne muscular dystrophy who underwent serial cardiac magnetic resonance between 2006 and 2019. Patients with Duchenne muscular dystrophy with an LV ejection fraction ≥55% on ≥1 cardiac magnetic resonance were identified and grouped into age-matched +DMDAC and -DMDAC. Within 3 years, +DMDAC had a subsequent cardiac magnetic resonance with a decline in LV ejection fraction ≥10% and absolute LV ejection fraction ≤50%. -DMDAC maintained an LV ejection fraction ≥55% on serial cardiac magnetic resonances. Two-dimensional and 3-dimensional global radial strain, global circumferential strain (GCS), and global longitudinal strain were measured using tissue tracking software and their ability to predict DMDAC onset was assessed. Multivariable analysis adjusted for late gadolinium enhancement.

Results: Thirty +DMDAC and 30 age-matched -DMDAC patients were included with a total of 164 studies analyzed. Before DMDAC onset, 2-dimensional global radial strain and GCS were significantly worse in +DMDAC compared with -DMDAC (25.1±6.0 versus 29.0±6.3, =0.011; -15.4%±2.4 versus -17.3%±2.6, =0.003). Three-dimensional GCS and global radial strain had similar findings. Among strain measures, 3-dimensional GCS had the highest area under the curve to predict DMDAC in our cohort. These findings persisted after adjusting for the presence of late gadolinium enhancement.

Conclusions: Reduced global radial strain and GCS may predict those at risk for developing DMDAC before onset of LV dysfunction and its clinical utility warrants further exploration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCIMAGING.120.011526DOI Listing
November 2020

Exercise testing and cardiac rehabilitation in patients treated for cancer.

J Thromb Thrombolysis 2020 Sep 3. Epub 2020 Sep 3.

Department of Clinical Cancer Prevention & Cardiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Cardiovascular disease (CVD) is a major competing cause of morbidity and mortality in patients with cancer. Cancer treatment can have detrimental short- and long-term cardiovascular effects. Moreover, cancer patients may have a significant loss in cardiorespiratory fitness, a key CVD risk factor, during and after cancer treatment. Exercise training has emerged as a potential intervention to improve fitness and reduce the risk of CVD in cancer. In this review, we discuss the role of cardiorespiratory fitness to predict cancer and CVD outcomes, as well as explore the impact of exercise training to improve fitness and other key outcomes in patients with cancer. The role of cardio-oncology rehabilitation will also be highlighted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11239-020-02265-7DOI Listing
September 2020

Spatial and Functional Distribution of Pathogenic Variants and Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy.

Circ Genom Precis Med 2020 10 25;13(5):396-405. Epub 2020 Aug 25.

Cardiovascular Medicine, University of Pennsylvania, Philadelphia (S.M.D.).

Background: Pathogenic variants in , encoding cardiac MyBP-C (myosin binding protein C), are the most common cause of familial hypertrophic cardiomyopathy. A large number of unique variants and relatively small genotyped hypertrophic cardiomyopathy cohorts have precluded detailed genotype-phenotype correlations.

Methods: Patients with hypertrophic cardiomyopathy and variants were identified from the Sarcomeric Human Cardiomyopathy Registry. Variant types and locations were analyzed, morphological severity was assessed, and time-event analysis was performed (composite clinical outcome of sudden death, class III/IV heart failure, left ventricular assist device/transplant, atrial fibrillation). For selected missense variants falling in enriched domains, myofilament localization and degradation rates were measured in vitro.

Results: Among 4756 genotyped patients with hypertrophic cardiomyopathy in Sarcomeric Human Cardiomyopathy Registry, 1316 patients were identified with adjudicated pathogenic truncating (N=234 unique variants, 1047 patients) or nontruncating (N=22 unique variants, 191 patients) variants in . Truncating variants were evenly dispersed throughout the gene, and hypertrophy severity and outcomes were not associated with variant location (grouped by 5'-3' quartiles or by founder variant subgroup). Nontruncating pathogenic variants clustered in the C3, C6, and C10 domains (18 of 22, 82%, <0.001 versus Genome Aggregation Database common variants) and were associated with similar hypertrophy severity and adverse event rates as observed with truncating variants. MyBP-C with variants in the C3, C6, and C10 domains was expressed in rat ventricular myocytes. C10 mutant MyBP-C failed to incorporate into myofilaments and degradation rates were accelerated by ≈90%, while C3 and C6 mutant MyBP-C incorporated normally with degradation rate similar to wild-type.

Conclusions: Truncating variants account for 91% of pathogenic variants and cause similar clinical severity and outcomes regardless of location, consistent with locus-independent loss-of-function. Nontruncating pathogenic variants are regionally clustered, and a subset also cause loss of function through failure of myofilament incorporation and rapid degradation. Cardiac morphology and clinical outcomes are similar in patients with truncating versus nontruncating variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.120.002929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676622PMC
October 2020

Implementation of a Pediatric Chest Pain Local Consensus Guideline Decreases the Total Tests Performed Without Negatively Affecting the Yield of Abnormal Cardiac Results.

Pediatr Cardiol 2020 Dec 24;41(8):1580-1586. Epub 2020 Jul 24.

Department of Pediatrics, University of Cincinnati College of Medicine, 3333 Burnett Ave., MLC 2003, Cincinnati, OH, USA.

Pediatric chest pain is common and though usually benign often leads to unnecessary diagnostic testing. There is limited evidence as to whether a local consensus guideline can decrease testing frequency without negatively affecting the overall yield. In addition, it is unknown whether the addition of pulmonary function testing to a cardiopulmonary exercise test increases the diagnostic yield in pediatric patients with chest pain. A retrospective chart review was performed on all new pediatric patients who presented with chest pain at our academic center's pediatric cardiology clinic 18 months before and after the implementation of a standard management guideline. Data from the encounter-associated echocardiogram, cardiopulmonary exercise test, and pulmonary function test, when available, were analyzed. There were no significant differences in patient volume or demographic characteristics in the 18 months before (n = 768) and after (n = 778) guideline implementation. There were significant reductions in the number of ordered echocardiograms (n = 131; 17% vs. n = 75; 9.6%, p < 0.001) and cardiopulmonary exercise tests (n = 46; 6% vs. n = 29; 4%, p = 0.04) with no concerning pathology discovered in either group. Associated pulmonary function testing performed prior to with exercise testing discovered abnormalities in 19% of the total patients tested. The implementation of a local consensus guideline for pediatric chest pain results in fewer unnecessary tests ordered. There was no concerning pathology before or after guideline implementation, therefore conclusions regarding the diagnostic yield of these guidelines are unfeasible. The addition of pulmonary function testing to cardiopulmonary exercise tests increases the potential diagnostic yield in these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00246-020-02414-yDOI Listing
December 2020

Skeletal Muscle Mass Is Linked to Cardiorespiratory Fitness in Youth.

Med Sci Sports Exerc 2020 12;52(12):2574-2580

The Heart Institute, Cincinnati Children's, Cincinnati, OH.

Introduction: Cardiorespiratory fitness (CRF) measured by oxygen consumption (V˙O2) during exercise is an important marker of health. The traditional method of indexing V˙O2 to total body mass is suboptimal because skeletal muscle mass (SMM), rather than fat and extracellular fluid, is the main contributor to CRF. The traditional estimating equations for peak V˙O2 in youth do not account for this. Bioelectric impedance analysis (BIA) is a noninvasive method to accurately measure body composition. The objectives of this study were to 1) examine the relationship of body composition indices and peak V˙O2 in healthy children, adolescents, and young adults, and 2) derive an optimized estimating equation incorporating BIA and compare its performance with traditional estimating equations.

Methods: A retrospective, cross-sectional, single-center study of patients <21 yr old referred for exercise testing who did not have underlying cardiovascular disease. All patients underwent BIA immediately before exercise testing. Univariable and multivariable linear regression models were constructed and tested for model performance.

Results: A total of 165 young healthy people (mean age 14 yr, 48% male) were studied. There was a strong and linear relationship between peak V˙O2 and SMM (R = 0.79). The sex difference in SMM explained the most variability in CRF between boys and girls. A generalized equation using SMM (peak V˙O2 = 302 - (23.7 × age) - (50.3 × [female = 1, male = 0]) + (81.8 × SMM)) had superior performance (R = 0.80) compared with estimating equations currently used in clinical practice (R = 0.67).

Conclusions: SMM is a stronger correlate of CRF than is total body mass in youth and may be a better scaling variable to estimate expected peak V˙O2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1249/MSS.0000000000002424DOI Listing
December 2020

A Validated Model for Sudden Cardiac Death Risk Prediction in Pediatric Hypertrophic Cardiomyopathy.

Circulation 2020 07 18;142(3):217-229. Epub 2020 May 18.

Division of Cardiology (A.M., T.P., S.M.), Hospital for Sick Children, Toronto, Ontario, Canada.

Background: Hypertrophic cardiomyopathy is the leading cause of sudden cardiac death (SCD) in children and young adults. Our objective was to develop and validate a SCD risk prediction model in pediatric hypertrophic cardiomyopathy to guide SCD prevention strategies.

Methods: In an international multicenter observational cohort study, phenotype-positive patients with isolated hypertrophic cardiomyopathy <18 years of age at diagnosis were eligible. The primary outcome variable was the time from diagnosis to a composite of SCD events at 5-year follow-up: SCD, resuscitated sudden cardiac arrest, and aborted SCD, that is, appropriate shock following primary prevention implantable cardioverter defibrillators. Competing risk models with cause-specific hazard regression were used to identify and quantify clinical and genetic factors associated with SCD. The cause-specific regression model was implemented using boosting, and tuned with 10 repeated 4-fold cross-validations. The final model was fitted using all data with the tuned hyperparameter value that maximizes the c-statistic, and its performance was characterized by using the c-statistic for competing risk models. The final model was validated in an independent external cohort (SHaRe [Sarcomeric Human Cardiomyopathy Registry], n=285).

Results: Overall, 572 patients met eligibility criteria with 2855 patient-years of follow-up. The 5-year cumulative proportion of SCD events was 9.1% (14 SCD, 25 resuscitated sudden cardiac arrests, and 14 aborted SCD). Risk predictors included age at diagnosis, documented nonsustained ventricular tachycardia, unexplained syncope, septal diameter -score, left ventricular posterior wall diameter score, left atrial diameter score, peak left ventricular outflow tract gradient, and presence of a pathogenic variant. Unlike in adults, left ventricular outflow tract gradient had an inverse association, and family history of SCD had no association with SCD. Clinical and clinical/genetic models were developed to predict 5-year freedom from SCD. Both models adequately discriminated between patients with and without SCD events with a c-statistic of 0.75 and 0.76, respectively, and demonstrated good agreement between predicted and observed events in the primary and validation cohorts (validation c-statistic 0.71 and 0.72, respectively).

Conclusion: Our study provides a validated SCD risk prediction model with >70% prediction accuracy and incorporates risk factors that are unique to pediatric hypertrophic cardiomyopathy. An individualized risk prediction model has the potential to improve the application of clinical practice guidelines and shared decision making for implantable cardioverter defibrillator insertion. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT0403679.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365676PMC
July 2020

Hypertrophic Cardiomyopathy With Left Ventricular Systolic Dysfunction: Insights From the SHaRe Registry.

Circulation 2020 04 31;141(17):1371-1383. Epub 2020 Mar 31.

Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (P.M., N.K.L., C.Y.H.).

Background: The term "end stage" has been used to describe hypertrophic cardiomyopathy (HCM) with left ventricular systolic dysfunction (LVSD), defined as occurring when left ventricular ejection fraction is <50%. The prognosis of HCM-LVSD has reportedly been poor, but because of its relative rarity, the natural history remains incompletely characterized.

Methods: Data from 11 high-volume HCM specialty centers making up the international SHaRe Registry (Sarcomeric Human Cardiomyopathy Registry) were used to describe the natural history of patients with HCM-LVSD. Cox proportional hazards models were used to identify predictors of prognosis and incident development.

Results: From a cohort of 6793 patients with HCM, 553 (8%) met the criteria for HCM-LVSD. Overall, 75% of patients with HCM-LVSD experienced clinically relevant events, and 35% met the composite outcome (all-cause death [n=128], cardiac transplantation [n=55], or left ventricular assist device implantation [n=9]). After recognition of HCM-LVSD, the median time to composite outcome was 8.4 years. However, there was substantial individual variation in natural history. Significant predictors of the composite outcome included the presence of multiple pathogenic/likely pathogenic sarcomeric variants (hazard ratio [HR], 5.6 [95% CI, 2.3-13.5]), atrial fibrillation (HR, 2.6 [95% CI, 1.7-3.5]), and left ventricular ejection fraction <35% (HR, 2.0 [95% CI, 1.3-2.8]). The incidence of new HCM-LVSD was ≈7.5% over 15 years. Significant predictors of developing incident HCM-LVSD included greater left ventricular cavity size (HR, 1.1 [95% CI, 1.0-1.3] and wall thickness (HR, 1.3 [95% CI, 1.1-1.4]), left ventricular ejection fraction of 50% to 60% (HR, 1.8 [95% CI, 1.2, 2.8]-2.8 [95% CI, 1.8-4.2]) at baseline evaluation, the presence of late gadolinium enhancement on cardiac magnetic resonance imaging (HR, 2.3 [95% CI, 1.0-4.9]), and the presence of a pathogenic/likely pathogenic sarcomeric variant, particularly in thin filament genes (HR, 1.5 [95% CI, 1.0-2.1] and 2.5 [95% CI, 1.2-5.1], respectively).

Conclusions: HCM-LVSD affects ≈8% of patients with HCM. Although the natural history of HCM-LVSD was variable, 75% of patients experienced adverse events, including 35% experiencing a death equivalent an estimated median time of 8.4 years after developing systolic dysfunction. In addition to clinical features, genetic substrate appears to play a role in both prognosis (multiple sarcomeric variants) and the risk for incident development of HCM-LVSD (thin filament variants).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.119.044366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182243PMC
April 2020

Profound Iron Deficiency Anemia and Irreversible Dilated Cardiomyopathy in a Child.

Case Rep Cardiol 2019 10;2019:7513782. Epub 2019 Oct 10.

Cincinnati Children's Hospital Medical Center, Heart Institute, Cincinnati, OH, USA.

Iron deficiency anemia has been associated with a secondary and potentially reversible cardiomyopathy. The pathophysiologic paradigm has been that the hematologic disease begets cardiac dysfunction. There may be, however, a point at which myocardial injury is irreversible in susceptible individuals. We present the case of a 4-year-old, developmentally normal, child who presented with iron deficiency anemia and a dilated cardiomyopathy with congestive heart failure. Despite appropriate correction of the anemia, the patient developed decompensated heart failure requiring milrinone therapy and eventual heart transplantation. This report will alert clinicians to the potential for irreversible adverse cardiac remodeling and the importance of close pediatric cardiology consultation and serial assessment in order to implement appropriate heart failure therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2019/7513782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811802PMC
October 2019

Cost-utility of continuous-flow ventricular assist devices as bridge to transplant in pediatrics.

Pediatr Transplant 2019 12 19;23(8):e13576. Epub 2019 Sep 19.

Children's Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Objective: The initial costs of a CF-VAD exceed those of a PF-VAD. However, the safety profile of CF-VAD is superior and the possibility of outpatient device support may justify the additional initial costs. This study analyzed the cost-utility of CF-VAD use in the pediatric population.

Methods: A Markov-state transition model was constructed for the clinical course of the two VAD subtypes from implantation until death with variables extracted from internal financial records and the published literature. The modeled population consisted of pediatric heart failure patients who met indications for VAD implant (INTERMACS profile 1 or 2) and were size-eligible for either a PF-VAD or CF-VAD.

Results: The cost-utility analysis illustrated that CF-VAD is both more effective and less costly compared to PF-VAD at base-case conditions. Sensitivity analyses demonstrated that only in extreme conditions did a CF-VAD strategy not meet criteria for cost-effectiveness (if readmission rate >20% weekly, neurologic event rate >8% weekly, or CF-VAD discharge rates <18% in a month) or VAD support duration shortens to ≤12 weeks.

Conclusion: While the implantation costs of a CF-VAD exceed those of a PF-VAD, after 12 weeks of device support CF-VAD becomes the more cost-effective strategy if the anticipated outpatient device care is sufficiently long. The cost efficacy of the CF-VAD will be further heightened as initiatives that result in earlier and safer discharges, as well as reductions in readmission rates continue to be successful.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/petr.13576DOI Listing
December 2019

Contemporary Outcomes of Pediatric Restrictive Cardiomyopathy: A Single-Center Experience.

Pediatr Cardiol 2019 Apr 12;40(4):694-704. Epub 2018 Dec 12.

Cincinnati Children's Hospital Medical Center, Heart Institute, Cincinnati, OH, USA.

Background: Pediatric restrictive cardiomyopathy (RCM) has high mortality in historical cohorts, and traditional management often involves early referral for heart transplantation (HTx). This study sought to determine outcomes of pediatric RCM at a center that has favored medical management over early listing for HTx.

Methods: All patients (N = 43) with pure RCM phenotype (RCM, N = 26) and hypertrophic cardiomyopathy with restrictive physiology (RCM/HCM, N = 17) managed at our center over a 15-year period were investigated. Outcomes of those listed for HTx (N = 18) were compared to a benchmark of contemporaneous pediatric RCM patients in the UNOS database (N = 377). Proportional hazards models were used to determine predictors of adverse outcomes.

Results: The mean age was 11 ± 9 years and 49% were male. 14 of 18 patients listed received HTx. Overall mortality (12%) was identical between the phenotypes; however, RCM patients were more likely to be listed (P = 0.001) and receive HTx (P = 0.02) compared to RCM/HCM. Prior to HTx, 60% had documented arrhythmia, 16% had cardiac arrest, and 7% required mechanical circulatory support. 4 of 17 patients with an ICD/PM received device therapies (four of five shocks appropriate for VT/VF, and two effective anti-tachycardia pacing interventions). Outcomes of those listed for HTx at our center were similar to the UNOS benchmark. In multivariate analysis, markers of congestive heart failure were associated with adverse outcomes.

Conclusion: Heart failure and arrhythmia treatments can delay or possibly prevent the need for HTx in some cases of pediatric RCM. Survival post-HTx is not compromised using this approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00246-018-2043-0DOI Listing
April 2019

Cardiopulmonary Rehabilitation Therapy in Congenital Heart Disease: What Will it Take to Gain Traction?

Semin Thorac Cardiovasc Surg 2018 1;30(4):470-471. Epub 2018 Sep 1.

Cincinnati Children's Hospital Medical Center, Heart Institute, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.semtcvs.2018.08.009DOI Listing
January 2019

Can we heal with steel and sharpen our risk prediction tools in obstructive hypertrophic cardiomyopathy?

J Thorac Cardiovasc Surg 2018 08 3;156(2):760-761. Epub 2018 Apr 3.

Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtcvs.2018.03.103DOI Listing
August 2018

Cardiac Rehabilitation Improves Cardiometabolic Health in Young Patients with Nonischemic Dilated Cardiomyopathy.

Tex Heart Inst J 2018 02 1;45(1):27-30. Epub 2018 Feb 1.

Nonischemic dilated cardiomyopathy is deadly and costly, and treatment options are limited. Cardiac rehabilitation has proved safe and beneficial for adults with various types of heart failure. Therefore, we retrospectively evaluated the hypothesis that rehabilitation is safe and improves cardiometabolic health in young patients with nonischemic dilated cardiomypathy. From 2011 through 2015, 8 patients (4 males) (mean age, 20.6 ± 6.6 yr; range, 10-31 yr) underwent rehabilitation at our institution. They were in American Heart Association class C or D heart failure and were on maximal medical therapy. Their mean left ventricular ejection fraction at baseline was 0.26 ± 0.15. Two patients had a left ventricular assist device, and 2 were inpatients. To evaluate safety, we documented adverse events during rehabilitation sessions. Clinical endpoints were measured at baseline, immediately after completing rehabilitation, and after one year. Patients attended 120 of 141 possible sessions (85%), with no adverse events. There were no marked changes in mean left ventricular ejection fraction or body mass index. The patients' mean waist circumference decreased by 1.37 ± 0.6 in (n=5; 95% CI, -2.1 to -0.63). Their 6-minute walk distance increased by a mean of 111 ± 75 m (n=5; 95% CI, 18-205). In our small sample of young patients with nonischemic dilated cardiomyopathy, cardiac rehabilitation was feasible and was associated with minimal risk. Our findings suggest that prospective studies in this population are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14503/THIJ-17-6249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832081PMC
February 2018

Association of Habitual Physical Activity With Cardiovascular Risk Factors and Target Organ Damage in Adolescents and Young Adults.

J Phys Act Health 2018 03 27;15(3):176-182. Epub 2017 Nov 27.

Background: We aimed to (1) compare a subjective and objective measure of habitual physical activity (PA), (2) determine the association of PA and cardiovascular risk factors, and (3) test the hypothesis that PA is an independent determinant of target organ damage in youth.

Methods: Cross-sectional analysis of youth with and without type 2 diabetes [mean age = 22 (3.9) y]. PA was measured with International Physical Activity Questionnaire and Actical accelerometer. Target organ damage was assessed with echocardiography and peripheral arterial testing. Subjects were stratified into tertiles of total PA, and differences were tested by analysis of variance and χ tests. General linear models tested for independent associations.

Results: The correlation between International Physical Activity Questionnaire and accelerometry was weak (r = .23, P = .0003). Less active subjects had worse cardiovascular risk profiles and target organ damage, including stiffer arteries (P < .01). These outcome differences did not reach statistical significance when adjusted for covariates, such as lipid levels and glycemic control.

Conclusion: Survey assessment of PA is complicated by inaccurate reporting. There is a strong association of habitual PA with cardiovascular risk factor clustering. PA may exert its beneficial effect on arterial stiffness in obese youth through improved glycemic control.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1123/jpah.2017-0276DOI Listing
March 2018

Regional variation in quality of life in patients with a Fontan circulation: A multinational perspective.

Am Heart J 2017 Nov 2;193:55-62. Epub 2017 Aug 2.

Cincinnati Children's Hospital Medical Center, Cincinnati, OH. Electronic address:

Background: Impaired quality of life (QOL) is associated with congenital heart disease (CHD) and country of residence; however, few studies have compared QOL in patients with differing complexities of CHD across regional populations. The current study examined regional variation in QOL outcomes in a large multinational sample of patients with a Fontan relative to patients with atrial septal defects (ASDs) and ventricular septal defects (VSDs).

Methods: From the Assessment of Patterns of Patient-Reported Outcomes in Adults with Congenital Heart disease-International Study (APPROACH-IS), 405 patients (163 Fontan and 242 ASD/VSD) across Asia, Europe, and North America provided consent for access to their medical records and completed a survey evaluating QOL (0 to 100 linear analog scale). Primary CHD diagnosis, disease complexity, surgical history, and documented history of mood and anxiety disorders were recorded. Differences in QOL, medical complications, and mood and anxiety disorders between Fontan and ASD/VSD patients, and across geographic regions, were examined using analysis of covariance. Hierarchical regression analyses were conducted to identify variables associated with the QOL ratings.

Results: Patients with a Fontan reported significantly lower QOL, and greater medical complications and mood and anxiety disorders relative to patients with ASD/VSD. Inpatient cardiac admissions, mood disorders, and anxiety disorders were associated with lower QOL among patients with a Fontan, and mood disorders were associated with lower QOL among patients with ASD/VSD. Regional differences for QOL were not observed in patients with a Fontan; however, significant differences were identified in patients with ASD/VSD.

Conclusions: Regional variation of QOL is commonplace in adults with CHD; however, it appears affected by greater disease burden. Among patients with a Fontan, regional variation of QOL is lost. Specific attempts to screen for QOL and mood and anxiety disorders among CHD patients may improve the care of patients with the greatest disease burden.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ahj.2017.07.019DOI Listing
November 2017

Neonatal Enterovirus Myocarditis With Severe Dystrophic Calcification: Novel Treatment With Pocapavir.

J Investig Med High Impact Case Rep 2017 Jul-Sep;5(3):2324709617729393. Epub 2017 Sep 14.

Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH, USA.

Dystrophic myocardial calcification occurs in the setting of myocardial injury and normal serum calcium. We present a case of a neonate with prominent dystrophic calcification and severe left ventricular systolic dysfunction in the setting of enterovirus myocarditis. These findings are superbly illustrated by multiple imaging modalities. The patient was treated with the novel antiviral, pocapavir, in addition to a standard heart failure regimen. The dystrophic calcification persisted but the left ventricle remodeled significantly. To our knowledge, this is the first reported use of pocapavir for this indication. The literature regarding enterovirus myocarditis and pocapavir is briefly reviewed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2324709617729393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602221PMC
September 2017

Cardiovascular adaptation to the Fontan circulation.

Congenit Heart Dis 2017 Dec 10;12(6):699-710. Epub 2017 Aug 10.

Leuven University Hospital, Leuven, Belgium.

Although medium-term survival following Fontan operations in the modern era has improved dramatically, late cardiovascular and extracardiac morbidity are common and are associated with impaired quality of life and premature late mortality. This serves as a reminder of the extraordinary adaptations required of the cardiovascular system when the systemic arterial, systemic venous and pulmonary circulations are placed in series coupled to a single ventricular pump. This article reviews the key features and principles that govern interactions between the ventricle, systemic arterial circulation, the systemic venous and pulmonary circulatory compartments, the microcirculation, and lymphatic circulations. The overarching aim is to provide insight into the integrative pathophysiology that governs the Fontan circulation and stimulate thoughtful approaches to advance research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/chd.12526DOI Listing
December 2017

Two pediatric cases of variant neurogenic stress cardiomyopathy after intracranial hemorrhage.

Pediatrics 2014 Oct 8;134(4):e1211-7. Epub 2014 Sep 8.

Department of Medicine, Division of Cardiology, University of Washington, Seattle, Washington.

Takotsubo cardiomyopathy, also known as stress-induced cardiomyopathy, is an acquired form of left ventricular systolic dysfunction seen in the setting of physiologic stress and the absence of coronary artery disease. It is thought to be caused by excessive sympathetic stimulation. It is well described in the adult literature associated with subarachnoid hemorrhage where it is known as neurogenic stress cardiomyopathy (NSC), but few such pediatric cases have been reported. We describe our experience with 2 children (13- and 10-year-old girls) who presented with spontaneous intracranial hemorrhage followed by pulmonary edema and shock. Echocardiography revealed similar patterns of left ventricular wall motion abnormalities consistent with NSC, inverted Takotsubo variant. One child progressed to death, whereas the other made a remarkable recovery, including significant improvement in cardiac function over the course of 1 week. We argue that at least 1 of these cases represents true stress-induced cardiomyopathy. This report will alert pediatricians to this transient cardiomyopathy that is likely underdiagnosed in pediatric intensive care. We also highlight the challenges of managing both shock and elevated intracranial pressure in the setting of NSC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1542/peds.2013-1881DOI Listing
October 2014

Ictal asystole: an indication for pacemaker implantation and emerging cause of sudden death.

Pacing Clin Electrophysiol 2012 Jul 7;35(7):e193-6. Epub 2011 Aug 7.

Pediatric Residency Program, University of Washington, Seattle, Washington 98195, USA.

Ictal asystole is being recognized as a potential mechanism of sudden unexplained death in epilepsy (SUDEP). We report a case of a patient without known cardiac disease presenting with ictal asystole resulting in syncope, trauma, and need for pacemaker implantation. The management of ictal asystole is also briefly reviewed. This case is notable for the asystolic episode wholly captured on video-electroencephalogram/electrocardiogram, the serious risk of trauma and death posed to the patient, and its implications for the mechanism of ictal asystole. This report will alert physicians to the possibility of ictal arrhythmias as a cause of syncope and SUDEP in vulnerable patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1540-8159.2011.03179.xDOI Listing
July 2012

STAM and Hrs down-regulate ciliary TRP receptors.

Mol Biol Cell 2007 Sep 20;18(9):3277-89. Epub 2007 Jun 20.

Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin, Madison, WI 53705, USA.

Cilia are endowed with membrane receptors, channels, and signaling components whose localization and function must be tightly controlled. In primary cilia of mammalian kidney epithelia and sensory cilia of Caenorhabditis elegans neurons, polycystin-1 (PC1) and transient receptor polycystin-2 channel (TRPP2 or PC2), function together as a mechanosensory receptor-channel complex. Despite the importance of the polycystins in sensory transduction, the mechanisms that regulate polycystin activity and localization, or ciliary membrane receptors in general, remain poorly understood. We demonstrate that signal transduction adaptor molecule STAM-1A interacts with C. elegans LOV-1 (PC1), and that STAM functions with hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) on early endosomes to direct the LOV-1-PKD-2 complex for lysosomal degradation. In a stam-1 mutant, both LOV-1 and PKD-2 improperly accumulate at the ciliary base. Conversely, overexpression of STAM or Hrs promotes the removal of PKD-2 from cilia, culminating in sensory behavioral defects. These data reveal that the STAM-Hrs complex, which down-regulates ligand-activated growth factor receptors from the cell surface of yeast and mammalian cells, also regulates the localization and signaling of a ciliary PC1 receptor-TRPP2 complex.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1091/mbc.e07-03-0239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1951776PMC
September 2007