Young Hypertrophic Cardiomyopathy Patients Research Articles

Biomarkers and Proteomics in Sarcomeric Hypertrophic Cardiomyopathy in the Young-FGF-21 Highly Associated with Overt Disease.

Background: Any difference in biomarkers between genotype-positive individuals with overt hypertrophic cardiomyopathy (HCM), and genotype-positive but phenotype-negative individuals (G+P-) in HCM-associated pathways might shed light on pathophysiological mechanisms. We studied this in young HCM patients. Methods: 29 HCM patients, 17 G+P--individuals, and age- and sex-matched controls were prospectively included. We analyzed 184 cardiovascular disease-associated proteins by two proximity extension assays, categorized into biological pathways, and analyzed with multivariate logistic regression analysis. Significant proteins were dichotomized into groups above/below median concentration in control group. Results: Dichotomized values of significant proteins showed high odds ratio (OR) in overt HCMphenotype for Fibroblast growth factor-21 (FGF-21) 10 (p = 0.001), P-selectin glycoprotein ligand-1 (PSGL-1) OR 8.6 (p = 0.005), and Galectin-9 (Gal-9) OR 5.91 (p = 0.004). For G+P-, however, angiopoietin-1 receptor (TIE2) was notably raised, OR 65.5 (p = 0.004), whereas metalloproteinase inhibitor 4 (TIMP4) involved in proteolysis, in contrast, had reduced OR 0.06 (p = 0.013). Conclusions: This study is one of the first in young HCM patients and G+P- individuals. We found significantly increased OR for HCM in FGF-21 involved in RAS-MAPK pathway, associated with cardiomyocyte hypertrophy. Upregulation of FGF-21 indicates involvement of the RAS-MAPK pathway in HCM regardless of genetic background, which is a novel finding.

Preventing Atrial Fibrillation in Hypertrophic Cardiomyopathy using Angiotensin-Converting Enzyme (ACE) Inhibitors and Angiotensin Receptor Blockers (ARBs)

Hypertrophic cardiomyopathy (HCM), a genetic cardiovascular disease, is the leading cause of cardiac death in young people, often due to atrial fibrillation (AF). AF is generally treated using antiarrhythmics and anticoagulants, which have adverse side effects after long-term use, and are therefore unsuitable for young HCM patients. AF is characterized by a rapid and irregular atrial heartbeat, marked by a short action potential duration and atrial effective refractory period in atrial cardiomyocytes. Prior studies have indicated that the renin-angiotensin system is involved in lowering both, so it has been hypothesized that angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), which inhibit the renin-angiotensin system, could prevent AF. Therefore, in this study, we propose a research protocol to examine the viability of ACE inhibitors and ARBs as prophylactic measures against the development of AF in HCM patients. To test this, we suggest extracting atrial cardiomyocytes from HCM patients by performing enzyme dissociation on myocardial tissue. The isolated cardiomyocytes will then be treated in vitro with an ACE inhibitor, an ARB, a combination of both, or a control saline solution, and the patch-clamp technique will be used to determine the frequency and duration of their action potentials. We expect action potential duration and atrial effective refractory period to be longer in treated cells, while neither medication will provide a greater advantage, and, as prior research suggests, the combination will not yield significant benefits. The study will continue by testing the effects of ACE inhibitors and ARBs on the function of atrial myocardial organoids created from differentiated stem cells with an HCM mutation. The results of this study could present a new preventative measure against AF for HCM patients which would be safe for long-term use.

Analysis of risk stratification and prevention of sudden death in pediatric patients with hypertrophic cardiomyopathy: Dilemmas and clarity.

Hypertrophic cardiomyopathy (HCM) has been considered the most common cause of sudden death (SD) in the young. However, introduction of implantable cardioverter-defibrillators (ICDs) in HCM has proved highly effective and the mainstay of preventing SD in children, adolescents, and adults by terminating malignant ventricular tachyarrhythmias. Nevertheless, ICD decision making is generally regarded as more difficult in pediatrics, and the strategy for selecting ICD patients from this population remains without consensus. Prospective studies in HCM children and adolescents have shown the American Heart Association/American College of Cardiology traditional major risk marker strategy to be reliable with >90% sensitivity in selecting patients for SD prevention. International data in >2000 young HCM patients assembled over 20 years who were stratified by major risk markers showed ICDs effectively prevented SD in 20%. Alternatively, novel quantitative risk scoring initiatives provide 5-year risk estimates that are potentially useful as adjunctive tools to facilitate discussion of prophylactic ICD risks vs benefit but are as yet unsupported by prospective outcome studies. Risk scoring strategies are characterized by reasonable discriminatory statistical power (C-statistic 0.69-0.76) for identifying patients with SD events but with relatively low sensitivity, albeit with specificity comparable with the risk marker strategy. While some reticence for obligating healthy-appearing young patients to lifelong device implants is understandable, underutilization of the ICD in high-risk children and adolescents can represent a lost opportunity for fulfilling the long-standing aspiration of SD prevention. This review provides a critical assessment of the current strengths and weaknesses of SD risk stratification strategies in young HCM patients in an effort to clarify clinical decision making in this challenging subpopulation.

Clinical features of hypertrophic cardiomyopathy depending on the hereditary factor

The objective was to study the clinical features of symptomatic hypertrophic cardiomyopathy (HCM) depending on the form (familial / non-familial), the age of onset and the presence of arterial hypertension (AH).Methods and materials. During 6 years, we examined 250 HCM patients, 100 patients with symptomatic HCM aged from 18 to 86 years were included in the study. Results. Patients with the clinical manifestations onset at a young age more often had a familial form of the disease, an autosomal dominant type of inheritance, an asymmetric HCM with reverse curve interventricular septal morphology. On the contrary, patients with the clinical manifestations onset at the age of ≥45 years had non-familial form of the disease and asymmetric HCM with basal interventricular septal hypertrophy. The young HCM patients with associated AH more often were obese, had CHF of III–IV functional class (NYHA), larger anteroposterior left atrial diameter than patients without AH and more often needed interventricular septal reduction. HCM patients and associated AH with the disease onset at the age of ≥45 years significantly more often had angina syndrome. Absolute indications for interventricular septal reduction in HCM patients with the disease onset ≥45 years of age were determined only for HCM patients and associated AH. At the same time, 50 % of HCM+AH patients both at a young age and in the older group, had obesity. Conclusions. The interventricular septal morphology differs significantly depending on the age of clinical manifestations onset. Co-existing AH and obesity are predictors of the progressive HCM course and an increase in the proportion of patients with absolute indications for interventricular septal reductions regardless of the age of clinical manifestations onset.

Abstract P556: Temporal and Global Trends of the Incidence of Sudden Cardiac Death in Hypertrophic Cardiomyopathy: A Meta-Analysis

Introduction: Since hypertrophic cardiomyopathy(HCM) initial description, sudden cardiac death (SCD) has been the most feared complication of HCM. Hypothesis: Temporal, geographical, and age-related trends of SCD rates in HCM have drastically decreased over time. Methods: Databases were systematically searched to Nov 2021 for studies reporting on SCD event rates in HCM. Patients with SCD equivalents (appropriate ICD shocks and non-fatal SCD) were excluded. Random-e!ects model was utilized to pool study estimates calculating the overall incidence rates(IR) for each time-era, geographical region, and age-group. We analyzed 2 eras (before vs. after 2000, following implementation of ICD in HCM). Following 2000, 5-year intervals were used to reflect the temporal change in SCD. Results: 98 studies(N=70,510patients and 431,407patient-years) met inclusion criteria. Overall rate of HCM SCD was 0.43%/year (95% CI: 0.37-0.50%; I2=75%; SCD events:1,938; person-years of follow-up: 408,715), with young patients(<18 years) demonstrating a>2-fold-risk for SCD vs. adults(18- 60years) (IR:1.09%; 95% CI: 0.69-1.73% vs. IR: 0.43%; 95% CI: 0.37-0.50%)(P-value for subgroup di!erences:<0.01). Contemporary SCD rates from 2015-present were 0.32%/year; significantly lower compared to 2000 or earlier (IR: 0.32%; 95% CI:0.20-0.52%, vs. IR: 0.73%; 95% CI:0.53-1.02%,respectively). Reported HCM-SCD rates were lowest in North America (IR: 0.28%;95% CI:0.18-0.43%) and highest in Asia(IR: 0.67%; 95% CI:0.54-0.84%). Conclusions: Contemporary HCM-related SCD are low (0.32%/year) representing a 2-fold decrease compared to prior treatment eras, with young HCM patients at the highest risk. SCD risk stratification maturation and primary prevention ICD application are likely responsible for the notable decline in SCD trends. Moreover, worldwide geographical disparities in SCD was evident, underscoring the need to increase access to SCD prevention for all HCM patients.

Abstract 10951: Temporal and Global Trends of the Incidence of Sudden Cardiac Death in Hypertrophic Cardiomyopathy: A Meta-Analysis

Introduction: Since hypertrophic cardiomyopathy(HCM) initial description, sudden cardiac death (SCD) has been the most feared complication of HCM. Hypothesis: Temporal, geographical, and age-related trends of SCD rates in HCM have drastically decreased over time. Methods: Databases were systematically searched to Nov 2021 for studies reporting on SCD event rates in HCM. Patients with SCD equivalents (appropriate ICD shocks and non-fatal SCD) were excluded. Random-effects model was utilized to pool study estimates calculating the overall incidence rates(IR) for each time-era, geographical region, and age-group. We analyzed 2 eras (before vs. after 2000, following implementation of ICD in HCM). Following 2000, 5-year intervals were used to reflect the temporal change in SCD. Results: 98 studies (N=70,510patients and 431,407patient-years) met inclusion criteria. Overall rate of HCM SCD was 0.43%/year (95% CI: 0.37-0.50%; I 2 =75%; SCD events:1,938; person-years of follow-up: 408,715), with young patients(<18 years) demonstrating a>2-fold-risk for SCD vs. adults(18-60years) (IR:1.09%; 95% CI: 0.69-1.73% vs. IR: 0.43%; 95% CI: 0.37-0.50%)(P-value for subgroup differences:<0.01). Contemporary SCD rates from 2015-present were 0.32%/year; significantly lower compared to 2000 or earlier (IR: 0.32%; 95% CI:0.20-0.52%, vs. IR: 0.73%; 95% CI:0.53-1.02%,respectively). Reported HCM-SCD rates were lowest in North America (IR: 0.28%;95% CI:0.18-0.43%) and highest in Asia(IR: 0.67%; 95% CI:0.54-0.84%). Conclusions: Contemporary HCM-related SCD are low (0.32%/year) representing a 2-fold decrease compared to prior treatment eras, with young HCM patients at the highest risk. SCD risk stratification maturation and primary prevention ICD application are likely responsible for the notable decline in SCD trends. Moreover, worldwide geographical disparities in SCD was evident, underscoring the need to increase access to SCD prevention for all HCM patients.

Ventricular arrhythmia and sudden cardiac death in hypertrophic cardiomyopathy: From bench to bedside.

Patients with hypertrophic cardiomyopathy (HCM) mostly experience minimal symptoms throughout their lifetime, and some individuals have an increased risk of ventricular arrhythmias and sudden cardiac death (SCD). How to identify patients with a higher risk of ventricular arrythmias and SCD is the priority in HCM research. The American College of Cardiology/American Heart Association (ACC/AHA) and the European Society of Cardiology (ESC) both recommend the use of risk algorithms to identify patients at high risk of ventricular arrhythmias, to be selected for implantation of implantable cardioverters/defibrillators (ICDs) for primary prevention of SCD, although major discrepancies exist. The present SCD risk scoring systems cannot accurately identify early-stage HCM patients with modest structural remodeling and mild disease manifestations. Unfortunately, SCD events could occur in young asymptomatic HCM patients and even as initial symptoms, prompting the determination of new risk factors for SCD. This review summarizes the studies based on patients' surgical specimens, transgenic animals, and patient-derived induced pluripotent stem cells (hiPSCs) to explore the possible molecular mechanism of ventricular arrhythmia and SCD. Ion channel remodeling, Ca2+ homeostasis abnormalities, and increased myofilament Ca2+ sensitivity may contribute to changes in action potential duration (APD), reentry circuit formation, and trigger activities, such as early aferdepolarization (EAD) or delayed afterdepolarization (DAD), leading to ventricular arrhythmia in HCM. Besides the ICD implantation, novel drugs represented by the late sodium current channel inhibitor and myosin inhibitor also shed light on the prevention of HCM-related arrhythmias. The ideal prevention strategy of SCD in early-stage HCM patients needs to be combined with gene screening, hiPSC-CM testing, machine learning, and advanced ECG studies, thus achieving individualized SCD prevention.

Prediction and Prevention of Sudden Death in Young Patients (

Highly reliable identification of adults with hypertrophic cardiomyopathy (HC) at risk for sudden death (SD) has been reported. A significant controversy remains, however, regarding the most reliable risk stratification methodology for children and adolescents with HC. The present study assesses the accuracy of SD prediction and prevention with prophylactic implantable cardioverter-defibrillators (ICDs) in young HC patients. The study group is comprised of 146 HC patients <20 years of age evaluated consecutively over 17 years with prospective risk stratification and ICD decision-making. We relied on ≥1 established individual risk markers considered major within each patient's clinical profile, based on an enhanced American College of Cardiology /American Heart Association (ACC/AHA) guidelines algorithm. Of the 60 largely asymptomatic patients implanted with primary prevention ICDs at age 15 ± 4 years, 9 (15%) experienced device therapy terminating potentially lethal ventricular tachyarrhythmias and restoring sinus rhythm at 19 ± 6 years (range 9 to 29), 5.1 ± 6.0 years after implant; 3 patients had multiple appropriate ICD discharges. The individual risk marker algorithm was associated with 100% sensitivity in predicting SD events (95%CI: 69, 100) and 63% specificity for identifying patients without events (95%CI: 54, 71). Of these patients with device therapy, massive left ventricular hypertrophy (absolute wall thickness ≥30 mm) was the most common predictor, present in 70% of patients either alone or in combination with other risk markers. Each of the 146 study patients have survived to date at 22 ± 5 years, including all 86 without ICD recommendations. In conclusion, an enhanced ACC/AHA risk stratification strategy, based on established individual risk markers, was highly reliable in prospectively predicting SD events in children and adolescents with HC, and preventing arrhythmia-based catastrophes in this susceptible high risk population.

Hypertrophic Cardiomyopathy and Sudden Death Initially Identified at Autopsy

Hypertrophic cardiomyopathy (HC) is associated with a well-recognized risk for unexpected sudden death (SD). Most such reported patients have been referred to dedicated centers and/or expert cardiologists for risk stratification, with the number of SDs decreasing sharply due to penetration of the implantable cardioverter-defibrillator (ICDs) into HC practice. However, the clinical circumstances, and morphologic features of HC patients who incur SD without the opportunity to be considered for preventive intervention with ICDs are largely undefined. Using the long-standing unique Jesse Edwards Registry (St. Paul, Minnesota), we studied 86 selected heart specimens from young HC patients who died suddenly and unexpectedly without prior clinical evaluation, ages 31 ± 16 years. The patients were predominantly male (87%) with only modest phenotypic expression and maximum LV wall thickening of only 18 ± 4 mm. SD events occurred predominantly with sedentary/mild activities (66%) often in bed or asleep (32%), but also during physical activity (22%) including with organized competitive sports. This largely unappreciated sub-population of patients with HC (and SD) is characterized by mild-to-moderate degree of LV hypertrophy, representing a clinical challenge which is particularly relevant in the current ICD era for HC, with the potential for SD prevention.

Cardiac Magnetic Resonance Imaging Features in Hypertrophic Cardiomyopathy Diagnosed at

Hypertrophic cardiomyopathy (HC) is the most common inherited cardiomyopathy, with varied timing of phenotypic and clinical presentation. Literature describing cardiac magnetic resonance (CMR) imaging and late gadolinium enhancement (LGE) in young patients with HC is limited. This study included patients diagnosed with HC at young age (<21 years) between January 1990 and January 2015 who underwent transthoracic echocardiography and CMR with assessment of LGE at a single tertiary referral center. LGE was quantified via a method of 6 standard deviations and patients were grouped based upon presence or absence of LGE (≤1% and >1% LGE, respectively). Sudden cardiac death (SCD) risk was assessed in patients >16 years of age using the European SCD risk score. A composite outcome of New York Heart Association class III-IV symptoms, aborted SCD, heart transplantation, and all-cause mortality was assessed via Kaplan-Meier curves with log-rank analysis. Overall, 126 patients were included (78 male; 62%). Median age of diagnosis was 15 (12 to 18) years. LGE was present in 81 (64%) patients, although only 4 (3%) patients had LGE >15%. Median age at CMR imaging was 19 (15 to 23) years. Patients with LGE had greater wall thickness (25 ± 8 mm vs 22 ± 7 mm, p = 0.01). Median European SCD risk score was 4.7 (2.9 to 6.5). Median follow-up was 6.5 (2.5 to 13) years with 26 patients (21%) meeting the composite outcome. There were no significant differences in composite outcome since age of diagnosis when stratified by presence/absence of LGE (p = 1.0). The presence of LGE in young HC patients was not an independent risk factor for cardiovascular morbidity and mortality. Wall thickness was greater in patients with LGE. There remains a need for further evaluation of this unique HC cohort.

Hypertrophic Cardiomyopathy in Children, Adolescents, and Young Adults Associated With Low Cardiovascular Mortality With Contemporary Management Strategies.

Youthful age has been considered the time of greatest risk for patients with hypertrophic cardiomyopathy (HCM), largely because of the possibility of sudden death. The last 2 decades have witnessed more reliable identification of at-risk patients and utilization of implantable cardioverter-defibrillators for prevention of sudden death, and other contemporary treatment options. Whether such management advances have significantly altered the considerable mortality rate for young HCM patients remains unresolved. We studied long-term outcome in 474 consecutive HCM patients between 7 and 29 years of age presenting at 2 referral institutions. Over 7.1±5.1 years of follow-up (6.0 [3.0, 10.0]), 452 patients (95%) survived, with 95% experiencing no or mild symptoms. HCM-related death occurred in 18 patients (3%; 0.54%/y): arrhythmic sudden death (n=12), progressive heart failure and heart transplant complications (n=5), or postoperatively (n=1). In contrast, aborted life-threatening events occurred in 63 other high-risk patients (13%) with implantable cardioverter-defibrillator interventions for ventricular tachyarrhythmias (n=31), resuscitated out-of-hospital cardiac arrest (n=20), or heart transplant for advanced heart failure (n=12), 1.8%/y, 3-fold higher than HCM mortality. Five- and 10-year survival (considering only HCM deaths) was high (97% and 94%, respectively), virtually identical to that reported in middle-aged adult HCM patients (98% and 94%, P=0.23). In a large hospital-based cohort of young HCM patients, representing an age group considered at greatest risk, low mortality rates can be achieved with the application of contemporary cardiovascular treatment strategies, largely because of reliable identification of high-risk patients who benefited from implantable cardioverter-defibrillators for sudden death prevention, thereby creating the opportunity for extended longevity and good quality of life.

Regional Stress-Induced Ischemia in Non-fibrotic Hypertrophied Myocardium in Young HCM Patients.

The relationship between hypertrophy, perfusion abnormalities and fibrosis is unknown in young patients with hypertrophic cardiomyopathy (HCM). Since mounting evidence suggests causal relationship between myocardial ischemia and major adverse cardiac events, we sought to investigate whether (1) regional myocardial perfusion is decreased in young HCM patients and in individuals at risk of HCM, and (2) hypoperfused areas are larger than areas with fibrosis. HCM patients (n = 12), HCM-risk subjects (n = 15) and controls (n = 9) were imaged on a 1.5 T MRI scanner. Myocardial hypertrophy was assessed on cine images. Perfusion images were acquired during adenosine hyperemia and at rest. Maximum upslope ratios of perfusion (stress/rest) were used for semiquantitative analysis. Fibrosis was assessed by late gadolinium enhancement (LGE). Results are presented as median and range. Perfusion in HCM-risk subjects and in non-hypertrophied segments in HCM patients showed no difference compared to controls (P = ns). Hypertrophic segments in HCM patients without LGE showed decreased perfusion compared to segments without hypertrophy [1.5 (1.1–2.3) vs. 2.0 (1.8–2.6), P < 0.001], and hypertrophic segments with LGE showed even lower perfusion using a segmental analysis [0.9 (0.6–1.8), P < 0.05]. The extent of hypoperfused myocardium in HCM patients during adenosine exceeded the extent of fibrosis on LGE [20 (0–48) vs. 4 (0–7) % slice area, P < 0.05] and hypoperfused areas at rest (P < 0.001). Regional perfusion is decreased in hypertrophied compared to non-hypertrophied myocardium and is lowest in fibrotic myocardium in young HCM patients but does not discriminate HCM-risk subjects from controls. The stress-induced hypoperfused regions exceed regions with LGE, indicating that hypoperfusion precedes fibrosis and may be a more sensitive marker of diseased myocardium in HCM.

Genotype-phenotype Correlations of Hypertrophic Cardiomyopathy When Diagnosed in Children, Adolescents, and Young Adults.

Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiovascular disease and a leading cause of identifiable sudden cardiac death (SCD) in the young. Herein, we sought to determine the genotype-phenotype correlations in a cohort of unrelated, genotyped patients diagnosed with HCM at a young age, as well as to characterize the differences between HCM diagnosed in adulthood and HCM diagnosed at a young age. From 1999 to 2011, 1053 unrelated patients diagnosed with HCM were enrolled in research-based genetic testing. The electronic medical record was reviewed to identify those with HCM diagnosed at ≤21 years (N = 137, mean age at diagnosis 13.2 ± 6 years, 64% male). From this cohort of patients recruited from a tertiary care referral center, the genetic test was positive in 71 (52%), which was significantly higher than patients diagnosed >21 years (31%; P < .001). Genotype-positive patients had increased maximum left ventricular wall thickness (24.9 ± 8.0 vs. 21.6 ± 7.4 mm, P = .01) and higher incidence of reverse-curve ventricular septal morphology (71% vs. 40%, P < .001). Unrelated to genotype status, 26/137 patients (19%) experienced significant HCM-related morbidity/mortality including progressive heart failure symptoms in 12, transplantation in 4, and death in 10. Among patients diagnosed with HCM during the first two decades of life, the yield of genetic testing is significantly higher than when diagnosed at later age. While the phenotype of young HCM patients is worse than patients whose HCM is diagnosed at later age, the phenotypes of genotype-positive and genotype-negative young patients were similar. Independent of genotype, nearly 30% of the patients with follow-up in this study had symptom progression, transplant, or death.

SERUM BIOMARKERS OF EARLY STAGES OF HYPERTROPHIC CARDIOMYOPATHY IN A YOUNG POPULATION

Background: Hypertrophic cardiomyopathy (HCM) is the most common monogenic cardiac disorder and the leading cause of sudden cardiac death in the young. Although in a majority of HCM cases there are gene mutations coding for sarcomere proteins, the onset for the clinical consequences of these mutations are difficult to predict, as these mutations do not show any clear relationship to the degree of myocardial hypertrophy. Hence identification of early markers for this disease is important. The aim of this study was to investigate novel serum biomarkers reflecting myocardial remodeling, microfibrosis and coronary endotheliopathy in young presymtomatic HCM patients and in individuals at risk for developing HCM. Methods: Eighty-nine participants (18 HCM patients, 14 HCM-risk individuals, and 57 healthy controls) with median age of 15 (range 0-30) years underwent assessment with echocardiography and serum analysis for myostatin, cathepsin S, endostatin, type I collagen degradation marker (ICTP), matrix metalloproteinase (MMP) 9, vascular (VCAM) and intercellular adhesion molecules (ICAM). In some individuals, myocardial perfusion was measured both at rest and after adenosine via magnetic resonance. Results: Both cathepsin S and endostatin were increased in the HCM group (p0.3) and diastolic function, expressed as E/e' (p0.3). In the HCM-risk group, myostatin was decreased (p0.1). Conclusion: To the best of our knowledge, this is the first study to suggest early onset changes in biomarkers of myoblast regulation, endothelial function and matrix remodeling in young presymptomatic HCM patients and in HCM-risk individuals. (Less)

Regional adenosine-induced hypoperfusion without hyperenhancement on LGE-MRI in young HCM patients: comparison to subjects at risk of HCM and healthy volunteers

Background The relation between hypoperfusion and fibrosis is not completely understood in hypertrophic cardiomyopathy (HCM). One hypothesis is that hypoperfusion is a primary cause of fibrosis. Therefore, the aim of this study was to use cardiac magnetic resonance (CMR) to 1) measure if regional perfusion is decreased in young patients with HCM and in subjects at risk of HCM compared to normal controls and 2) determine if regional myocardial perfusion is decreased in areas with left ventricular hypertrophy (LVH) without detectable fibrosis.

Abstract 14017: Contemporary Management Strategies Provide Low Mortality Rates for Young Patients with Hypertrophic Cardiomyopathy

Background: Historically, youthful age has been considered the time period of greatest risk for patients with hypertrophic cardiomyopathy (HCM), largely a consequence of increased risk of sudden cardiac death. However, the last two decades have witnessed emergence of an expanded risk stratification algorithm resulting in more reliable identification of at-risk patients and enhanced utilization of implantable cardioverter-defibrillators (ICD) for sudden death prevention. However, whether these advances have significantly altered mortality rates for young HCM patients is currently unresolved. Objective: Define the clinical course and adverse event rate in children and young adults with HCM. Methods: We studied the long-term outcomes of 321 consecutive HCM patients presenting at 2 institutions between 10 and 29 years of age, and followed over 7.2 ± 4.8 years. Results: Over follow-up, 302 patients (94%) survived to 27 ± 5 years, with the majority (96%) experiencing no or mild symptoms at last evaluation. HCM-related death occurred in 16 patients (5%; 0.7%/year): arrhythmic sudden death (n=12), complications following heart transplant (n=3), and progressive heart failure (n=1). In contrast, aborted HCM-related mortality occurred in 41 other high-risk HCM patients (implantable cardioverter-defibrillator (ICD) interventions for ventricular tachyarrhythmia [n =24], resuscitated out of hospital cardiac arrest [n=7], and heart transplant for advanced unrelenting heart failure [n=10]), 2.0%/year, and at a rate almost 3-fold higher than actual HCM mortality. Survival at 5- and 10-years (considering only HCM deaths) was excellent at 97% and 92%, and not significantly different from survival rates recently reported in HCM patients identified during mid-life (ages 30 to 59 years old; 98% and 94%, p=0.23). Conclusions: In a cohort of young HCM patients contemporary treatment strategies have resulted in low mortality (&lt;1%/year), due largely to identification of high-risk patients who benefit from sudden death prevention with the ICD, creating the opportunity for extended longevity.

Implanted Defibrillators in Young Hypertrophic Cardiomyopathy Patients: A Multicenter Study

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease, with an annual risk of sudden cardiac death (SCD) estimated at 1 %. Limited data are available regarding both the risk of SCD in the young HCM population and the use of implantable cardioverter-defibrillators (ICDs). This retrospective study included all patients with HCM who underwent ICD implantation for primary or secondary prevention of SCD before the age of 30 years at five institutions between 1995 and 2009. There were 99 devices implanted in 73 patients. Appropriate shocks occurred for 11 % of all the patients. None of the previously identified conventional risk factors for SCD in HCM patients were associated with increased risk of appropriate shocks in the young study cohort. During a median follow-up period of 2.4 years, inappropriate shocks occurred for 22 % of the patients. Older age at implant was associated with a decreased risk of inappropriate shock. Those who underwent implantation in the earlier decade had a higher incidence of inappropriate shocks. Late complications including lead fracture or dislodgement, generator malfunction, and infection occurred for 32 % of the patients. Three patients died (4 %), one of whom had an arrhythmic sudden death. A greater proportion of primary prevention implantations was performed for patients from the latter decade. Over time, ICD use in young HCM patients has become increasingly primary prevention oriented. Shock rates mirror those reported in adult series, and there is a substantial incidence of device complications.

Circulating Matrix Metalloproteinases in Adolescents With Hypertrophic Cardiomyopathy and Ventricular Arrhythmia

Myocardial fibrosis is a hallmark of hypertrophic cardiomyopathy (HCM) and a risk factor for ventricular arrhythmia. Fibrosis can be reflected in circulating matrix remodeling protein concentrations. We explored differences in circulating markers of extracellular matrix turnover between young HCM patients with versus without history of serious arrhythmia. Using multiplexed and single ELISA, matrix metalloproteinases (MMPs) 1, 2, 3, and 9; tissue inhibitor of metalloproteinases (TIMPs) 1, 2, and 4; and collagen I carboxyterminal peptide (CICP) were measured in plasma from 45 young HCM patients (80% male patients; median age, 17 years [interquartile range, 15-20]). Participants were grouped into serious ventricular arrhythmia history (VA) versus no ventricular arrhythmia history (NoVA). Differences in MMPs between groups were examined nonparametrically. Relationships between MMPs and ventricular arrhythmia were assessed with linear regression, adjusted for interventricular septal thickness, family history of sudden death, abnormal exercise blood pressure, and implantable cardioverter-defibrillator (ICD). In post hoc sensitivity analysis, age was substituted for ICD. The 14 VA patients were older than 31 NoVA patients (median, 19 versus 17 years; P=0.03). All 14 VA and 12 NoVA patients had an ICD. MMP3 concentration was significantly higher in the VA group (VA median, 12.9 μg/mL [interquartile range, 5.7-16.7 μg/mL] versus NoVA, 5.8 μg/mL [interquartile range, 3.7-10.0 μg/mL]; P=0.01). On multivariable analysis, VA was independently associated with increasing MMP3 (standardized β, 0.37; P=0.01). Post hoc adjustment for age attenuated this association. Circulating MMP3 may be a marker of ventricular arrhythmia in adolescent patients with HCM. Because of our role as pediatric providers, we cannot exclude age-related confounding.

Risk Stratification and Role of Implantable Defibrillators for Prevention of Sudden Death in Patients With Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death (SCD) in young people, including trained athletes. It is now 30 years since the introduction of implantable cardioverter-defibrillators (ICDs) to clinical cardiovascular practice and coronary artery disease, and now device therapy represents the most significant therapeutic innovation and the only definitive strategy for prolonging the life of HCM patients. ICDs have proved effective in preventing SCD in young HCM patients with appropriate intervention rates of 11% for secondary and 4% for primary prevention, despite massive left ventricular (LV) hypertrophy, LV outflow obstruction, diastolic dysfunction or microvascular ischemia. Targeting candidates for prophylactic ICD therapy can be complex, compounded by the unpredictability of the arrhythmogenic substrate, the absence of a dominant risk factor, and difficulty in assembling randomized trials. However, a single major risk factor is often sufficient to justify an ICD, although additional markers and other disease features can resolve ambiguous decision-making. Nevertheless, the absence of all risk factors does not convey absolute immunity to SCD. The current risk factor algorithm, when combined with a measure of individual physician judgment (and patient autonomy considerations), is an effective guide to identifying high-risk HCM patients. ICDs have altered the natural history of HCM for many patients and provided an opportunity to achieve many decades of productive life, and the potential for normal or near-normal longevity. Indeed, prevention of SCD has now become a new paradigm in the management of HCM.

Author's reply

Thank you for your comments on our work. As you mentioned, it is sometimes difficult to distinguish hypertrophic cardiomyopathy (HCM) from athlete's heart. Delayed gadolinium enhancement (DGE) in cardiac magnetic resonance (CMR) and plasma brain natriuretic peptide (BNP) levels may be useful to detect high risk HCM patients in young athletes. However, changes in these parameters may be smaller in young HCM patients than in our study population (mean age 67.4 years). Moreover, cardiac hypertrophy progresses rapidly in young people, especially in adolescence [[1]Maron B.J. Spirito P. Wesley Y. Arce J. Development and progression of left ventricular hypertrophy in children with hypertrophic cardiomyopathy.N Engl J Med. 1986; 315: 610-614Crossref PubMed Scopus (262) Google Scholar]. A single examination of CMR and/or BNP may not be sensitive enough to exclude high risk HCM in young people. Further studies are necessary to establish the usefulness of DGE in CMR and/or plasma BNP levels for diagnosing HCM in young athletes.