Age and Genotype Impact Disease Burden in Hypertrophic Cardiomyopathy:
Insights from the Sarcomeric Human Cardiomyopathy RegistryCarolyn Y. Ho, MD1, Sharlene M. Day2, MD; Euan A. Ashley, MRCP, DPhil3; Michelle Michels, MD, PhD4; Alexandre C. Pereira, MD, PhD5; Daniel Jacoby, MD6; Jonathan Fox, MD, PhD7; Colleen A. Caleshu, ScM3;
Allison L. Cirino, MS1; James S. Ware, PhD MRCP8; Adam S. Helms, MD2; Steven D. Colan, MD9; Franco Cecchi, MD10; Francesca Girolami, BS10; James Signorovich, PhD11; Eric Green, MD, PhD7; Iacopo Olivotto,
MD10 for the SHaRe Investigators 1Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA 2 Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA 3Stanford Center for Inherited Heart Disease, Stanford, CA, USA
4Department of Cardiology, Thoraxcenter, Erasmus MC Rotterdam, The Netherlands 5Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil 6Yale University, New Haven, CT
7MyoKardia, Inc., South San Francisco, CA, USA
8National Heart & Lung Institute & NIHR Royal Brompton Cardiovascular Biomedical Research Unit, Imperial College London, London, England
9Department of Cardiology, Boston Children’s Hospital, Boston, MA, USA
10Referral Center for Cardiomyopathies, Careggi University Hospital, Florence, Italy 11Analysis Group***
*Address for Correspondence:
Carolyn Y. Ho, MD
Cardiovascular Division
Brigham and Women’s Hospital
75 Francis Street
Boston, MA 02115
word limit 2700 (intro-discussion) – currently 2767 max 5 tables and figs
ABSTRACT
Background: The Sarcomeric Human Cardiomyopathy Registry (SHaRe) was established to address unresolved questions regarding natural history and prognosis in hypertrophic cardiomyopathy (HCM). SHaRe leverages longitudinal datasets cumulatively spanning over 24,000 patient-years to more accurately estimate lifetime disease risk and the influence of genotype on outcomes.
Method: A registry was created by centralizing datasets from eight cardiomyopathy centers. All-cause death, cardiac arrest, cardiac transplantation, appropriate implantable cardioverter-defibrillator (ICD) therapy, atrial fibrillation, stroke, left ventricular ejection fraction (LVEF)<50%, and New York Heart Association Functional Class III/IV symptoms were analyzed individually and as composite endpoints. Analyses were stratified by age of diagnosis and sarcomere mutation status.
Results: The study cohort included 4591 HCM patients with mean (standard deviation) age of diagnosis 44.29 (18.5) years; 37% female. During mean follow-up of 5.4 (6.9) years, 395 patients (9%) died (61 suddenly) and 127 (2.8%) had resuscitated cardiac arrest. Patients <40 years old at diagnosis had 89% lifetime risk of meeting the overall composite outcome, versus 36% in patients >60 years at diagnosis. Heart failure and atrial fibrillation events dominated, with peak incidence between ages 50-70. Lifetime cumulative incidence of ventricular arrhythmias was 2% in patients >60 years versus 41% in patients <18 years at diagnosis. Patients with sarcomere variants (pathogenic and unknown significance) had worse outcomes than patients without mutations.
Conclusions: The cumulative burden of HCM is substantial and disproportionately borne by patients diagnosed earlier in life and with sarcomere mutations. Heart failure and atrial commonly develop during middle age and later, indicating the need for lifelong surveillance.
INTRODUCTION
Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder characterized by myocyte hypertrophy, disarray, and fibrosis. HCM has been the focus of intense clinical and basic science
investigation for decades. These efforts have provided remarkable insights into both the molecular basis and clinical course of disease-- defining sarcomere mutations as the genetic basis of HCM,1 and
improving understanding of natural history from the early perception of a highly mortal condition, to one often affording nearly normal longevity in the current era.2-4 However, accurate comprehension of HCM remains limited by small cohort sizes, phenotypic diversity, sparse longitudinal data, and lack of
systematic integration of genetic information to more precisely define disease etiology. As a result, many fundamental questions remain unanswered. The natural history of disease and the factors governing prognosis or disease burden are not yet fully defined.
The Sarcomeric Human Cardiomyopathy Registry (SHaRe) is an international database of patients with genetic cardiomyopathies assembled by experienced HCM centers (Supplemental Figure 1A) using highly curated datasets with a central goal of creating one of the largest and most comprehensive collaborative registries of HCM patients to date. In the present study, we sought to harness the scale of this data, spanning over 24,000 patient-years, to accurately characterize the natural history of HCM, to precisely define present-day estimates of risk, and to determine how genotype impacts disease.
METHODS
Participating Sites and Creation of the Centralized Database
SHaRe was established by eight experienced centers (Supplemental Figure 1A) that maintain longitudinal databases capturing clinical, genetic, and outcomes data on patients and families under care or participating in research protocols. Data definitions were harmonized for key demographic, historical, clinical, and genetic parameters. Data from site databases were mapped to corresponding fields in the
centralized database, spanning 762 discrete fields. The dataset resides in a Protected Health Information-free secure database server, using a mapping scheme to convert site values to standardized SHaRe values (Boston Advanced Analytics, Boston, MA). Ongoing data collection occurs via quarterly uploads from site databases.
Study Population, Genetic Testing, and Variant Classification
Criteria for inclusion included: site diagnosis of HCM (typically defined as unexplained left ventricular hypertrophy, integrating familial disease and genotype as appropriate), at least one clinic visit at a SHaRe site since 1960, and at least one echocardiographic assessment of left ventricular wall thickness (Supplemental Figure 1B). Genetic testing was available at all sites, using different platforms available over time. Each site designated variants as pathogenic, likely pathogenic, unknown significance (VUS), or likely benign/benign using standard criteria,5 focusing on the 8 sarcomere genes associated with HCM (myosin binding protein C (MYBPC3), myosin heavy chain (MYH7), cardiac troponin T (TNNT2), cardiac troponin I (TNNI3), alpha-tropomyosin (TPM1), myosin essential and regulatory light chains (MLY2, MYL3), and actin (ACTC)). All variants in the SHaRe database underwent additional systematic review by a subgroup of SHaRe investigators (A.L.C, S.M.D, J.S.W, C.Y.H.; Supplemental Methods). Genotyped patients were given one of the following designations: SARC(+)=pathogenic or likely pathogenic variant in any of the above sarcomere genes; SARC(U)=sarcomere VUS present; SARC(2+)= more than one pathogenic or likely pathogenic sarcomere mutation; SARC(-)= no pathogenic, likely pathogenic, or VUS identified in a sarcomere gene. Patients were excluded if they had pathogenic, likely pathogenic or unknown significance variants in non-sarcomere genes indicating another diagnosis (e.g. metabolic or storage disease).
Composite outcomes were defined to capture outcomes and disease burden.
Ventricular Arrhythmic Composite: first occurrence of sudden cardiac death (SCD), resuscitated cardiac arrest, or appropriate implantable cardiovertor-defibrillator (ICD) therapy.
Heart Failure Composite: first occurrence of cardiac transplantation and/or left ventricular assist device (LVAD) implantation, left ventricular ejection fraction (LVEF) <50% (indicative of end-stage HCM/systolic dysfunction in HCM),3,6,7 or NYHA class III-IV symptoms.
Overall Composite: first occurrence of any component of the ventricular arrhythmic or heart failure composite endpoint, all-cause mortality, atrial fibrillation, stroke, or death.
Statistical Analysis
Retrospective data collected from the ongoing prospective registry study were analyzed. Natural history was described in terms of age at first occurrence of each composite outcome and individual components using Kaplan-Meier analyses. Age at first event was right-censored at the patient’s last recorded follow-up or at first occurrence of outcome events. Patients with missing data were dropped from analyses. Additional descriptive analyses of cumulative incidence and age group-specific incidence rates were derived from the Kaplan-Meier analyses.
Among the genotyped cohort, times to event were described among patients stratified by sarcomere genotype, and were compared using hazard ratios based on Cox proportional hazards models with family-specific frailty effects to account for correlation due to relatedness. Selected outcomes were also analyzed stratified by age of diagnosis (<18, 18-40, 40-60 and > 60 years) and, separately, with time to event measured from the time of the first clinic visit rather than time from birth. Additional details are provided in Supplemental Methods.
Clinical Characteristics
Of HCM patients receiving care at a SHaRe site between 1960 and December 2016 (n=5661), 4591 met inclusion criteria and comprise the Full HCM Cohort (Supplemental Figure 1B). Baseline characteristics and descriptive information regarding outcomes are summarized in Table 1. The majority of individuals were the family proband (first family member presenting for care at the site); affected relatives comprised 12.0% of the cohort (552/4591). Mean (SD) follow up time was 5.4 (6.9) years, representing a total of 24,791 patient-years. Mean age of diagnosis was 44.3 (18.4) years and 37.1% (1704/4591) were female.
During follow-up, 395 patients (8.6%) died at mean age 61.8 (18.3) years; 61 died suddenly (15.4% of deaths; 1.3% of the cohort; mean age 51.4 (20.1) years). Additionally, 127 patients had resuscitated cardiac arrest (2.8% of the cohort; mean age 40.8 (18.6) years). Forty-five percent of the cohort met the overall composite outcome at mean age of 52.7 (17.0) years. Events were most frequently atrial fibrillation (24.6% of the cohort, mean age 55.2 (14.8) years) and heart failure (25.2%, mean age 54.1 (16.7) years), while 6.2% of patients met the ventricular arrhythmia composite (mean age 45.8 (19.2) years).
To investigate the impact of sarcomere mutations, analyses were then restricted to the Genotyped HCM Cohort (Supplemental Figure 1B; n=2763). As shown in Table 1, 46.3% had positive results (SARC(+), n=1279; including 34 subjects who carried two or more pathogenic or likely pathogenic mutations (SARC(2+)), 9.2% had variants of unknown significance (SARC(U), n=253), and 44.6% had negative results (SARC(-), n=1231). Supplemental Figure 3 summarizes genetic testing results in
probands. The mean age of diagnosis was 11.7 years younger in SARC(+) compared with SARC(-) patients (37.3 (17.1) versus 49.0 (17.4), p<0.001) (Table 1).
Mortality from HCM was assessed relative to the general population. Data from SHaRe sites in the United States were compared with United States general population mortality rates from 1999-2014 using Centers for Disease Control Wonder database (http://wonder.cdc.gov/). Compared with the US general population, mortality was >4-fold higher for young HCM patients (20-29 years; 0.39% versus 0.09%, p<0.05) and 3-fold higher in HCM patients age 60-69 years (1.33% versus 3.99%, P<0.001; Figure 1).
Lifetime morbidity from HCM was analyzed by examining the cumulative incidence of events from birth to age 70 years. Analyses were stratified by age at diagnosis (Figure 2A-D). Younger age at diagnosis was associated with markedly increased cumulative incidence of events throughout life. Patients <40 years old at diagnosis had a 91% cumulative incidence of the overall composite outcome by age 70 years (Figure 2A), with a slightly higher burden in patients with pediatric-onset (94%, age of diagnosis <18 years) compared with adult-onset disease (91%, age of diagnosis 18-40 years;
Supplemental Figure 3). In contrast, the cumulative incidence of the overall composite outcome was 35% in patients >60 years at diagnosis. For all age at diagnosis strata, outcomes were again dominated by heart failure (Figure 2B) and atrial fibrillation (Figure 2C). Of those patients who developed symptomatic heart failure, over 80% had left ventricular ejection fraction >55%. The cumulative incidence of
malignant ventricular arrhythmias was 34% in patients diagnosed <40 years but rarely encountered (2%) in the oldest age stratum (Figure 2D).
Sarcomere Mutations Are Associated With Earlier Onset and Higher Prevalence of Events
Survival analysis demonstrates that both SARC(+) and SARC(U) patients had significantly earlier onset and higher prevalence of the overall composite outcome than SARC(-) HCM (Figure 3A). Similar patterns were seen for the heart failure and ventricular arrhythmia composites and atrial fibrillation (Supplemental Figure 4). By Cox analyses, outcomes were consistently worse in SARC(+) versus SARC(-)
across all composite and individual outcomes (Figure 3B). SARC(+) patients had at least twice the risk of death, heart failure, malignant arrhythmias, and atrial arrhythmias than SARC(-); the risk for cardiac transplant or VAD support was over 4-times higher (HR 4.6 [2.3-9.3]). Compared with patients with only one mutation, the SARC(2+) cohort had substantially higher risk for transplant/LVAD (HR 7.5 [2.7-20.5] and stroke (HR 5.1 [2.1-12.7]; Figure 3C). Comparing patients with mutations in MYH7 and MYBPC3, MYH7 mutation carriers had approximately 2-fold increased risk for NYHA class III-IV symptoms, need for transplantation/LVAD, and atrial fibrillation (Figure 3D). No significant differences in outcomes were observed in patients with thick (n=1161) versus thin filament mutations (n=110) (Supplemental Figure 5).
Predictors of Clinical Outcomes in the Genotyped HCM Cohort
Multivariable models were developed to identify predictors of the composite outcomes and atrial fibrillation (Table 2). For all outcomes, age at diagnosis was the most powerful predictor, with age at diagnosis <40 years associated with ~7-fold excess hazard. After controlling for age at diagnosis, proband status, sex, and race, the presence of a sarcomere mutation carried ~60% increase risk for all outcomes, most prominent for ventricular arrhythmia (HR 1.9 [1.3, 2.6], p<0.01). Females had 23% greater risk for the heart failure composite but 22% decreased risk for atrial fibrillation. An increased hazard was associated with the family proband for the ventricular arrhythmia composite (HR 6.1 [2.5, 14.9]), potentially reflecting referral bias. As anticipated, patients with founder mutations in MYBPC3 had a slightly milder prognosis with ~30% decreased risk for the overall and heart failure composites, and atrial fibrillation (Supplemental Table 1). Patients with multiple pathogenic or likely pathogenic
sarcomere mutations had over 2-fold increased risk for the overall composite and over 4-fold increased risk for ventricular arrhythmias relative to patients without sarcomere mutations (Supplemental Table 2).
DISCUSSION
SHaRe represents the largest comprehensive HCM cohort assembled to date. By examining the lifetime experience of patients with adult-onset HCM, SHaRe provides greater insights into natural history. Age of diagnosis and genotype emerged as important predictors of outcome, although not traditionally factored into determining prognosis. The cumulative burden of HCM is substantial and particularly for patients diagnosed earlier in life and those with sarcomere mutations. Additionally, adverse events are most frequent in mid-life and later, indicating a window of opportunity for disease-modifying therapy.
Morbidity and Mortality in HCM
Published HCM natural history studies encompass a median of 3700 patient-years of follow up, including overlapping cohorts.2,8-14 With current-day management, these studies report low mortality, including mortality equivalent or better than the age-matched general population.9,12-14 However, these reports compared HCM-related mortality (excluding cardiac transplantation) in patients to overall mortality in the general population, and focused on isolated age groups without accounting for immortal time bias. In contrast, this study harnesses data from over 24,000 patient-years of follow up, allowing more representative and precise characterization of event rates and outcomes throughout life. Data from SHaRe demonstrate that HCM patients have significantly higher mortality rates than the United States general population. While absolute mortality is low in young patients, it is 4-fold higher than expected for 20-29 year olds. Additionally, although prior studies (combined n=1700) reported sudden cardiac death as the leading cause of death in HCM, accounting for ~40% of deaths,2,8 our data indicate that SCD accounts for 15% of all death; heart failure and non-cardiac death both more common.
However, the 34% cumulative incidence of lethal arrhythmias in patients diagnosed under the age of 18 years merits special attention.
The majority of patients diagnosed before age 40 will experience important HCM-related complications by the age of 70, most commonly heart failure (79%) and atrial fibrillation (76%). These event rates are much higher than seen in the general US population of similar age, for which a 40-year old has a lifetime risk of ~10% for atrial fibrillation and ~20% for heart failure.15 However, SHaRe
demonstrates that regardless of age of diagnosis, the majority of HCM-related complications occur later in life, peaking between 50 and 70 years. Therefore, the level of clinical surveillance should not be lowered in older HCM patients despite recent reports showing a substantially reduced risk of sudden death in older HCM cohorts and favorable outcome in these age groups.9,13,16 While ventricular arrhythmias and sudden death are indeed rare after age 60 (2% cumulative incidence in SHaRe), this study indicates that all other risks are greatest in this age group, including that of AF, heart failure, and overall mortality. These findings underscore the critical need to better understand the driving factors and to develop effective treatments to prevent and/or delay the adverse remodeling that leads to heart failure and atrial fibrillation, rather than relying on palliative treatments after these complications have developed.
Furthermore, the extended time span from HCM diagnosis to most severe manifestations indicates that adverse remodeling is progressive throughout life. As such, there is a window of
opportunity for disease-modifying therapies. Although interventions aimed at preventing HCM should ideally target the preclinical phase of disease in young, at-risk mutation carriers,17,18 the possibility of interrupting disease progression even after full development should not be discarded. Indeed,
translational approaches such as metabolic modulation,19 attenuation of fibrosis,17,20 or allosteric myosin inhibitors21 may be instrumental to stabilizing the disease in an early, relatively stable phase, thereby preventing adverse outcomes.
Evidence from prior smaller studies indicated an excess hazard and earlier presentation associated with sarcomere mutations.10,11,22,23 Analyzing a large multicenter cohort with rigorously curated genetic variants, we convincingly demonstrate that HCM caused by sarcomere mutations is associated with worse outcomes. Sarcomere mutation carriers manifest at an earlier age and have a greater burden of HCM-related complications. By age 50 years, ~35% of SARC(+) patients had reached the overall composite endpoint, compared with 15% of SARC(-). Even after adjusting for earlier age at presentation, significant excess hazard was seen in sarcomere mutation carriers. These data suggest a role for genetic testing in the clinical management of HCM to guide prognosis.
The impact of variants of unknown significance on outcome has not been previously assessed. In contrast with previous studies, only variants with a high degree of evidence for pathogenicity were considered SARC(+); variants of unknown significance were analyzed separately as the SARC(U) group. Our results indicate that variants of unknown significance carry clinical consequence. Outcomes for the SARC(U) group were intermediate between SARC(+) and SARC(-), emphasizing that these variants have clinical relevance even if adjudication of pathogenicity remains uncertain in individual patients. This finding likely reflects our inability to fully discriminate benign from pathogenic variants, such that the SARC(U) reflects outcomes from a mixture of patients with disease-causing variants and benign polymorphisms. Improved methods to determine variant pathogenicity are clearly needed to improve risk stratification and provide the opportunity for predictive testing for family members.
Limitations
As a registry-based observational study, no inferences about causality for the observed
associations can be made. Data were captured from clinical encounters without standardized testing or image analysis across sites. Further follow up and confirmation of key findings in other large cohorts, such as the European HCM Registry,24,25 are needed. While ascertainment of historical lifetime events
from medical history was as complete as possible, mean follow-up time was relatively short and non-uniform. Accordingly, there may not have been adequate time for events to accrue in the older stratum, and some patients were lost to follow-up. As only 422 patients (9%) were <18 years old at initial clinic visit, SHaRe primarily represents an adult-onset cohort. Dedicated expansion and study of the pediatric-onset cohort are needed to better understand how disease presenting in childhood differs from that presenting in adulthood.
Conclusions
The cumulative morbidity and mortality of HCM is substantial, and borne disproportionately by patients diagnosed earlier in life and patients with sarcomere mutations. Younger age at diagnosis and the presence of a sarcomere mutation were strong multivariable predictors of adverse events, and should be incorporated into discussions of prognosis risk prediction for individual HCM patients. Disease burden is dominated by heart failure and atrial fibrillation, developing later in life. These findings highlight the importance of continued surveillance in older age groups currently considered at low risk for HCM complications, and highlight the critical need for developing disease-modifying therapies.
FUNDING SOURCES
CYH is supported by funding from the National Institutes of Health (1P50HL112349 and 1U01HL117006). IO, FC and FG are supported by the Italian Ministry of Health (Left ventricular hypertrophy in aortic valve disease and hypertrophic cardiomyopathy: genetic basis, biophysical correlates and viral therapy
models” (RF-2013-02356787), and NET-2011-02347173 (Mechanisms and treatment of coronary
microvascular dysfunction in patients with genetic or secondary left ventricular hypertrophy); and by the ToRSADE project (FAS-Salute 2014, Regione Toscana).
ACKNOWLEDGEMENTS
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Table 1. Baseline Characteristics and Outcomes **Pending Update**
Baseline Characteristics
Full HCM Cohort Genotyped HCM Subset (N = 2,765) p-value Sarcomere (+) Sarcomere (U) Sarcomere (-)
N=4,593 N=1,280 (46.3%) N=253 (9.1%) N=1,232 (44.6%)
Female, n (%) 1704 (37) 504 (39) 85 (34) 419 (34) <0.05
Age at diagnosis, years, median [IQR] 45.8 [30.9-58.1] 37.5 [23.6-49.8] 44.0 [31.4-54.1] 51.1 [38.3-61.7] <0.001 Follow-up Time, years, median [IQR] 2.9 [0.3-7.9] 5.4 [1.5-10.6] 2.7 [0.3-7.0] 3.2 [0.4-7.5] <0.001
Mean ± SD 5.4 ± 7.0 7.8 ± 8.5 5.2 ± 6.7 5.1 ± 6.2 Race, n (%) <0.001 White 3913 (85) 1157 (90) 205 (81) 1075 (87) Black 141 (3) 22 (2) 9 (4) 42 (3) Other/Not Reported 539 (12) 101 (8) 39 (15) 115 (9) Family History HCM, n (%) 1,629 (35) 742 (58) 101 (40) 302 (25) <0.001 Family Proband, n (%) 4,041 (88) 998 (78) 229 (91) 1,178 (96) <0.001
NYHA Class III-IV, n (%) 597 (13) 134 (10) 33 (13) 167 (14) <0.001
Maximal LVWT, mm, median [IQR] 18 [15-22] 19 [15-23] 18 [15-23] 17 [15-21] <0.001
LVEF, %, median [IQR] 65 [60-71] 65 [60-70] 65 [60-73] 65 [60-72] <0.01
Peak gradient >30 mmHg, n (%) 1291 (28) 263 (21) 78 (31) 462 (38) <0.001
Apical Hypertrophy, n (%) 148 (3) 30 (2) 6 (2) 66 (5) <0.001
Outcomes
All-Cause Death, n (%) 395 (9) 105 (8) 17 (7) 82 (7)
Sudden Death, n (%) 61 (1) 23 (2) 3 (1) 13 (1)
Resuscitated Cardiac Arrest, n (%) 127 (3) 42 (3) 7 (3) 35 (3)
Appropriate ICD Firing, n (%) 148 (3) 70 (5) 11 (4) 33 (3)
Atrial Fibrillation, n (%) 1,132 (25) 339 (26) 74 (29) 309 (25)
Stroke, n (%) 221 (5) 57 (4) 14 (6) 56 (5)
Overall Composite, n (%) 2,184 (48) 635 (50) 127 (50) 602 (49)
Ventricular Arrhythmia Composite, n (%) 286 (6) 114 (9) 18 (7) 69 (6)
Table 2. Multivariable Models Predicting Outcomes in the Genotyped HCM Cohort
*All models included sarcomere status (three-level definition), gender, race and proband status.
Number of Events
Number of Patients
FIGURE LEGENDS
Figure 1. Age-specific mortality in HCM compared with the general US population from 1999-2014 Data from United States SHaRe sites were compared with the CDC Wonder database
(http://wonder.cdc.gov/) to estimate US general population mortality rates from 1999-2014. Error bars represent 95% confidence intervals
HCM Pts at Risk
(Middle of Age Range)
Figure 2. Age at diagnosis impacts the lifetime cumulative burden of events Cumulative incidence of events from birth for the:
A. Overall composite outcome B. Heart failure composite C. Atrial fibrillation
D. Ventricular arrhythmia composite
Incidence curves are stratified by age of diagnosis <40 years, 40-60 years and >60 years.
Atrial Fibrillation
Figure 3. Impact of Sarcomere Mutations on Clinical Outcomes
Analyses were performed in the Genotyped HCM Subset. Carriers of pathogenic, likely pathogenic and variants of unknown significance in sarcomere mutations have worse clinical outcomes than HCM patients without sarcomere mutations. Mutation carriers have earlier and more prevalent outcomes, particularly those with pathogenic and likely pathogenic variants.
A. Kaplan-Meier Survival curve for the overall composite endpoint (Death, Cardiac Arrest, Txp/VAD, ICD shock, AF, Stroke, LVEF<55%, NYHA III-IV)
B. Forest plot showing hazard ratios for the composite endpoints and their individual components for patients with and without sarcomere mutations. Sarcomere mutation carriers have a higher risk of all individual components of the composite endpoints.
C. Patients with multiple pathogenic or likely pathogenic sarcomere mutations compared with those with only one mutation
D. Patients with MYH7 variants compared with patients with MYBPC3 variants
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