Age and Genotype Impact Disease Burden in Hypertrophic Cardiomyopathy:Insights from the Sarcomeric Human Cardiomyopathy Registry

Carolyn 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, USA2 Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA3Stanford Center for Inherited Heart Disease, Stanford, CA, USA4Department of Cardiology, Thoraxcenter, Erasmus MC Rotterdam, The Netherlands5Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil6Yale University, New Haven, CT7MyoKardia, Inc., South San Francisco, CA, USA8National Heart & Lung Institute & NIHR Royal Brompton Cardiovascular Biomedical Research Unit,

Imperial College London, London, England9Department of Cardiology, Boston Children’s Hospital, Boston, MA, USA10Referral Center for Cardiomyopathies, Careggi University Hospital, Florence, Italy11Analysis Group***

*Address for Correspondence:Carolyn Y. Ho, MDCardiovascular DivisionBrigham and Women’s Hospital75 Francis StreetBoston, MA 02115cho@partners.org

word limit 2700 (intro-discussion) – currently 2767 max 5 tables and figs40 refs – currently 25

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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.

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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,

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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).

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Outcome Definitions

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.

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RESULTS

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).

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Natural History of HCM: Impact of Age on Mortality and Cumulative Burden of Disease

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

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(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

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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.

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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.

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Genotype Influences Outcome

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,

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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.

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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

Funding for SHaRe has been provided through an unrestricted research grant from Myokardia, Inc

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Table 1. Baseline Characteristics and Outcomes **Pending Update**

Baseline CharacteristicsFull 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 ± 6.2Race, 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)Transplant or LVAD, n (%) 75 (2) 34 (3) 1 (0) 10 (1)

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Overall Composite, n (%) 2,184 (48) 635 (50) 127 (50) 602 (49)Ventricular Arrhythmia Composite, n (%) 286 (6) 114 (9) 18 (7) 69 (6)HF Composite, n (%) 1,407 (31) 449 (35) 78 (31) 376 (31)

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Table 2. Multivariable Models Predicting Outcomes in the Genotyped HCM Cohort

*All models included sarcomere status (three-level definition), gender, race and proband status.

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Heart Failure Composite

Overall Composite Ventricular Arrhythmia Composite

Number of Events Number of Patients

186 2633

Number of Events Number of Patients

719 2639

Number of Events Number of Patients

1188 2588 Atrial Fibrillation

Number of Events Number of Patients

593 2357

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

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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.

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A.

D.C.

B.Overall Composite Ventricular Arrhythmia Composite

Heart Failure Composite 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

21

22

Age, Years

Prop

ortio

n fr

ee o

fO

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ll Co

mpo

site

Endp

oint

A.

Pairwise Comparisons: Log-rank p-valueSARC(+) vs SARC(-) p<0.001SARC(U) vs SARC(-) p<0.05SARC(+) vs SARC(U) p<0.001

23

SARC (-) Worse

SARC (+) Worse

B.

Hazard Ratios: MYH7 (N=377) vs MYBPC3 (N=746)

Hazard Ratios: Sarc(2+)(N=34) vs Sarc(+)(N=1210) C. D.

Hazard Ratios: SARC(+) (N=1279) vs SARC(-) (N=1235)