Age and Genotype Impact Disease Burden in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry Carolyn Y. Ho, MD 1 , Sharlene M. Day 2 , MD; Euan A. Ashley, MRCP, DPhil 3 ; Michelle Michels, MD, PhD 4 ; Alexandre C. Pereira, MD, PhD 5 ; Daniel Jacoby, MD 6 ; Jonathan Fox, MD, PhD 7 ; Colleen A. Caleshu, ScM 3 ; Allison L. Cirino, MS 1 ; James S. Ware, PhD MRCP 8 ; Adam S. Helms, MD 2 ; Steven D. Colan, MD 9 ; Franco Cecchi, MD 10 ; Francesca Girolami, BS 10 ; James Signorovich, PhD 11 ; Eric Green, MD, PhD 7 ; Iacopo Olivotto, MD 10 for the SHaRe Investigators 1 Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA 2 Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA 3 Stanford Center for Inherited Heart Disease, Stanford, CA, USA 4 Department of Cardiology, Thoraxcenter, Erasmus MC Rotterdam, The Netherlands 5 Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil 6 Yale University, New Haven, CT 7 MyoKardia, Inc., South San Francisco, CA, USA 8 National Heart & Lung Institute & NIHR Royal Brompton Cardiovascular Biomedical Research Unit, Imperial College London, London, England 9 Department of Cardiology, Boston Children’s Hospital, Boston, MA, USA 10 Referral Center for Cardiomyopathies, Careggi University Hospital, Florence, Italy 11 Analysis Group*** *Address for Correspondence: Carolyn Y. Ho, MD Cardiovascular Division Brigham and Women’s Hospital 75 Francis Street Boston, MA 02115 [email protected]word limit 2700 (intro-discussion) – currently 2767 max 5 tables and figs 40 refs – currently 25 1
30
Embed
flore.unifi.it · Web viewword limit 2700 (intro-discussion) – currently 27 6. 7 max 5 tables and figs. 40 refs – currently 25. ABSTRACT. Background: ...
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
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 [email protected]
word limit 2700 (intro-discussion) – currently 2767 max 5 tables and figs40 refs – currently 25
(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
8
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.
9
Partners Information Systems, 03/30/17,
Is this too confrontational vs prior studies? How can language be softened and made more diplomatic
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.
10
carolyn ho, 03/30/17,
Confirm numbers
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,
11
Partners Information Systems, 03/27/17,
check numbers
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.
12
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
13
REFERENCES1. Seidman CE, Seidman JG. Identifying sarcomere gene mutations in hypertrophic cardiomyopathy: a
personal history. Circ Res 2011;108:743-50.2. Elliott PM, Gimeno JR, Thaman R, et al. Historical trends in reported survival rates in patients with
hypertrophic cardiomyopathy. Heart 2006;92:785-91.3. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA Guideline for the Diagnosis and Treatment of
Hypertrophic Cardiomyopathy: Executive Summary: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011.
4. Maron BJ, Rowin EJ, Casey SA, Maron MS. How Hypertrophic Cardiomyopathy Became a Contemporary Treatable Genetic Disease With Low Mortality: Shaped by 50 Years of Clinical Research and Practice. JAMA Cardiol 2016;1:98-105.
5. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405-24.
6. Harris KM, Spirito P, Maron MS, et al. Prevalence, clinical profile, and significance of left ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy. Circulation 2006;114:216-25.
7. Elliott PM, Anastasakis A, Borger MA, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014;35:2733-79.
8. Maron BJ, Olivotto I, Spirito P, et al. Epidemiology of hypertrophic cardiomyopathy-related death: revisited in a large non-referral-based patient population. Circulation 2000;102:858-64.
9. Maron BJ, Rowin EJ, Casey SA, et al. Risk stratification and outcome of patients with hypertrophic cardiomyopathy >=60 years of age. Circulation 2013;127:585-93.
10. Lopes LR, Rahman MS, Elliott PM. A systematic review and meta-analysis of genotype-phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations. Heart 2013;99:1800-11.
11. Li Q, Gruner C, Chan RH, et al. Genotype-positive status in patients with hypertrophic cardiomyopathy is associated with higher rates of heart failure events. Circulation Cardiovascular genetics 2014;7:416-22.
12. Maron BJ, Casey SA, Haas TS, Kitner CL, Garberich RF, Lesser JR. Hypertrophic cardiomyopathy with longevity to 90 years or older. The American journal of cardiology 2012;109:1341-7.
13. Maron BJ, Rowin EJ, Casey SA, et al. Hypertrophic Cardiomyopathy in Adulthood Associated With Low Cardiovascular Mortality With Contemporary Management Strategies. J Am Coll Cardiol 2015;65:1915-28.
14. Maron BJ, Rowin EJ, Casey SA, et al. Hypertrophic Cardiomyopathy in Children, Adolescents, and Young Adults Associated With Low Cardiovascular Mortality With Contemporary Management Strategies. Circulation 2016;133:62-73.
15. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation 2016;133:e38-360.
16. Maron BJ, Casey SA, Hauser RG, Aeppli DM. Clinical course of hypertrophic cardiomyopathy with survival to advanced age. J Am Coll Cardiol 2003;42:882-8.
17. Ho CY, Lakdawala NK, Cirino AL, et al. Diltiazem Treatment for Pre-Clinical Hypertrophic Cardiomyopathy Sarcomere Mutation Carriers: A Pilot Randomized Trial to Modify Disease Expression. JACC Heart failure 2014.
18. Ho CY. Integrating Genetics and Medicine: Disease-Modifying Treatment Strategies for Hypertrophic Cardiomyopathy. Prog Pediatr Cardiol 2016;40:21-3.
14
19. Abozguia K, Elliott P, McKenna W, et al. Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy. Circulation 2010;122:1562-9.
20. Teekakirikul P, Eminaga S, Toka O, et al. Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-beta. J Clin Invest 2010;120:3520-9.
21. Green EM, Wakimoto H, Anderson RL, et al. A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice. Science 2016;351:617-21.
22. Olivotto I, Girolami F, Ackerman MJ, et al. Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. Mayo Clin Proc 2008;83:630-8.
23. Lopes LR, Syrris P, Guttmann OP, et al. Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. Heart 2015;101:294-301.
24. Elliott P, Charron P, Blanes JR, et al. European Cardiomyopathy Pilot Registry: EURObservational Research Programme of the European Society of Cardiology. Eur Heart J 2016;37:164-73.
25. Guttmann OP, Pavlou M, O'Mahony C, et al. Predictors of atrial fibrillation in hypertrophic cardiomyopathy. Heart 2016.
15
Table 1. Baseline Characteristics and Outcomes **Pending Update**