A, Risk stratification model used to identify highest-risk patients who may be candidates for primary prevention of sudden death by use of the implantable cardioverter-defibrillator (ICD). Risk markers appear in boxes to the left. B, Intracardiac electrograms 5 years after primary prevention of ICD therapy for a 36-year-old man with massive hypertrophy and family history of sudden death. Tracing I, Ventricular tachycardia (VT) at 200 beats per minute begins abruptly during sleep. Tracing II, Defibrillator senses VT and charges. Tracing III, VT deteriorates to ventricular fibrillation (VF). Tracing IV, Defibrillator automatically issues a 20-J shock (arrow) restoring sinus rhythm. C, Flow diagram summarizing outcome of ICD therapy for 506 high-risk patients in an international registry.32 D, Flow diagram summarizing outcome of ICD therapy for 224 children and adolescents (<20 years of age).33 ACC/AHA indicates American College of Cardiology/American Heart Association; BP, blood pressure; CAD, coronary artery disease; EF, ejection fraction; LV, left ventricular; LGE, late gadolinium enhancement; LVH, left ventricular hypertrophy; and NSVT, nonsustained ventricular tachycardia.
aSudden death uncommon after 60 years of age.
The current mortality rate of 0.5% per year was achieved with contemporary management strategies after 50 years of clinical research and practice. Adapted from Maron et al.1
aImplantable cardioverter-defibrillator intervention: heart transplant/surgical myectomy and resuscitated cardiac arrest/hypothermia.
A, Hypertrophic cardiomyopathy (HCM)–related mortality with contemporary treatment interventions (mortality in relation to age at presentation). B, Deaths averted by treatment exceed HCM-related deaths, overall, and among patients 29 years of age or younger and patients 30 to 59 years of age at presentation.
Specific treatment strategies responsible for evolution from 1.5% per year in the pre-ICD era to 0.5% year currently. Mortality rate depicted for general population refers specifically to adults 30 to 59 years of age. ICD indicates implantable cardioverter-defibrillator; and RCA, resuscitated cardiac arrest.
Most patients have an uncomplicated and benign course without major complications. However, individual patients can experience adverse disease progression along 1 or more of the complication pathways, each nevertheless associated with a potentially effective treatment strategy. AF indicates atrial fibrillation; ICD, implantable cardioverter-defibrillator; and RF, radiofrequency.
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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(1):98–105. doi:10.1001/jamacardio.2015.0354
Hypertrophic cardiomyopathy (HCM) is a relatively common genetic heart disease encumbered throughout much of its almost 60-year history by a large measure of misunderstanding and the perception of a grim outcome without effective treatment options. However, it is now apparent that the majority of patients affected with HCM can achieve normal or near-normal life expectancy without disability, and usually do not require major treatment interventions. Nevertheless, for those patients with HCM who are at risk for (or experience) disease-related complications, a constellation of comprehensive nonpharmacologic management strategies have evolved over the last 15 years, altering the natural history and disease course for many, including implantable defibrillators, heart transplant, external defibrillation/therapeutic hypothermia, advances in surgical myectomy, and alcohol ablation. In particular, expanded contemporary risk stratification strategies have led to a more reliable selection of patients likely to achieve primary prevention of sudden death with implantable defibrillators. Most recently, large cohort studies using current management strategies and therapeutic measures have shown that it is now possible to achieve significantly improved survival with a low HCM-related mortality of 0.5% per year across all ages, and including children and young adults characteristically with the most aggressive disease course. These clinical management initiatives, instituted by the practicing cardiology community, have succeeded in preserving life and restoring an active lifestyle for thousands of patients with HCM, while providing many with a measure of reassurance and a reasonable expectation for an extended (if not normal) life span.
Almost since its inception, hypertrophic cardiomyopathy (HCM) has been regarded as a clinically and morphologically heterogeneous genetic heart disease1,2 often associated with a generally unfavorable prognosis, unrelenting progression, premature death, and encumbered by ineffective treatment strategies.3,4 Although this perspective is becoming less entrenched,5 contrary myths persist,6-11 and new management approaches, as yet, may not have penetrated systematically into the consciousness of the practicing community. In this review, the treatment advances that are now available to patients with HCM, and that have reduced disease-related mortality and improved quality of life, are presented and discussed.
Hypertrophic cardiomyopathy was first described at autopsy in 195812 and subsequently came to be regarded as the most common nontraumatic cause of sudden death among young adults. This disease emerged as a clinical entity largely through the work of Braunwald et al13 at the National Institutes of Health in the 10 years from 1958 to 1968, which began the formative investigational era for HCM.
Initially, HCM was regarded as a disease of left ventricular (LV) outflow obstruction, largely without management strategies that could favorably influence its course.13 However, the ventricular septal myectomy operation to relieve obstruction and reverse heart failure symptoms was soon introduced first at the National Institutes of Health (and selectively elsewhere, including Mayo Clinic).14,15 The myectomy operation was gradually recognized as an important treatment for heart failure symptoms,15-20 despite periodic misguided efforts that casted doubt on the pathophysiologic significance of the subaortic gradient.21 In 1964, pharmacologic therapy to mitigate symptoms with β-blockers was introduced to patients with HCM by Braunwald,5-13 and it persists as a first-line therapy, even now, and was later followed by the calcium antagonist verapamil22 and the negative inotrope/antiarrhythmic disopyramide.23
Beginning in the early 1990s, a few patients with nonobstructive HCM and unrelenting heart failure were referred for heart transplantation.24 However, the devastating and highly visible complication of unexpected arrhythmic sudden death remained, without any preventive strategies, as the greatest source of anxiety among patients with HCM.1,5,25,26 When HCM was recognized as an important trigger for arrhythmic sudden death among young competitive athletes,27 expert consensus recommendations were formulated over the last 30 years that included excluding such individuals from intense competitive sports, reducing the risk of sudden death, and creating a safer athletic environment.28
Over the last several years, the effectiveness of major innovative nonpharmacologic cardiovascular management strategies for HCM have been studied in selected high-risk subsets of patients. With drug therapy ineffective against sudden death,29 the implantable cardioverter-defibrillator (ICD) was formally introduced to patients with HCM 15 years ago, the results of which were published as a retrospective multicenter study30 showing the power of device therapy in preventing sudden death due to ventricular tachyarrhythmias (ventricular tachycardia or fibrillation) and establishing the ICD era for HCM and other genetic heart diseases. The effectiveness of the ICD in patients with HCM is notable given the structural and functional differences from atherosclerotic coronary artery disease, for which the ICD was originally designed by Mirowski and Mower.31
Several sizeable single and multicenter registry studies, largely from the United States/Canada30,32-35 and Australia,36 but also from Europe (ie, Poland, Germany, the Netherlands, and Spain),37-43 as well as an international meta-analysis,38 have shown that the ICD reliably terminated potentially lethal ventricular tachycardia or fibrillation and automatically restored sinus rhythm in a large number of patients of all ages with HCM, including children44-46 (10% per year for secondary prevention and 4% per year for primary prevention in adults), while also documenting the not-inconsequential risks for inappropriate shocks and other device-related complications to be weighed in any ICD decision (Figure 1).30,32-43
Furthermore, strategies for selecting the most optimal candidates for primary prevention (risk stratification) have matured and evolved over the last 20 years as the data obtained from larger numbers of patients have been assembled and as additional markers of risk have been added25,26,47-49 (ie, extensive late gadolinium enhancement48 and LV apical aneurysms49 by contemporary imaging modalities such as tomographic and high-resolution contrast-cardiovascular magnetic resonance). However, the HCM risk algorithm is not yet complete, and a small minority of patients without conventional markers may still be at risk of sudden death.50 Nevertheless, it is clear that the translation of the ICD to HCM clinical practice represents a paradigm change in management by altering the clinical course of the disease for many young patients.
For many years, surgical septal myectomy has provided a quality-of-life benefit by returning most severely symptomatic patients with HCM to a full active lifestyle, by virtue of relieving impedance to LV outflow and mitral regurgitation, normalizing LV pressures, and consequently reversing heart failure symptoms.1,15-17,20,51-58Quiz Ref ID During the last 15 to 20 years, septal myectomy has undergone a substantial evolution. The procedure has benefited from modern myocardial preservation and other advances in surgical techniques, such as extended (myectomy) resection distally and mitral valve repair with chordal cutting, extension, or plication of the leaflets and mobilization of the papillary muscles.15,51,52
Together, these advances have transformed septal myectomy from a highly morbid operation with a reported mortality rate of up to 6%14 to one of the safest open-heart procedures currently available, with a low operative mortality rate of 0.4% at experienced centers.53 Importantly, myectomy can also convey enhanced survival equivalent to that of the general population and also reduce the risk of sudden death. Long-term survival from all causes among patients who have undergone a myectomy is excellent (90% at 5 years and 83% at 10 years), exceeding that among patients with obstructive HCM who have not undergone myectomy.15 Indeed, it is reasonable to assume that heart failure would progress unchecked (despite pharmacologic therapy) with death and/or profound disability inevitable in a substantial proportion of patients with HCM for whom surgical myectomy (or alcohol septal ablation) were unavailable. In this way, surgical myectomy has contributed to the overall reduction in mortality attached to the disease over the last 10 years. Percutaneous alcohol septal ablation is an established but selective alternative therapy to surgical myectomy that has been shown to significantly reduce LV outflow gradient and heart failure symptoms,58-67 but without a duration of follow-up comparable to that of surgical myectomy, and with the persistent concern that the alcohol-induced transmural scar may be arrhythmogenic.58
Quiz Ref IDA heart transplant is presently the only definitive option for relieving heart failure symptoms and preserving life for patients with nonobstructive HCM who have advanced (end-stage) disease refractory to maximum pharmacologic management.68-71 A heart transplant for a patient with HCM has the capability of extending life, with posttransplant survival rates that exceed those among patients with ischemic cardiomyopathy (ie, 1-year survival rate of 85%, 5-year survival rate of 75%, and 10-year survival of 61%).71 For patients with HCM, heart transplantation can be regarded as a qualified success tempered by the youthful age of many recipients relative to normal life expectancy, the long-term risks associated with immunosuppressive drugs (eg, cancer), and the limited number of acceptable donors.
Redefining the natural history and clinical course of HCM with the advantage of current treatment interventions has cast this disease in a much more favorable light than considered even a few years ago. The initial assessments of the clinical outcome of patients with HCM 35 to 40 years ago reported annual HCM-related mortality rates in the range of 3% to 6%3,4 (Figure 2). This was attributable to the paucity of management options and also to the referral patterns to tertiary centers, which were skewed by disproportionate numbers of high-risk patients. Perhaps more than any other number introduced into the HCM literature the now obsolete 5% to 6% mortality estimate per year has somehow persisted and impaired our understanding of the natural history of HCM. Later, in the pre-ICD era, data from less selective community-based populations created a more realistic annual mortality rate for the disease in the range of 1.5% to 2.0% (Figure 2).72
Recent studies44-46 on the natural history of HCM and the clinical outcomes associated with HCM have been conducted using large established patient populations consecutively assembled and longitudinally assessed for more than 25 years, encompassing the particularly long period over which patients with HCM may present (ie, about 75 years). More than 1900 patients from the Minneapolis Heart Institute and Tufts Medical Center in Boston were analyzed in 3 separate cohorts according to age at presentation (ie, ≤29 years [children, adolescents, and adults]; 30-59 years [midlife]; and ≥60 years [advanced age]) (Figure 3 and Figure 4).44-46 This combined (and now updated) patient population provides objective evidence of a cardiovascular mortality benefit directly attributable to contemporary management strategies: prevention of sudden death by ICD (n = 86), alleviation of refractory heart failure in the absence of outflow obstruction by heart transplant (n = 45), reversal of heart failure due to marked LV outflow obstruction by septal myectomy (or selectively alcohol ablation) (n = 412), and modern external defibrillation techniques often importantly combined with therapeutic hypothermia to reverse out-of-hospital cardiac arrest and prevent neurologic sequelae73 (n = 30). Treatment interventions for HCM occurred in patients at relatively young ages: appropriate defibrillator discharges (mean [SD] age, 38  years); heart transplant (mean [SD] age, 40  years); and myectomy/ablation (mean [SD] age, 49  years). A low threshold for administering preventive anticoagulant agents to at-risk patients with atrial fibrillation was responsible for the rarity of embolic stroke–related deaths (ie, 0.4%).44-46
By virtue of introducing these treatments, it was possible to achieve a low HCM-related mortality rate of 0.5% per year, virtually identical across the 3 age groups44-46 (10-fold less than the initial mortality estimates for patients with HCM, and 3- or 4-fold less than during the pre-ICD era 15-20 years ago) (Figure 3). Furthermore, such management options were responsible for the preservation of the lives of 161 high-risk cohort patients in whom device therapy averted potentially life-threatening ventricular tachyarrhythmias (but also 412 other patients with the advantage of surgical myectomy and alcohol ablation) (Figure 4).
Overall, the 5- and 10-year mortality rates were 97% and 94%, respectively. Survival free from HCM-related death exceeded that expected in the general population, matched for age and sex in those patients presenting at 60 years of age or older, and was similar to the general population for patients in midlife. Notably, the low mortality rate of 0.5% per year among adult patients with HCM that was afforded by contemporary treatment options44,45 was also observed among young patients (ie, children, adolescents, and young adults), the age group considered historically to have the most aggressive disease course and to be at the greatest risk.46
The patients with HCM-related mortality averted by these treatment interventions outnumbered the patients with HCM-related deaths by a ratio of almost 2:1, most striking in the age group of 29 years of age or younger (3.5:1) (Figure 3). Similarly, appropriate ICD interventions interrupting ventricular tachycardia or fibrillation and out-of-hospital defibrillation greatly exceeded sudden deaths by 3.7:1.
In the most recent cardiovascular evaluation, 90% of cohort patients were asymptomatic or only mildly symptomatic (New York Heart Association functional classes I/II). Indeed, disabling heart failure symptoms developing after ICD interventions are rare in patients with HCM without evidence that the mechanism of death shifts from sudden death to progressive heart failure, in contrast to coronary artery disease.1,44
Therefore, in accord with US/Canada (American College of Cardiology/American Heart Association) guidelines and consensus panels,18,19 the vast majority of vulnerable high-risk patients in the Minneapolis-Boston cohort analysis were prospectively and reliably selected for prophylactic ICD therapy. Of the study patients who did die suddenly without the ICD, 80% had either declined a formal defibrillator recommendation or had been evaluated in the pre-ICD era for HCM, while some of the remaining patients would potentially be identified by new additions to the risk stratification algorithm (such as extensive late gadolinium enhancement).42 This clinical experience clearly dispels the myth that HCM risk markers are unreliable event predictors and that sudden death is inevitable for many patients. The US/Canada (American College of Cardiology/American Heart Association) guidelines have proven effective in identifying candidates for the ICD, but the efficacy of the statistical/mathematical model recently promoted as part of the comprehensive European Society of Cardiology guidelines74,75 is presently unresolved.76
Quiz Ref IDThe decrease in arrhythmic sudden deaths due to penetration of ICD therapy into the population of patients with HCM has changed the mortality profile of the disease. Advanced (end-stage) heart failure in the absence of outflow obstruction, with or without systolic dysfunction, is emerging as the predominant cause of death for patients with HCM, underscoring the need for novel treatment initiatives to extend survival in this patient subgroup. Indeed, while once considered largely an oddity within the natural history of HCM (with a prevalence of only 2%-3%), advanced heart failure may now be responsible for as many as 60% of HCM-related deaths and, consequently, is viewed much differently in the evolving clinical landscape of this complex genetic disease. Finally, HCM was responsible for only 25% of mortality in the Minneapolis-Boston cohort, with a large proportion of those deaths due to advanced heart failure in patients not considered for transplant listing or who died awaiting transplant.
The substantial progress made in HCM management detailed here was directly attributable to systematically applied clinical science and research intertwined with patient care, and it was driven by the energies of the practicing cardiology community. Therefore, these clinical strategies for HCM are distinct from the initiatives in molecular biology and basic science mandated by the National Institutes of Health 25 years ago,77 focusing instead on single disease-causing sarcomere mutations and cellular mechanisms,78,79 and skeptical of clinical risk stratification strategies.6-11Quiz Ref ID Genetic research has provided important insights into the biologic processes and molecular basis of HCM as a disease of the sarcomere, the identification of potential therapeutic pharmacologic targets, the diagnosis of phenocopies such as Fabry disease and LAMP2 cardiomyopathy, and the possible role of multiple sarcomere mutations.78-85Quiz Ref ID In addition, commercial genetic testing now provides the potential to screen entire families and detect gene carriers, including some who may be at risk for developing the HCM phenotype, but also importantly, with the power of genotyping, to exclude unaffected family members.78,79 However, in contrast to the clinical management initiatives reported here and occurring over this same period of time, the single-gene mutational hypothesis has not proved relevant for predicting clinical course for individual patients, formulating management strategies, preventing sudden death, or improving patient’s quality of life.19,79-81
Recent comprehensive cohort data have underscored the range of therapies now available to patients with HCM (Figure 5) and redefined the mortality risk and potential for survival implicit in this disease. This paradigm has altered the historical perception of HCM as relentless and uniformly progressive, and a frequent cause of premature death, and also underscores the understanding achieved recently with regard to the natural history and the effectiveness of therapeutic interventions for this inherited heart disease.
Indeed, it is time for patients and physicians to put aside old myths and misconceptions and recognize what is possible in HCM, thus permitting a measure of optimism to pervade this disease, which has too frequently been encumbered by negativity. These accomplishments over the past 2 decades provide important reassurance to many patients with HCM who can now aspire to an acceptable quality of life and an extended (if not normal) life span (ie, the “dawn of a better day” cited by Dr Paolo Spirito of Genoa, Italy).86
Our data also underscore the advantage of evaluating and treating patients in emerging multidisciplinary centers of excellence dedicated to HCM.20 However, we understand that, at this time, our data may not be easily replicated in many other countries and cultures, or even in all practices in the United States. Highly populous countries such as India87 and China may not yet possess all the necessary resources to take full advantage of the recent advances in management strategies, and many patients from diverse cultures may not be psychologically amenable to major treatment interventions, such as the ICD.
However, unmet needs remain in the management of patients with HCM, including a more specific risk stratification algorithm with reduction in excess device implants, targeted pharmacologic therapy to control symptoms, improved strategies for reversing or controlling advanced heart failure unrelated to obstruction, and, for genetics, refining the classification of pathogenic (disease-causing) sarcomere mutations and its relation to outcome. Nevertheless, the clinical initiatives and low mortality rates reported here represent what can now be achieved when contemporary management options and decision making are used in the care of patients with HCM.
Accepted for Publication: December 11, 2015.
Corresponding Author: Barry J. Maron, MD, Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, 920 E 28th St, Ste 620, Minneapolis, MN 55407 (firstname.lastname@example.org).
Published Online: March 2, 2016. doi:10.1001/jamacardio.2015.0354.
Author Contributions: Drs B. J. Maron and M. S. Maron had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: B. J. Maron, M. S. Maron.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: All authors.
Administrative, technical, or material support: B. J. Maron, Rowin, Casey.
Study supervision: B. J. Maron, Casey, M. S. Maron.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
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