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Available online at www.sciencedirect.com
www.elsevier.com/locate/tcm
The 20 advances that have defined contemporary hypertrophic cardiomyopathy Barry J. Marona,n and Martin S. Maronb a
Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Suite 620, 920 E, 28th Street, Minneapolis, MN 55407 b Hypertrophic Cardiomyopathy Center, Tufts Medical Center, Boston, MA
abstract Hypertrophic cardiomyopathy (HCM) emerged as a distinct disease entity in about 1960. Over the subsequent 55-year time span, HCM has undergone vast changes in its perception by the cardiovascular community, often fraught with controversy and misunderstanding, but ultimately benefiting from innovations in therapy and diagnosis, such as echocardiography and cardiovascular magnetic resonance imaging, implantable defibrillators, surgical myectomy and alcohol ablation, and heart transplantation. Once considered an oddity and exotic disease, HCM can now take its place as a contemporary and treatable disease with relatively low mortality risks. Here we have listed and discussed what we believe to be the 20 most important advances in the evolution of HCM based on more than 50 years of our combined experience with this complex genetic disease. & 2015 Elsevier Inc. All rights reserved.
Although there are reports of a disease consistent with hypertrophic cardiomyopathy (HCM) as far back as almost 150 years from France and then Germany, the modern disease is generally considered to date from the observations of Teare and Brock in 1957–1959 [1]. Through this more than 50-year history, HCM has evolved remarkably from a rare “exotic” and interesting disease with little or no effective therapeutic options and grim prognosis to ultimately a contemporary condition consistent with normal life expectancy for which all potential complications are treatable [2,3]. In this review, we will describe these striking developments in the context of 20 landmark events or developments (Fig. 1).
Initial recognition: Teare (pathology) and Brock (clinical) In the late 1950s, 2 almost simultaneous reports brought HCM into the consciousness of the cardiovascular community: one
based on novel observations at autopsy and the other hemodynamic and based on early cardiac catheterization [1]. In the former, Donald Teare [4], the coroner of London described 8 young people (aged 15–45 years; mean ¼ 27) with sudden death that he attributed to asymmetric hypertrophy mimicking a cardiac tumor. This remarkable paper is notable for the detailed morphologic observations that have become acknowledged features of HCM such as disorganized arrangement of myocytes, crypt-like evaginations of the left ventricular (LV) wall, asymmetric patterns of LV wall thickening, extensive fibrosis, and distortion of the mitral valve, but also the familial nature of the disease, recognition that syncope and exercise are risk factors, the importance of heart failure in disease progression, and T-wave inversion on ECG. In the second paper, Brock [5] observed 4 patients initially thought to have aortic stenosis, but who proved to have no impedance to LV outflow at cardiac catheterization and surgery. These papers, and several other early reports, set the stage for the initial seminal clinical work on HCM.
Dr. Maron reports personal fees from GeneDx and grant from Medtronic, USA for research support outside the submitted work. The authors have indicated there are no conflicts of interest. n Corresponding author. Tel.: þ1 612 863 3996; fax: þ1 612 863 3875. E-mail addresses: [email protected], [email protected] (B.J. Maron). http://dx.doi.org/10.1016/j.tcm.2014.09.004 1050-1738/& 2015 Elsevier Inc. All rights reserved.
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Fig. 1 – Timeline of the advances in HCM over 50 years. ACC ¼ American College of Cardiology; AHA ¼ American Heart Association; CMR ¼ cardiovascular magnetic resonance; echo ¼ echocardiography; ESC ¼ European Society of Cardiology; HCMA ¼ Hypertrophic Cardiomyopathy Association; ICD ¼ implantable cardioverter-defibrillator; SD ¼ sudden death.
The Braunwald Group (National Institutes of Health; Bethesda, MD) In the decade between 1958 and 1968 at the National Heart Institute (Bethesda, MD), Dr. Eugene Braunwald and a team of investigators provided the initial systematic description of this disease, which they termed idiopathic hypertrophic subaortic stenosis (IHSS) [6–8]. The selection of this name underscored that they were largely describing the obstructive form of this disease, which was most easily discernable, given that this was a pre-echocardiographic era in which diagnostic techniques were limited to physical examination (recognition of a loud systolic heart murmur) or invasive left heart cardiac catheterization (documentation of the subaortic gradient). The intensive Braunwald initiative brought HCM into the arena of cardiovascular medicine as a “new” and unique clinical entity, including the first comprehensive description of dynamic LV outflow tract obstruction, notably presented in the seminal American Heart Association (AHA) monograph describing the first cohort of 64 patients with IHSS [6]. However, in these early days, there was little in the way of effective therapy to offer patients, reflected by the early appraisal by Dr. Braunwald: “At this time, we are aware of no method of management that can specifically and favorably influence the course of a patient with idiopathic ventricular hypertrophy.”
Beta-blockers In 1962, beta-adrenergic blocking drugs (initially propranolol) were introduced as the first pharmacologic agents for HCM patients to control symptoms of exercise intolerance. Later, verapamil was added (1979) as an alternative medication (primarily for nonobstructive patients), and more recently disopyramide has been used by some investigators in obstructive HCM. Each of these drugs has had success in reducing and controlling heart failure symptoms in many patients but has had no impact on likelihood of sudden death.
The surgical myectomy operation Although the nonobstructive form of HCM had first been recognized in 1962 by the Braunwald group, during at least the first decade of HCM most interest was in those treatments
targeted to relieve obstruction to LV outflow obstruction [6–8]. In this regard, the surgical septal myectomy operation was formulated to abolish outflow gradients (and normalize LV pressure) by resection of a small amount of muscle from the thickened basal ventricular septum, thereby widening the outflow tract and eliminating systolic anterior motion of the mitral valve, eventually defined as the mechanism by which obstruction occurs in HCM [8]. Several surgeons experimented with the myectomy (or myotomy) operation in the early 1960s, including John Kirklin at Mayo Clinic and Mr. Cleland in the UK (who abandoned the procedure after a brief experience). However, credit for designing, refining, and promoting the myectomy operation in cardiovascular surgery belongs to Dr. Andrew G. Morrow of NIH, after whom the operation is widely known (the Morrow procedure) [8]. More recently, the original Morrow procedure has been modified as an extended myectomy by Dr. Joseph Dearani at Mayo Clinic to account for diverse morphologic abnormalities that may be present within the LV chamber and contribute to outflow obstruction. Surgical myectomy survives (and in fact flourishes) in the U.S. after 50 years. It is the preferred treatment option for patients with severe unrelenting and drug-refractory heart failure symptoms due to dynamic LV outflow obstruction, even in the current interventional cardiology era (Fig. 2). Long-term data are now available showing that the myectomy operation consistently and reliably reduces heart failure symptoms and restores quality of life (often to the asymptomatic state), as well as enhancing survival equivalent to that expected in the general U.S. population [9]. Therefore, and most importantly, the myectomy operation has demonstrated that progressive heart failure in HCM is a treatable and reversible process [2,3], now performed most commonly at Mayo Clinic, Cleveland Clinic, Mount Sinai Hospital (NYC), and Tufts Medical Center.
LV outflow obstruction: Debate and resolution Even while the myectomy operation was evolving, in the mid-1960s a major debate in cardiology addressed whether LV outflow gradients in HCM were “real,” i.e., represented true mechanical impedance to outflow, or altenatively were simply artifacts of the unique contractility pattern and therefore not a physiologic component of the clinical disease [10,11]. This debate was ultimately resolved at the 1966 AHA meeting in New York in favor of obstruction by the demonstration with transeptal catheterization that elevated LV pressures
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were present at rest or with physiologic provocation in most HCM patients (i.e., 70%), making HCM a predominantly obstructive disease [14].
Echocardiography
Fig. 2 – Clinical significance and implications of LV outflow tract obstruction. (A) Patients with outflow gradients 430 mmHg at rest are at greater risk for HCM-related progressive heart failure or heart failure or stroke death. (Adapted with permission from Maron et al. [13].) (B) Abolition of LV outflow gradient by surgical septal myectomy is associated with long-term survival (with respect to all-cause mortality) similar to that expected in age- and sex-matched general U.S. population, exceeding that in a comparison group of symptomatic nonoperated patients with obstruction. (Adapted with permission from Ommen et al. [9].) were present in the sub-mitral region of the LV, removed from the potential for catheter-entrapment or cavity obliteration (which can produce hemodynamic pressure tracings that mimic obstruction) [10,11]. The early belief that muscular apposition of the septum and LV free wall was responsible for obstruction, as advanced by Dr. Morrow in the operating room, was replaced a few years later by demonstration with echocardiography that mechanical obstruction occurs due to systolic anterior motion of the mitral valve (SAM) with prolonged basal ventricular septal contact (described initially by Dr. Pravin Shah with echocardiography in the late 1960s) [12]. Any uncertainty regarding the pathophysiologic significance of outflow obstruction in HCM was ultimately dispelled by a series of clinical studies showing: 1) subaortic gradients to be strongly related to outcome (particularly heart failure) (Fig. 2) [13,14], and also 2) the evidence that such gradients
The widespread introduction of M-mode (one-dimensional) echocardiography to HCM in the early 1970s changed the disease for practicing cardiologists and researchers in several important ways. Instead of diagnosis dependent upon the nuances of a systolic murmur heard on physical examination or by invasive left heart cardiac catheterization and angiography, rapid non-invasive diagnosis was possible for the first time with echocardiography by demonstrating ventricular septal hypertrophy and the characteristic asymmetric pattern of LV wall thickening, with the opportunity to measure LV wall thickness quantitatively [15]. This novel diagnostic power of echocardiography at that point in the evolution of HCM cannot be underestimated, allowing recognition of the hypertrophied non-dilated LV as the diagnostic sine qua non, and expansion of the disease spectrum to include the large proportion of patients without LV outflow obstruction under (basal) resting conditions, although first suggested by Braunwald et al. [16] in 1962. Introduction of 2-dimensional echocardiography in the late 1970s provided enhanced capability for imaging the overall LV chamber and the pattern of hypertrophy more extensively, still fundamental to HCM diagnosis after 35 years [17]. With the introduction of the Doppler mode, it became possible to reliably assess the LV outflow tract gradients rapidly, non-invasively, and in quantitative terms without the need for serial cardiac catheterizations [18]. Introduction of tomographic high-resolution cardiovascular magnetic resonance (CMR) imaging to HCM 10 years ago compensates for certain limitations of echocardiography, such as lower resolution and oblique cross-sectional planes.
Changing the name Hypertrophic cardiomyopathy has been historically characterized in the literature by a variety of names (n ¼ almost 100), which has periodically created confusion and uncertainty with respect to its diagnosis and management (Fig. 3) [19]. However, with the advent of echocardiography and full recognition of the nonobstructive form of the disease, it was essential to convert the disease nomenclature, which emphasized LV outflow obstruction, from idiopathic hypertrophic subaortic stenosis (IHSS) or hypertrophic obstructive cardiomyopathy (HOCM) to the more appropriate hypertrophic cardiomyopathy (HCM with or without obstruction), which is now in common usage. Adoption of hypertrophic cardiomyopathy (HCM) as the primary name has been crucial in unifying this heterogeneous disease both in terms of the literature and in clinical practice [19].
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Fig. 3 – Names that have been used to describe hypertrophic cardiomyopathy (HCM) in the literature.
Establishing prevalence of disease For much of the first 2 decades, HCM was perceived as a rare but “interesting” disease. This misconception affected its place within cardiovascular medicine, attitudes by and to patients, and grant funding for research. In 1995, the CARDIA study offered a prevalence figure of 1:500 for HCM in the general population based on phenotypic evidence by echocardiography (i.e., left ventricular hypertrophy), equivalent to 700,000 Americans affected by this disease [20]. Subsequently, a number of other reports from populations and countries with varied study designs reported a similar prevalence for HCM. More recently, penetration of genetic testing into the HCM population identifying gene-positive phenotypenegative family members at risk for developing disease and recognition of the frequency of sarcomere genes in the general population has raised the distinct possibility that 1:500 underestimates the true frequency with which HCM occurs in the general population. Prevalence could be as high as 1:200, establishing HCM as the most common genetic heart disease. HCM is regarded as a global disease, reported from 450 countries in patients of many races and ethnic groups.
conditions. This linkage of HCM to tragic events on the athletic field triggered creation of the 35-year-old U.S. National Registry of Sudden Death in Athletes and raised the footprint of the disease as an important cause of sudden death in the young [22,23], a condition to be considered prospectively by screening initiatives before participation in sports, and if identified clinically, a justifiable cause for removal from athletic competition to reduce risk. The latter recognition led to 3 Bethesda Conferences presenting specific
Sudden death in young athletes Recognition that HCM is the most common cause of sudden unexpected death in young competitive athletes in 1980 raised the visibility of HCM as an important cause of sudden death (Fig. 4) [21]. Remarkably, prior to this, sudden deaths in trained athletes were thought to result from a vague “sudden death syndrome” and not necessarily by defined pathologic
Fig. 4 – Cardiovascular causes of sudden death in young competitive athletes in the U.S.
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disqualification vs. eligibility criteria for competitive athletes with underlying cardiovascular abnormalities [24]. Forensic data from the U.S. has consistently shown HCM to be the single most common cardiac cause of sudden death in young athletes, responsible for about one-third of these events, and with a myriad of other largely genetic and/or congenital heart diseases (e.g., congenital coronary anomalies of wrong sinus origin, myocarditis, valvular heart disease, and arrhythmogenic right ventricular cardiomyopathy), each responsible for o5% of these cases [23]. The importance of HCM as a cause of death in athletes has ultimately triggered an ongoing debate on the optimal preparticipation screening strategy for detecting sports participants with this and other genetic and/or congenital heart disease [25].
Maturing of risk stratification The impetus for identifying reliable risk markers to predict future sudden death events accelerated and became a far more relevant issue when the implantable cardioverterdefibrillator (ICD) was introduced to the HCM patient population about 15 years ago, and the possibility for prevention of sudden death became a reality to patients with this disease (Fig. 5) [26]. By virtue of numerous retrospective and observational studies over 20 years, a risk stratification algorithm has been assembled, effective in identifying high-risk patients who benefit from primary prevention ICD therapy [27,28], but also including a small subset of patients (0.5% per year) without conventional risk markers who nevertheless may also be at risk for sudden death events. The strategy of using 1 or more major risk markers, judged to be relevant within the individual patient's clinical profile,
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for consideration of a prophylactic ICD has been the generally accepted management strategy for HCM patients in the U.S. [27,28]. Other approaches have been advanced with limited success (particularly by European investigators), such as numerical summing of risk factors, highly sophisticated mathematical modeling, and weighting of multiple risk factors. However, the most recent useful marker introduced into risk stratification takes advantage of contrast-CMR to quantitate late gadolinium enhancement [29].
Prevention of sudden death with the implantable defibrillator Unexpected and unanticipated sudden cardiac death has been the most devastating potential complication of HCM since its inception. HCM has come to be recognized as the most common cause of non-traumatic sudden death in young people. For decades, there was no therapeutic intervention (including drugs) capable of effectively mitigating this risk. Fifteen years ago, with development of transvenous lead systems, the ICD was translated to the HCM patient population both for secondary and primary prevention of sudden death [26]. In a series of studies comprising hundreds of HCM patients judged to be at high risk, the ICD has proven to be highly effective in terminating potentially lethal ventricular tachyarrhythmias and has significantly altered the natural course of the disease for many patients of all ages, including children implanted at o20 years of age (Fig. 5) [2,3,26,28,30]. An appropriate primary prevention intervention rate of 4% per year has been reported consistently. However, device-related complications, industry recalls, and inappropriate shock rates represent well-recognized limitations of ICD therapy that are
Fig. 5 – Pyramid profile of risk stratification model currently used to identify patients at the highest risk who may be candidates for ICDs and sudden death prevention. Major and minor risk markers appear in boxes at the left. At the right side are the results of ICD therapy in 730 children, adolescents, and adults assembled from registry studies. CAD ¼ coronary artery disease; EF ¼ ejection fraction; ICD ¼ implantable cardioverter-defibrillator; LV ¼ left ventricular; LGE ¼ late gadolinium enhancement; LVH ¼ left ventricular hypertrophy; NSVT ¼ nonsustained ventricular tachycardia; SD ¼ sudden death; VT/VF ¼ ventricular tachycardia/ventricular fibrillation; y ¼ years; * ¼ extensive LGE can be a primary risk marker but also an ICD decision arbitrator when assignment of high-risk status is ambiguous based on conventional risk markers. (Adapted with permission from Maron et al. [2].)
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weighed by patients in the process of shared decision-making concerning prophylactic implants [31,32].
Recognition that HCM is compatible with extended longevity The early years of HCM were encumbered by the belief that HCM was a disease with uniform or usually adverse prognosis. This perception was based not only on the paucity of management options available to effectively treat patients, but also reflected a scientific literature which disproportionately came from highly referred patient populations at tertiary centers (e.g., National Institutes of Health or Mayo Clinic) comprised largely of patients at highest risk or the most symptomatic. Consequently, asymptomatic low-risk patients were much less evident in the HCM literature. Over the last 15 years, new HCM centers with less biased patient selection have created a revised natural history for HCM, allowing emergence of the important principle that HCM is compatible with normal life expectancy (if not extended longevity) into the 80s or even 90s, very often without significant disability or the need for major interventions [2,3,33]. Such insights have provided important reassurance to many HCM patients who would otherwise have been under the misconception that HCM will ultimately be responsible for profound morbidity or death.
Altering the clinical course of HCM Earlier perceptions of the natural history of HCM were based on an era largely devoid of effective treatment options. However, due to major advances in cardiovascular medicine translated to the management of these patients, e.g., implantable cardioverter-defibrillators, advanced heart failure therapies including transplant, and modern resuscitation/defibrillation techniques with therapeutic hypothermia, we have witnessed a paradigm shift with a decrease in HCMrelated mortality to 0.5% per year in adult patients, similar to the expected all-cause mortality in the general population (Fig. 6) [2,3]. A related principle is the importance of advancing age in HCM in which stable patients surviving 460 years show a favorable future course with a very low event rate, similar to that in the general population, and with little need for considering prophylactic ICD therapy [33].
The Guidant affair In 2004, a 21-year-old college student with nonobstructive HCM died suddenly with an ICD that failed to defibrillate a lethal arrhythmia, and which previously had been implanted for primary prevention based on a high-risk clinical profile. Subsequently, it came to light that the ICD (Guidant Corporation) was known by the manufacturer to be prone to short-circuiting, although the managing cardiologists, electrophysiologists, and patients had not been informed of this possibility [31,32]. Even after this defect was recognized, the company continued to sell the same defibrillator model. Therefore, some patients with HCM (and other cardiac diseases) judged
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to be at risk of arrhythmic sudden death were treated with defibrillators that could not reliably prevent this event from occurring. The Guidant affair [31,32] became highly public, ultimately creating greater transparency between industry and the practicing cardiology community (and their patients). This event also paradoxically raised visibility for the potential power of the ICD in preventing sudden death in HCM.
Emergence of alternatives to myectomy, including alcohol septal ablation Although surgical myectomy is the preferred (gold standard) option for most patients with medically refractory severe heart failure symptoms due to LV outflow obstruction, some HCM patients are not optimal candidates for operation and alternative options have an important role in management decisions. In 1995, a novel percutaneous approach to reducing outflow gradient and heart failure symptoms by infusing absolute alcohol into the first major septal perforator artery (producing a transmural myocardial infarction) was introduced into the therapeutic armamentarium of obstructive HCM by Dr. Ulrich Sigwart [34]. Over the past 10 years, non-surgical alcohol ablation has penetrated into cardiovascular practice, and of particular note in the process has virtually abolished septal myectomy from most of Europe [2]. Consensus guideline panels from the US and Europe have consistently regarded surgical myectomy to be the preferred option for relieving severe drug-refractory symptoms due to outflow obstruction, with alcohol ablation being a selective alternative for patients who would be at generally higher operative risk with significant co-morbidities or marked aversion to surgery [34–36]. While alcohol ablation can substantially reduce the outflow tract gradient in HCM, and thereby reduce heart failure symptoms in HCM patients, the therapeutic effect of septal myectomy is generally superior and without conveying certain risks of ablation: ventricular tachyarrhythmias and sudden death evident in a minority of post-ablation patients, a higher rate of pacemaker implantation for complete heart block, and re-interventions for failed results. Although many HCM experts believe alcohol ablation has been used excessively in the treatment of this disease, it is also apparent that the introduction of this therapeutic option to the HCM patient population has focused attention on the treatment for LV outflow obstruction, and in the process has paradoxically increased the number of myectomies performed, as well as validated the pathophysiologic significance of outflow obstruction in HCM. Dual-chamber pacing was embraced as a treatment for symptomatic obstruction in HCM patients for a brief period 25 years ago [35]. Although anecdotal reports promoted pacing as a non-surgical alternative strategy for reducing LV outflow gradient and heart failure symptoms, ultimately the pacing option fell into disrepute based on (1) randomized studies showing the perceived symptom relief with pacing to be largely the consequence of a placebo response and (2) concerns raised about the reliability of some of the published data and claims of efficacy for pacing in obstructive HCM.
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Fig. 6 – Adverse pathways within the broad HCM clinical spectrum. Individual patients may be subject to disease progression with 1 or more of these complications, each of which is associated with potentially effective treatment options. Alternatively, most HCM patients probably experience benign course without requiring major interventions. AF ¼ atrial fibrillation; ICD ¼ implantable cardioverter-defibrillator.
Genetics
Cardiovascular magnetic resonance
Almost 25 years ago, the molecular basis of HCM was first studied with contemporary genomic methods. The Seidman laboratory [36] identified the first sarcomere gene mutations causing HCM, and over this time period, the genetic heterogeneity of HCM has proved to be extensive, now with almost 2000 individual mutations in 11 or more genes encoding proteins of the cardiac sarcomere and the Z-disc [37]. Two genes, beta-myosin heavy chain and myosin-binding protein C, together are responsible for the majority of all identified pathogenic mutations (Fig. 7). These seminal discoveries eventually made genetic testing and molecular diagnosis accessible to the practicing community for routine clinical application, with commercially available genetic panels testing for HCM mutations and phenocopies. The opportunity to screen at-risk family members has emerged as the strongest clinical application of genetic testing [2,38,39]. If a pathogenic mutation is identified in a family proband, then those family members who do not carry that mutation are probably not at risk for developing HCM. This contemporary era of genetic testing and diagnosis led to identification of novel subgroups of HCM patients: (1) those with a pathogenic mutation, but without LV hypertrophy, and at risk for developing disease, (i.e., genotype-positive/phenotype-negative) [40,41]; (2) delayed phenotypic penetrance with the development of LV hypertrophy after adolescence and into adulthood. Future potential developments may be in establishing the significance of multiple mutations and utilization of pre-implantation genetic diagnosis (PGD), which if successful would terminate the disease in subsequent generations.
Similar to the impact of echocardiography in the 1970s, cardiovascular magnetic resonance (CMR) has led to a contemporary evolution in imaging of the HCM heart [2,40,41]. Due in large part to its unique strengths, which include highspatial-resolution imaging in any plane (without obliquity), CMR provides superior characterization of the diverse morphologic expression of HCM, and as a result, has matured to become part of the routine evaluation of patients with this disease (Fig. 8). Indeed, CMR is a major innovation for the HCM patient population, superior to echocardiography for diagnosis by (for example) identifying segmental areas of increased LV wall thickness not reliably seen (or underestimated) by 2-D echocardiography [40]. In addition, CMR is responsible for increased recognition of high-risk subgroups, including those with scarred apical aneurysms, systolic dysfunction, and massive LVH, as well as characterizing the complex LV outflow tract anatomy, including papillary muscle and mitral valve morphology, which may impact management decisions for invasive septal reduction [40]. Most recently, contrast-enhanced CMR data provides the unique capability to quantify myocardial fibrosis, which has led to an enhanced risk stratification model for this disease, and more precise selection of patients who become candidates for primary prevention of sudden death with ICDs, even those without other conventional risk markers [29].
Advanced heart failure With the increasing use of ICDs for the primary prevention of sudden death, heart failure progression/death has emerged
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Fig. 7 – Genetics and family screening strategies in HCM. Cardiac sarcomere showing the location of known HCM diseasecausing genes. Prevalence for each of the 11 genes in which there is the most evidence (derived from studies in unrelated HCM probands with positive genotyping) are shown in parentheses. (Adapted with permission from Maron et al. [2].)
Fig. 8 – Cardiovascular magnetic resonance images demonstrating diversity of the HCM phenotype. (A) Asymmetric hypertrophy of ventricular septum (VS), sparing the left ventricular (LV) free wall. (B) Focal hypertrophy sharply confined to basal anterior septum (arrows). (C) Thin-walled apical aneurysm (arrowheads) with muscular mid-ventricular apposition of hypertrophied septum and LV wall (asterisks) and distinct proximal (P) and distal (D) chambers. (Adapted with permission from Maron et al. [2].) (D) Extensive, transmural late gadolinium enhancement involving ventricular septum. (E) Massive thickening (i.e., 33 mm) confined to anterolateral wall, greatly underestimated by echocardiography (arrowheads). (Adapted with permission from Harris et al. [43].) (F) Genotype-positive phenotype-negative HCM family member with 3 myocardial crypts penetrating the thickness of basal inferior wall (arrows). LA ¼ left atrium; RA ¼ right atrium; RV ¼ right ventricle. (Adapted with permission from Maron et al. [2].)
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more prominently in the natural history of HCM [2,42–44]. The most recognizable form of advanced heart failure is the “end-stage” (or “burned-out”) form, characterized by impaired systolic function [ejection fraction (EF) r50%], and often associated with adverse LV remodeling with extensive myocardial scarring (Fig. 6). Such patients have been recognized increasingly over the last 20 years to be candidates for heart transplantation as the only definitive therapeutic option [2,42–44]. A small subset of nonobstructive HCM patients with preserved systolic function and little or no LV chamber remodeling, who nevertheless develop refractory heart failure symptoms due to diastolic dysfunction, have now also been identified as transplant candidates. HCM post-transplant survival has proved to be similar, or possibly more favorable, than that for patients with other cardiac diseases [46].
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[1] [2]
[3]
[4] [5]
[6]
Guidelines HCM achieved some standardization in diagnostic, management, and genetic testing strategies by virtue of expert consensus panels that considered all available data and have published recommendations for the practicing cardiovascular community [45–48]. The first of 2 such initiatives was the 2003 ACC/ESC consensus [46], and later in 2011 formal guidelines were published by ACC/AHA [47]. These documents advanced a systematic approach to HCM, but require periodic revitalization for this rapidly changing disease.
[7]
[8]
[9]
[10]
HCM centers and the internet Major development over the last 10 years has been emergence of multidisciplinary centers/clinics specifically dedicated to the care of HCM patients, as part of academic cardiology programs, the first in Sydney, Australia, at the Royal Prince Alfred Hospital [49]. This strategy devises a mechanism by which HCM patients are in effect segregated from the general cardiology environment and exposed to clinicians who are experts in this particular disease. In such a center, all therapeutic modalities are available (including surgical myectomy) performed by cardiologists or surgeons experienced with each of the treatment options relevant to HCM patients. For example, decisions for individual patients concerning surgical myectomy vs. alcohol septal ablation, or ICD placement, can be resolved within the same institution. The Internet has played an important role in promoting HCM centers by providing patients with easy access to reliable information about HCM with linkage to patient advocacy organizations such as the Hypertrophic Cardiomyopathy Association (HCMA), which assists in referrals to HCM centers and cardiologists most knowledgeable about this disease and its management [49]. A book explicitly describing HCM for patients is part of that initiative: “A Guide to Hypertrophic Cardiomyopathy: For Patients, Families, and Interested Physicians” (3rd ed.) [50].
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noninvasive assessment of left ventricular outflow tract pressure gradient in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 1992;19:91–9. Maron BJ, Epstein SE. Hypertrophic cardiomyopathy. A discussion of nomenclature. Am J Cardiol 1979;43:1242–4. Maron BJ, Gardin JM, Flack JM, Gidding SS, Bild D. Assessment of the prevalence of hypertrophic cardiomyopathy in a general population of young adults: echocardiographic analysis of 4111 subjects in the CARDIA study. Circulation 1995;92:785–9. Maron BJ, Roberts WC, McAllister HA, Rosing DR, Epstein SE. Sudden death in young athletes. Circulation 1980;62:218–29. Maron BJ. Sudden death in young athletes. N Engl J Med 2003;349:1064–75. Maron BJ, Doerer JJ, Haas TS, Tierney DM, Mueller FO. Sudden deaths in young competitive athletes: analysis of 1866 deaths in the U.S., 1980–2006. Circulation 2009;119: 1085–92. Maron BJ, Ackerman MJ, Nishimura RA, Pyeritz RE, Towbin JA, Udelson JE. Task force 4: hypertrophic cardiomyopathy and other cardiomyopathies, mitral valve prolapse, myocarditis and Marfan syndrome. In, 36th Bethesda Conference. Eligibility recommendations for competitive athletes with cardiovascular abnormalities (Maron BJ, Zipes DP). J Am Coll Cardiol 2005;45:1340–5. Maron BJ, Friedman RA, Kligfield P, Levine BD, Viskin S, Chaitman BR, et al. Assessment of the 12-lead electrocardiogram as a screening test for detection of cardiovascular disease in general healthy populations of young people (12–25 years of age). Circulation 2014;130:1303–34 and J Am Coll Cardiol 2014;64:1479–514. Maron BJ, Shen WK, Link MS, Epstein AE, Almquist AK, Daubert JP, et al. Efficacy of implantable cardioverterdefibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med 2000; 342:365–73. Maron BJ. Contemporary insights and strategies for risk stratification and prevention of sudden death in hypertrophic cardiomyopathy. Circulation 2010;121:445–56. Maron BJ, Spirito P, Shen WK, Haas TS, Formisano F, Link MS, et al. Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy. J Am Med Assoc 2007;298:405–12. Chan RH, Maron BJ, Olivotto I, Pencina MJ, Assenza GE, Haas TS, et al. Prognostic value of quantitative contrastenhanced cardiovascular magnetic resonance for the evaluation of sudden death risk in patients with hypertrophic cardiomyopathy. Circulation 2014;130:484–95. Maron BJ, Spirito P, Ackerman MJ, et al. Prevention of sudden cardiac death with the implantable cardioverterdefibrillator in children and adolescents with hypertrophic cardiomyopathy. J Am Coll Cardiol 2013;61:1527–35. Hauser RG, Maron BJ. Lessons from the failure and recall of an implantable cardioverter-defibrillator. Circulation 2005; 112:2040–2. Steinbrook R. The controversy over Guidant's implantable defibrillators. N Engl J Med. 2005;353:221–4. Maron BJ, Rowin EJ, Casey SA, Haas TS, Chan RHM, Udelson JE, et al. Risk stratification and outcome of patients with hypertrophic cardiomyopathy over 60 years of age. Circulation 2013;127:585–93. Sigwart U. Non-surgical myocardial reduction for hypertrophic obstructive cardiomyopathy. Lancet 1995;346:211–4. Maron BJ, Nishimura RA, McKenna WJ, Rakowski H, Josephson ME, Kieval RS. Assessment of permanent dual-chamber pacing as a treatment for drug-refractory symptomatic patients with obstructive hypertrophic cardiomyopathy: a
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randomized, double-blind cross-over study (M-PATHY). Circulation 1999;99:2927–33. Seidman CE, Seidman JG. Identifying sarcomere gene mutations in hypertrophic cardiomyopathy: a personal history. Circ Res 2011;108:743–50. Maron BJ, Maron MS, Semsarian C. Genetics of hypertrophic cardiomyopathy after 20 years: clinical perspectives. J Am Coll Cardiol 2012;60:705–15. Ho CY, Sweitzer NK, McDonough B, Maron BJ, Casey SA, Seidman JG, et al. Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation 2002;105:2992–7. Maron BJ, Yeates L, Semsarian C. Clinical challenges of genotype positive (þ)-phenotype negative () family members in hypertrophic cardiomyopathy. Am J Cardiol 2011; 107:604–8. Maron MS, Maron BJ, Harrigan C, Buros J, Gibson CM, Olivotto I. Hypertrophic cardiomyopathy phenotype revisited after 50 years with cardiovascular magnetic resonance. J Am Coll Cardiol 2009;54:220–8. Rickers C, Wilke NM, Jerosch-Herold M, Casey SA, Panse P, Panse N. Utility of cardiac magnetic resonance imaging in the diagnosis of hypertrophic cardiomyopathy. Circulation 2005;112:855–61. Melacini P, Basso C, Angelini A, Calore C, Bobbo F, Tokajuk B, et al. Clinicopathological profiles of progressive heart failure in hypertrophic cardiomyopathy. Eur Heart J 2010;31:2111–23. Harris KM, Spirito P, Maron MS, Zenovich AG, Formisano F, Lesser JR, et al. Prevalence, clinical profile and significance of left ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy. Circulation 2006;114:216–25. Maron MS, Kalsmith BM, Udelson JE, Li W, DeNofrio D. Survival after cardiac transplantation in patients with hypertrophic cardiomyopathy. Circ Heart Fail 2010;3:574–9. Maron BJ, Maron MS. Hypertrophic cardiomyopathy. Lancet 2013;381:242–55. Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ, Kuhn HJ, Seidman CE, et al. American College of Cardiology/ European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines Committee to develop an expert consensus document on hypertrophic cardiomyopathy. J Am Coll Cardiol 2003;42:1687–713; Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ, Kuhn HJ, Seidman CE, et al. American College of Cardiology/ European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines committee to develop an expert consensus document on hypertrophic cardiomyopathy. Eur Heart J 2003;24:1965–91. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, et al. ACCF/AHA guidelines for the diagnosis and treatment of hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;124:2761–96; Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, et al. ACCF/AHA guidelines for the diagnosis and treatment of hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2011;58:e212–60;
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cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm 2011;8:1308–39. Maron BJ. Hypertrophic cardiomyopathy centers. Am J Cardiol 2009;104:1158–9. Maron BJ, Salberg L. In: A guide to hypertrophic cardiomyopathy: for patients, families and interested physicians, 3rd ed. Oxford, UK: Wiley & Blackwell Publishers; 2014.
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Available online at www.sciencedirect.com
www.elsevier.com/locate/tcm
The 20 advances that have defined contemporary hypertrophic cardiomyopathy Barry J. Marona,n and Martin S. Maronb a
Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Suite 620, 920 E, 28th Street, Minneapolis, MN 55407 b Hypertrophic Cardiomyopathy Center, Tufts Medical Center, Boston, MA
abstract Hypertrophic cardiomyopathy (HCM) emerged as a distinct disease entity in about 1960. Over the subsequent 55-year time span, HCM has undergone vast changes in its perception by the cardiovascular community, often fraught with controversy and misunderstanding, but ultimately benefiting from innovations in therapy and diagnosis, such as echocardiography and cardiovascular magnetic resonance imaging, implantable defibrillators, surgical myectomy and alcohol ablation, and heart transplantation. Once considered an oddity and exotic disease, HCM can now take its place as a contemporary and treatable disease with relatively low mortality risks. Here we have listed and discussed what we believe to be the 20 most important advances in the evolution of HCM based on more than 50 years of our combined experience with this complex genetic disease. & 2015 Elsevier Inc. All rights reserved.
Although there are reports of a disease consistent with hypertrophic cardiomyopathy (HCM) as far back as almost 150 years from France and then Germany, the modern disease is generally considered to date from the observations of Teare and Brock in 1957–1959 [1]. Through this more than 50-year history, HCM has evolved remarkably from a rare “exotic” and interesting disease with little or no effective therapeutic options and grim prognosis to ultimately a contemporary condition consistent with normal life expectancy for which all potential complications are treatable [2,3]. In this review, we will describe these striking developments in the context of 20 landmark events or developments (Fig. 1).
Initial recognition: Teare (pathology) and Brock (clinical) In the late 1950s, 2 almost simultaneous reports brought HCM into the consciousness of the cardiovascular community: one
based on novel observations at autopsy and the other hemodynamic and based on early cardiac catheterization [1]. In the former, Donald Teare [4], the coroner of London described 8 young people (aged 15–45 years; mean ¼ 27) with sudden death that he attributed to asymmetric hypertrophy mimicking a cardiac tumor. This remarkable paper is notable for the detailed morphologic observations that have become acknowledged features of HCM such as disorganized arrangement of myocytes, crypt-like evaginations of the left ventricular (LV) wall, asymmetric patterns of LV wall thickening, extensive fibrosis, and distortion of the mitral valve, but also the familial nature of the disease, recognition that syncope and exercise are risk factors, the importance of heart failure in disease progression, and T-wave inversion on ECG. In the second paper, Brock [5] observed 4 patients initially thought to have aortic stenosis, but who proved to have no impedance to LV outflow at cardiac catheterization and surgery. These papers, and several other early reports, set the stage for the initial seminal clinical work on HCM.
Dr. Maron reports personal fees from GeneDx and grant from Medtronic, USA for research support outside the submitted work. The authors have indicated there are no conflicts of interest. n Corresponding author. Tel.: þ1 612 863 3996; fax: þ1 612 863 3875. E-mail addresses: [email protected], [email protected] (B.J. Maron). http://dx.doi.org/10.1016/j.tcm.2014.09.004 1050-1738/& 2015 Elsevier Inc. All rights reserved.
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Fig. 1 – Timeline of the advances in HCM over 50 years. ACC ¼ American College of Cardiology; AHA ¼ American Heart Association; CMR ¼ cardiovascular magnetic resonance; echo ¼ echocardiography; ESC ¼ European Society of Cardiology; HCMA ¼ Hypertrophic Cardiomyopathy Association; ICD ¼ implantable cardioverter-defibrillator; SD ¼ sudden death.
The Braunwald Group (National Institutes of Health; Bethesda, MD) In the decade between 1958 and 1968 at the National Heart Institute (Bethesda, MD), Dr. Eugene Braunwald and a team of investigators provided the initial systematic description of this disease, which they termed idiopathic hypertrophic subaortic stenosis (IHSS) [6–8]. The selection of this name underscored that they were largely describing the obstructive form of this disease, which was most easily discernable, given that this was a pre-echocardiographic era in which diagnostic techniques were limited to physical examination (recognition of a loud systolic heart murmur) or invasive left heart cardiac catheterization (documentation of the subaortic gradient). The intensive Braunwald initiative brought HCM into the arena of cardiovascular medicine as a “new” and unique clinical entity, including the first comprehensive description of dynamic LV outflow tract obstruction, notably presented in the seminal American Heart Association (AHA) monograph describing the first cohort of 64 patients with IHSS [6]. However, in these early days, there was little in the way of effective therapy to offer patients, reflected by the early appraisal by Dr. Braunwald: “At this time, we are aware of no method of management that can specifically and favorably influence the course of a patient with idiopathic ventricular hypertrophy.”
Beta-blockers In 1962, beta-adrenergic blocking drugs (initially propranolol) were introduced as the first pharmacologic agents for HCM patients to control symptoms of exercise intolerance. Later, verapamil was added (1979) as an alternative medication (primarily for nonobstructive patients), and more recently disopyramide has been used by some investigators in obstructive HCM. Each of these drugs has had success in reducing and controlling heart failure symptoms in many patients but has had no impact on likelihood of sudden death.
The surgical myectomy operation Although the nonobstructive form of HCM had first been recognized in 1962 by the Braunwald group, during at least the first decade of HCM most interest was in those treatments
targeted to relieve obstruction to LV outflow obstruction [6–8]. In this regard, the surgical septal myectomy operation was formulated to abolish outflow gradients (and normalize LV pressure) by resection of a small amount of muscle from the thickened basal ventricular septum, thereby widening the outflow tract and eliminating systolic anterior motion of the mitral valve, eventually defined as the mechanism by which obstruction occurs in HCM [8]. Several surgeons experimented with the myectomy (or myotomy) operation in the early 1960s, including John Kirklin at Mayo Clinic and Mr. Cleland in the UK (who abandoned the procedure after a brief experience). However, credit for designing, refining, and promoting the myectomy operation in cardiovascular surgery belongs to Dr. Andrew G. Morrow of NIH, after whom the operation is widely known (the Morrow procedure) [8]. More recently, the original Morrow procedure has been modified as an extended myectomy by Dr. Joseph Dearani at Mayo Clinic to account for diverse morphologic abnormalities that may be present within the LV chamber and contribute to outflow obstruction. Surgical myectomy survives (and in fact flourishes) in the U.S. after 50 years. It is the preferred treatment option for patients with severe unrelenting and drug-refractory heart failure symptoms due to dynamic LV outflow obstruction, even in the current interventional cardiology era (Fig. 2). Long-term data are now available showing that the myectomy operation consistently and reliably reduces heart failure symptoms and restores quality of life (often to the asymptomatic state), as well as enhancing survival equivalent to that expected in the general U.S. population [9]. Therefore, and most importantly, the myectomy operation has demonstrated that progressive heart failure in HCM is a treatable and reversible process [2,3], now performed most commonly at Mayo Clinic, Cleveland Clinic, Mount Sinai Hospital (NYC), and Tufts Medical Center.
LV outflow obstruction: Debate and resolution Even while the myectomy operation was evolving, in the mid-1960s a major debate in cardiology addressed whether LV outflow gradients in HCM were “real,” i.e., represented true mechanical impedance to outflow, or altenatively were simply artifacts of the unique contractility pattern and therefore not a physiologic component of the clinical disease [10,11]. This debate was ultimately resolved at the 1966 AHA meeting in New York in favor of obstruction by the demonstration with transeptal catheterization that elevated LV pressures
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were present at rest or with physiologic provocation in most HCM patients (i.e., 70%), making HCM a predominantly obstructive disease [14].
Echocardiography
Fig. 2 – Clinical significance and implications of LV outflow tract obstruction. (A) Patients with outflow gradients 430 mmHg at rest are at greater risk for HCM-related progressive heart failure or heart failure or stroke death. (Adapted with permission from Maron et al. [13].) (B) Abolition of LV outflow gradient by surgical septal myectomy is associated with long-term survival (with respect to all-cause mortality) similar to that expected in age- and sex-matched general U.S. population, exceeding that in a comparison group of symptomatic nonoperated patients with obstruction. (Adapted with permission from Ommen et al. [9].) were present in the sub-mitral region of the LV, removed from the potential for catheter-entrapment or cavity obliteration (which can produce hemodynamic pressure tracings that mimic obstruction) [10,11]. The early belief that muscular apposition of the septum and LV free wall was responsible for obstruction, as advanced by Dr. Morrow in the operating room, was replaced a few years later by demonstration with echocardiography that mechanical obstruction occurs due to systolic anterior motion of the mitral valve (SAM) with prolonged basal ventricular septal contact (described initially by Dr. Pravin Shah with echocardiography in the late 1960s) [12]. Any uncertainty regarding the pathophysiologic significance of outflow obstruction in HCM was ultimately dispelled by a series of clinical studies showing: 1) subaortic gradients to be strongly related to outcome (particularly heart failure) (Fig. 2) [13,14], and also 2) the evidence that such gradients
The widespread introduction of M-mode (one-dimensional) echocardiography to HCM in the early 1970s changed the disease for practicing cardiologists and researchers in several important ways. Instead of diagnosis dependent upon the nuances of a systolic murmur heard on physical examination or by invasive left heart cardiac catheterization and angiography, rapid non-invasive diagnosis was possible for the first time with echocardiography by demonstrating ventricular septal hypertrophy and the characteristic asymmetric pattern of LV wall thickening, with the opportunity to measure LV wall thickness quantitatively [15]. This novel diagnostic power of echocardiography at that point in the evolution of HCM cannot be underestimated, allowing recognition of the hypertrophied non-dilated LV as the diagnostic sine qua non, and expansion of the disease spectrum to include the large proportion of patients without LV outflow obstruction under (basal) resting conditions, although first suggested by Braunwald et al. [16] in 1962. Introduction of 2-dimensional echocardiography in the late 1970s provided enhanced capability for imaging the overall LV chamber and the pattern of hypertrophy more extensively, still fundamental to HCM diagnosis after 35 years [17]. With the introduction of the Doppler mode, it became possible to reliably assess the LV outflow tract gradients rapidly, non-invasively, and in quantitative terms without the need for serial cardiac catheterizations [18]. Introduction of tomographic high-resolution cardiovascular magnetic resonance (CMR) imaging to HCM 10 years ago compensates for certain limitations of echocardiography, such as lower resolution and oblique cross-sectional planes.
Changing the name Hypertrophic cardiomyopathy has been historically characterized in the literature by a variety of names (n ¼ almost 100), which has periodically created confusion and uncertainty with respect to its diagnosis and management (Fig. 3) [19]. However, with the advent of echocardiography and full recognition of the nonobstructive form of the disease, it was essential to convert the disease nomenclature, which emphasized LV outflow obstruction, from idiopathic hypertrophic subaortic stenosis (IHSS) or hypertrophic obstructive cardiomyopathy (HOCM) to the more appropriate hypertrophic cardiomyopathy (HCM with or without obstruction), which is now in common usage. Adoption of hypertrophic cardiomyopathy (HCM) as the primary name has been crucial in unifying this heterogeneous disease both in terms of the literature and in clinical practice [19].
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Fig. 3 – Names that have been used to describe hypertrophic cardiomyopathy (HCM) in the literature.
Establishing prevalence of disease For much of the first 2 decades, HCM was perceived as a rare but “interesting” disease. This misconception affected its place within cardiovascular medicine, attitudes by and to patients, and grant funding for research. In 1995, the CARDIA study offered a prevalence figure of 1:500 for HCM in the general population based on phenotypic evidence by echocardiography (i.e., left ventricular hypertrophy), equivalent to 700,000 Americans affected by this disease [20]. Subsequently, a number of other reports from populations and countries with varied study designs reported a similar prevalence for HCM. More recently, penetration of genetic testing into the HCM population identifying gene-positive phenotypenegative family members at risk for developing disease and recognition of the frequency of sarcomere genes in the general population has raised the distinct possibility that 1:500 underestimates the true frequency with which HCM occurs in the general population. Prevalence could be as high as 1:200, establishing HCM as the most common genetic heart disease. HCM is regarded as a global disease, reported from 450 countries in patients of many races and ethnic groups.
conditions. This linkage of HCM to tragic events on the athletic field triggered creation of the 35-year-old U.S. National Registry of Sudden Death in Athletes and raised the footprint of the disease as an important cause of sudden death in the young [22,23], a condition to be considered prospectively by screening initiatives before participation in sports, and if identified clinically, a justifiable cause for removal from athletic competition to reduce risk. The latter recognition led to 3 Bethesda Conferences presenting specific
Sudden death in young athletes Recognition that HCM is the most common cause of sudden unexpected death in young competitive athletes in 1980 raised the visibility of HCM as an important cause of sudden death (Fig. 4) [21]. Remarkably, prior to this, sudden deaths in trained athletes were thought to result from a vague “sudden death syndrome” and not necessarily by defined pathologic
Fig. 4 – Cardiovascular causes of sudden death in young competitive athletes in the U.S.
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disqualification vs. eligibility criteria for competitive athletes with underlying cardiovascular abnormalities [24]. Forensic data from the U.S. has consistently shown HCM to be the single most common cardiac cause of sudden death in young athletes, responsible for about one-third of these events, and with a myriad of other largely genetic and/or congenital heart diseases (e.g., congenital coronary anomalies of wrong sinus origin, myocarditis, valvular heart disease, and arrhythmogenic right ventricular cardiomyopathy), each responsible for o5% of these cases [23]. The importance of HCM as a cause of death in athletes has ultimately triggered an ongoing debate on the optimal preparticipation screening strategy for detecting sports participants with this and other genetic and/or congenital heart disease [25].
Maturing of risk stratification The impetus for identifying reliable risk markers to predict future sudden death events accelerated and became a far more relevant issue when the implantable cardioverterdefibrillator (ICD) was introduced to the HCM patient population about 15 years ago, and the possibility for prevention of sudden death became a reality to patients with this disease (Fig. 5) [26]. By virtue of numerous retrospective and observational studies over 20 years, a risk stratification algorithm has been assembled, effective in identifying high-risk patients who benefit from primary prevention ICD therapy [27,28], but also including a small subset of patients (0.5% per year) without conventional risk markers who nevertheless may also be at risk for sudden death events. The strategy of using 1 or more major risk markers, judged to be relevant within the individual patient's clinical profile,
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for consideration of a prophylactic ICD has been the generally accepted management strategy for HCM patients in the U.S. [27,28]. Other approaches have been advanced with limited success (particularly by European investigators), such as numerical summing of risk factors, highly sophisticated mathematical modeling, and weighting of multiple risk factors. However, the most recent useful marker introduced into risk stratification takes advantage of contrast-CMR to quantitate late gadolinium enhancement [29].
Prevention of sudden death with the implantable defibrillator Unexpected and unanticipated sudden cardiac death has been the most devastating potential complication of HCM since its inception. HCM has come to be recognized as the most common cause of non-traumatic sudden death in young people. For decades, there was no therapeutic intervention (including drugs) capable of effectively mitigating this risk. Fifteen years ago, with development of transvenous lead systems, the ICD was translated to the HCM patient population both for secondary and primary prevention of sudden death [26]. In a series of studies comprising hundreds of HCM patients judged to be at high risk, the ICD has proven to be highly effective in terminating potentially lethal ventricular tachyarrhythmias and has significantly altered the natural course of the disease for many patients of all ages, including children implanted at o20 years of age (Fig. 5) [2,3,26,28,30]. An appropriate primary prevention intervention rate of 4% per year has been reported consistently. However, device-related complications, industry recalls, and inappropriate shock rates represent well-recognized limitations of ICD therapy that are
Fig. 5 – Pyramid profile of risk stratification model currently used to identify patients at the highest risk who may be candidates for ICDs and sudden death prevention. Major and minor risk markers appear in boxes at the left. At the right side are the results of ICD therapy in 730 children, adolescents, and adults assembled from registry studies. CAD ¼ coronary artery disease; EF ¼ ejection fraction; ICD ¼ implantable cardioverter-defibrillator; LV ¼ left ventricular; LGE ¼ late gadolinium enhancement; LVH ¼ left ventricular hypertrophy; NSVT ¼ nonsustained ventricular tachycardia; SD ¼ sudden death; VT/VF ¼ ventricular tachycardia/ventricular fibrillation; y ¼ years; * ¼ extensive LGE can be a primary risk marker but also an ICD decision arbitrator when assignment of high-risk status is ambiguous based on conventional risk markers. (Adapted with permission from Maron et al. [2].)
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weighed by patients in the process of shared decision-making concerning prophylactic implants [31,32].
Recognition that HCM is compatible with extended longevity The early years of HCM were encumbered by the belief that HCM was a disease with uniform or usually adverse prognosis. This perception was based not only on the paucity of management options available to effectively treat patients, but also reflected a scientific literature which disproportionately came from highly referred patient populations at tertiary centers (e.g., National Institutes of Health or Mayo Clinic) comprised largely of patients at highest risk or the most symptomatic. Consequently, asymptomatic low-risk patients were much less evident in the HCM literature. Over the last 15 years, new HCM centers with less biased patient selection have created a revised natural history for HCM, allowing emergence of the important principle that HCM is compatible with normal life expectancy (if not extended longevity) into the 80s or even 90s, very often without significant disability or the need for major interventions [2,3,33]. Such insights have provided important reassurance to many HCM patients who would otherwise have been under the misconception that HCM will ultimately be responsible for profound morbidity or death.
Altering the clinical course of HCM Earlier perceptions of the natural history of HCM were based on an era largely devoid of effective treatment options. However, due to major advances in cardiovascular medicine translated to the management of these patients, e.g., implantable cardioverter-defibrillators, advanced heart failure therapies including transplant, and modern resuscitation/defibrillation techniques with therapeutic hypothermia, we have witnessed a paradigm shift with a decrease in HCMrelated mortality to 0.5% per year in adult patients, similar to the expected all-cause mortality in the general population (Fig. 6) [2,3]. A related principle is the importance of advancing age in HCM in which stable patients surviving 460 years show a favorable future course with a very low event rate, similar to that in the general population, and with little need for considering prophylactic ICD therapy [33].
The Guidant affair In 2004, a 21-year-old college student with nonobstructive HCM died suddenly with an ICD that failed to defibrillate a lethal arrhythmia, and which previously had been implanted for primary prevention based on a high-risk clinical profile. Subsequently, it came to light that the ICD (Guidant Corporation) was known by the manufacturer to be prone to short-circuiting, although the managing cardiologists, electrophysiologists, and patients had not been informed of this possibility [31,32]. Even after this defect was recognized, the company continued to sell the same defibrillator model. Therefore, some patients with HCM (and other cardiac diseases) judged
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to be at risk of arrhythmic sudden death were treated with defibrillators that could not reliably prevent this event from occurring. The Guidant affair [31,32] became highly public, ultimately creating greater transparency between industry and the practicing cardiology community (and their patients). This event also paradoxically raised visibility for the potential power of the ICD in preventing sudden death in HCM.
Emergence of alternatives to myectomy, including alcohol septal ablation Although surgical myectomy is the preferred (gold standard) option for most patients with medically refractory severe heart failure symptoms due to LV outflow obstruction, some HCM patients are not optimal candidates for operation and alternative options have an important role in management decisions. In 1995, a novel percutaneous approach to reducing outflow gradient and heart failure symptoms by infusing absolute alcohol into the first major septal perforator artery (producing a transmural myocardial infarction) was introduced into the therapeutic armamentarium of obstructive HCM by Dr. Ulrich Sigwart [34]. Over the past 10 years, non-surgical alcohol ablation has penetrated into cardiovascular practice, and of particular note in the process has virtually abolished septal myectomy from most of Europe [2]. Consensus guideline panels from the US and Europe have consistently regarded surgical myectomy to be the preferred option for relieving severe drug-refractory symptoms due to outflow obstruction, with alcohol ablation being a selective alternative for patients who would be at generally higher operative risk with significant co-morbidities or marked aversion to surgery [34–36]. While alcohol ablation can substantially reduce the outflow tract gradient in HCM, and thereby reduce heart failure symptoms in HCM patients, the therapeutic effect of septal myectomy is generally superior and without conveying certain risks of ablation: ventricular tachyarrhythmias and sudden death evident in a minority of post-ablation patients, a higher rate of pacemaker implantation for complete heart block, and re-interventions for failed results. Although many HCM experts believe alcohol ablation has been used excessively in the treatment of this disease, it is also apparent that the introduction of this therapeutic option to the HCM patient population has focused attention on the treatment for LV outflow obstruction, and in the process has paradoxically increased the number of myectomies performed, as well as validated the pathophysiologic significance of outflow obstruction in HCM. Dual-chamber pacing was embraced as a treatment for symptomatic obstruction in HCM patients for a brief period 25 years ago [35]. Although anecdotal reports promoted pacing as a non-surgical alternative strategy for reducing LV outflow gradient and heart failure symptoms, ultimately the pacing option fell into disrepute based on (1) randomized studies showing the perceived symptom relief with pacing to be largely the consequence of a placebo response and (2) concerns raised about the reliability of some of the published data and claims of efficacy for pacing in obstructive HCM.
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Fig. 6 – Adverse pathways within the broad HCM clinical spectrum. Individual patients may be subject to disease progression with 1 or more of these complications, each of which is associated with potentially effective treatment options. Alternatively, most HCM patients probably experience benign course without requiring major interventions. AF ¼ atrial fibrillation; ICD ¼ implantable cardioverter-defibrillator.
Genetics
Cardiovascular magnetic resonance
Almost 25 years ago, the molecular basis of HCM was first studied with contemporary genomic methods. The Seidman laboratory [36] identified the first sarcomere gene mutations causing HCM, and over this time period, the genetic heterogeneity of HCM has proved to be extensive, now with almost 2000 individual mutations in 11 or more genes encoding proteins of the cardiac sarcomere and the Z-disc [37]. Two genes, beta-myosin heavy chain and myosin-binding protein C, together are responsible for the majority of all identified pathogenic mutations (Fig. 7). These seminal discoveries eventually made genetic testing and molecular diagnosis accessible to the practicing community for routine clinical application, with commercially available genetic panels testing for HCM mutations and phenocopies. The opportunity to screen at-risk family members has emerged as the strongest clinical application of genetic testing [2,38,39]. If a pathogenic mutation is identified in a family proband, then those family members who do not carry that mutation are probably not at risk for developing HCM. This contemporary era of genetic testing and diagnosis led to identification of novel subgroups of HCM patients: (1) those with a pathogenic mutation, but without LV hypertrophy, and at risk for developing disease, (i.e., genotype-positive/phenotype-negative) [40,41]; (2) delayed phenotypic penetrance with the development of LV hypertrophy after adolescence and into adulthood. Future potential developments may be in establishing the significance of multiple mutations and utilization of pre-implantation genetic diagnosis (PGD), which if successful would terminate the disease in subsequent generations.
Similar to the impact of echocardiography in the 1970s, cardiovascular magnetic resonance (CMR) has led to a contemporary evolution in imaging of the HCM heart [2,40,41]. Due in large part to its unique strengths, which include highspatial-resolution imaging in any plane (without obliquity), CMR provides superior characterization of the diverse morphologic expression of HCM, and as a result, has matured to become part of the routine evaluation of patients with this disease (Fig. 8). Indeed, CMR is a major innovation for the HCM patient population, superior to echocardiography for diagnosis by (for example) identifying segmental areas of increased LV wall thickness not reliably seen (or underestimated) by 2-D echocardiography [40]. In addition, CMR is responsible for increased recognition of high-risk subgroups, including those with scarred apical aneurysms, systolic dysfunction, and massive LVH, as well as characterizing the complex LV outflow tract anatomy, including papillary muscle and mitral valve morphology, which may impact management decisions for invasive septal reduction [40]. Most recently, contrast-enhanced CMR data provides the unique capability to quantify myocardial fibrosis, which has led to an enhanced risk stratification model for this disease, and more precise selection of patients who become candidates for primary prevention of sudden death with ICDs, even those without other conventional risk markers [29].
Advanced heart failure With the increasing use of ICDs for the primary prevention of sudden death, heart failure progression/death has emerged
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Fig. 7 – Genetics and family screening strategies in HCM. Cardiac sarcomere showing the location of known HCM diseasecausing genes. Prevalence for each of the 11 genes in which there is the most evidence (derived from studies in unrelated HCM probands with positive genotyping) are shown in parentheses. (Adapted with permission from Maron et al. [2].)
Fig. 8 – Cardiovascular magnetic resonance images demonstrating diversity of the HCM phenotype. (A) Asymmetric hypertrophy of ventricular septum (VS), sparing the left ventricular (LV) free wall. (B) Focal hypertrophy sharply confined to basal anterior septum (arrows). (C) Thin-walled apical aneurysm (arrowheads) with muscular mid-ventricular apposition of hypertrophied septum and LV wall (asterisks) and distinct proximal (P) and distal (D) chambers. (Adapted with permission from Maron et al. [2].) (D) Extensive, transmural late gadolinium enhancement involving ventricular septum. (E) Massive thickening (i.e., 33 mm) confined to anterolateral wall, greatly underestimated by echocardiography (arrowheads). (Adapted with permission from Harris et al. [43].) (F) Genotype-positive phenotype-negative HCM family member with 3 myocardial crypts penetrating the thickness of basal inferior wall (arrows). LA ¼ left atrium; RA ¼ right atrium; RV ¼ right ventricle. (Adapted with permission from Maron et al. [2].)
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more prominently in the natural history of HCM [2,42–44]. The most recognizable form of advanced heart failure is the “end-stage” (or “burned-out”) form, characterized by impaired systolic function [ejection fraction (EF) r50%], and often associated with adverse LV remodeling with extensive myocardial scarring (Fig. 6). Such patients have been recognized increasingly over the last 20 years to be candidates for heart transplantation as the only definitive therapeutic option [2,42–44]. A small subset of nonobstructive HCM patients with preserved systolic function and little or no LV chamber remodeling, who nevertheless develop refractory heart failure symptoms due to diastolic dysfunction, have now also been identified as transplant candidates. HCM post-transplant survival has proved to be similar, or possibly more favorable, than that for patients with other cardiac diseases [46].
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Guidelines HCM achieved some standardization in diagnostic, management, and genetic testing strategies by virtue of expert consensus panels that considered all available data and have published recommendations for the practicing cardiovascular community [45–48]. The first of 2 such initiatives was the 2003 ACC/ESC consensus [46], and later in 2011 formal guidelines were published by ACC/AHA [47]. These documents advanced a systematic approach to HCM, but require periodic revitalization for this rapidly changing disease.
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HCM centers and the internet Major development over the last 10 years has been emergence of multidisciplinary centers/clinics specifically dedicated to the care of HCM patients, as part of academic cardiology programs, the first in Sydney, Australia, at the Royal Prince Alfred Hospital [49]. This strategy devises a mechanism by which HCM patients are in effect segregated from the general cardiology environment and exposed to clinicians who are experts in this particular disease. In such a center, all therapeutic modalities are available (including surgical myectomy) performed by cardiologists or surgeons experienced with each of the treatment options relevant to HCM patients. For example, decisions for individual patients concerning surgical myectomy vs. alcohol septal ablation, or ICD placement, can be resolved within the same institution. The Internet has played an important role in promoting HCM centers by providing patients with easy access to reliable information about HCM with linkage to patient advocacy organizations such as the Hypertrophic Cardiomyopathy Association (HCMA), which assists in referrals to HCM centers and cardiologists most knowledgeable about this disease and its management [49]. A book explicitly describing HCM for patients is part of that initiative: “A Guide to Hypertrophic Cardiomyopathy: For Patients, Families, and Interested Physicians” (3rd ed.) [50].
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