Version May 2024
INTRODUCTION — Hypertrophic cardiomyopathy (HCM) is a genetically determined heart muscle disease caused by mutations in one of several sarcomere genes which encode components of the contractile apparatus. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing".)
HCM is characterized by an enormous diversity in both phenotypic expression and clinical course (figure 1). The location, pattern, and extent of left ventricular hypertrophy (LVH) are heterogeneous, although the most common location for increased wall thickness is the basal anterior septum in continuity with the anterior free wall. HCM patients can develop one or more of the following morphologic abnormalities:
●Left ventricular (LV) outflow tract obstruction (see "Hypertrophic cardiomyopathy: Morphologic variants and the pathophysiology of left ventricular outflow tract obstruction")
●Diastolic dysfunction
●Myocardial ischemia
●Mitral regurgitation
●Systolic dysfunction (ie, LV ejection fraction [LVEF] <50 percent)
These structural and functional abnormalities can produce a variety of symptoms, including:
●Fatigue
●Dyspnea
●Chest pain
●Palpitations
●Presyncope or syncope
In broad terms, the symptoms related to HCM can be categorized as those related to heart failure (HF), chest pain, or arrhythmias. Patients with HCM have an increased incidence of both supraventricular and ventricular arrhythmias and are at an increased risk for sudden cardiac death (SCD). (See "Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation" and "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death".)
For the majority of patients with HCM, LVH is not progressive, and the clinical course is relatively benign. A small subset of patients, however, will progress to an advanced form of the disease that is characterized by systolic dysfunction with other adverse LV remodeling such as LV dilation and wall thinning present in some patients as well. Such patients are managed according to the standard approach to patients with HF due to systolic dysfunction. (See "Overview of the management of heart failure with reduced ejection fraction in adults".)
The natural history of HCM will be reviewed here. Other issues such as the clinical manifestations, diagnosis and evaluation, and treatment of this disorder are discussed separately. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation" and "Hypertrophic cardiomyopathy: Management of patients without outflow tract obstruction" and "Hypertrophic cardiomyopathy: Management of patients with outflow tract obstruction".)
DEVELOPMENT OF HYPERTROPHY
Hypertrophy and fibrosis — HCM can present in infancy and childhood, but, more commonly, LV hypertrophy (LVH) develops during the adolescent period [1]. In the majority of HCM patients, LV wall thickness measurements do not typically change once early adulthood is reached. However, progressive wall thinning may occur in patients with initially severe hypertrophy. In a series of 106 patients with initial wall thickness ≥30 mm, more than 5 mm of wall thinning was seen in 41 of the 71 patients who underwent serial assessment (58 percent); the duration of follow-up was a significant predictor of thinning [2].
A multitude of pathologic studies in children and young adults with HCM who died suddenly demonstrated that increased wall thickness is due to myocyte hypertrophy and an expanded extracellular matrix composed of interstitial and replacement fibrosis. [3]. The mechanisms leading to increased collagen matrix in HCM are not well defined but may be mediated by angiotensin II, an observation supported by studies using genetic mouse models of HCM in which increased interstitial fibrosis was attenuated by an angiotensin II receptor blocker [4]. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing", section on 'Renin-angiotensin system polymorphisms'.)
The amount and distribution of hypertrophy in patients with HCM may be related to the underlying genetic mutation. In a study comparing 150 patients with one of the more commonly seen thick filament mutations (eg, myosin heavy chain, myosin binding protein C) with 80 patients with one of the rarer thin filament mutations (eg, troponin T or I, alpha-tropomyosin, cardiac actin), patients with a thin filament mutation had significantly less hypertrophy, which was more often in an atypical location (ie, not the basal septum/anterior wall), and were less likely to have LV outflow tract obstruction [5]. While there was no difference in rate of ventricular arrhythmias or SCD depending on the mutation in this study, patients with a thin filament mutation were more likely to develop severe HF symptoms. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing", section on 'Mutations in sarcomeric protein genes'.)
A separate study has also shown evidence that serum markers of myocardial fibrosis may be present in HCM family members who carry a disease causing mutation but no LVH (genotype positive/phenotype negative). Levels of serum C-terminal propeptide of type I procollagen (PICP) were significantly higher in mutation carriers without LV as compared with controls (31 percent higher). It remains unresolved whether increases in serum markers of collagen turnover reflect a true increase in myocardial fibrosis in genotype positive phenotype negative patients. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on 'Cardiovascular magnetic resonance'.)
The presence of late gadolinium enhancement (LGE) on contrast-enhanced cardiac magnetic resonance (CMR) imaging represents myocardial fibrosis. In one systemic review of LGE in patients with HCM, which included 1063 patients from four cohorts, 60 percent of patients had LGE [6]. While the numbers of events were small, those patients with LGE had significantly higher total mortality (odds ratio [OR] 4.5, 95% CI 1.5-13.0), cardiac mortality (OR 2.9, 95% CI 1.0-8.4), and HF mortality (OR 5.7, 95% CI 1.0-31.1) compared with patients without LGE. The role of CMR in patients with HCM is discussed in detail separately. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on 'Cardiovascular magnetic resonance'.)
Late onset disease — Although most HCM disease expression develops during childhood and adolescence, late-onset disease is recognized (ie, LVH developing between ages 20 and 50 years) and was first noted in patients with mutations in cardiac myosin binding protein-C. Most cross-sectional studies of families with mutations in the cardiac myosin binding protein-C gene, which account for approximately 15 percent of cases of familial HCM, have shown that the proportion of proven carriers of the mutation who have hypertrophy increases with age [7-10].
In one cross-sectional study of 16 probands and 574 family members at risk, 58 percent of patients aged less than 50 years with a mutation in the cardiac myosin binding protein C gene had hypertrophy [8]. However, a later age at onset with cardiac myosin binding protein-C gene mutations has not been noted in all series [11,12]. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing", section on 'Cardiac myosin binding protein-C gene'.)
In contrast to familial early-onset HCM (which results from defects in the beta myosin heavy chain, cardiac troponin T, and alpha tropomyosin genes in more than 45 percent of cases), the onset of HCM in older patients is in some series associated with mutations in the cardiac myosin binding protein-C, troponin I, and alpha myosin heavy chain genes [10]. In addition, the likelihood of identifying any mutation may be lower in late-onset HCM [13].
Additionally, HCM patients who are identified late in life (age >60 years) are at low risk for HCM-related death or adverse events compared with early-onset disease. Within one cohort of 428 patients presenting at age 60 years or greater who were followed for an average of six years, 89 percent of the deaths (133 out of 149) were non-HCM related, with HCM-related mortality of only 0.6 percent per year [14]. In addition, a substantial proportion of older HCM patients also had ≥1 conventional risk factors for sudden death. (See "Hypertrophic cardiomyopathy: Morphologic variants and the pathophysiology of left ventricular outflow tract obstruction", section on 'Obstructive HCM in older adults'.)
In a small subset of patients, sigmoid septal morphology (with maximal LV wall thickness ≥15 mm) is part of the phenotypic spectrum of HCM. A sigmoid shaped basal septum can also be observed in older individuals without HCM, but in these cases the maximal wall thickness of the septum is normal. Among HCM patients, this morphologic subtype appears to be less commonly associated with a mutation than other morphologic variants. (See "Hypertrophic cardiomyopathy: Morphologic variants and the pathophysiology of left ventricular outflow tract obstruction", section on 'Sigmoid septal morphology'.)
Relation to restrictive cardiomyopathy — Restrictive cardiomyopathy is characterized by restrictive filling and reduced diastolic volume of the left and/or right ventricle despite normal or near-normal systolic function and wall thickness [15]. Primary forms are uncommon, while secondary forms usually present at the advanced stage of an infiltrative disease (sarcoidosis, amyloidosis) or a systemic storage disease (eg, hemochromatosis). Idiopathic restrictive cardiomyopathy is uncommon, and may be familial and present in children and young adults. (See "Restrictive cardiomyopathies".)
Several observations suggest that idiopathic restrictive cardiomyopathy may be part of the spectrum of familial HCM:
●Some cases of restrictive cardiomyopathy have extensive myocyte and myofibrillar disarray at explant or postmortem, findings similar to those seen in HCM [16,17].
●Some patients with primary restrictive cardiomyopathy have a family history of HCM, and mutations in sarcomeric contractile protein genes can lead to restrictive and/or HCM within the same family [16-18].
The frequency and clinical significance of this relationship was illustrated in 1226 patients from 688 consecutive HCM families [16]. A restrictive phenotype was seen in 19 patients (1.5 percent) and was associated with a relatively poor prognosis, with a 44 percent rate of death, heart transplantation, or implantable cardioverter-defibrillator (ICD) discharge. Genotyping was feasible in 15 of 16 probands: mutations were found in eight, four in the beta-myosin heavy chain gene and four in the cardiac troponin I gene. A troponin I mutation has also been identified in six of nine unrelated individuals transplanted for idiopathic restrictive cardiomyopathy [18]. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing".)
ADVANCED HEART FAILURE
HCM with LV systolic dysfunction (ejection fraction <50 percent) — A small proportion of patients with HCM (<5 to 8 percent) eventually progress to a stage of disease associated with adverse LV remodeling with reduced systolic performance (LVEF <50 percent). In some patients, there is cavity dilation and wall thinning due to a process of extensive myocardial fibrosis, as demonstrated by histologic examination in hearts removed at time of heart transplant and on cardiac magnetic resonance imaging with extensive late gadolinium enhancement (figure 2) [2,19-26]. Not all patients with HCM and LV systolic dysfunction will demonstrate cavity dilation or wall thinning, and therefore the unifying definition is considered when a patient achieves an LVEF <50 percent.
This phase, previously termed "end-stage" or "burned out" HCM, is best described as "HCM with LV systolic dysfunction." HCM with LV systolic dysfunction is associated with a marked increase in the risk of SCD [25,26]. The mechanism of LV dysfunction is uncertain, but diffuse myocardial ischemia due to microvascular dysfunction leading to a process of substantial cell death and repair process in the form of myocardial replacement fibrosis may be important [24,27]. Among a cohort of 30 patients with HCM and LV systolic dysfunction who underwent transplantation, histologic review of the explanted heart revealed extensive myocardial fibrosis averaging 37 percent of the total myocardium [24]. The degree of microvascular dysfunction assessed by quantitative PET imaging is an independent predictor of clinical deterioration and death [28]. HCM with LV systolic dysfunction is associated with a high mortality rate and overall poor prognosis [23,29].
The prevalence of HCM with LV systolic dysfunction, which has been estimated in a variety of cohorts, appears to range from 4 to 8 percent:
●Among 6793 patients from the multicenter international SHaRE registry, 553 patients (8 percent) developed HCM with LV systolic dysfunction [25].
●Among 2447 patients from a single referral center, 118 patients (5 percent) developed HCM with LV systolic dysfunction [26].
●Data from other smaller cohorts (5 percent) and pooled cohort analyses (4 percent) have shown similar rates of HCM with LV systolic dysfunction [22,23].
Although uncommon, the transition to HCM with LV systolic dysfunction represents a significant change. Patients with LVEF between 50 and 60 percent, as well as those with significant LGE by CMR, should be followed more closely as the risk of progression to HCM with LV systolic dysfunction is increased in these subsets of patients [25,26]. Clinically, patients with HCM with LV systolic dysfunction typically present with HF signs and symptoms. Early detection of LV dysfunction and/or dilation should prompt consideration of more aggressive interventions, including standard drug treatment for systolic HF (eg, angiotensin converting enzyme or aldosterone inhibitors), possibly cardiac resynchronization therapy (CRT; ie, biventricular pacing), and early consideration for heart transplantation. Among patients treated with these contemporary HF therapies, approximately 50 percent stabilize with New York Heart Association (NYHA) class I or II HF symptoms, while the remaining 50 percent developed refractory HF symptoms, with a significant increase in mortality and the need for cardiac transplantation.
The role of CRT in patients with HCM and systolic dysfunction is fairly limited, with mixed results in a number of small studies. While the response is not durable in all patients, some studies have demonstrated an improvement in HF symptoms and LVEF in a subset of patients, raising consideration for CRT in delaying advanced HF therapies including cardiac transplantation. Clinical predictors for response to CRT in patients with HCM with LV systolic dysfunction have not been identified.
●Among 150 patients with HCM with LV systolic dysfunction seen at a single referral center between 2004 and 2017, 20 patients (1.3 percent) were identified with LVEF ≤50 percent, NYHA class III/IV symptoms refractory to drug therapy, and QRS duration >120 ms [30]. Following CRT device implantation in these 20 patients, 14 patients (70 percent) had a favorable response at one year with improvement to NYHA class I/II symptom status. Five of the 14 "responders" ultimately had recurrent NYHA class III/IV symptoms at 3.9 years of mean follow-up. These data suggest a role for CRT in patients with HCM with LV systolic dysfunction and drug refractory HF as a therapeutic intervention to potentially delay the need for advance HF therapies such as LV assist devices (LVADs) or cardiac transplantation.
●Among 2447 patients with HCM from a single referral center, of the 118 patients (5 percent) who developed HCM with LV systolic dysfunction, 29 patients with QRS>120 ms underwent CRT at mean age of 51 years [26]. Among these patients, 18 of the 29 (62 percent) experienced a clinical improvement with decrease in symptoms to class I or II.
●From the Mayo Clinic cohort of 2073 patients with HCM, nine patients were identified with HCM and LVEF <50 percent who had received CRT; these patients were matched with control subjects with HCM in a 1:1 fashion [31]. Over a mean follow-up of 13 years, there was no significant difference in outcomes between the two groups, with five patients from the CRT group and two from the control group requiring LVAD or cardiac transplantation.
●Among an Italian cohort of 61 patients with HCM with LV systolic dysfunction, 13 underwent CRT (mean age at CRT 49 years, 12 patients with left bundle branch block, 8 patients with NYHA class II symptoms, 5 with NYHA class III/IV symptoms) [32]. One year following CRT, 7 of the 13 patients had ≥1 NYHA functional class improvement, while the others had no improvement or worsening of symptoms. Following an average of 5.2 years, there was no significant improvement in symptoms compared with baseline.
Due to the increased risk of ventricular tachycardia and SCD events, the 2020 American Heart Association/American College of Cardiology HCM guidelines recommend that, in HCM patients with LV systolic dysfunction, prophylactic ICD implantation for primary prevention of sudden death should be considered, particularly if awaiting heart transplantation [33]. (See "Heart transplantation in adults: Indications and contraindications" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Overview of the management of heart failure with reduced ejection fraction in adults".)
Mortality among patients with HCM with LV systolic dysfunction treated with contemporary management strategies is approximately 2 percent per year [26]. While contemporary mortality in HCM with LV systolic dysfunction is significantly lower than previous estimates (in earlier eras with different therapeutic approaches), it is approximately 10-fold higher than mortality in patients with HCM without LV systolic dysfunction (0.2 percent per year) [23].
Nonobstructive with preserved systolic function (ejection fraction ≥50 percent) — The clinical profile of advanced HF in HCM also includes nonobstructive patients (ie, patients with HCM but no significant LV outflow tract [LVOT] obstruction) with preserved systolic function (LVEF ≥50 percent) without significant LV remodeling, with average LV wall thicknesses of 22 mm, normal LV cavity dimensions, and usually very little myocardial fibrosis on contrast-enhanced cardiac magnetic resonance imaging [34]. The cause for HF in this subgroup of patients appears to be LV diastolic dysfunction due to impaired filling resulting in a low-output HF state. The time period between onset of symptoms and listing for heart transplant is on average eight years, underscoring the importance of close longitudinal follow-up in nonobstructive patients with HCM and HF symptoms and a low threshold to pursue cardiovascular evaluation for heart transplantation once symptoms become substantial.
The characteristics of HCM patients with advanced HF and preserved systolic function (LVEF ≥50 percent) were evaluated in a retrospective analysis combining two cohorts that included a total of 2100 patients [34]. The following findings were noted:
●Twenty patients (1 percent) were classified as advanced HF NYHA class III/IV listed for heart transplant without LVOT obstruction. The mean age at diagnosis of HCM with LV systolic dysfunction was 32 years, but there was a very wide age range (12 to 61 years).
●In patients with LVEF ≥50 percent, LV remodeling and cavity dilation were uncommon. Mean maximal LV wall thickness was 22 mm, and LV end-diastolic cavity size was 39 mm with no or minimal myocardial scarring (≤5 percent of LV mass).
●The average duration from the onset of HCM symptoms to transplant listing was eight years, with a mean age of 42 years at time of listing.
The primary indication for transplant listing was NYHA III/IV refractory to optimal medical therapy and, in the majority of patients, at least one additional criterion including: peak VO2 ≤14 mL/kg/min or <50 percent predicted for age; elevated LV filling pressures or impaired cardiac index on invasive hemodynamic study; and acute hemodynamic deterioration requiring inotropic therapy or mechanical support.
●Twelve of the 20 patients underwent heart transplant and were alive without symptoms an average of 2.3 years after transplant.
Heart transplant — In patients with HCM and advanced HF symptoms due to either LV systolic dysfunction (LVEF <50 percent) or with preserved systolic function (LVEF ≥50 percent), transplant listing should be based on the extent of functional limitation and should take into account objective measures such as the results of cardiopulmonary exercise testing and invasive hemodynamics [35]. However, in HCM, severity of HF symptoms are not always substantiated by traditional heart transplant testing. For example, 10 percent of HCM patients considered for transplant demonstrate peak VO2 measurements that are outside of traditional transplant cutoff values (>14 mL/kg/min) [35]. Given the complexities and challenges unique to advanced HF in HCM patients, such patients may benefit from evaluation at transplant centers that have experience with this cohort of patients.
Patients with HCM listed for transplant have similar waitlist outcomes, including mortality, compared with other pretransplant populations [35,36]. A number of treatment interventions should be considered to provide some HCM patients the opportunity to survive to transplant, including primary prevention ICD therapy, inotropic therapy, and, in select patients with greater LV chamber diameter, LV assist device [35]. Outcomes for patients with HCM who undergo cardiac transplantation appear as good as, if not better than, transplant recipients with other etiologies of cardiomyopathy [35,36]. In a review of 31,473 patients (including 661 with HCM) from the Scientific Registry of Transplant Recipients who underwent orthotopic heart transplantation between 1999 and 2016, one-year survival for patients with HCM was similar to patients with other nonischemic cardiomyopathies (91.6 versus 91.3 percent) and significantly better than patients with ischemic cardiomyopathy (91.6 versus 87.5 percent) [36]. At five years, patients with HCM had significantly better survival (82.5 percent) compared with patients with other nonischemic (77.2 percent) and ischemic (75.3 percent) etiologies.
Phenocopies of sarcomeric HCM — Increased LV wall thickness in a pattern similar to that observed in sarcomeric HCM has also been observed in other diseases associated with mutations in genes related to carbohydrate metabolism, PRKAG2 and LAMP2 [37,38]. Although these disorders share a similar morphologic expression as patients with sarcomeric HCM, they also have some unique features and different natural history. Progressive conduction system disease requiring pacemaker implantation is common with PRKAG2 mutations [37], while progression to end-stage HF and increased risk of VT in early adulthood is common in males (X-linked) with LAMP2 mutations [38].
The characteristics of these disorders are described separately. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing", section on 'PRKAG2 and LAMP2 genes' and "Lysosome-associated membrane protein 2 deficiency (glycogen storage disease IIb, Danon disease)".)
Approximately 25 percent of Noonan patients have increased LV wall thickness similar to the pattern of hypertrophy observed in patients with sarcomeric HCM, while Fabry disease may also mimic HCM. Screening for Fabry disease among patients with suspected HCM is discussed separately. (See "Fabry disease: Cardiovascular disease".)
SYMPTOMS — The majority of clinically identified patients with HCM have no or minor symptoms [39]. Thus, affected children and adolescents are often diagnosed during family screening. Patients who are asymptomatic, or have minor symptoms, have a better prognosis than those with more severe symptoms. (See 'Risk factors' below.)
Patients with mild to moderate limitation may have a stable clinical course with effective therapy, or may experience slow progression of symptoms with advancing age. Typical symptoms include dyspnea, chest pain, syncope, and palpitations. An in-depth discussion of the clinical manifestations of HCM is presented separately. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation".)
DISEASE-RELATED COMPLICATIONS — The major disease-related complications of HCM are ventricular arrhythmias leading to sudden death, chest pain, progressive HF symptoms or HF death, atrial arrhythmias including atrial fibrillation, and embolic stroke [33].
Mortality — In series published in the 1980s, the annual mortality of patients with HCM in referral center populations was 4 to 6 percent per year [40-44]. However, lower annual mortality rates have been observed in more recent series from large unselected HCM patient populations (approximately 1 percent or less per year) [39,45-52]. In a report from a referral population of 312 patients, 73 (23 percent) lived at least 75 years [53]. HCM can now be considered a disease compatible with normal life expectancy for the vast majority of patients with this disease.
The most comprehensive contemporary data come from a review of 956 adults (mean age 42) seen between 1988 and 2002; the outcomes were compared with those in natural history studies published between 1960 and 2003 [54]. The following findings were noted:
●The annual rates of HF death or transplantation and stroke-related deaths were 0.55 and 0.07 percent, respectively.
●Published sudden death rates over the last 10 years of the study were lower than in previously published reports (median 1 versus 2 percent).
●The more recent studies were larger and included less severely affected patients as manifested by fewer patients with New York Heart Association (NYHA) class III or IV HF (table 1) and fewer patients who underwent septal myectomy.
Similar outcomes have been reported in younger patients. Among a cohort of 474 patients younger than 30 years of age at presentation (mean age 20.2 years) who were evaluated at two referral centers between 1992 and 2013, the annual HCM-related mortality rate was 0.54 percent per year over an average of 7.1 years of follow-up [50]. Additionally, 63 patients (13 percent of cohort; 1.8 percent per year) had aborted life-threatening events (including appropriate ICD interventions, resuscitated sudden cardiac arrest, or heart transplant).
The major causes of death in HCM are SCD, HF, and stroke [48,54]. In a review of 744 consecutive and largely unselected patients, 51 percent of deaths were due to SCD, 36 percent were due to progressive HF, and 13 percent were due to stroke associated with atrial fibrillation [48]. SCD was most common in young patients, while death from HF or stroke occurred more frequently in midlife and beyond. Advanced HF has emerged as a significant problem in more patients with HCM due to the improvements in SCD risk stratification in clinical cardiology practice [51].
In a series of 428 HCM patients presenting at age ≥60 years and followed for close to six years, risk was low for disease related morbidity and mortality, including sudden death (even with conventional risk factors). Non-HCM related co-morbidities have a greater impact on survival once HCM patients achieve older age [14].
One retrospective report from European centers showed an increase in life-long mortality associated with HCM. Among 4893 patients with HCM followed for a median follow-up of over six years, 14.7 percent reached the composite endpoint of all-cause mortality, aborted sudden death, or heart transplant [55]. Compared with survival of an age-matched group without HCM, survival was less among patients with HCM over time. However, this study included patients beginning in 1980, prior to the introduction of many contemporary risk stratification and treatment therapies such as the risk stratification algorithm and ICD for SCD prevention, and invasive septal reduction therapies including alcohol septal ablation and contemporary surgical techniques for myectomy.
Risk factors — As noted, patients with HCM have an increased risk of death from several causes (SCD, HF, and stroke). The following discussion will review factors associated with overall mortality in HCM patients. Because of their potential impact on the decision to implant a cardioverter-defibrillator, risk factors have also been evaluated for their specific association with SCD. This issue discussed in detail separately. (See "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death", section on 'Risk stratification'.)
Age at diagnosis — The excess death rate appears to vary with the age of the patient at diagnosis.
●Among 1085 patients with idiopathic HCM (not associated with another syndrome) who were enrolled in the Pediatric Cardiomyopathy registry between 1990 and 2009, the risk of death or cardiac transplantation after two years of follow-up was markedly and significantly higher for patients diagnosed prior to one year of age (21 percent compared with 3 percent for patients diagnosed after age one year) [56].
●In a review of 277 outpatients who were followed for eight years, the mean age of death from HCM was 56 years [39]. The annual mortality compared with the general population was substantially increased in those identified during childhood (1.3 versus 0.08 percent) but not in those identified in adulthood (2.2 versus 1.9 percent).
●Similar data on survival in adults were noted in a series from the Mayo Clinic in which 37 patients with HCM and a mean age of 59 years had one and five year survival rates (95 and 92 percent) that did not differ from an age and sex matched population without HCM [47]. However, some mutations associated with late onset disease do not have a benign course [19]. (See 'Late onset disease' above.)
Females — HCM is underdiagnosed in females [57,58]. In addition, females are often diagnosed later than males and with more advanced symptoms at the time of diagnosis [57-60]. Females do not appear to be at greater risk for sudden death or other adverse disease-related events compared with males with HCM [48,57,60]. There are mixed data on the impact of sex on overall survival, with some data suggesting higher overall mortality in females but other data suggesting no difference in mortality between males and females [58,59].
Symptom status — The presence of symptoms in patients with HCM is associated with worse outcomes compared with asymptomatic patients with HCM [39,53,61-63]. In the above report of 277 outpatients, 90 percent were asymptomatic at presentation; during the eight year follow-up, 69 percent remained asymptomatic or had only mild symptoms, while 25 percent had incapacitating symptoms or died [39]. Factors that increased the likelihood of HCM-related death included advanced symptoms at diagnosis; other adverse risk factors were atrial fibrillation associated with an embolic stroke, basal outflow obstruction ≥30 mmHg, and marked LV hypertrophy >25 mm. Similar findings were noted in a series of 128 adults with HCM (followed for 9 to 11 years), among whom the 58 patients who were asymptomatic at presentation had a lower annual cardiac mortality than those with symptoms (0.9 versus 1.9 percent) that was entirely due to a lower annual rate of sudden death (0.1 versus 1.4 percent) [61].
Many patients who report a lack of symptoms or only minimal symptoms may actually be limiting activity (consciously or unconsciously) to avoid the development of symptoms. Among a single-center cohort of 426 asymptomatic or minimally symptomatic patients with HCM who underwent exercise stress echocardiography, 82 percent of patients failed to reach their age-predicted metabolic equivalents (METs) during exercise stress testing [64]. During an average follow-up of 8.7 years, the risk of death, appropriate ICD shock, or HF admission was significantly lower for patients who achieved greater workloads during exercise (1 percent in patients achieving >100 percent age-predicted METs versus 12 percent in patients who achieved <85 percent of age-predicted METs). (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on 'Exercise testing'.)
Not surprisingly, the mortality risk is markedly increased in patients who develop severe symptoms (NYHA class III or IV), (table 1). (See 'Heart failure' below.)
Obstruction — Regardless of the presence of symptoms, LV outflow tract (LVOT) obstruction at rest that is ≥30 mmHg is an independent predictor of progressive HF symptoms, HF, and stroke death in patients with HCM. In a multicenter study of 1101 patients with HCM, 273 (25 percent) had LVOT obstruction at rest with a peak gradient ≥30 mmHg [62]. At a mean follow-up of six years, 127 patients (12 percent) died, and 216 surviving patients (20 percent) had progression to NYHA class III or IV HF (table 1). After adjusting for age, sex, HF at entry, presence of atrial fibrillation, and LV wall thickness ≥30 mm, patients with LVOT obstruction had a higher rate of HCM-related mortality (relative risk 1.6, 95% CI 1.1-2.4).
A subsequent report of 526 consecutive patients with HCM, 141 of whom (27 percent) had LVOT obstruction, noted that the prognostic value of LVOT obstruction varied with the severity of symptoms during mean follow-up of 4.5 years [63]. At initial evaluation, LVOT obstruction was a significant predictor of mortality among patients with no or mild symptoms at presentation (adjusted HR 2.4). However, after the onset of severe symptoms, NYHA functional class becomes the dominant marker of prognosis, independent of the LVOT gradient.
Pharmacologic therapy (eg, beta blockers) can improve symptoms due to LVOT obstruction. Nonpharmacologic approaches (eg, surgical myectomy and nonsurgical septal ablation) are warranted in patients with NYHA class III/IV limiting symptoms (table 1) despite maximum tolerated drug therapy, and they are highly effective at improving functional limitation and restoring quality of life by abolishing outflow gradients. (See "Hypertrophic cardiomyopathy: Management of patients without outflow tract obstruction" and "Hypertrophic cardiomyopathy: Management of patients with outflow tract obstruction".)
Coronary disease and stress-induced ischemia — The adverse effect of coronary artery disease (CAD) on prognosis in HCM was illustrated in a study of 433 adult patients [65]. Severe CAD was defined as the presence of a single luminal stenosis of ≥50 percent in the left main coronary artery, ≥70 percent in other major epicardial branches, or two stenoses of ≥50 percent. Ten-year overall survival was 46 percent, 71 percent, and 77 percent for patients with severe, mild-to-moderate, and no coronary artery disease, respectively. The risk of death with severe CAD and HCM far exceeds historical death rates of CAD patients with normal LV function (eg, 12-year survival of 73 percent in the CASS registry) [66]. In addition, the presence of coexistent CAD in patients who died suddenly without HCM risk factors suggests that this particular comorbidity is prognostically important, although selection bias in the data makes it difficult to draw definitive conclusions regarding the impact of these risk factors on each other [67].
In HCM, exercise testing provides an objective measure of the patient's physical limitations and exercise stress testing can detect important abnormalities such as arrhythmia, exercise-induced hypotension, or ischemia. Marked (>5mm) ST segment depression is common in HCM patients due to microvascular ischemia and therefore is not specific for detection of obstructive epicardial CAD. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on 'Exercise testing'.)
Stress-induced ischemia is associated with an increased risk of cardiac events and perhaps reduced survival [68-70]. If often occurs in the absence of significant angiographic CAD in patients with HCM and may reflect coronary microvascular dysfunction [27,28,71].
In a series of 158 older HCM patients (age 18 to 88) who were referred for stress testing with nuclear imaging, the nuclear images were abnormal (with fixed and/or reversible defects) in 62 percent of patients and, of 47 patients who underwent coronary angiography after rMPI, only 10 had significant CAD [68]. Ten-year survival was significantly lower in those with abnormal (with fixed and/or reversible defects) SPECT images (67 versus 90 percent with a normal test) and in those with reversible defects (64 versus 90 percent without reversible defects). Given the low specificity for nuclear imaging to detect significant CAD in patients with HCM, CT angiography or coronary catheterization should be considered if a patient's pretest probability of CAD is moderate to high.
Heart failure — Progression to NYHA class III or IV HF (table 1) occurs in a minority of patients with HCM and is most often due to LVOT obstruction [19,62,63]. Among 4591 patients from the Sarcomeric Human Cardiomyopathy Registry (SHaRe) who were followed for a mean of 5.4 years, 22 percent developed HF (although no data were presented regarding how many of these patients with advanced HF had outflow obstruction nor were treatments associated with advanced HF due to marked obstruction, including septal myectomy or alcohol septal ablation, noted) [72]. Progression to severe HF symptoms is associated with a marked increase in cardiovascular mortality, particularly for HCM patients without LVOT obstruction. In different observational studies, patients with obstruction had a higher rate of progression to NYHA class III or IV or death from HF or stroke (relative risk 2.7, 95% CI 2.0-3.5) [62]. For patients with LVOT obstruction who progress to NYHA class III/IV, relief of obstruction with myectomy or alcohol septal ablation is associated with substantial improvement in symptoms and normal life expectancy.
It has been estimated that mortality in HCM is due to progressive HF in approximately one-third of patients, the majority of whom have the non-obstructive form of the disease [48]. Some patients develop a clinical picture similar to a dilated cardiomyopathy. Alternative diagnoses should always be considered when LV systolic dysfunction is seen together with significant hypertrophy. Amyloid cardiomyopathy and primary metabolic disorders such as Fabry disease, glycogen storage disease, and mitochondrial disease may present with these findings. (See 'Mortality' above and 'HCM with LV systolic dysfunction (ejection fraction <50 percent)' above and 'Phenocopies of sarcomeric HCM' above and "Heart failure: Clinical manifestations and diagnosis in adults".)
Treatment in these patients is the same as for any patient with systolic dysfunction, although there are no long-term data on the efficacy of angiotensin converting enzyme inhibitors or other vasodilators in HF associated with HCM. Patients with NYHA class III/IV symptoms refractory to medical therapy and obstruction ≥50 mmHg (at rest or with provocation) are candidates for invasive septal reduction therapy with surgical myectomy or alcohol septal ablation [73,74]. (See "Hypertrophic cardiomyopathy: Management of patients with outflow tract obstruction" and "Overview of the management of heart failure with reduced ejection fraction in adults".)
Arrhythmias — HCM is associated with both atrial and ventricular arrhythmias (figure 3). These issues are discussed in detail separately. (See "Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation" and "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death".)
Obesity — The prevalence of obesity is increased in HCM and associated with increased adverse disease-related complications including greater symptom burden and risk for progressive HF, as well as atrial fibrillation, compared with patients with normal weight [75]. There is no association between obesity and increased risk for sudden death in HCM. Whether weight reduction decreases these risks remains uncertain, but it would be prudent for HCM patients to engage in strategies for weight loss to achieve goal body mass index.
Stroke — Stroke and systemic embolic events are known complications of HCM, but there are few data about frequency and predictors of occurrence [76,77].
●Stroke and systemic embolic events were examined in a community-based cohort of 900 patients followed for 7.7 years [76]. The prevalence rate of stroke or peripheral embolization was 6 percent (incidence 0.8 percent per year); 41 percent of patients with a stroke died or were permanently disabled. Most of the events (72 percent) occurred in patients over age 50 and, in those over age 60, the incidence was 1.9 percent per year. With a multivariate analysis, embolic events were also associated with atrial fibrillation, which was present in 88 percent of those who had a stroke, and congestive symptoms. In spite of the relative paucity of data, expert opinion is generally to have a low clinical threshold to initiate anticoagulation for stroke prophylaxis in patients with HCM and atrial fibrillation due to the high observed risk of stroke.
●Similar findings were reported from a Japanese cohort of 593 patients with HCM (including 431 without known atrial fibrillation at baseline) who were followed for an average of 10.7 years, during which time the stroke/systemic embolic event rate was 1 percent per year [77]. Older age and larger left atrial size were markers of greater risk of stroke among patients without identified atrial fibrillation.
Infective endocarditis — Antibiotic prophylaxis was recommended in the past in HCM patients with outflow gradients and/or mitral valve abnormalities. However, the 2007 American Heart Association guideline for the prevention of infective endocarditis made major revisions, including the recommendation that prophylaxis is NOT indicated in patients with HCM with latent or resting obstruction or mitral valve disease [78]. (See "Prevention of endocarditis: Antibiotic prophylaxis and other measures".)
Infective endocarditis appears to be uncommon in HCM. Among a large, referral-based cohort with HCM, only 30 patients were diagnosed with infective endocarditis over an 11-year period (2006 to 2016), occurring equally in patients with and without LVOT obstruction and with similar rates of mitral and aortic valve involvement [79]. While embolic complications occurred in 10 patients (33 percent) and 11 patients (37 percent) required surgery, one-year mortality was low (7 percent).
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Hypertrophic cardiomyopathy in adults (The Basics)" and "Patient education: Hypertrophic cardiomyopathy in children (The Basics)")
●Beyond the Basics topic (see "Patient education: Hypertrophic cardiomyopathy (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Development of hypertrophy – Phenotypic expression of hypertrophic cardiomyopathy (HCM) with left ventricular hypertrophy (LVH) usually occurs during adolescence with wall thickness measurements that remain stable throughout life in the majority of patients. However, early onset disease in HCM can occur in infancy and early childhood, and late-onset disease occurring in mid-life has also been recognized. (See 'Development of hypertrophy' above.)
●Heart failure symptoms – Progression to New York Heart Association (NYHA) class III or IV HF (table 1) occurs in a minority of patients with HCM and is most often associated with LV outflow tract obstruction (LVOT; ≥30 mmHg). Progression to severe HF symptoms is associated with a marked increase in cardiovascular mortality, particularly in nonobstructed HCM patients. In patients with obstruction and class III/IV symptoms, relief of the gradient is associated with substantial improvement in HF symptoms and normal longevity. (See 'Heart failure' above.)
●Arrhythmias – HCM is associated with an age-related increase in the prevalence of supraventricular arrhythmias, particularly atrial fibrillation. (See "Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation".)
●Diastolic dysfunction – Patients with nonobstructive HCM with preserved systolic function (LVEF ≥50 percent) may also develop advanced HF symptoms due to low cardiac output syndrome related to impaired LV filling. Such patients who develop significant functional limitation despite medical therapy, usually in the absence of adverse LV remodeling, should undergo consideration for heart transplant. In a subgroup of these patients, traditional objective transplant measures with peak VO2 are not present. In select patients, additional therapeutic interventions should be considered as a bridge to transplant, including primary prevention implantable cardioverter-defibrillator (ICD), intravenous inotropic drugs, and LV assist device. (See 'Nonobstructive with preserved systolic function (ejection fraction ≥50 percent)' above.)
●End-stage hypertrophic cardiomyopathy – A small proportion of patients with HCM (<5 percent) will develop the high-risk phenotype of HCM with LV systolic dysfunction, associated with reduced systolic function (LV ejection fraction [LVEF] <50 percent). In some cases, there is relative LV dilation and wall thinning, with greater resemblance to the morphologic and functional features of dilated cardiomyopathy. HCM with LV systolic dysfunction raises consideration for aggressive therapy, including consideration for primary prevention ICD, conventional heart failure (HF) therapy, and early consideration for transplant evaluation. (See 'HCM with LV systolic dysfunction (ejection fraction <50 percent)' above.)
●Heart transplantation – Patients with HCM with LV systolic dysfunction, as well as those with preserved systolic function (LVEF ≥50 percent) who develop advanced HF symptoms despite drug therapy, may be candidates for transplant. Extent of functional limitation and other important results from objective testing, including cardiopulmonary exercise testing and invasive hemodynamics, support transplant listing in HCM. Mortality on transplant list for patients with HCM is similar to non-HCM causes of HF, although outcomes for patients with HCM who undergo cardiac transplantation appear as good compared with transplant recipients with other etiologies of cardiomyopathy. (See 'Heart transplant' above.)
●Risk of mortality – HCM is compatible with normal life expectancy for the majority of patients, with annual mortality rates of referral-based HCM populations of 1 percent, with the major causes of death being sudden cardiac death (SCD), HF, and stroke. SCD is more common in young patients, while death from HF or stroke is more common in mid-life and beyond. (See 'Mortality' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Perry Elliott, MD, who contributed to earlier versions of this topic review.
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
