Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death

INTRODUCTION — Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease caused by mutations in one of several sarcomere genes that encode components of the contractile apparatus of the heart. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing".)

HCM is characterized by left ventricular (LV) hypertrophy of various morphologies, with a wide array of clinical manifestations and hemodynamic abnormalities (figure 1). Depending in part upon the site and extent of cardiac hypertrophy, patients with HCM can develop one or more of the following abnormalities:

●LV outflow obstruction. (See "Hypertrophic cardiomyopathy: Morphologic variants and the pathophysiology of left ventricular outflow tract obstruction".)

●Diastolic and systolic dysfunction.

●Myocardial ischemia.

●Mitral regurgitation.

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 are prone to both atrial and ventricular arrhythmias. Many of these arrhythmias are asymptomatic, but some can precipitate hemodynamic collapse and sudden cardiac death (SCD). SCD is a catastrophic and unpredictable complication of HCM and in some patients may be the first presentation of the disease.

The assessment of risk for arrhythmic SCD is a critical component of the clinical evaluation of nearly all patients with HCM and will be reviewed here. The management of patients following risk assessment and following a documented ventricular arrhythmia is discussed separately. (See "Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk".)

Other issues related to ventricular arrhythmias and SCD, as well as other clinical manifestations, natural history, diagnosis and evaluation, and treatment of patients with HCM, are discussed separately. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation" and "Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation" and "Hypertrophic cardiomyopathy: Natural history and prognosis" and "Hypertrophic cardiomyopathy: Management of patients without outflow tract obstruction" and "Hypertrophic cardiomyopathy: Management of patients with outflow tract obstruction".)

EPIDEMIOLOGY — Ventricular arrhythmias are common in patients with HCM and can range from isolated ventricular premature beats (VPBs) to nonsustained ventricular tachycardia (NSVT) to sustained VT and ventricular fibrillation. While the frequency of ventricular arrhythmias is highly variable, clinically documented sustained VT is relatively rare, with the annual incidence of sudden cardiac arrest (SCA) in clinically identified HCM referral populations being approximately 1 percent, with even lower reported rate in HCM patients in the general community [1-5].

The frequency of ventricular tachyarrhythmias detected by ambulatory monitoring in patients with HCM has been evaluated in a variety of studies [1,6-12]. As an example, in a study of 178 patients who underwent 24-hour ambulatory monitoring, VPBs were highly prevalent (seen in 88 percent; 12 percent had ≥500 VPBs) and NSVT was present in 31 percent [1]. However, there is no evidence to suggest that frequent VPBs are, by themselves, indicative of an increased risk of sustained ventricular arrhythmia. This is similar to other forms of heart disease in which treatment of VPBs alone is warranted only in symptomatic patients. (See "Premature ventricular complexes: Treatment and prognosis".)

Other studies have shown lower rates of NSVT (typically asymptomatic), with ranges of 15 to 31 percent of patients with HCM [1,6-8]. NSVT is more likely in older patients and is associated with greater LV wall thickening and New York Heart Association (NYHA) class III or IV symptoms (table 1). Episodes are most frequent during sleep and other periods of heightened vagal tone.

The prevalence of NSVT is less common in young patients (<40 years old) with HCM, and therefore when present is of greater predictive value for SCD than when it occurs in older patients. Among one cohort of 428 patients ≥60 years of age with HCM, the risk of arrhythmic SCD was 0.2 percent per year, lower than the younger HCM population and significantly lower than the risk of non-HCM-related death [13].

PATHOGENESIS OF ARRHYTHMIAS — An abnormal myocardial substrate comprised of myocyte disarray (picture 1), interstitial fibrosis, and replacement fibrosis provides the likely structural nidus for the generation of ventricular arrhythmias in patients with HCM. This substrate can be acted upon by potential triggers and/or modifiers, including myocardial ischemia, LV outflow tract obstruction, and abnormal vascular response with inappropriate vasodilatation, as well as the impact of high adrenergic states (eg, during competitive sports, etc) that can lower the threshold for initiating VT/ventricular fibrillation.

CLINICAL MANIFESTATIONS — The presentation of ventricular arrhythmias in patients with HCM is highly variable, ranging from an absence of symptoms to palpitations to SCA, but in general the presentation of ventricular arrhythmias is similar to their presentation in other types of patients without HCM.

●Most patients with ventricular premature beats (VPBs) or nonsustained VT (NSVT) will be asymptomatic or have intermittent palpitations.

●Sustained VT most often results in palpitations, presyncope, or syncope.

●SCA, although rare, can be the initial presentation of sustained VT or ventricular fibrillation (VF).

More detailed discussions of the presenting symptoms of VPBs, NSVT, sustained VT, and VF are discussed elsewhere. (See "Premature ventricular complexes: Clinical presentation and diagnostic evaluation", section on 'Symptoms' and "Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management", section on 'History and associated symptoms' and "Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation", section on 'History and associated symptoms'.)

EVALUATION — Since the underlying abnormal myocardial substrate in HCM can evolve over time, nearly all patients with known or suspected HCM should undergo serial evaluations assessing SCD risk every 12 to 24 months, particularly young and middle-aged HCM patients who were previously considered low or intermediate risk, but who still remain eligible for primary prevention implantable cardioverter-defibrillator (ICD) therapy [14]. Such evaluations should include the following (see "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on 'Diagnostic evaluation'):

●History and physical examination.

●Interim family history, with emphasis on any relatives with SCD, syncope, or ICD placement, as well as any new diagnoses of HCM.

●Echocardiography.

●24- to 48-hour ambulatory electrocardiographic (ECG) monitoring. Although the benefit of performing longer-term ambulatory monitoring initially to identify nonsustained ventricular tachycardia (NSVT) can be considered, this strategy has not been systematically evaluated.

●Exercise (stress) echocardiography testing at initial evaluation to assess for symptoms, provoked LV outflow tract (LVOT) obstruction, arrhythmias, myocardial ischemia, and blood pressure (BP) response. Exercise testing is not generally repeated on an annual basis, unless warranted by the presence of new limiting symptoms, for the purpose of evaluating for a provoked LVOT gradient.

●Cardiac magnetic resonance (CMR) imaging. Our experts have differing approaches to utilizing CMR in HCM, with currently no clear consensus on how to best apply this advanced imaging technique for HCM diagnosis. Some experts proceed with CMR only when diagnosis of HCM remains uncertain following echocardiography while other experts perform CMR in all patients with suspected or diagnosed HCM to most reliably assess LV morphology, including maximal LV wall thickness, as well as to further inform risk stratification with assessment of extent of late gadolinium enhancement. (See 'Risk stratification' below.)

In a patient who has an ICD, tests for the purpose of risk stratification of sudden death (eg, ambulatory monitoring for NSVT and exercise testing to assess BP response) are not typically repeated.

RISK STRATIFICATION — Patients with HCM have an increased risk of death from several causes, including SCD, HF, and stroke. Established major risk factors and risk modifiers for SCD include:

●Prior cardiac arrest or sustained ventricular arrhythmias

●Family history of first-degree or close relative <50 years of age with SCD judged definitely or likely due to HCM

●Recent syncope suspected to be arrhythmic in origin

●Massive LV hypertrophy (LVH) ≥30 mm anywhere in LV wall

●LV apical aneurysm of any size

●End-stage HCM with LV ejection fraction (LVEF) <50 percent

Risk modifiers include:

●Late gadolinium enhancement on cardiac magnetic resonance imaging

●Patient Age

●Multiple bursts of NSVT on ambulatory monitoring

These established risk factors have greatest weight in young and middle age patients, but risk stratification for SCD should still be performed in all patients with HCM, independent of symptoms or hemodynamic status. The risk factors associated with SCD have also been evaluated for their more general association with overall mortality and outcomes. Several society guidelines for HCM as well as ventricular arrhythmias and SCD have outlined the risk factors for SCD in patients with HCM (figure 2) [3,6,14-18]. (See "Hypertrophic cardiomyopathy: Natural history and prognosis", section on 'Mortality'.)

Prior arrhythmic events — Patients with HCM who are at the highest risk of SCD are those with prior SCA or sustained ventricular tachyarrhythmias [14]. In the absence of a clearly identifiable and reversible cause for SCD, such patients do not require additional risk stratification and should undergo implantation of an ICD for secondary prevention of SCD. (See "Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk", section on 'Implantable cardioverter-defibrillators (ICDs)'.)

Established major risk markers — Because ventricular arrhythmias can be life-threatening, the ability to identify patients at high risk for SCD due to ventricular arrhythmias is critical among patients with HCM. Retrospective observational cohort studies have demonstrated that the presence of ≥1 of the major risk factors is associated with an elevated SCD risk, and it is reasonable to consider primary prevention ICD therapy (table 2) after taking into account the overall clinical profile of the individual patient, including age and the benefits and risks of long-term device therapy. (See "Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk", section on 'Implantable cardioverter-defibrillators (ICDs)'.)

The major risk factors for SCD that are most commonly cited include the following (table 3) [3,14-16,19]:

●Family history of SCD – A family history of HCM-related SCD is associated with an increased risk of SCD in other affected family members [20,21]. This risk is particularly high if there are multiple SCD events in one family, and if the events occurred in younger patients [20,21]. In a report of 41 relatives from eight families, 31 (75 percent) died from their heart disease, including 18 before 25 years of age, 23 with SCD, and in 15 of these 23 patients, SCD was the initial manifestation of the disease [21].

Families with multiple sudden deaths under the age of 40 years, however, are uncommon (approximately 5 percent), whereas a single sudden death is seen in up to 25 percent of families, but is of low positive predictive accuracy (<15 percent) [6,22].

●Syncope – Syncope, if it is not clearly attributable to another cause (eg, neurocardiogenic syncope), is a risk factor for SCD in patients with HCM [6,23]. The predictive power for syncope is greatest when it occurs in relatively close proximity to the clinical evaluation (<6 months) and in young patients. Its predictive strength is significantly less when the event has occurred remote to the time of visit and/or it has occurred in older patients [23]. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation".)

●Massive LVH – LV wall thickness ≥30 mm is seen in approximately 10 percent of patients with HCM and is associated in the majority of studies with an increased risk of SCD, particularly in patients less than 30 years of age [24-28]. The positive predictive value of massive LVH, however, is relatively low [24,25], although expert opinion would support strong consideration for ICD if massive LVH is confirmed, particularly in young patients [26].

Both echocardiography and cardiac magnetic resonance (CMR) imaging are used in clinical practice to determine maximal wall thickness [29]. One report from a large HCM referral center suggested a discrepancy between echocardiography and CMR imaging in the classification of massive LVH in 70 percent of patients (44 of 63 patients), with massive LVH identified more commonly on CMR (83 versus 48 percent) [30]. However, the data pertaining to increased sudden death risk in patients with HCM and massive LVH are derived from echocardiographic studies. For this reason, we recommend that if massive LVH (≥30 mm) is identified by echocardiography, using reliable measurements, the patients should be considered high risk with consideration of primary prevention ICD therapy. In patients with echo-derived measurements that are <30 mm but in whom CMR demonstrates massive LVH (echocardiography underestimated wall thickness), it would be reasonable to consider an increased risk for SCD as well, with consideration given to placement of an ICD for primary prevention.

The relation of massive LVH and sudden death has been highlighted in a number of studies:

•In a single-center referral population of 1766 patients with HCM, including 92 with massive LVH, who were initially seen between 2004 and 2015 and followed for an average of 5.3 years, SCD events were significantly more common in patients with massive LVH (3 versus 0.8 percent per year) [31].

•In a study of 480 patients, including 43 with massive LVH, who were followed for a mean of 6.5 years, the risk of SCD was zero for a wall thickness ≤15 mm, compared with 1.8 percent per year for a wall thickness ≥30 mm; the incidence of SCD almost doubled for each 5 mm increase in wall thickness (figure 3) [24]. The cumulative risk 20 years after the initial diagnosis was close to 0 for those with a thickness ≤19 mm, compared with 40 percent for a wall thickness ≥30 mm.

•In a similar study of 630 patients, maximal wall thickness ≥30 mm was associated with sudden death, but only in the cohort who had an additional risk factor (ie, adverse family history, NSVT on Holter, syncope, or abnormal BP response on exercise) [25].

●LV apical aneurysm – Patients with HCM who have an LV apical aneurysm include a cohort in whom the risk of life-threatening arrhythmia appears increased [29,32,33]. Patients with HCM and LV apical aneurysm constitute a small number of patients, with outcome data supported by a small number of observational studies. Therefore, decisions regarding high-risk status should be considered on an individual basis, taking into consideration the entire clinical profile of the patient.

Thin-walled apical aneurysms are almost always associated with transmural scar (ie, apical late gadolinium enhancement [LGE]), which represent a structural nidus for the generation of sustained monomorphic VT. Apical aneurysms most notably occur in association with midventricular hypertrophy, which often produces mid-cavitary obstruction resulting in high apical systolic pressures, which likely promotes the adverse LV remodeling that ultimately develops into a thin-walled scarred akinetic apex. Patients with apical aneurysms often come to medical attention because of the dramatically abnormal ECG with precordial ST segment elevation and giant T wave inversions, most notably in leads V3 and V4, a similar ECG pattern to HCM patients with only hypertrophy at the apex (without aneurysm). This phenotype is distinct from HCM patients with increased wall thickness confined to the apex, without associated wall thinning (ie, apical HCM). (See "Hypertrophic cardiomyopathy: Morphologic variants and the pathophysiology of left ventricular outflow tract obstruction", section on 'Apical HCM'.)

Among a cohort of 1940 consecutive patients with HCM seen at one of two high-volume referral centers and who underwent echocardiography with LV opacification and/or CMR, 93 patients (4.8 percent) were found to have an LV apical aneurysm [33]. Of the 54 patients who received an ICD for primary prevention, 18 patients (33 percent) experienced a life-threatening ventricular arrhythmia requiring ICD intervention, resulting in an arrhythmic event rate of 4.7 percent per year (compared with 0.9 percent per year in the patients without an LV apical aneurysm), with no difference in the risk of SCD based on the size of the aneurysm. In contrast to the general population of patients with HCM without an apical aneurysm, risk of SCD persists into the seventh decade of life (and beyond) among patients with HCM and LV apical aneurysm. In one cohort of 118 such patients, 36 percent of SCD (and aborted SCD) events occurred in patients ≥60 years of age [34].

In addition, patients with HCM with apical aneurysm represent the only subgroup of patients with HCM in whom radiofrequency ablation appears successful at treating life-threatening recurrent VT. In this series, recurrent VT requiring ≥2 ICD shocks occurred in 13 patients, of which six underwent radiofrequency ablation with no recurrence of VT. Of note, the high-risk phenotype of HCM with apical aneurysm stands in contrast to apical HCM patients who, in the absence of any of the conventional sudden death risk factors, are in fact at low risk for experiencing life-threatening VT/VF. (See "Hypertrophic cardiomyopathy: Morphologic variants and the pathophysiology of left ventricular outflow tract obstruction", section on 'Apical HCM' and "Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk", section on 'Implantable cardioverter-defibrillators (ICDs)' and "Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk", section on 'Catheter ablation'.)

●End-stage with LVEF <50 percent — A small proportion of patients with HCM (<5 percent) eventually progress to a stage of disease associated with adverse LV remodeling with reduced systolic performance (LVEF <50 percent). This phase has been termed "end-stage" or "burned out" HCM. Once end-stage HCM develops, further deterioration is progressive in a subset of patients, with death from progressive HF, SCD, or the need for heart transplantation. With conventional cardiovascular therapies, some end-stage patients can experience a relatively benign course in which HF symptoms can remain stable over many years. (See "Hypertrophic cardiomyopathy: Natural history and prognosis", section on 'HCM with LV systolic dysfunction (ejection fraction <50 percent)'.)

Risk modifiers — Several other factors contribute to the overall SCD risk profile of patients with HCM:

●LGE on CMR imaging – LGE on CMR imaging is common in HCM and appears to represent the structural nidus for ventricular tachyarrhythmias in patients with HCM with myocardial fibrosis [35,36]. The presence and extent of LGE is associated with markers of disease severity, including the magnitude of LVH and the presence of nonsustained ventricular arrhythmias. How best to integrate LGE in HCM management strategies remains controversial, even among HCM experts. However, based on the totality of data evaluating LGE and outcomes in HCM, we suggest considering the results of contrast-enhanced CMR with LGE in assessing risk of SCD to provide a more complete evaluation of patients who may benefit from primary prevention ICD therapy. More data to inform this management issue will also be forthcoming following the completion of a Nation Institutes of Health (NIH)-funded study, Novel Markers of Prognosis in Hypertrophic Cardiomyopathy (HCMR), involving 40 centers and more than 2500 patients, anticipated to be completed over the next seven years [37].

In addition, there are a number of methods that have been used to quantify LGE in HCM, but there is no expert consensus on which technique should be universally employed in clinical practice. The lack of standardization with respect to the preferred strategy for quantification of LGE in HCM represents a challenge. The two most commonly employed methods to identify high-signal intensity LGE pixels in the LV wall include applying a grayscale threshold several standard deviations (five or six) above mean signal intensity within a region of "nulled" myocardium and the full-width at half maximum method. Both of these techniques are highly reproducible and reliably represent total fibrosis burden as demonstrated by histopathologic analysis of ventricular septal tissue removed in HCM patients undergoing surgical myectomy [38].

•In patients without any of the conventional SCD risk markers, the presence of extensive LGE on CMR may identify high-risk status and prompt consideration for primary prevention ICD therapy.

•In patients with HCM in whom risk assessment remains ambiguous or uncertain after assessment with the conventional risk factors, extensive LGE can be utilized as a potential arbitrator to help resolve difficult ICD decision-making, with extensive LGE swaying decision-making potentially toward ICD, and no (or minimal) LGE swaying decision-making potentially away from an ICD.

•The absolute amount of LGE is highly predictive of SCD. However, the pattern of LGE is more variable, with the only consistent LGE pattern observed in HCM being LGE confined to the right ventricular insertion point area, where it has been shown not to be associated with increased risk for SCD.

•Of note, decisions regarding device therapy in both of these clinical scenarios should be made in the context of a fully informed patient, taking into account the desires and wishes of the patient in a shared decision-making manner.

•In a cohort of 1293 patients with HCM who underwent CMR and were followed for a median of 3.3 years, LGE was present in 548 patients (42 percent), and the primary end point of SCD events (including SCD and appropriate ICD shocks for documented VT or VF) occurred in 37 patients (3 percent) [39]. Risk of SCD events increased with the amount of LGE present (adjusted hazard ratio 1.46 for each 10 percent increase in LGE, 95% CI 1.12-1.92), particularly among patients with apparent low risk based on the traditional clinical features. In addition, the absence of LGE was associated with lower risk and a source of reassurance for patients.

•In a 2018 cohort study from a single, high-volume referral center, which included 1423 adult patients (age ≥18 years) who underwent CMR between 2008 and 2015, 706 patients (50 percent) had LGE identified on CMR imaging [40]. LGE involving ≥15 percent of the myocardium was associated with a significantly greater risk of SCD or appropriate ICD therapy.

•In a 2016 meta-analysis, which included 2993 patients from five cohorts, the presence of LGE on CMR imaging was associated with significantly greater risk for total mortality (OR 1.8, 95% CI 1.2-2.7), cardiovascular mortality (OR 2.9, 95% CI 1.5-5.6), and SCD (OR 3.4, 95% CI 2.0-5.9) [41]. For every additional 10 percent of the myocardium affected by LGE, there was an incremental increase in total mortality of approximately 30 percent, with an incremental increase of nearly 60 percent in cardiovascular mortality, SCD, and HF death. Patients with LGE have also been shown to be more likely to have SCD or aborted SCD with an ICD shock [42].

●Age at time of SCD risk assessment – Risk of SCD is greatest in young patients with HCM (<30 years of age), and this risk decreases but is not eliminated through mid-life [20]. Patients with HCM who are >60 years of age are at a very low risk for any HCM-related adverse events, including SCD [13]. Indeed, risk of SCD in older patients is very low (<1 percent), even among those patients with one or more of the conventional risk factors [13,43,44]. Conversely, the presence of the major risk factors is of greater prognostic significance in young and middle-aged patients with HCM. The impact of age at HCM diagnosis on overall mortality risk (ie, in addition to SCD) is discussed separately. (See "Hypertrophic cardiomyopathy: Natural history and prognosis", section on 'Age at diagnosis'.)

●NSVT – The presence of multiple asymptomatic runs of NSVT (most commonly defined as ≥3 beats at >120 beats per minute) is associated with an increased risk for SCD in patients with HCM, although the effect of a patient's age plays a role in the associated risk [8-11,45]. Multiple bursts of NSVT are associated with increased risk, particularly in young patients and in patients with symptoms of impaired consciousness [1,7-10,46,47]. Although the data for relating characteristics of NSVT to SCD risk are scant, it would be reasonable to give greater weight to increased risk of SCD in patients with HCM with NSVT that is frequent, prolonged, and particularly fast, while a single, slow, short burst of NSVT on ambulatory monitoring is itself not associated with increased risk of future life-threatening VT/ventricular fibrillation (VF), and in the absence of any other conventional risk factors does not form the basis for primary prevention ICD. For patients with HCM and an ICD, NSVT is associated with an increased risk of appropriate ICD therapies for VT/VF [48].

•In a study of 178 adult patients with HCM aged 20 to 50 years who underwent 24-hour ambulatory ECG monitoring and were followed for an average of 5.5 years, NSVT was common (31 percent), with a relatively low annual sudden death rate (1.1 percent). In this cohort of older patients, there was a smaller increase in risk with NSVT (1.6 versus 0.9 percent per year in patients with and without NSVT, defined as ≥3 beats at 120 beats per minute) [1].

•In a series of 531 patients with HCM, of whom 104 had NSVT, the presence of NSVT was associated with an increased risk of SCD in patients less than 30 years of age (odds ratio [OR] 4.4 compared with no NSVT, 95% CI 1.5-12.3) [8]. There was, however, no relation among duration, frequency, or rate of NSVT episodes and prognosis at any age.

Uncertain risk modifiers — Several other clinical factors contribute in an uncertain way to the overall SCD risk profile of patients with HCM:

●Myocardial ischemia – There are conflicting data as to whether myocardial ischemia is a risk factor for SCD in patients with HCM. In a series of 23 young patients with HCM (age 6 to 23 years), ischemia was associated with a history of cardiac arrest or syncope [49]. In contrast, there was no relation between the presence of ischemia and outcomes in a larger prospective series of 216 unselected patients with HCM [50].

The relationship between ischemia and outcomes is likely dependent upon both the age of the patient and the etiology of ischemia (eg, severe small vessel-mediated ischemia versus atherosclerotic obstructive coronary artery disease [CAD]). Patients with HCM and coincident CAD have mortality rates that exceed those of CAD patients with normal LV function [51]. The impact of stress-induced ischemia on overall mortality risk (ie, in addition to SCD) is presented separately. (See "Hypertrophic cardiomyopathy: Natural history and prognosis", section on 'Mortality'.)

●Genotype – There appear to be high-risk genotypes for SCD, particularly related to troponin T disease and several of the beta myosin-heavy chain mutations [52]. However, the available data are derived from a small number of families and may be skewed on this basis [14,16]. Moreover, most mutations are novel (ie, "private mutations"), and thus a certain genotype may be associated with higher risk in a specific family but would not be associated with the same consequences in other unrelated patients and families. For this reason, clinical decisions about risk for sudden death and need for primary prevention ICD are not made based on the results of genetic testing. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing".)

●LV outflow tract (LVOT) gradient – The majority of natural history studies involving patients with HCM have failed to show an association between LVOT gradient and adverse prognosis [20,44,46,47,53]. Two large studies, however, have shown a weak association of LVOT gradients with overall disease-related mortality and sudden death [54,55]. The impact of LVOT obstruction on overall morbidity (ie, HF symptoms and risk for atrial fibrillation) is discussed separately. (See "Hypertrophic cardiomyopathy: Natural history and prognosis", section on 'Mortality'.)

•In a multicenter, multinational study of 1101 patients (273 [25 percent] with resting LVOT gradient ≥30 mmHg) followed for a mean of six years, the probability of HCM-related death and of SCD was slightly greater in those with LVOT gradient of at least 30 mmHg (relative risk [RR] 2) [55].

•In a single-center study of 917 patients (288 [31 percent] with resting LVOT gradient ≥30 mmHg) followed for a median of 61 months, survival free from mortality/transplant was significantly lower in patients with LVOT gradients (87 versus 90 percent), as was survival free from sudden death/ICD discharge (91 versus 96 percent) [54]. LVOT obstruction was independently associated with SCD, and there was a significant trend towards lower sudden death/ICD survival in patients with increasing LVOT obstruction.

The incidence of SCD in patients with obstruction also varies substantially based upon the number of additional risk factors (figure 4) [54]. For patients with an outflow gradient ≥30 mmHg but no additional risk factors, the annual incidence of SCD or ICD discharge was low.

There are also a number of practical limitations to using LVOT gradient as a clinical risk factor for sudden death. Gradients are present in large numbers of patients, which would ultimately lead to significant overtreatment with ICDs in this disease. Additionally, gradients can be abolished and/or significantly mitigated with drugs or invasive septal reduction therapy. Nonrandomized retrospective cohort studies suggest that risk of SCD or appropriate ICD shocks is very low following septal myectomy [56,57]. However, surgical myectomy in asymptomatic or mildly symptomatic patients is not indicated solely as a therapy to decrease sudden death risk. In contrast, septal ablation has not been demonstrated to reduce SCD or ICD discharge rates.

However, for those patients in whom risk remains ambiguous after assessment with the conventional sudden death risk factors, the presence of a high LVOT gradient can be used as a potential arbitrator to help resolve difficult ICD decision-making. (See "Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk", section on 'Nonpharmacologic treatment of LV outflow tract obstruction'.)

Impact of number of risk factors — It is reasonable to consider ICD in patients with one major risk factor, since SCD risk is increased. Decisions about high-risk status in patients with one risk factor should be individualized based on the strength of the specific risk factor and the individual patient situation. The presence of two or more risk factors for SCD is associated with even greater SCD risk. In patients in whom sudden death risk remains uncertain after assessment with the major risk markers or who are uncertain about pursuing ICD therapy, the presence of a risk modifier may be associated with additional sudden death risk and therefore may help resolve ICD decision-making.

Identification of high-risk patients may be improved by using multiple factors [6,54,58,59]. In a study of 368 patients (mean age 37 years) who were followed for a mean of 3.6 years, estimated six-year SCD-free survival was associated with the number of risk factors (figure 5) [6]:

●Zero risk factors (55 percent of the cohort) – 95 percent survival

●One risk factor (33 percent of the cohort) – 93 percent survival

●Two or three risk factors (12 percent of the cohort) – 72 percent survival

Data from a multicenter registry of ICDs in patients with HCM published in 2007 suggested that a single risk factor may be sufficient justification for consideration of ICD implantation [60]. Subsequently, in a 2019 single-center study of 2094 consecutive patients evaluated over a 17-year period at a tertiary HCM referral center, 527 patients were implanted with a primary prevention ICD based on clinical evaluation and the presence of one or more high-risk markers [61]. Cumulative five-year likelihood of appropriate ICD intervention was 10.5 percent, with 82 primary prevention ICD recipients (15.6 percent) experiencing VT or VF requiring ICD therapy, whereas only five patients (0.3 percent) without an ICD experienced SCD (including two patients in whom primary prevention ICD was declined by the patient).

Data in low-risk patients are limited, but those meeting the following profile probably have an incidence of SCD of <0.5 percent per year [14,16,62]:

●None of the five major risk factors

●No or only mild symptoms of HF

●Left atrium ≤45 mm

●LV wall thickness <20 mm

●LV outflow gradient <50 mmHg

Risk prediction model — While the risk of SCD in patients with HCM can be estimated from large populations, individualized risk prediction offers the hope of the most accurate risk assessment and appropriate interventions. Given the complexity of SCD risk assessment in patients with HCM and the mixed data on the HCM Risk-SCD calculator, we feel that additional studies are warranted to further validate and refine this risk model in other HCM populations, along with the need for additional comparisons with the current United States guideline-based approach using a number of noninvasive risk markers [63,64]. As with risk prediction in any situation, the ability to discriminate patients with HCM at risk of SCD has been most successful in patients deemed at higher risk.

In a retrospective cohort study involving 3675 patients from six European centers (2082 in the development cohort and 1593 in the validation cohort) with a median follow-up of 5.7 years, the primary outcome of SCD or appropriate ICD shock occurred in 198 patients (118 patients with SCD, 27 with aborted SCD, and 53 with appropriate ICD shock) [65]. Using the derived model (which incorporated parameters of age, maximal LV wall thickness, left atrial diameter, LVOT gradient, family history of SCD, NSVT, and unexplained syncope), which can be accessed online, investigators predicted that for every 16 ICDs implanted, one patient would be saved from SCD every five years.

Subsequent studies looking at validation of the HCM Risk-SCD calculator have reported widely varying results in terms of the accuracy of the score for predicting SCD [66-69].

●In the largest reported validation cohort (International External Validation Study of the 2014 European Society of Cardiology Guidelines on Sudden Cardiac Death Prevention in Hypertrophic Cardiomyopathy [EVIDENCE-HCM] cohort), which included 2147 patients with HCM and no prior history of SCD from 14 centers in the United States, Europe, the Middle East, and Asia, 44 patients experienced an SCD event (defined as SCD, successful resuscitation from SCA, or appropriate ICD intervention for VT/VF) over the five-year follow-up (0.5 percent per year) [70]. Among patients with high predicted risk (≥6 percent, n = 297), the five-year incidence of SCD was significantly higher (8.9 percent) compared with patients with intermediate (4 to 6 percent, n = 326) or low (<4 percent, n = 1524) predicted risk (five-year incidence 1.8 and 1.4 percent, respectively).

●In a cohort of 706 patients with HCM and no prior history of SCD who were seen at two European referral centers, 42 patients (5.9 percent) experienced an SCD event (defined as SCD, successful resuscitation from SCA, or appropriate ICD intervention for VT/VF) over the five-year follow-up (1.2 percent per year) [66]. Patients with an SCD event had significantly greater estimated five-year risk of SCD using the HCM Risk-SCD calculator (4.9 versus 2.8 percent in patients without SCD), with the calculator resulting in improved risk assessment compared with 2003 and 2011 society guidelines.

●The HCM Risk-SCD calculator has also been retrospectively applied to a cohort of 2094 patients with HCM seen at a large United States referral center [61]. The HCM Risk-SCD calculator accurately predicted patients at low risk without SCD events (92 percent specificity), but the sensitivity of a high-risk classification was only 34 percent for predicting SCD events, suggesting that the majority of patients at risk for SCD would have been missed using only the calculator to quantify risk. In contrast, the enhanced 2011 ACC/AHA guideline criteria had sensitivity and specificity of 87 and 78 percent, respectively, suggesting greater likelihood of preventing SCD with an ICD at the expense of slightly higher use of ICDs in patients without SCD events.

●The HCM Risk-SCD model and the conventional risk factors from the American College of Cardiology/American Heart Association (ACC/AHA) guidelines were compared in a cohort of 288 patients (mean age 52 years, 66 percent male, 25 percent with LVOT obstruction ≥30 mmHg) with HCM from a single referral center in the United Kingdom, among whom 14 patients experienced SCD or equivalent (resuscitation from cardiac arrest or appropriate ICD shock for VF or VT >200 beats per minute) over a mean follow-up of 5.6 years [71]. Compared with the conventional ACC/AHA risk factors, the HCM Risk-SCD model more accurately predicted low-risk patients who did not require an ICD (220 of 274 patients [82 percent] compared with 157 of 274 patients [57 percent]) but also failed to identify a significantly greater number of high-risk patients who experienced SCD or equivalent (6 of 14 patients [43 percent] compared with 1 of 14 patients [7 percent]).

●The presence of LGE identified on CMR may aid in further risk stratifying patients following calculation of the HCM Risk-SCD score. Among 354 patients with HCM and calculated HCM Risk SCD score suggesting low to intermediate five-year risk (<6 percent), patients with LGE extent ≥10 percent had much higher five-year rates of hard cardiac events including SCD, resuscitated cardiac arrest, appropriate ICD therapies, and sustained VT (23 versus 3 percent) [72]. (See 'Risk modifiers' above.)

In a 2019 meta-analysis which included 7291 patients with HCM (including the original HCM Risk-SCD cohort and five subsequent cohorts), 70 percent of patients were identified as low risk, 15 percent as intermediate risk, and 15 percent as high risk [73]. In total, 184 SCD events occurred, with 68 percent occurring in the intermediate and high risk (prevalence of SCD events 1, 2.4, and 8.4 percent in low, intermediate, and high risk groups, respectively). The majority of patients with HCM are stratified as low risk for SCD, but the greatest number of appropriate ICD therapies occur in this low-risk group. Conversely, patients identified as being at high risk of SCD are more likely to receive an appropriate ICD shock, but overall this group receives the lowest number of appropriate ICD therapies. However, proportionally, since the denominator is much larger in low-risk patients, the percentage of patients with ICD shocks is greatest in the high-risk group. This essentially means that, similar to other risk prediction scenarios, the risk score discriminates best those patients with HCM at highest risk for sudden death, but may fail to identify a significant number of patients who have low-risk scores but who are at high risk for sudden death.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiomyopathy" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Cardiac implantable electronic devices".)

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 5^th to 6^th 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 10^th to 12^th 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 topic (see "Patient education: Hypertrophic cardiomyopathy in adults (The Basics)")

●Beyond the Basics topic (see "Patient education: Hypertrophic cardiomyopathy (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Patients with hypertrophic cardiomyopathy (HCM) are prone to ventricular arrhythmias. Ventricular arrhythmias can range from isolated ventricular premature beats (VPBs) to nonsustained ventricular tachycardia (NSVT) to sustained VT and ventricular fibrillation (VF). While the frequency of ventricular arrhythmias is highly variable, the annual incidence of sudden cardiac death (SCD) in the clinically identified general HCM patient population is approximately 1 percent. (See 'Introduction' above and 'Epidemiology' above.)

●The presentation of ventricular arrhythmias in patients with HCM is highly variable, ranging from an absence of symptoms to palpitations to SCD. Most patients with VPBs or NSVT will be asymptomatic or have intermittent palpitations, while on rare occasions SCD can be the initial presentation of sustained VT or VF. (See 'Clinical manifestations' above.)

●Since the underlying abnormal myocardial substrate in HCM can evolve over time, all patients with known or suspected HCM should undergo serial evaluations for SCD risk stratification, including history and physical examination, interim family history, echocardiography, ambulatory electrocardiographic (ECG) monitoring, and exercise testing (on a case-by-case basis). With the emerging role of extensive late gadolinium enhancement (LGE) informing risk assessment, contrast-enhanced cardiac magnetic resonance (CMR) should also be considered. It is reasonable to repeat SCD risk assessment every 12 to 24 months in patients who remain at risk and potentially eligible for an implantable cardioverter-defibrillator (ICD) for primary prevention of SCD. (See 'Evaluation' above.)

●Major risk factors and risk modifiers associated with an increased risk of SCD in patients with HCM include (see 'Risk stratification' above):

•Prior or sustained ventricular arrhythmias.

•Family history of close relative with SCD due to HCM.

•Syncope suspected to be arrhythmic in origin, particularly when occurring relatively recently to time of evaluation and in younger patients.

•Multiple bursts of NSVT on ambulatory ECG monitoring.

•Massive LV hypertrophy ≥30 mm anywhere in LV wall.

•LV apical aneurysm.

•End-stage HCM with LV ejection fraction <50 percent.

•The results of contrast-enhanced CMR with extensive LGE (ie, myocardial scarring) can be used to help arbitrate ICD decision-making if risk remains ambiguous or uncertain following conventional risk stratification assessment.

•Age at time of sudden death risk assessment

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledges Perry Elliott, MD, who contributed to earlier versions of this topic review.