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Hypertrophic Cardiomyopathy–Related Sudden Cardiac Death in Young People in Ontario

Originally publishedhttps://doi.org/10.1161/CIRCULATIONAHA.119.040271Circulation. 2019;140:1706–1716

Abstract

Background:

Hypertrophic cardiomyopathy (HCM) is considered a leading cause of sudden cardiac death (SCD) in younger people. The incidence of HCM-related SCD and its relationship to exercise have not been well studied in large comprehensive studies outside of tertiary care settings. This study sought to estimate the incidence of HCM-related SCD and its association with exercise in a large unselected population.

Methods:

Using the Office of the Chief Coroner of Ontario database encompassing all deaths attended by the coroner, we identified all HCM-related SCDs in individuals 10 to 45 years of age between 2005 and 2016 (70 million person-years). Confirmation of HCM was based on typical macroscopic and microscopic features (definite HCM-related SCD). Sudden deaths with a prior clinical diagnosis of HCM but no autopsy were considered probable HCM-related SCDs. Cases with typical features but no myofiber disarray were considered possible HCM. The completeness of data was verified in a subset of patients in the Toronto area with the use of a registry of all emergency medical services–attended cardiac arrests, with an autopsy rate of 94%. To estimate the number of HCM-related aborted cardiac arrests and lives potentially saved by implantable cardioverter-defibrillators, all de novo implantations for secondary prevention and all implantations and appropriate shocks for primary prevention in patients with HCM 10 to 45 years of age, respectively, were identified with the use of a registry containing data on implantable cardioverter-defibrillator implantations from all implanting sites throughout Ontario.

Results:

Forty-four, 3, and 6 cases of definite, probable, and possible HCM-related SCDs, respectively, were identified, corresponding to estimated annual incidence rates of 0.31 per 1000 HCM person-years (95% CI, 0.24–0.44) for definite HCM-related SCD, 0.33 per 1000 HCM person-years (95% CI, 0.34–0.62) for definite or probable HCM-related SCD, and 0.39 per 1000 HCM person-years (95% CI, 0.28–0.49) for definite, probable, or possible HCM-related SCD (estimated 140 740 HCM person-years of observation). The estimated annual incidence rate for HCM-related SCD plus aborted cardiac arrest and HCM-related life-threatening arrhythmia (SCD, aborted cardiac arrest, and appropriate implantable cardioverter-defibrillator shocks) was 0.84 per 1000 HCM person-years (95% CI, 0.70–1.0). The majority (70%) of SCDs occurred in previously undiagnosed individuals. Most SCDs occurred during rest (64.8%) or light activity (18.5%).

Conclusions:

The incidence of HCM-related SCD in the general population 10 to 45 years of age is substantially lower than previously reported, with most cases occurring in previously undiagnosed individuals. SCDs are infrequently related to exercise.

Clinical Perspective

What Is New?

  • The incidence of hypertrophic cardiomyopathy–related sudden cardiac death in the general population 10 to 45 years of age is an order of magnitude lower than previously reported.

  • Most cases of hypertrophic cardiomyopathy–related sudden cardiac death occur in previously undiagnosed individuals.

  • Hypertrophic cardiomyopathy–related sudden cardiac death is infrequently related to exercise.

What Are the Clinical Implications?

  • The majority of cases occurred in undiagnosed individuals, demonstrating the challenge of further reducing sudden cardiac death in this condition.

  • Exercise guidelines in hypertrophic cardiomyopathy may be too restrictive.

Introduction

Editorial, see p 1717

Hypertrophic cardiomyopathy (HCM) is one of the most common heritable cardiac conditions with an estimated prevalence in the general population of >1:500.1–5 It is believed to be one of the leading causes of sudden cardiac death (SCD) in the young. The reported incidence of SCD in patients known to have HCM varies widely, usually cited as an average of 0.5%/y to 1%/y (5–10 cases per 1000 HCM person-years) in contemporary studies.6–13 Exercise is thought to promote ventricular tachyarrhythmia; hence, avoidance of intense physical activity and competitive sport is recommended by international guidelines.14,15 However, the precise incidence of SCD and, in particular, the risk of SCD during exercise in HCM are not clearly known.

Most previous studies included patients with HCM followed up at referral centers, identified because of symptoms, abnormal cardiac testing, or family screening, and hence may have suffered from selection bias.9,11,12 As a result, the incidence rate of SCD in HCM in the general population may have been overestimated. Very few prior studies included autopsy and systematically sought details on circumstances of death.16–18

The Office of the Chief Coroner of Ontario (OCCO) maintains a centralized, comprehensive database encompassing all sudden deaths attended by the coroner in the province of Ontario. The population of Ontario consists of 13.6 million residents and is ethnically and culturally diverse with >25% of residents being visible minority groups. Hence, the OCCO database enables us to assess the true incidence rate and circumstances (specifically the association with exercise) of HCM-related SCD in a large unselected and diverse population.

Methods

The data, analytical methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedure. The original autopsy results and histology slides are the property of the Coroner of Ontario and were made available as part of a data-sharing agreement.

Data Collection

In the province of Ontario, with a population of 13.6 million residents, coroners are required to investigate any death that is sudden, unexpected, or from nonnatural causes. By protocol, every unexpected sudden death in an individual <45 years of age is subject to autopsy except for cases with a well-documented cardiac history. All autopsies follow a standardized protocol, which includes a careful macroscopic and microscopic examination of the cardiac tissue.19 Notably, microscopic examination is performed in every autopsy regardless of the presence of macroscopic hypertrophy. When the diagnosis of HCM is uncertain, the heart is sent to a specialized cardiovascular forensic pathologist for further examination.

The coroner’s investigative statement includes personal information about the deceased and pertinent details of the death investigation such as circumstances, environment, and manner of death and the immediate medical cause of death with contributory factors. Information is obtained from witnesses, family members, medical practitioners, medical records, and police reports. The investigative statement contains a narrative summary and other important details, including medical history, medications, substance abuse, and symptoms before death. Toxicology testing includes screening for ethanol and drugs of abuse and for 300 prescription and over-the-counter drugs. Toxicology is performed in all cases unless an anatomic cause of death is found at autopsy and toxicology is not considered contributory.

Using the OCCO database, we identified potential cases of HCM-related SCD in individuals 10 to 45 years of age during calendar years 2005 to 2016 (70 million person-years of observation using 2011 Canada census data) by searching cases using the key words hypertrophic cardiomyopathy, hypertrophy, or cardiomyopathy as the cause of death or contributory factors. Ages were rounded up to nearest year. The lower age cutoff was chosen at 10 years because HCM does not usually manifest before puberty, so including younger ages may have led to an underestimation of the true incidence rate.

The study was approved by the Research Ethics Board of St Michael’s Hospital.

Confirmation of HCM Cases

A forensic pathologist made the diagnosis of HCM as the underlying pathology using accepted pathological criteria for the diagnosis of HCM as part of a predefined autopsy protocol under the direction of the chief forensic pathologist for Ontario.19

Confirmation of HCM was based on marked cardiomyocyte hypertrophy with pleomorphic to bizarre nuclei, the presence of geographic regions of myofiber disarray, interstitial and replacement-type fibrous tissue deposition, and commonly altered intramural coronary arteries, that is, thickening of the vessel wall and a decrease in luminal size.20–22 Cases with macroscopic and microscopic characteristics of HCM but no identifiable myofiber disarray were considered to have possible HCM because these individuals could potentially have been clinically diagnosed with HCM. All cases were reviewed by the primary author (A.W.S.) with individual review of equivocal cases by a nationally renowned cardiovascular and forensic pathologist of the Ontario Forensic Pathology Service who is the director of the Ontario Forensic Pathology Molecular Autopsy Program (K.C.).

Verification of Cause of Death

All cases were subsequently reviewed independently of the coroner by the primary author (A.W.S.). In cases when there was disagreement between the coroner and the primary reviewer, a joint deliberation process ensued between the primary author (A.W.S.) and the senior author (P.D.), in consultation with the cardiovascular and forensic pathologist of the Ontario Forensic Pathology Service (K.C.), and resolved by consensus. After a review of all available information for each case, the cause of death was determined to be one of the following: HCM-related SCD, nonsudden death caused by a complication of HCM, or death resulting from a cause unrelated to HCM. The sudden deaths of individuals with a prior clinical diagnosis of HCM but no autopsy were considered probable HCM-related SCD because they may have had other causes.

Physical Activity Level at the Time of Death

Physical activity level at the time of death was determined from the coroner’s investigative statement. An estimated metabolic equivalent score was assigned to each type of physical activity on the basis of the criteria described by Ainsworth et al23,24 and was classified as during sleep, at rest, during light activities of daily living, or during moderate to vigorous exercise (estimated workload >3 metabolic equivalents).

Validation of the Calculated Incidence of HCM-Related SCD With a Comprehensive Cardiac Arrest Database

To verify the completeness of the coroner database, we used the Greater Toronto Area (which makes up about half of the Ontario population) cardiac arrest registry database, which contains every out-of-hospital cardiac arrest (OHCA) attended by emergency medical services (EMS) in a population of 6.6 million (2.7 million 10–45 years of age). Every OHCA (in those 10–45 years of age) between 2009 and 2012 (10.8 million person-years) was matched to a coroner record; 93.9% of fatal OHCAs in individuals 10 to 45 years of age were investigated by the coroner, including 100% of deaths in a public place; 94.6% of those without advanced decomposition had an autopsy.25

Estimation of Aborted HCM-Related Cardiac Arrests and Number of Lives Potentially Saved by Implantable-Cardioverter Defibrillators in Ontario

The Ontario implantable cardioverter-defibrillator (ICD) database is a prospective registry of patients through reporting mandated by the Ministry of Health and Long-Term Care. The database includes comprehensive data on ICD implantations performed between February 2007 and February 2011 from all ICD-implanting sites throughout Ontario with last follow-up on May 14, 2012, and a mean±SD follow-up of 2.8±1.3 years.26 To estimate the number of lives potentially saved by ICDs in Ontario, all de novo ICDs implanted for primary prevention in patients with HCM who were 10 to 45 years of age and all appropriate ICD shocks were identified with the use of the Ontario ICD database; all shocks were considered to be a potential death averted. To estimate the number of HCM-related aborted cardiac arrests (ie, cardiac arrest with survival) in Ontario, all de novo ICD implantations for secondary prevention in patients with HCM were identified with the ICD database. Given the short follow-up, we imputed the potential number of appropriate ICD shocks over a 12-year period. To do this, we multiplied the number of shocks seen in the 2.8-year period by 4 to give the 12-year estimate.

Statistical Analysis

Data are presented as mean±SD for normally distributed variables and as median (interquartile range) for nonnormally distributed variables. Continuous variables were compared with the Student t test. Categorical variables were compared with χ2 statistics or the Fisher exact test as appropriate. The at-risk population included people with HCM who were 10 to 45 years of age. To estimate the size of the at-risk population, we used the total number of people 10 to 45 years of age (census data) and estimated a prevalence of HCM of 1:500 (ie, the number of all people 10–45 years of age was divided by 500). Incidence rates were calculated from the HCM-related SCD cases relative to the appropriate at-risk population size for Ontario and the Greater Toronto Area for the OCCO and EMS databases, respectively, with 95% CIs derived from the Poisson distribution in which the relationship between the Poisson and χ2 distributions was used to calculate the exact confidence limits. To account for possible variability in the population of Ontario during the study period, the population in the middle of the study period (2011) as provided by the Canadian Census Data was used for all calculations. To compare the difference between the incidence rates in women and men, Poisson distribution and test-based methods were used to construct the CIs. Two-sided exact significance was reported by using the mid P value rule.27 Events that occurred in ≤5 individuals from the Ontario ICD database are not reported for privacy purposes but are included in the analysis and reported in summary data. The associations between exercise-related SCD and age (continuous variable), age <20 years (dichotomous variable), sex, previous diagnosis of HCM, and maximal wall thickness at autopsy were examined with unadjusted correlation tests (Spearman test). Odds ratios were derived from the 2×2 contingency table. All tests were 2-tailed, and a value of P<0.05 was considered significant. All calculations and data analyses were performed with STATA14 software.

Results

Estimation of Annual Incidence Rate of HCM-Related SCD With the OCCO Database

Over a 12-year period, 44 and 6 cases of definite and possible HCM-related SCD, respectively, were identified at autopsy, in addition to 3 cases of probable HCM-related SCD, equivalent to a total of 4.4 cases per year. This corresponded to estimated annual incidence rates of 0.31 per 1000 HCM person-years (95% CI, 0.24–0.44) for definite HCM-related SCD, 0.33 per 1000 HCM person-years (95% CI, 0.25–0.44) for definite or probable HCM-related SCD, and 0.38 per 1000 HCM person-years (95% CI, 0.28–0.49) for definite, probable, or possible HCM-related SCD (estimated 140 740 HCM person-years; Figure 1).

Figure 1.

Figure 1. Identification and classification of all sudden deaths with left ventricular hypertrophy (LVH) in individuals 10 to 45 years of age between 2005 and 2016 in the Office of the Chief Coroner of Ontario database. MI indicates myocardial infarction; and SCD, sudden cardiac death. *Assuming a prevalence of 1:500. †Isolated LVH: alcoholic cardiomyopathy, 1; alcoholic cardiomyopathy, alcohol intoxication, and hypothermia, 1; dilated cardiomyopathy, 1; ischemic heart disease, 3; hypertensive cardiomyopathy (HCM), 3; hypertensive and ischemic cardiomyopathy, 2; obesity-related cardiomyopathy, 2; alcohol- and obesity-related cardiomyopathy, 1; hypertensive and obesity-related cardiomyopathy, 4; hypertensive and alcoholic cardiomyopathy, 1; hypertensive cardiomyopathy and olanzapine intoxication, 1; sickle cell crisis, 1; idiopathic LVH, 1; and idiopathic LVH and oxycodone intoxication, 1. ‡LVH associated with other structural cardiac abnormalities: severe aortic regurgitation, 2; after repair of tetralogy of Fallot, 1; and dysplastic mitral valve, 1.

Estimation of Sex-Dependent Incidence of HCM-Related SCD With the OCCO Database

The annual incidence rate for men was significantly higher than that for women (definite HCM-related SCD, 0.53 per 1000 HCM person-years [95% CI, 0.37–0.73] versus 0.098 of 1000 HCM person-years [95% CI, 0.04–0.20]; definite or probable HCM-related SCD, 0.63 per 1000 HCM person-years [95% CI, 0.46–0.85] versus 0.11 per 1000 HCM person-years [95% CI, 0.05–0.22]; definite, probable, or possible HCM-related SCD, 0.63 per 1000 HCM person-years [95% CI, 0.46–0.85] versus 0.13 per 1000 HCM person-years [95% CI, 0.06–0.24], respectively; P<0.001 for all rates).

Validation of HCM-Related SCD Incidence Rate With a Registry of All EMS-Attended Cardiac Arrests

Every EMS record (n=1993) containing prehospital details of all EMS-attended OHCAs with no obvious cause in individuals 10 to 45 years of age in the Greater Toronto Area (calendar years 2009–2012) was reviewed. Of the 1993 OHCAs, 29.9% (595 of 1993) had confirmed cardiac causes (the causes in the remaining 70.1% have been previously described).25 Complete data were available on 555 cases, that is, 93.3% of cases.25 Five cases of definite HCM-related SCD in individuals 10 to 45 years of age were identified. If we assume an incidence of HCM of 1:500 in the population in this age group, this corresponds to an estimated annual incidence rate of 0.23 per 1000 HCM person-years (95% CI, 0.075–0.54). All 5 of these cases were present and identified in the OCCO database. In addition, 2 cases of HCM-related aborted SCD (with survival) were identified. The sum of deaths and aborted cardiac arrests corresponds to an estimated annual rate of 0.32 per 1000 HCM person-years (95% CI, 0.13–0.67).

Estimation of the Number of Aborted HCM-Related Cardiac Arrests With the Ontario ICD Database

Fifteen de novo ICD implantations for secondary prevention in patients with HCM who were 10 to 45 years of age in Ontario during a 4-year period (2007–2011; equivalent to 45 implantations in 12 years) were identified. Adding this to the measured SCD corresponds to an estimated annual incidence rate of HCM-related SCD (including aborted cardiac arrest) of 0.70 per 1000 HCM person-years (95% CI, 0.56–0.85).

Estimation of Number of Lives Potentially Saved by ICDs With the Ontario ICD Database

One hundred eleven de novo ICD implantations for primary prevention in patients with HCM who were 10 to 45 years of age were performed in Ontario during a 4-year period (2007–2011) with <6 appropriate shocks during a mean follow-up of 2.8±1.3 years (equivalent to <21.4 cases in 12 years). Adding this to the measured SCD and aborted cardiac arrest rate yields an estimated annual incidence rate of HCM-related life-threatening arrhythmia (including SCD, aborted cardiac arrest, and appropriate shocks) of 0.84 per 1000 HCM person-years (95% CI, 0.70–1.0).

Clinical Characteristics, Circumstances of Death, and Association With Exercise in the OCCO Database

The clinical characteristics of the individuals in the OCCO database are summarized in the Table. The median age at time of SCD was 35.5 years (interquartile range, 26–42 years). Men made up the majority of cases (83.6%). Most cases (70%) occurred in individuals without a previous diagnosis of HCM.

Table. Clinical Characteristics of Individuals With and Without a Prior Diagnosis of HCM in the OCCO Database

VariableAll Patients (n=53)Known to Have HCM (n=16)Not Known to Have HCM (n=37)P Value
Median age (IQR), y35.5 (26–42)34.5 (26–42)37.0 (26–39.5)0.96
Male sex, n (%)44 (83.0)12 (75.0)32 (86.5)0.42
Comorbidities, n (%)
 Hypertension2 (3.8)0 (0)2 (5.4)0.42
 Diabetes mellitus2 (3.8)0 (0)2 (5.3)1.00
 Dyslipidemia3 (5.7)0 (0)3 (8.1)0.54
 TIA/stroke0 (0)0 (0)0 (0)1.00
 Ischemic heart disease0 (0)0 (0)0 (0)1.00
 Smoking7 (13.2)2 (12.5)5 (13.5)1.00
 Obesity*19 (17.0)3 (25)16 (48.5)0.19
 Atrial fibrillation1 (1.9)1 (6.25)0 (0)0.29
 β-Blockers6 (11.3)6 (37.5)0 (0)0.0003

HCM indicates hypertrophic cardiomyopathy; IQR, interquartile range; OCCO, Office of the Chief Coroner of Ontario; and TIA, transient ischemic attack.

*Data were available for 84.9% of the patients (89% of patients not known to have HCM and 75% of patients with a previous clinical diagnosis of HCM).

†Body mass index ≥30 kg/m2 at autopsy.

‡Data were available for 92.6% of the patients.

The vast majority of deaths occurred during rest (64.8%) or light activity (18.5%) in patients with and without a prior diagnosis of HCM (87.5% and 84.2%, respectively). Thirty percent of the events occurred during sleep. Eight cases (14.8%) occurred during moderate or vigorous exercise, and 1 case (1.85%) occurred within 30 minutes after exercise as follows: running/jogging, 4; biking, 1; ball game, 1; gym class, 1; swimming, 1; and snow blowing, 1 (Figure 2). Exercise-related SCD was negatively associated with age (r=−0.52 [95% CI, −0.69 to −0.29]). The proportion of exercise-related SCDs was significantly higher in individuals ≤20 years of age compared with individuals >20 years of age. Nearly 80% of HCM-related SCDs in individuals ≤20 years of age were related to exercise, whereas <5% of SCDs in individuals >20 years of age were associated with exercise (77.8% versus 4.8%; P<0.001, r=0.64 [95% CI, 0.44–0.77]). The odds ratio for exercise-related SCD in an individual >20 years versus ≤20 years of age was 70 (95% CI, 8.4–538; P<0.001).

Figure 2.

Figure 2. Level of activity at time of sudden death in the Office of the Chief Coroner of Ontario database.

ICD Use in Patients With a Prior Clinical Diagnosis of HCM in the OCCO Database

Among the 16 patients with a prior diagnosis of HCM, 1 patient had an ICD in situ that delivered shocks during ventricular fibrillation but failed to prevent the SCD. The indication for the ICD was a family history of sudden death. The ICD was later inspected and found to be functioning properly.

Left Ventricular Outflow Tract Obstruction in Patients With a Prior Clinical Diagnosis of HCM in the OCCO Database

Six of the 16 patients (37.5%) with a prior diagnosis of HCM had a prior diagnosis of left ventricular (LV) outflow tract obstruction; 1 was status postsurgical septal myectomy and 2 were status post–alcohol septal ablation.

Autopsy Findings

The mean heart weight was 602±200 g, and the mean heart weight indexed to body surface area was 285±81 g/1.73 m2. The mean maximal wall thickness was 2.54±0.8 cm (range, 0.9–4.4 cm; Figures I and II in the online-only Data Supplement). The mean maximal wall thickness was ≥3 cm in 31% and ≥2.5 cm in 50%. In 57.1% of the cases, there was asymmetric septal hypertrophy. There were no significant differences in the mean heart weight, heart weight indexed to body surface area, and maximal wall thickness between individuals with and those without a prior clinical diagnosis of HCM (566±100 g versus 613±222 g, P=0.5; 284±40 g/1.73 m2 versus 286±93 g/1.73 m2, P=0.72; 2.8±0.8 cm versus 2.5±0.8 cm, P=0.22, respectively). However, asymmetric hypertrophy was significantly more prevalent among patients with a prior clinical diagnosis of HCM than those without (83.3% versus 48.6%; P=0.047). Disarray was present in 92% and 81% of cases with and without a prior diagnosis of HCM, respectively (P=0.66).

Discussion

In a 12-year period covering 70 million person-years of an Ontario population 10 to 45 years of age, we found only 44, 3, and 6 cases of definite, probable, and possible HCM-related SCD, respectively, whereas we expected to find ≈704 to 1408 cases on the basis of the previously reported incidence of HCM-related SCD. Assuming an HCM prevalence of 1:500, we found an annual incidence of SCD of 0.31 to 0.39 per 1000 HCM person-years (in those 10–45 years of age), which is an order of magnitude lower than previously reported. Because the EMS database verified that >94% of individuals with OHCAs in the age range studied received an autopsy, our estimate most likely does not underestimate the true incidence by >10%. Furthermore, these findings were validated in a registry of all EMS-attended OHCAs in the Greater Toronto Area with a follow-up of 10.8 million person-years.

The low incidence of SCD found in the present study is supported by findings of a recent unselected cohort from Australasia in which 3% of SCDs in individuals <35 years of age were ascribed to HCM, equivalent to an annual incidence of 0.6 per 1000 HCM person-years.18 A population-based study from Oregon that examined HCM-related sudden cardiac arrests (including 10.7% survivors to hospital discharge) in individuals 5 to 59 years (mean age, 47.8 years) over 7.7 million person-years of follow-up found an incidence of SCD of 2 to 3 per 1000 HCM person-years. However, unlike the present study, it had selective autopsy data with autopsies available for only 33% of cases.28 Notably, for 40% of cases, neither autopsy nor echocardiography was available for which imputation was conducted, likely overestimating the incidence. The prevalence of HCM is usually cited as 1:500.2,4,5 This estimated prevalence of HCM was initially reported in the CARDIA study (Coronary Artery Risk Development in Young Adults), which included echocardiographic studies of 4111 unrelated individuals 23 to 35 years in the United States.2 Subsequent international studies that included different populations and used different study designs demonstrated a similar prevalence.5,29,30

However, recent studies suggest that HCM prevalence might be as high as 1:3001,3; in athletes, the prevalence of HCM, diagnosed with an echocardiogram and cardiac magnetic resonance imaging, may be as high as 1:114.31 If HCM is more common than previously thought, our findings suggest that the incidence of HCM-related SCD may be even lower than our estimates above.

The substantially lower estimated incidence of HCM-related SCD in the present study compared with previous studies may be caused by the inclusion of only patients with HCM followed up at HCM-dedicated centers in the previous studies, which may have suffered from selection bias.4,6–8 Notably, both the European Society of Cardiology guidelines and the American Heart Association guidelines include solely studies examining the incidence of SCD in patients with known HCM followed up by cardiologists rather than in general populations.4,9,14,15 In contrast, our study included the entire population of Ontario and hence represents the incidence of SCD in an unselected large region and population rather than among a selected group of individuals known to have HCM and receiving specialist or subspecialist care. A recent large international external validation study of the 2014 European Society of Cardiology guidelines found an annual incidence of HCM-related SCD among low-risk patients (defined as patients with a calculated risk of HCM-related SCD of <4% over 5 years by the European Society of Cardiology risk calculator) of 0.27% (2.7 per 1000 HCM person-years).12,13 Unlike the present study, all these low-risk patients had a prior diagnosis of HCM and were followed up at tertiary centers. In addition, most previous studies also included aborted (resuscitated) cardiac arrests. However, because the survival rate of OHCA in the general population is ≈10%,28,32,33 capturing all cases of aborted HCM-related OHCA would not have increased the estimated incidence rate considerably. The EMS registry–based database in the more limited geographic area, which includes all EMS-attended OHCAs without exception, indicated only 2 cases of HCM-related OHCAs with successful resuscitation and survival over a 4-year period. This corresponds to an annual incidence rate of HCM-related OHCA accounting for both deceased and survivors of 0.31 per 1000 HCM person-years (95% CI, 0.12–0.66). This incidence is similar to the incidence calculated for the entire population of Ontario. Furthermore, the ICD database, which includes all ICD implantations in Ontario, indicated an average of only 3.75 ICD implantations for secondary prevention for documented sustained ventricular tachycardia/ventricular fibrillation or aborted cardiac arrests per year. After inclusion of all ICD implantations for secondary prevention in Ontario, the calculated incidence remained substantially lower compared with previous studies. The calculated incidence rate may have overestimated the true incidence rate because not all episodes of sustained ventricular tachycardia are life-threatening arrhythmias. Previous studies also considered an appropriate ICD discharge as equivalent to SCD. This may have led to an overestimation of the true rate of SCD because it has been shown that appropriate ICD therapies exceed actual SCD mortality by a factor of 2. The ICD database in Ontario indicated an average of <2 appropriate shocks per year in ICD implantations for primary prevention. After the inclusion of appropriate shocks, the incidence rate remained substantially lower than reported in previous studies.

In contrast to previous studies, we used stringent diagnostic histological criteria to identify HCM. No consensus exists on the pathological diagnosis of HCM. Myofiber disarray remains the principal histological hallmark of HCM and is regarded by most cardiac pathologists as vital for the diagnosis of HCM.6,34,35 In some cases, myofiber disarray may be subtle, and hence, a definite diagnosis cannot be made histologically.16,36,37

However, in clinical practice, histological examination for myofiber disarray is not part of the clinical diagnosis of HCM; cases without myofiber disarray would likely have been diagnosed with clinical HCM if they had been investigated. To address this and to provide a better assessment of the incidence of SCD in patients with clinical HCM, which may be more relevant in the context of current clinical and investigative standards, we included cases of unexplained hypertrophy and some histological criteria for HCM but no myofiber disarray as possible HCM-related SCD. To provide an estimate of the incidence of SCD in patients with clinical HCM, we have calculated the incidence of SCD in patients with any of possible, probable, and definite HCM. Even after the inclusion of these cases, the estimated annual incidence remained substantially lower compared with previous studies.

The study cohort included 2 different populations: individuals without a prior diagnosis of HCM with SCD as the first manifestation of HCM, who made up the majority of cases (70%), and individuals with a prior diagnosis of HCM, who made up the minority of cases (30%). Notably, consistent with our findings, autopsy-based studies from the United Kingdom and Oregon found that only 20% of SCDs occurred in individuals known to have HCM.28,35 The low number of SCDs in previously diagnosed individuals (16 SCDs in 12 years) in the present study represents a much lower incidence than previously reported in this group of individuals. This lower-than-expected incidence of SCD may be the result of an overestimation of the incidence in previous studies and a decline of the incidence of SCD in patients with diagnosed HCM with increased use of modern therapies, including ICD, medications, and septal reduction. However, given the very small absolute number of shocks in implantations for primary prevention, the benefit from ICD therapy is overshadowed by death from undetected HCM and our inability to optimally predict risk in known HCM. During the study period, 149 septal myectomies were performed at the Toronto General Hospital, where the vast majority of myectomies in Ontario are performed. Although septal myectomy has been shown to reduce the risk of SCD of patients with obstructive HCM, it is difficult to assess its contribution to the observed low incidence rate. Although we detected no significant difference in the degree of overall hypertrophy, asymmetric hypertrophy was much less frequent in the previously undiagnosed group, seen in only ≈50% of the cases. Further studies are needed to examine the phenotypic differences between individuals with and those without a clinical diagnosis of HCM and the relative risks of SCD to improve our detection of the latter group, in whom most SCDs occur.

Incidence of HCM-Related SCD in the Older Population (46–65 Years of Age)

The coroner’s protocol also applies to individuals 46 to 65 years of age, which enables us to assess the incidence of HCM-related SCD in this older age group. However, because we could not validate the coroner’s adherence to the protocol in this older age group, we did not include these data in the main analysis. The incidence rate in the older age group was significantly higher than that in the younger age group yet also substantially lower than previously reported (0.5 per 1000 HCM person-years [95% CI, 0.41–0.73], 0.68/1000 HCM person-years ([95% CI, 0.52–0.87], and 0.76/1000 HCM person-years [95% CI, 0.59–0.96] for definite; definite or probable; and definite, probable, or possible, respectively). In contrast, a recent study found that the risk of HCM-related SCD among patients with HCM with no conventional risk factors was independently and inversely associated with age.8 Similarly, the highest prevalence of HCM-related SCD in a pathology-registry study of 184 HCM-related SCDs was found to be in the third and fourth decades of life.35 However, unlike our study, these studies included selected populations made up of patients with a prior clinical diagnosis of HCM.

The low incidence observed in the present study likely represents the incidence in the general HCM population (mainly in patients with nondiagnosed HCM) but not necessarily in the subset of patients with HCM seen in specialized clinics. Although the risk of SCD in most individuals with HCM is extremely low, a small proportion of individuals with HCM are indeed at increased risk of SCD. Whereas ICDs prolong life in selected high-risk patients with HCM, the fact that the majority of individuals with SCD who were known to have HCM and were followed up by a cardiologist did not receive an ICD (because they were presumably deemed to be low-risk) demonstrates the limitations of the current models for risk stratification for SCD in HCM and the challenge in identifying high-risk individuals among those diagnosed. The other remaining challenge is the identification of high-risk individuals among those not previously known to have HCM. Our findings suggest that intensive case finding, for example, by electrocardiographic screening, will identify previously undiagnosed individuals who are likely at very low risk of sudden death.

Incidence of HCM-Related SCD in Men Versus Women

We have found a 5.5-fold greater incidence rate of HCM-related SCD in men compared with women. Previous studies have been inconsistent. In line with our findings, studies examining SCDs in large unselected populations found that men made up >85% of cases of HCM-related SCDs.18,28,35 However, studies in patients with HCM found no differences in the incidence of SCD between the sexes.38 In another study, female sex was found to be independently associated with all-cause mortality.39 Current guidelines do not consider sex as a predictor for SCD, presumably because few studies examined the potential impact of sex on HCM outcome and had inconsistent findings.

LV Wall Thickness

In about half of the cases, the maximal wall thickness was ≥2.5 cm; in nearly a third, it was ≥3 cm. Although it has been shown that the LV wall thickness is greater postmortem than antemortem, our findings support the role of severe hypertrophy in the risk stratification for SCD in HCM.40,41

Association Between SCD and Exercise

High-intensity exertion is believed to induce fatal arrhythmias in predisposed individuals. Therefore, all current guidelines recommend that patients with HCM avoid high-intensity exercise or competitive sports.14,15 It is noteworthy that the European Society of Cardiology guidelines acknowledge that documented ventricular arrhythmias during exercise are very rare in HCM and that most ICD treatments occur in the absence of exertion or tachycardia.14 We have found that nearly 85% of cases occurred during rest or light activity. Because the proportion of SCDs related to exercise was similar between individuals with and those without an antemortem diagnosis of HCM, exercise restriction is unlikely to explain the low frequency of exercise-related SCD observed in the present study. Our findings are consistent with a recent autopsy study that demonstrated that 80% of events occurred during rest or sleep.35 In addition, a prospective study on sudden death in young adults (≤35 years of age) in Australasia found that most SCDs in HCM occurred during rest or light activity.18 Furthermore, studies examining sports-related SCD in the general population consistently show that HCM accounts for 6% to 7% of the cases.42–44

The estimated incidence rate of HCM-related SCD associated with exercise in the present study was 0.064 per 1000 HCM person-years. This low incidence is nevertheless 10-fold higher than the overall risk of cardiac arrest during competitive sports in the general population of 0.76 per 100 000 person-years in individuals 12 to 45 years of age.45 The low frequency of SCD in HCM and its rarity during exercise may be relevant in the consideration of the value of preparticipation screening for HCM, which is mandatory in several countries, and in exercise restriction recommendations.46

Study Limitations

The present study may have underestimated the annual incidence rate of HCM-related SCD because not all cases of sudden death receive an autopsy; however, 94% of all people in Ontario who die suddenly at <45 years of age receive an autopsy. It is possible that the genetic and ethnic profile of HCM in Ontario might result in a lower incidence rate of SCD than in other populations. However, the population of Ontario is ethnically and culturally diverse, and the prevalence of clinical HCM has been shown to be similar across multiple geographies, ethnicities, and races. It is plausible that the cooler temperatures in Ontario act as a protective factor by inducing peripheral vasoconstriction and increased afterload, resulting in decreased LV outflow tract gradients. Data on appropriate shocks for patients with HCM receiving an ICD for primary prevention were available only for a mean follow-up of 2.8 years. Because patients with HCM can receive appropriate shocks at variable time intervals after implantation, the imputed total number of shocks over the entire follow-up period may have underestimated the incidence of appropriate shocks. Yet previous studies found that the rates of first appropriate intervention are stable in both the pediatric and adult populations.47–49 Furthermore, given the small number of appropriate shocks (<6 shocks in 2.8 years of follow-up after implantation), our estimate is unlikely to meaningfully underestimate the true incidence over the entire follow-up period.

Conclusions

We found an incidence of HCM-related SCD in the general population in individuals 10 to 45 years that is an order of magnitude lower than found in previous studies. The majority of cases occurred in undiagnosed individuals, which demonstrates the challenge of further reducing SCD in this condition. SCDs were infrequently related to exercise, which suggests that exercise guidelines in HCM may be too restrictive. Further studies are needed to understand the true incidence of HCM-related SCD and its risk factors.

Acknowledgments

The authors thank the OCCO and the Ontario Forensic Pathology Service for their assistance.

Footnotes

Sources of Funding, see page 1715

https://www.ahajournals.org/journal/circ

The online-only Data Supplement, podcast, and transcript are available with this article at https://www.ahajournals.org/doi/suppl/10.1161/circulationaha.119.040271.

Paul Dorian, MD, St Michael’s Hospital, 30 Bond St, 6-050 Donnelly Wing, Toronto, ON, M5B 1W8, Canada. Email

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