- Email: [email protected]
Family History of Sudden Death Should Be a Primary Indication for Implantable Cardioverter Defibrillator in Hypertrophic Cardiomyopathy
Canadian Journal of Cardiology
-
(2015) 1e5
Point/Counterpoint
Family History of Sudden Death Should Be a Primary Indication for Implantable Cardioverter Defibrillator in Hypertrophic Cardiomyopathy Martin S. Maron, MD Hypertrophic Cardiomyopathy Center, Division of Cardiology, Tufts Medical Center, Boston, Massachusetts, USA
ABSTRACT
RESUM E
Hypertrophic cardiomyopathy (HCM) is the leading cause of sudden death in young patients. A number of noninvasive clinical markers, including family history, have formed the basis for a risk stratification strategy aimed at identifying high-risk patients with HCM. The observation that sudden death can occur in multiple relatives of the same family, and clinical studies in which a family history of HCM-related sudden death emerges as an independent predictor of sudden death, support the principle that family history should be considered a risk factor which, in the appropriate clinical scenario, can form the basis for recommending prophylactic implantable cardioverter defibrillator therapy.
La cardiomyopathie hypertrophique (CMH) est la cause principale de mort subite chez les jeunes patients. Plusieurs marqueurs cliniques ce dents familiaux, ont constitue la base non invasifs dont les ante gie de stratification du risque visant la de tection des pad’une strate s à un risque e leve . L’observation selon tients atteints de CMH expose laquelle la mort subite peut survenir chez de nombreux membres de la tudes cliniques selon lesquelles les ante ce dents même famille, et les e e à la CMH apparaissent comme des familiaux de mort subite lie dicteurs inde pendants de mort subite soutiennent le principe que pre ce dents familiaux devraient être conside re s comme des facles ante nario clinique approprie , peuvent teurs de risque qui, selon le sce constituer la base de la recommandation d’un traitement prophylacfibrillateur cardioverteur implantable. tique à l’aide d’un de
Since the original description of hypertrophic cardiomyopathy (HCM) > 55 years ago,1 sudden death has been the most visible and devastating consequence of this disease.2-4 Over this time, a number of noninvasive clinical risk markers, including family history, have emerged to aid in identifying patients at high risk for sudden death who may be candidates for lifesaving primary preventive therapy with an implantable cardioverter-defibrillator (ICD).3-9 Indeed, this contemporary risk stratification strategy has now resulted in a substantial reduction in sudden death, providing the opportunity for extended longevity in the vast majority of patients with HCM.10,11 However, what evidence supports family history as a sudden death risk marker for which to base a recommendation to implant an ICD for primary prevention?
experience of HCM investigators and clinicians, who observed clusters of sudden death in select HCM families.2,3 In fact, it was a malignant family history of several siblings who died suddenly early in life that was the impetus for referring Mr. Claude Brady to the National Institutes of Health in Bethesda, Maryland in 1958, where he became the first patient clinically diagnosed with HCM.12 After these early observations, numerous studies and case reports have included detailed pedigrees of high-risk families in which the tragic consequence of sudden death has occurred in multiple young family members across generations and often with sudden death as the only disease manifestation incurred by these patients.13,14 Although these highly malignant HCM families compose a small segment of the diverse HCM disease spectrum, they suggest that in select families a strong link does exist between related family members and risk of sudden death events caused by HCM.
Historical Observations The inclusion of family history into the clinical practice of risk stratification was initially based largely on the clinical Received for publication April 8, 2015. Accepted May 7, 2015. Corresponding author: Dr Martin S. Maron, Tufts Medical Center, 800 Washington Street, No. 70, Boston, Massachusetts 02111, USA. Tel.: þ1617-636-8066; fax: þ1-617-636-7175. E-mail: [email protected] See page 4 for disclosure information.
Cohort Studies After this early observational period, a number of longitudinal follow-up studies in large cohorts of patients with HCM have identified family history as a strong independent predictor for the risk of future sudden death in other related family members based on multivariate analysis (Table 1).15-17 In several of these investigations, a family
http://dx.doi.org/10.1016/j.cjca.2015.05.004 0828-282X/Ó 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
2
Canadian Journal of Cardiology Volume - 2015
Table 1. Family history of sudden death as a predictor of sudden death events or appropriate ICD shock for VT/VF in patients with HCM
No. patients Elliott et al.16 D’Andrea et al.15 Maron et al.6 Bos et al.17
917 123 383 177
Age (y) 43 39 41 45
15 6 16 14
Follow-up (mo)
No. patients with family history of SD
Family history as predictor for SD, HR (95% CI)
Rate of ICD shock/100 person-years, HR (95% CI)
278 28 67 91
1.8 (1.0-3.5) 1.28 (1.1-1.4) e e
e e 2.7 (1.1-5.1) 2.2 (0.6-5.6)
61 48 48 60
10 8 36 36
CI, confidence interval; HCM, hypertrophic cardiomyopathy; HR, hazard ratio; ICD, implantable cardioverter defibrillator; SD, sudden death; VT/VF, ventricular tachycardia/ventricular fibrillation.
history of HCM-related sudden death was associated with a substantial (20%) relative increase in risk compared with patients with HCM with no family history of sudden death.15,16 The totality of these studies suggest that a family history of sudden increases risk approximately 1.0% per year for other clinically affected relatives, compared with 0.5% per year for patients with HCM with none of the conventional risk markers. In addition, results from contemporary trials of ICD implantation for primary prevention in HCM have also provided insight into the importance of family history as a risk factor (Table 1).5,6 Among the largest of these studies, the HCM ICD registry, 383 patients with HCM underwent ICD placement for primary prevention based on the presence of 1 of the conventional risk factors, with an appropriate intervention rate for ventricular tachycardia/ ventricular fibrillation (VT/VF) of 3.6% per year over the follow-up period.6 A substantial proportion of these patients underwent ICD implantation based on the presence of only 1 conventional risk factor, including family history of HCMrelated sudden death; an important subgroup of these patients received a potentially lifesaving device intervention for ventricular tachyarrhythmia (Fig. 1A). Indeed, the rate of appropriate ICD interventions for patients undergoing implantation based only on family history was substantial (2.7 per 100 person-years) and was greater than the intervention rate for patients with HCM who underwent ICD implantation for other single risk factors, such as massive left ventricular hypertrophy, and was nearly identical to that of
patients with nonsustained ventricular tachyarrhythmia on ambulatory Holter monitoring (Fig. 1B).6 Similar results were also observed in a recent ICD study of pediatric patients with HCM in which an important subgroup of children who underwent implantation of an ICD for primary prevention based only on a family history of HCM-related sudden death received a potentially lifesaving shock for VT/VF.7 More recently, direct evidence has emerged for an investigation focused specifically on family history as a predictor within a large population of patients with HCM who experienced an appropriate ICD intervention for ventricular tachyarrhythmia (Table 1). In this study by Bos et al.,17 risk of device intervention was similar for patients with HCM who underwent implantation solely for a family history of sudden death and for other patients who also experienced an appropriate shock with a single risk factor other than family history. The ICD event rate for patients with a family history of HCM-related sudden death as the sole risk factor was 2fold greater in this select population than the sudden death rate reported in a general HCM population.17 Of note, the highest rates of appropriate ICD interventions were in those patients with multiple risk factors, including family history. In summary, if family history had not been considered an indicator of higher risk status in these studies, an important subgroup of predominantly young asymptomatic patients with HCM may have remained unprotected from lifethreatening ventricular arrhythmias without the ICD (Fig. 2).
Figure 1. (A) Among a large cohort of patients with hypertrophic cardiomyopathy (HCM) with implantable cardioverter-defibrillators (ICDs) for primary prevention of sudden death (SD),6 the rate of appropriate shock for ventricular tachyarrhythmias is similar for patients who underwent implantation based on the presence of 1 conventional risk marker and patients who underwent implantation with 2 risk factors. (B) In the same HCM study cohort,6 we see the rate of appropriate shocks for ventricular tachyarrhythmias among patients implanted with an ICD based on the presence of 1 risk factor, including family history of HCM-related sudden death. LVH, left ventricular hypertrophy; NSVT, nonsustained ventricular tachycardia.
Martin S. Maron ICD for Family History of Sudden Death
Figure 2. Family history as a risk factor for sudden death (SD) in hypertrophic cardiomyopathy (HCM). A 35-year-old asymptomatic man with nonobstructive HCM who underwent implantation with an implantable cardioverter-defibrillator (ICD) for primary prevention based solely on a family history of HCM-related sudden death in his brother; he experienced 2 potentially lifesaving shocks for ventricular fibrillation 6 and 15 years after the device was initially implanted.
Family History as a Risk Marker Taken together, these clinical observations and retrospective studies make a compelling argument that family history alone can convey increased future risk to other relatives diagnosed with HCM. This concept is reflective of the broader principles related to risk stratification in this complex genetic heart disease, which is associated with tremendous heterogeneity in phenotypic expression and clinical course. For example, although the risk of sudden death risk does increase with the number of risk factors,4 the presence of 1 marker may itself be enough, depending on the clinical profile of the patient, to consider risk unacceptably high for that individual patient with HCM and lead to recommendation of ICD implantation for primary prevention.5-8 This concept is supported by the fact that in the HCM ICD registry study, the rate of appropriate ICD interventions among patients with a single sudden death risk marker (including family history) did not differ significantly from those with multiple risk markers.6 In this regard, strict adherence to a strategy in which 2 risk factors must be present in an individual patient to consider high-risk status will lead inevitably to an important subset of patients with a single risk factor who are left unprotected from sudden death.3 For these reasons, the recent 2011 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) expert consensus task force guidelines for HCM considered it reasonable to implant an ICD for primary prevention in patients with only 1 risk factor, particularly when the marker is family history of HCM sudden death, unexplained syncope, or massive left ventricular hypertrophy.18 Conversely, it should be emphasized that not all patients with a family history of sudden death should be recommended for prophylactic ICD implantation.3,17,18 Rather, the decision to proceed with ICD placement in this clinical scenario
3
involves consideration of a number of important points, including the strength of evidence supporting HCM as cause of death, the age at which those deaths occurred, and how closely related the deceased are to the patient.3 Furthermore, recent data have demonstrated that the risk of sudden death is extremely low among patients with HCM who have achieved advanced age ( 60 years), even in the presence of conventional risk factors. Therefore, although all decisions regarding prophylactic ICD implantation in HCM should be individualized, aggressive ICD implantation for primary prevention should generally be avoided among elderly patients with HCM. Compared with a number of the other markers that are predicated on discrete cut points, such as wall thickness 30 mm or multiple bursts of nonsustained ventricular tachycardia on ambulatory Holter monitoring, clarifying family history can often be challenging because medical records are often not available or the reports remain ambiguous. For these reasons, it is not uncommon that a certain degree of uncertainty surrounds clinical ICD decision making when only 1 single risk factor of family history is present. Resolving this “grey zone” of risk stratification in HCM requires taking into consideration the desires of the fully informed patient, including a detailed and transparent discussion of the risks and potentially lifesaving benefits of the device, in order to resolve this challenging management decision. Limitations and the Grey Area of Risk Stratification Incorporating family history as a potential clinical risk marker has historically been limited by the enormous variability in the definition used in published studies.4,13-17 For example, some investigators have considered a single sudden death event in any related family member (or only first-degree relatives), whereas others have even required at least 2 firstdegree relatives to have died suddenly for family history to count as a risk factor.4,13-17 This latter definition is particularly problematic and not in line with current practice patterns in the United States, because it implies that when evaluating a patient with HCM who has had a relative with sudden death, the practicing cardiologist must essentially wait until another family member dies of HCM before recommending ICD therapy for primary prevention. These inconsistencies ultimately led to an expert consensus definition provided in the 2011 ACCF/AHA task force guidelines for HCM, which considers 1 sudden death (or more) in a first-degree family member reasonable to consider recommending ICD therapy for primary prevention.18 The strength of this definition is in eliminating potentially unnecessary ICD implantation based on a remote history of sudden death, a clinical scenario in which it is increasingly difficult to determine the precise cause of death. In contrast, sudden deaths that occur in nonefirst-degree relatives are not always necessarily irrelevant to risk assessment. For this reason, ICD decision making for patients with HCM and a history of sudden death in a nonefirst-degree family member should be considered on a case-by-case basis. Most recently, a novel scoring strategy to identify high-risk patients with HCM by predicting sudden death over 5 years was promoted in the European Society of Cardiology 2014
4
guideline standards for the management of HCM.19 However, a recent study validating this risk score in an independent HCM cohort demonstrated that most patients experiencing sudden death or appropriate ICD interventions would not have been considered ICD candidates by the risk score, including some young patients with a family history of sudden death as a risk marker.20 For this reason, decisions regarding risk stratification and ICD decision making in this complex and phenotypically diverse disease continues to require not only physician judgement, applying the current conventional noninvasive risk factors, but also a framework in which fully informed patients participate directly in shared decision making. Genotyping and Risk Stratification The observation that sudden deaths can cluster in related family members initially promoted the idea of a new paradigm in HCM, in which sarcomere mutations could be a predictor of outcome and could identify patients who may benefit from implantation of an ICD as primary prevention based solely on the presence of a particularly “malignant” mutation.13 More recently, however, numerous studies among large cohorts of unrelated patients have demonstrated that sarcomere mutations cannot be classified as either “benign” or “malignant” with respect to predicting an adverse outcome in this disease, although patients with HCM with a pathogenic mutation are at greater risk for adverse events than are those with no identified mutation.14,21 For this reason, a specific mutation cannot be used to identify other patients with HCM in unrelated families as at increased risk for sudden death.22 However, whether private mutations, unique to individual families with HCM, may be responsible for promoting sudden death (or other adverse events) within that specific family remains uncertain but represents an area that deserves closer investigation to help clarify the inevitably complex association that may exist between mutations and outcome. In conclusion, based on > 50 years of observation, and recent well-constructed clinical studies of general and highrisk HCM cohorts, a family history of HCM-related sudden death is an important risk factor that in the appropriate clinical scenario may lead to potentially lifesaving therapy with implantation of a primary prevention ICD to prevent sudden death. Disclosures The author has no conflicts of interest to disclose. References 1. Teare D. Asymmetrical hypertrophy of the heart in young adults. Br Heart J 1958;20:1-8. 2. Maron BJ, Maron MS. Hypertrophic cardiomyopathy. Lancet 2013;381: 242-55. 3. Maron BJ. Contemporary insights and strategies for risk stratification and prevention of sudden death in hypertrophic cardiomyopathy. Circulation 2010;121:445-56. 4. Elliott PM, Poloniecki J, Dickie S, et al. Sudden death in hypertrophic cardiomyopathy: identification of high risk patients. J Am Coll Cardiol 2000;36:2212-8.
Canadian Journal of Cardiology Volume - 2015 5. Maron BJ, Shen W-K, Link MS, et al. Efficacy of implantable cardioverter defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med 2000;342:365-73. 6. Maron BJ, Spirito P, Shen W-K, et al. Implantable cardioverterdefibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy. JAMA 2007;298:405-12. 7. Maron BJ, Spirito P, Ackerman MJ, et al. Prevention of sudden cardiac death with the implantable cardioverter-defibrillator in children and adolescents with hypertrophic cardiomyopathy. J Am Coll Cardiol 2013;61: 1527-35. 8. Vriesendorp PA, Schinkel AF, Van Cleemput J, et al. Implantable cardioverter-defibrillators in hypertrophic cardiomyopathy: patient outcomes, rate of appropriate and inappropriate interventions, and complications. Am Heart J 2013;166:496-502. 9. Christiaans I, van Engelen K, van Langen IM, et al. Risk stratification for sudden cardiac death in hypertrophic cardiomyopathy: systematic review of clinical risk markers. Europace 2010;12:313-21. 10. Rowin EJ, Maron MS, Casey SA, et al. Evidence for reduced mortality in an adult cohort with hypertrophic cardiomyopathy. Circulation 2013;128:A13294. 11. Maron BJ, Braunwald E. Evolution of hypertrophic cardiomyopathy to a contemporary treatable disease. Circulation 2012;126:1640-4. 12. Maron BJ, Bonow R, Salberg L, Roberts W, Braunwald E. The first patient clinically identified with hypertrophic cardiomyopathy. Am J Cardiol 2008;102:1418-20. 13. Watkins H, Rosenzweig A, Hwang DS, et al. Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. N Engl J Med 1992;326:1108-14. 14. Ackerman MJ, VanDriest SL, Ommen SR, et al. Prevalence and agedependence of malignant mutations in the beta-myosin heavy chain and troponin T gene in hypertrophic cardiomyopathy. J Am Coll Cardiol 2002;39:2042-8. 15. D’Andrea A, Caso P, Severino S, et al. Prognostic value of intra-left ventricular electromechanical asynchrony in patients with hypertrophic cardiomyopathy. Eur Heart J 2006;27:1311-8. 16. Elliott PM, Gimeno JR, Tome MT, et al. Left ventricular outflow tract obstruction and sudden death risk in patients with hypertrophic cardiomyopathy. Eur Heart J 2006;27:1933-41. 17. Bos JM, Maron BJ, Ackerman MJ, et al. Role of family history of sudden death in risk stratification and prevention of sudden death with implantable defibrillators in hypertrophic cardiomyopathy. Am J Cardiol 2010;106:1481-6. 18. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2011;58:e212-60. 19. Elliott PM, Anastasakis A, Borger MA, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: The Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014;35:2733-79.
Martin S. Maron ICD for Family History of Sudden Death 20. Maron BJ, Casey SA, Garberich RF, Rowin EJ, Maron MS. Independent assessment of the European Society of Cardiology sudden death risk model for hypertrophic cardiomyopathy. Am J Cardiol, in press. 21. Van Driest SL, Ackerman MJ, Ommen SR, et al. Prevalence and severity of benign mutations in the beta-myosin heavy chain, cardiac troponin T,
5
and alpha-tropomyosin genes in hypertrophic cardiomyopathy. Circulation 2002;106:3085-90. 22. Maron BJ, Maron MS, Semsarian C. Genetics of hypertrophic cardiomyopathy after 20 years: clinical perspectives. J Am Coll Cardiol 2012;60:705-15.
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(2015) 1e5
Point/Counterpoint
Family History of Sudden Death Should Be a Primary Indication for Implantable Cardioverter Defibrillator in Hypertrophic Cardiomyopathy Martin S. Maron, MD Hypertrophic Cardiomyopathy Center, Division of Cardiology, Tufts Medical Center, Boston, Massachusetts, USA
ABSTRACT
RESUM E
Hypertrophic cardiomyopathy (HCM) is the leading cause of sudden death in young patients. A number of noninvasive clinical markers, including family history, have formed the basis for a risk stratification strategy aimed at identifying high-risk patients with HCM. The observation that sudden death can occur in multiple relatives of the same family, and clinical studies in which a family history of HCM-related sudden death emerges as an independent predictor of sudden death, support the principle that family history should be considered a risk factor which, in the appropriate clinical scenario, can form the basis for recommending prophylactic implantable cardioverter defibrillator therapy.
La cardiomyopathie hypertrophique (CMH) est la cause principale de mort subite chez les jeunes patients. Plusieurs marqueurs cliniques ce dents familiaux, ont constitue la base non invasifs dont les ante gie de stratification du risque visant la de tection des pad’une strate s à un risque e leve . L’observation selon tients atteints de CMH expose laquelle la mort subite peut survenir chez de nombreux membres de la tudes cliniques selon lesquelles les ante ce dents même famille, et les e e à la CMH apparaissent comme des familiaux de mort subite lie dicteurs inde pendants de mort subite soutiennent le principe que pre ce dents familiaux devraient être conside re s comme des facles ante nario clinique approprie , peuvent teurs de risque qui, selon le sce constituer la base de la recommandation d’un traitement prophylacfibrillateur cardioverteur implantable. tique à l’aide d’un de
Since the original description of hypertrophic cardiomyopathy (HCM) > 55 years ago,1 sudden death has been the most visible and devastating consequence of this disease.2-4 Over this time, a number of noninvasive clinical risk markers, including family history, have emerged to aid in identifying patients at high risk for sudden death who may be candidates for lifesaving primary preventive therapy with an implantable cardioverter-defibrillator (ICD).3-9 Indeed, this contemporary risk stratification strategy has now resulted in a substantial reduction in sudden death, providing the opportunity for extended longevity in the vast majority of patients with HCM.10,11 However, what evidence supports family history as a sudden death risk marker for which to base a recommendation to implant an ICD for primary prevention?
experience of HCM investigators and clinicians, who observed clusters of sudden death in select HCM families.2,3 In fact, it was a malignant family history of several siblings who died suddenly early in life that was the impetus for referring Mr. Claude Brady to the National Institutes of Health in Bethesda, Maryland in 1958, where he became the first patient clinically diagnosed with HCM.12 After these early observations, numerous studies and case reports have included detailed pedigrees of high-risk families in which the tragic consequence of sudden death has occurred in multiple young family members across generations and often with sudden death as the only disease manifestation incurred by these patients.13,14 Although these highly malignant HCM families compose a small segment of the diverse HCM disease spectrum, they suggest that in select families a strong link does exist between related family members and risk of sudden death events caused by HCM.
Historical Observations The inclusion of family history into the clinical practice of risk stratification was initially based largely on the clinical Received for publication April 8, 2015. Accepted May 7, 2015. Corresponding author: Dr Martin S. Maron, Tufts Medical Center, 800 Washington Street, No. 70, Boston, Massachusetts 02111, USA. Tel.: þ1617-636-8066; fax: þ1-617-636-7175. E-mail: [email protected] See page 4 for disclosure information.
Cohort Studies After this early observational period, a number of longitudinal follow-up studies in large cohorts of patients with HCM have identified family history as a strong independent predictor for the risk of future sudden death in other related family members based on multivariate analysis (Table 1).15-17 In several of these investigations, a family
http://dx.doi.org/10.1016/j.cjca.2015.05.004 0828-282X/Ó 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
2
Canadian Journal of Cardiology Volume - 2015
Table 1. Family history of sudden death as a predictor of sudden death events or appropriate ICD shock for VT/VF in patients with HCM
No. patients Elliott et al.16 D’Andrea et al.15 Maron et al.6 Bos et al.17
917 123 383 177
Age (y) 43 39 41 45
15 6 16 14
Follow-up (mo)
No. patients with family history of SD
Family history as predictor for SD, HR (95% CI)
Rate of ICD shock/100 person-years, HR (95% CI)
278 28 67 91
1.8 (1.0-3.5) 1.28 (1.1-1.4) e e
e e 2.7 (1.1-5.1) 2.2 (0.6-5.6)
61 48 48 60
10 8 36 36
CI, confidence interval; HCM, hypertrophic cardiomyopathy; HR, hazard ratio; ICD, implantable cardioverter defibrillator; SD, sudden death; VT/VF, ventricular tachycardia/ventricular fibrillation.
history of HCM-related sudden death was associated with a substantial (20%) relative increase in risk compared with patients with HCM with no family history of sudden death.15,16 The totality of these studies suggest that a family history of sudden increases risk approximately 1.0% per year for other clinically affected relatives, compared with 0.5% per year for patients with HCM with none of the conventional risk markers. In addition, results from contemporary trials of ICD implantation for primary prevention in HCM have also provided insight into the importance of family history as a risk factor (Table 1).5,6 Among the largest of these studies, the HCM ICD registry, 383 patients with HCM underwent ICD placement for primary prevention based on the presence of 1 of the conventional risk factors, with an appropriate intervention rate for ventricular tachycardia/ ventricular fibrillation (VT/VF) of 3.6% per year over the follow-up period.6 A substantial proportion of these patients underwent ICD implantation based on the presence of only 1 conventional risk factor, including family history of HCMrelated sudden death; an important subgroup of these patients received a potentially lifesaving device intervention for ventricular tachyarrhythmia (Fig. 1A). Indeed, the rate of appropriate ICD interventions for patients undergoing implantation based only on family history was substantial (2.7 per 100 person-years) and was greater than the intervention rate for patients with HCM who underwent ICD implantation for other single risk factors, such as massive left ventricular hypertrophy, and was nearly identical to that of
patients with nonsustained ventricular tachyarrhythmia on ambulatory Holter monitoring (Fig. 1B).6 Similar results were also observed in a recent ICD study of pediatric patients with HCM in which an important subgroup of children who underwent implantation of an ICD for primary prevention based only on a family history of HCM-related sudden death received a potentially lifesaving shock for VT/VF.7 More recently, direct evidence has emerged for an investigation focused specifically on family history as a predictor within a large population of patients with HCM who experienced an appropriate ICD intervention for ventricular tachyarrhythmia (Table 1). In this study by Bos et al.,17 risk of device intervention was similar for patients with HCM who underwent implantation solely for a family history of sudden death and for other patients who also experienced an appropriate shock with a single risk factor other than family history. The ICD event rate for patients with a family history of HCM-related sudden death as the sole risk factor was 2fold greater in this select population than the sudden death rate reported in a general HCM population.17 Of note, the highest rates of appropriate ICD interventions were in those patients with multiple risk factors, including family history. In summary, if family history had not been considered an indicator of higher risk status in these studies, an important subgroup of predominantly young asymptomatic patients with HCM may have remained unprotected from lifethreatening ventricular arrhythmias without the ICD (Fig. 2).
Figure 1. (A) Among a large cohort of patients with hypertrophic cardiomyopathy (HCM) with implantable cardioverter-defibrillators (ICDs) for primary prevention of sudden death (SD),6 the rate of appropriate shock for ventricular tachyarrhythmias is similar for patients who underwent implantation based on the presence of 1 conventional risk marker and patients who underwent implantation with 2 risk factors. (B) In the same HCM study cohort,6 we see the rate of appropriate shocks for ventricular tachyarrhythmias among patients implanted with an ICD based on the presence of 1 risk factor, including family history of HCM-related sudden death. LVH, left ventricular hypertrophy; NSVT, nonsustained ventricular tachycardia.
Martin S. Maron ICD for Family History of Sudden Death
Figure 2. Family history as a risk factor for sudden death (SD) in hypertrophic cardiomyopathy (HCM). A 35-year-old asymptomatic man with nonobstructive HCM who underwent implantation with an implantable cardioverter-defibrillator (ICD) for primary prevention based solely on a family history of HCM-related sudden death in his brother; he experienced 2 potentially lifesaving shocks for ventricular fibrillation 6 and 15 years after the device was initially implanted.
Family History as a Risk Marker Taken together, these clinical observations and retrospective studies make a compelling argument that family history alone can convey increased future risk to other relatives diagnosed with HCM. This concept is reflective of the broader principles related to risk stratification in this complex genetic heart disease, which is associated with tremendous heterogeneity in phenotypic expression and clinical course. For example, although the risk of sudden death risk does increase with the number of risk factors,4 the presence of 1 marker may itself be enough, depending on the clinical profile of the patient, to consider risk unacceptably high for that individual patient with HCM and lead to recommendation of ICD implantation for primary prevention.5-8 This concept is supported by the fact that in the HCM ICD registry study, the rate of appropriate ICD interventions among patients with a single sudden death risk marker (including family history) did not differ significantly from those with multiple risk markers.6 In this regard, strict adherence to a strategy in which 2 risk factors must be present in an individual patient to consider high-risk status will lead inevitably to an important subset of patients with a single risk factor who are left unprotected from sudden death.3 For these reasons, the recent 2011 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) expert consensus task force guidelines for HCM considered it reasonable to implant an ICD for primary prevention in patients with only 1 risk factor, particularly when the marker is family history of HCM sudden death, unexplained syncope, or massive left ventricular hypertrophy.18 Conversely, it should be emphasized that not all patients with a family history of sudden death should be recommended for prophylactic ICD implantation.3,17,18 Rather, the decision to proceed with ICD placement in this clinical scenario
3
involves consideration of a number of important points, including the strength of evidence supporting HCM as cause of death, the age at which those deaths occurred, and how closely related the deceased are to the patient.3 Furthermore, recent data have demonstrated that the risk of sudden death is extremely low among patients with HCM who have achieved advanced age ( 60 years), even in the presence of conventional risk factors. Therefore, although all decisions regarding prophylactic ICD implantation in HCM should be individualized, aggressive ICD implantation for primary prevention should generally be avoided among elderly patients with HCM. Compared with a number of the other markers that are predicated on discrete cut points, such as wall thickness 30 mm or multiple bursts of nonsustained ventricular tachycardia on ambulatory Holter monitoring, clarifying family history can often be challenging because medical records are often not available or the reports remain ambiguous. For these reasons, it is not uncommon that a certain degree of uncertainty surrounds clinical ICD decision making when only 1 single risk factor of family history is present. Resolving this “grey zone” of risk stratification in HCM requires taking into consideration the desires of the fully informed patient, including a detailed and transparent discussion of the risks and potentially lifesaving benefits of the device, in order to resolve this challenging management decision. Limitations and the Grey Area of Risk Stratification Incorporating family history as a potential clinical risk marker has historically been limited by the enormous variability in the definition used in published studies.4,13-17 For example, some investigators have considered a single sudden death event in any related family member (or only first-degree relatives), whereas others have even required at least 2 firstdegree relatives to have died suddenly for family history to count as a risk factor.4,13-17 This latter definition is particularly problematic and not in line with current practice patterns in the United States, because it implies that when evaluating a patient with HCM who has had a relative with sudden death, the practicing cardiologist must essentially wait until another family member dies of HCM before recommending ICD therapy for primary prevention. These inconsistencies ultimately led to an expert consensus definition provided in the 2011 ACCF/AHA task force guidelines for HCM, which considers 1 sudden death (or more) in a first-degree family member reasonable to consider recommending ICD therapy for primary prevention.18 The strength of this definition is in eliminating potentially unnecessary ICD implantation based on a remote history of sudden death, a clinical scenario in which it is increasingly difficult to determine the precise cause of death. In contrast, sudden deaths that occur in nonefirst-degree relatives are not always necessarily irrelevant to risk assessment. For this reason, ICD decision making for patients with HCM and a history of sudden death in a nonefirst-degree family member should be considered on a case-by-case basis. Most recently, a novel scoring strategy to identify high-risk patients with HCM by predicting sudden death over 5 years was promoted in the European Society of Cardiology 2014
4
guideline standards for the management of HCM.19 However, a recent study validating this risk score in an independent HCM cohort demonstrated that most patients experiencing sudden death or appropriate ICD interventions would not have been considered ICD candidates by the risk score, including some young patients with a family history of sudden death as a risk marker.20 For this reason, decisions regarding risk stratification and ICD decision making in this complex and phenotypically diverse disease continues to require not only physician judgement, applying the current conventional noninvasive risk factors, but also a framework in which fully informed patients participate directly in shared decision making. Genotyping and Risk Stratification The observation that sudden deaths can cluster in related family members initially promoted the idea of a new paradigm in HCM, in which sarcomere mutations could be a predictor of outcome and could identify patients who may benefit from implantation of an ICD as primary prevention based solely on the presence of a particularly “malignant” mutation.13 More recently, however, numerous studies among large cohorts of unrelated patients have demonstrated that sarcomere mutations cannot be classified as either “benign” or “malignant” with respect to predicting an adverse outcome in this disease, although patients with HCM with a pathogenic mutation are at greater risk for adverse events than are those with no identified mutation.14,21 For this reason, a specific mutation cannot be used to identify other patients with HCM in unrelated families as at increased risk for sudden death.22 However, whether private mutations, unique to individual families with HCM, may be responsible for promoting sudden death (or other adverse events) within that specific family remains uncertain but represents an area that deserves closer investigation to help clarify the inevitably complex association that may exist between mutations and outcome. In conclusion, based on > 50 years of observation, and recent well-constructed clinical studies of general and highrisk HCM cohorts, a family history of HCM-related sudden death is an important risk factor that in the appropriate clinical scenario may lead to potentially lifesaving therapy with implantation of a primary prevention ICD to prevent sudden death. Disclosures The author has no conflicts of interest to disclose. References 1. Teare D. Asymmetrical hypertrophy of the heart in young adults. Br Heart J 1958;20:1-8. 2. Maron BJ, Maron MS. Hypertrophic cardiomyopathy. Lancet 2013;381: 242-55. 3. Maron BJ. Contemporary insights and strategies for risk stratification and prevention of sudden death in hypertrophic cardiomyopathy. Circulation 2010;121:445-56. 4. Elliott PM, Poloniecki J, Dickie S, et al. Sudden death in hypertrophic cardiomyopathy: identification of high risk patients. J Am Coll Cardiol 2000;36:2212-8.
Canadian Journal of Cardiology Volume - 2015 5. Maron BJ, Shen W-K, Link MS, et al. Efficacy of implantable cardioverter defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med 2000;342:365-73. 6. Maron BJ, Spirito P, Shen W-K, et al. Implantable cardioverterdefibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy. JAMA 2007;298:405-12. 7. Maron BJ, Spirito P, Ackerman MJ, et al. Prevention of sudden cardiac death with the implantable cardioverter-defibrillator in children and adolescents with hypertrophic cardiomyopathy. J Am Coll Cardiol 2013;61: 1527-35. 8. Vriesendorp PA, Schinkel AF, Van Cleemput J, et al. Implantable cardioverter-defibrillators in hypertrophic cardiomyopathy: patient outcomes, rate of appropriate and inappropriate interventions, and complications. Am Heart J 2013;166:496-502. 9. Christiaans I, van Engelen K, van Langen IM, et al. Risk stratification for sudden cardiac death in hypertrophic cardiomyopathy: systematic review of clinical risk markers. Europace 2010;12:313-21. 10. Rowin EJ, Maron MS, Casey SA, et al. Evidence for reduced mortality in an adult cohort with hypertrophic cardiomyopathy. Circulation 2013;128:A13294. 11. Maron BJ, Braunwald E. Evolution of hypertrophic cardiomyopathy to a contemporary treatable disease. Circulation 2012;126:1640-4. 12. Maron BJ, Bonow R, Salberg L, Roberts W, Braunwald E. The first patient clinically identified with hypertrophic cardiomyopathy. Am J Cardiol 2008;102:1418-20. 13. Watkins H, Rosenzweig A, Hwang DS, et al. Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. N Engl J Med 1992;326:1108-14. 14. Ackerman MJ, VanDriest SL, Ommen SR, et al. Prevalence and agedependence of malignant mutations in the beta-myosin heavy chain and troponin T gene in hypertrophic cardiomyopathy. J Am Coll Cardiol 2002;39:2042-8. 15. D’Andrea A, Caso P, Severino S, et al. Prognostic value of intra-left ventricular electromechanical asynchrony in patients with hypertrophic cardiomyopathy. Eur Heart J 2006;27:1311-8. 16. Elliott PM, Gimeno JR, Tome MT, et al. Left ventricular outflow tract obstruction and sudden death risk in patients with hypertrophic cardiomyopathy. Eur Heart J 2006;27:1933-41. 17. Bos JM, Maron BJ, Ackerman MJ, et al. Role of family history of sudden death in risk stratification and prevention of sudden death with implantable defibrillators in hypertrophic cardiomyopathy. Am J Cardiol 2010;106:1481-6. 18. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2011;58:e212-60. 19. Elliott PM, Anastasakis A, Borger MA, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: The Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014;35:2733-79.
Martin S. Maron ICD for Family History of Sudden Death 20. Maron BJ, Casey SA, Garberich RF, Rowin EJ, Maron MS. Independent assessment of the European Society of Cardiology sudden death risk model for hypertrophic cardiomyopathy. Am J Cardiol, in press. 21. Van Driest SL, Ackerman MJ, Ommen SR, et al. Prevalence and severity of benign mutations in the beta-myosin heavy chain, cardiac troponin T,
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and alpha-tropomyosin genes in hypertrophic cardiomyopathy. Circulation 2002;106:3085-90. 22. Maron BJ, Maron MS, Semsarian C. Genetics of hypertrophic cardiomyopathy after 20 years: clinical perspectives. J Am Coll Cardiol 2012;60:705-15.