Hypertrophic Cardiomyopathy, Sudden Death, and Implantable Cardiac Defibrillators: Title and subTitle BreakHow Low the Bar?

Hypertrophic cardiomyopathy (HCM) is a relatively common disorder (occurring in approximately 1 in 500 adults in the general population)^{1 - 2} and has the widely recognized clinical findings of massive myocardial hypertrophy and dynamic left ventricular outflow tract obstruction. Once thought to be a disease of unknown etiology, HCM is now recognized as a genetic disorder often caused by a mutation in at least 1 of 12 genes that encode the proteins of the cardiac sarcomere.³

Knowledge about HCM has changed dramatically over the past few decades, by virtue of increased recognition of this disorder due to heightened awareness of the disease and wider use of noninvasive imaging modalities. Initially, HCM was thought to be a deadly disease of the young, because patients presented with severely limiting symptoms (dyspnea, angina, and syncope) or even sudden cardiac death.⁴ However, patients with HCM can present with a wide spectrum of cardiac manifestations. The degree of hypertrophy is highly variable, ranging from only mild hypertrophy to severe massive hypertrophy, with a variable time course of onset. The dynamic left ventricular outflow tract obstruction is only a part of the complex pathophysiologic process affecting these patients, and other abnormalities such as diastolic dysfunction, myocardial ischemia, mitral regurgitation, and cardiac arrhythmias play important roles. Although HCM was once thought to be a disease with an extremely poor prognosis, the majority of patients with HCM are asymptomatic throughout life, and the survival of population-based series of these patients is comparable to that of an age-matched, sex-matched control population.⁵

Despite the relatively benign course for the majority of patients with HCM, this disease continues to be the most common cause of sudden death in young individuals (including trained athletes) and may cause sudden death in patients of all ages.⁶ Sudden death results primarily from ventricular arrhythmias that, in turn, are likely related to an abnormal substrate of disorganized muscle cell structure and a multitude of possible inciting events, such as ischemia, abnormal autonomic milieu, atrial arrhythmias, or bradycardia. However, these devastating events occur infrequently and thus pose a tremendous management dilemma for clinicians.

Implantable cardiac defibrillators (ICDs) are an effective therapy to prevent sudden death in patients with HCM,⁷ but there is no method to consistently identify patients at high risk of sudden death. Data from retrospective studies have identified risk factors associated with an increased incidence of sudden death.^{8 - 9} These risk factors are only clinical surrogates used to attempt to identify an abnormal underlying substrate or triggers of arrhythmia. The positive predictive values of any 1 of these risk factors is less than 20% to 25%.^{2 ,8 - 9} In addition, although the negative predictive value of the risk factors are near 90%, some patients (approximately 3%-5%) without identifiable risk factors die suddenly.^{8 - 9}

In this issue of JAMA, Maron and colleagues¹⁰ present important timely data on the relationship between clinical risk profile and the use and efficacy of ICD intervention in patients with HCM. The authors report data from a multicenter registry study of ICDs implanted in 506 patients with HCM, who underwent follow-up for a mean of approximately 4 years. In these relatively young patients (mean age, 42 years) in whom ICDs were implanted for either secondary prevention or primary prevention, ICD interventions appropriately terminated serious ventricular arrhythmias in 20% of patients. The intervention rates were 11% per year for secondary prevention and 4% per year for primary prevention.

Patients who had received an ICD for only a single risk factor had a similar likelihood of appropriate ICD intervention (ie, device discharge) as did patients with 2 or more risk factors. The measured risk factors included (1) a family history of sudden death due to hypertrophic cardiomyopathy, (2) massive left ventricular hypertrophy, (3) nonsustained ventricular tachycardia on Holter monitoring, and (4) prior unexplained syncope. The authors conclude that ICD interventions for life-threatening ventricular arrhythmias were frequent and highly effective, and recommend that a single marker of high risk for sudden death may be sufficient to justify consideration for prophylactic ICD in selected patients with HCM.

Although any clinician would certainly wish to prevent the devastating consequence of sudden cardiac arrest in such patients, the recommendation to consider ICD implantation for all patients with HCM and a single risk factor must be viewed with caution. Considering that an estimated 500 000 patients with HCM are living in the United States¹ and that nearly 50% of these patients will have at least 1 risk factor,¹¹ the number of potential candidates for ICD implantation is not trivial. The decision to recommend an ICD must include a full discussion with the patient about the potential benefits and risks of the device, including the risks of important complications. In the study by Maron et al,¹⁰ ICD-related complications included infection in 19 patients (4%), hemorrhage/thrombosis in 8 (2%), lead fractures in 34 (7%), and fatal device malfunction in 1. The risk of severe tricuspid regurgitation after device implantation has been increasingly recognized, and this complication may require open-heart surgery in some patients.¹² Moreover, the psychological trauma of inappropriate shocks—reported in 136 (27%) of patients in the current study—in a young, otherwise asymptomatic adolescent has far-reaching consequences that cannot be captured in a registry study.

As Maron et al point out, the patients in their registry were evaluated by institutions that have a large degree of experience and expertise in treating patients with HCM. Thus, the decision to proceed with implantation of an ICD was not necessarily based solely on the finding of any 1 risk factor or on the number of risk factors but most likely on a decision made by an experienced clinician using all available pertinent information about an individual patient. For instance, massive hypertrophy (septal thickness greater than 3 cm) has been implicated as a risk factor for sudden death in patients with HCM, based on several retrospective studies.¹³ However, other studies have shown that an increase in wall thickness alone is not necessarily a significant risk factor if it is not associated with other clinical risk factors.¹¹ Sorajja et al¹⁴ found that young patients (< 30 years) with massive hypertrophy have a high incidence of sudden death but middle-aged or elderly patients with massive hypertrophy do not. Similarly, syncope may result from multiple etiologies, especially in older patients, so that multiple episodes of syncope in a young person may pose a more ominous warning sign than a single syncopal event in an elderly person. A strong family history of a young sibling with known HCM who died suddenly would be more worrisome than that of an older relative who died suddenly from unknown causes.

The study by Maron et al did not include the additive risk of other known factors associated with increased risk of sudden death, such as an abnormal blood pressure response on treadmill testing, concomitant coronary artery disease,¹⁵ and severe left ventricular outflow tract obstruction.¹⁶ Several new modalities, including cardiac magnetic resonance imaging, may aid in further identification of patients at risk for sudden death.¹⁷ The finding of delayed gadolinium enhancement, potentially identifying areas of myocardial fibrosis or scarring—a substrate for ventricular arrhythmia—has shown some promise that warrants further investigation.

The report by Maron et al¹⁰ provides some insight about the possible influence of other interventions on the occurrence of sudden death in patients with HCM. Appropriate ICD discharge was observed in 25% of patients who were receiving amiodarone therapy, indicating that even the most potent antiarrhythmic agent will not prevent sudden death. Appropriate ICD discharge was observed 4 times more frequently in patients who had undergone prior alcohol septal ablation compared with those who had undergone prior surgical myectomy, highlighting the importance of possible detrimental effects of new treatments. Moreover, strenuous exertion is associated with sudden death, even in low-risk patients with HCM.

The sudden death of a young, otherwise healthy patient with HCM is a tragic event, and all efforts should be made to prevent it. All patients with HCM should be assessed for risk of sudden cardiac death as recommended in the American College of Cardiology/European Society of Cardiology Clinical Expert Consensus Document for HCM.⁹ Patients who have experienced cardiac arrest or documented sustained ventricular tachycardia definitely should be considered for implantation of an ICD. Patients with 2 or more risk factors likely present a high enough risk to warrant implantation of an ICD. However, the decision to implant an ICD in any patient, especially one with a single risk factor, must include a thorough and earnest discussion of the accuracy of the current risk assessment tools, the risks and benefits of ICD therapy, and the individual patient's viewpoints on procedures, devices, and death. Such an approach will allow the patient-physician team to arrive at an individualized decision regarding ICD implantation