Correspondence *Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA

Email gersh.bernard@mayo.edu

The case

A 47-year-old woman with obstructive hypertrophic cardiomyopathy (HCM) presented with severe chest pain with both atypical and exertional features. Her symptoms had initially improved with verapamil, but had recently progressed despite the addition of -receptor antagonists. She had no other symptoms, no history of other cardiac disease or hypertension, and no family history of either HCM or sudden cardiac death (SCD). A loud (grade III/VI), diffuse systolic ejection murmur was heard over the precordium.

Resting electrocardiography and transthoracic echocardiography were performed. The patient's left ventricular cavity was small with severe asymmetric ventricular septal hypertrophy (maximum thickness 26 mm) and hyperdynamic systolic function. Systolic anterior motion of the mitral valve was present and was closely related to the development of a dynamic left ventricular outflow tract gradient (31 mm Hg at rest, 74 mm Hg after amyl nitrite administration) and mitral regurgitation. Thallium 201 stress perfusion imaging showed lateral wall ischemia. Coronary angiography revealed no overt coronary artery disease or myocardial bridging. Intracoronary, Doppler-derived flow-velocity measurements of the patient's coronary flow reserve were carried out following administration of adenosine as intracoronary boluses (maximum bolus dose 36 g), revealing an impaired flow reserve. The maximum ratio of peak diastolic to baseline coronary flow velocity following adenosine administration was 1.8 in the left anterior descending artery and 1.6 in the left circumflex artery (normal ratio >3.0).

During the first 8 h of ambulatory electrocardiographic recording with a Holter monitor, the patient developed a mild sinus tachycardia. At about 16:00 h, her ventricular rate accelerated to about 150 beats/min, with mild ST-segment depression in lead V5 (Figure 1A,B). Polymorphic ventricular tachycardia developed within the next 10 min, and rapidly degenerated into ventricular fibrillation (Figure 1C). The patient was successfully resuscitated within 3 min by witnesses and suffered no neurological sequelae. She had experienced no prodromal symptoms or ventricular ectopy apart from one premature ventricular beat recorded in the preceding 8 h of ambulatory electrocardiographic monitoring. Of note, the patient continued taking her verapamil and -blocker throughout these clinical evaluations.

Figure 1 Ambulatory electrocardiographic recording of the onset of sudden cardiac death in a patient with hypertrophic cardiomyopathy.

(A) Plot of heart rates during daytime activity. The patient's heart rate increased to about 150 beats/min at 16:00 h. (B) Electrocardiogram of the patient at 16:00 h showing the onset of ventricular flutter. The results revealed ST-segment depression in lead V5 during the initial episode of sinus tachycardia. (C) Electrocardiogram showing rapid development of the patient's heart rhythm from sinus tachycardia to ventricular flutter and, finally, ventricular fibrillation.

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Surgical septal myectomy was performed to reduce the outflow-tract obstruction, and a cardioverter-defibrillator was implanted. The defibrillator has not discharged since implantation 8 years ago, and the patient has survived with no history or evidence of sustained ventricular arrhythmias. Following septal myectomy she has also remained free from all other cardiovascular symptoms.

Discussion of diagnosis

HCM is a common, inheritable cardiac disorder with a prevalence of 1 per 500 people in the general population.¹ The disorder affects sarcomeric proteins, resulting in myocyte disarray, cardiac fibrosis and myocardial hypertrophy. HCM can be detected by physical examination and electrocardiography. Abnormalities include left ventricular hypertrophy, systolic ejection murmur that increases with preload-reducing maneuvers such as Valsalva strain, squat-to-stand movement, or both. Two-dimensional echocardiography can also help to establish the diagnosis. The typical finding is myocardial hypertrophy without local or systemic etiologies. Continuous-wave Doppler imaging can reveal the presence of left ventricular outflow tract obstruction at rest or following exercise, Valsalva strain, or provocative testing with amyl nitrite. Most patients with HCM have mild cardiac morbidity, but SCD is a catastrophic complication that affects 2–4% of children and 1–2% of adults annually.² Careful evaluation of the patient's personal and family history can help to identify patients at increased risk of SCD. Maximum exercise tests and ambulatory electrocardiographic monitoring are also useful.

This case describes a patient with HCM who was successfully resuscitated after the onset of a lethal arrhythmia captured by multilead ambulatory electrocardiographic monitoring. Such cases are rare because of the unpredictable nature of SCD.^{3, 4, 5, 6} Although the underlying mechanisms of SCD in patients with HCM are poorly understood, arrhythmias might arise from a complex interplay between an electrically vulnerable myocardial substrate and various triggers including autonomic dysfunction, abnormal vascular responses and hemodynamic disturbances. Certain arrhythmias, including sustained monomorphic ventricular tachycardia and various supraventricular tachycardias, have also been observed during the onset of ventricular fibrillation in HCM patients. The observations in this report are consistent with a previously described arrhythmogenic mechanism in which supraventricular tachycardia induces ventricular flutter and subsequent fibrillation.

Myocardial ischemia is also an established complication in HCM;^{7, 8} it is aggravated by factors affecting myocardial oxygen supply, such as small-vessel disease and impaired flow reserve, and those affecting oxygen demand (i.e. myocardial hypertrophy, obstruction, or diastolic dysfunction). In this patient, radionuclide imaging showed the presence of myocardial ischemia, and intracoronary blood-flow-velocity measurements revealed impaired coronary flow reserve. During ambulatory electrocardiographic monitoring, she developed sinus tachycardia, with evidence of ischemia immediately preceding arrhythmia. Both of these cardiac abnormalities have been featured in other reports of SCD in HCM patients, captured by electrocardiography.^{3, 4, 5, 6}

In adult patients with HCM, abnormal myocardial perfusion revealed by radionuclide imaging has been associated with annual cardiac death rates higher than 3%.⁹ Similarly, Cecchi et al.⁹ have reported an association between such impairment, progression of heart failure and incidence of SCD. The pathophysiological mechanisms underlying impaired coronary flow reserve in HCM are unclear, but the condition could be caused by almost maximum vasodilatation in the basal state.¹⁰ In addition to external factors that precipitate ischemia, such as heightened adrenergic tone, the histologic abnormalities in the myocardium of patients with HCM could predispose towards the creation of micro re-entry circuits, which could degenerate into lethal arrhythmias.¹¹ Increased sympathetic activity preceded the onset of SCD in this patient, and has frequently been observed in patients with HCM who have died suddenly. Upward titration of this patient's medications and septal myectomy might have helped to ameliorate her risk of SCD, but the onset of SCD is a major indication for defibrillator implantation.

Treatment and management

The major aims of disease management in HCM are relief of cardiac symptoms and monitoring the risk of SCD. All patients with HCM are advised to avoid vigorous physical exercise, as this is associated with increased incidence of SCD. Negative inotropic medications, such as -adrenergic receptor antagonists, calcium-channel blockers and disopyramide, can provide effective relief of symptoms, including angina, exertional dyspnea, and syncope or presyncope. For symptomatic patients with obstruction who are unable to tolerate medications or whose symptoms persist despite medical treatment, the main therapeutic options are surgical septal myectomy and percutaneous septal ethanol ablation. Surgical myectomy is considered the gold standard treatment and provides a substantial reduction in left ventricular outflow tract obstruction, improved coronary flow reserve and long-term symptom relief in more than 90% of patients with HCM. Although the incidence of sudden death following surgical myectomy is reportedly low,¹² prevention of SCD is not an indication for septal reduction therapy. Selection of suitable candidates for surgical myectomy or septal ablation is individualized, with consideration of the associated risks for each procedure. Dual-chamber pacing is reserved for the minority of patients who have contraindications to either surgery or septal ablation.

Risk stratification of patients with HCM can help to reassure patients at low risk of SCD and identify high-risk patients who could benefit from implantation of a prophylactic cardioverter-defibrillator. Established risk factors for SCD in patients with HCM include a personal history of SCD, nonsustained ventricular tachycardia, abnormal vascular response to exercise, a family history of SCD due to HCM, massive myocardial hypertrophy, and recurrent unexplained syncope. Outflow tract obstruction has been associated with adverse outcomes in several studies, but its prognostic significance remains controversial. Electrophysiology studies involving induction of ventricular tachycardia and ventricular fibrillation in patients with HCM have been described, but their value when compared with noninvasive methods is unclear. Screening with electrocardiography and echocardiography should be recommended to all first-degree relatives to enable risk stratification of affected family members. All patients with HCM should receive genetic counseling. Although early studies suggested poor survival for patients with some genetic mutations, the presence of such mutations in isolation is not prognostic. Because of this unclear prognostic significance, and the considerable expertise required in genotype analysis, the procedure is not routinely used in the clinical setting. Importantly, with the exception of history of SCD, the positive predictive value of individual risk factors is relatively low (about 10%).¹³ Absence of all the established risk factors, however, has high specificity.

Although recommendations for prophylactic therapy with a cardioverter-defibrillator will depend on the individual case, this treatment should be considered for patients with a history of SCD or multiple risk factors. When cardioverter-defibrillators are implanted for primary prevention of SCD, the annual rate of device discharge for therapy of lethal arrhythmia is 4–5%, but when they are implanted for secondary prevention of SCD, the device discharge rate exceeds 11% per year.¹⁴ The occurrence of SCD in patients with HCM is characteristically heterogeneous, with intervals of several years between such events. Until the underlying mechanisms of SCD associated with HCM have been elucidated, all patients considered to be at high risk of SCD should receive cardioverter-defibrillator therapy.

Conclusion

Management of HCM should focus on reducing severe cardiovascular symptoms and identifying patients at high risk of SCD. The underlying cause of SCD in patients with HCM is poorly understood, but the importance of myocardial ischemia is increasingly recognized. Myocardial ischemia carries prognostic implications, and might be altered by established therapies such as physical activity recommendations, -adrenergic antagonists or septal myectomy. The effect on myocardial ischemia of novel therapies such as percutaneous ethanol ablation is, however, unclear. For patients at increased risk of SCD, the standard therapy remains implantation of a cardioverter-defibrillator.

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Subject areas under which this article appears: Intervention | Cardiomyopathy and heart failure