Hypertrophic cardiomyopathy (HCM), defined clinically by the presence of hypertrophy of a nondilated left ventricle without loading conditions or other recognized causes of hypertrophy, occurs in 1 per 500 individuals in the general population, with approximately 700,000 cases in the US population.¹ HCM, inherited with an autosomal dominant Mendelian pattern, is the most common familial heart disease and the most common cause of sudden death in athletes and adolescents. HCM is caused by 1 of more than 1500 different mutations of genes encoding sarcomeric proteins. This genetic heterogeneity and the diverse and unpredictable phenotypic expressions, clinical manifestations, and prognosis limit the value of genetic testing or projections based on affected family members. The vast majority of individuals who are genotype positive/phenotype positive are asymptomatic or minimally symptomatic and are undiagnosed. Heart failure is the most common clinical presentation of HCM in adults. Diagnosis may be difficult due to compensating adjustments in lifestyle that minimize symptoms and nonspecific physical and electrocardiogram (ECG) findings. Elevation of left atrial pressure results from diastolic dysfunction and mitral regurgitation. Limitations of cardiac output in HCM resulting in fatigue, dyspnea, presyncope, and syncope are commonly related to left ventricular outflow tract (LVOT) obstruction and low end-diastolic volume because of diastolic dysfunction. LVOT obstruction (LVOT pressure gradient ≥30 mm Hg) is present in one-third of HCM patients at rest and in an additional one-third with provocation with Valsalva maneuver, nitroglycerin, post-extrasystolic potentiation, or exercise echocardiography, a preferred method of evaluating patients with no resting LVOT gradient but marked exercise tolerance. The presence of LVOT obstruction is a predictor of HCM-related progressive heart failure and heart failure death,² and relief of obstruction surgically results in better survival than achieved by patients without this treatment.³ Relief of LVOT obstruction is a principle goal of both medical and septal reduction therapies.

The cardiac surgeons Drs. Brock and Morrow coined the term functional aortic stenosis in the 1950s to describe the absence of expected LVOT obstruction in the cardioplegia-arrested heart during open heart surgery, and in the 1960s, Braunwald et al⁴ used the newly developed techniques of left heart catheterization to investigate the pathophysiology of obstructive HCM. These hemodynamic studies demonstrated highly variable LVOT obstruction depending on physiologic and pharmacologic maneuvers, which altered loading conditions and contractility (Fig. 49-1). The advent of echocardiography in the early 1970s introduced a powerful new tool for understanding the pathophysiology, diagnosis, and prognosis of HCM and for monitoring treatment of HCM (Figs. 49-2 and 49-3). LVOT obstruction results from several mechanisms, including narrowing of the LVOT by septal hypertrophy, anterior location of the mitral valve encroaching on the LVOT, and systolic anterior motion (SAM) of the anterior mitral valve leaflet leading to SAM-septal contact (see Figs. 49-2 and 49-3). The anterior leaflet of the mitral valve is longer in patients with HCM, and this favors its sail-like movement into the LVOT resulting in (1) a pressure gradient between the left ventricle (LV) and aorta and (2) a posteriorly directed jet of mitral regurgitation (see Fig. 49-3C). In symptomatic patients without a resting LVOT pressure gradient, provocation with Valsalva maneuver (see Fig. 49-1B) or exercise echocardiography must be considered. LVOT obstruction adversely impacts long-term outcomes with respect to morbidity and mortality. Recently, cardiac magnetic resonance imaging (MRI) has become a valuable adjunctive imaging strategy, offering greater spatial resolution and detection of hard-to-see structures by echocardiography, including LVOT membranes, anomalies of the mitral subvalvular apparatus, focal segmental LV hypertrophy, and apical abnormalities. Contrast-induced MRI hyperenhancement techniques provide an estimate of myocardial fibrosis, with absence of hyperenhancement being associated with lower risk of sudden death (SD) and hyperenhancement of ≥15% of LV mass being associated with a doubling of risk of SD.¹

Treatment of patients with obstructive HCM is aimed at relief of symptoms and preventing SD (Table 49-1). Strategies to achieve the latter include abstaining from intense competitive sports and implantable cardioverter-defibrillator (ICD) implantation in high-risk patients,^5,6 as well as treatment strategies to reduce LVOT obstruction. The 2011 American College of Cardiology (ACC)/American Heart Association (AHA) guideline statement “stand alone” Class I indications for ICD are prior cardiac arrest and sustained ventricular arrhythmias (ventricular fibrillation [VF] or ventricular tachycardia [VT]); Class II indications are SD in a first-degree relative, LV wall thickness ≥30 mm, and unexplained syncope.⁵ Other SD risk factors to be considered include nonsustained VT and abnormal blood pressure response to exercise. In a 2-center longitudinal study of 1000 patients with HCM presenting at 30 to 59 years of age, 5- and 10-year survival rates (confined to HCM death) were 98% and 94%, respectively, and were not different from the expected all-cause mortality in the general US population.⁷ This 0.5% per year mortality rate achieved by contemporary management strategies compares favorably to the 3% to 6% per year mortality rate reported in early HCM referral cohorts and the 1.5% per year mortality rate in the 1990s prior to utilization of current strategies. Although not included in the 2011 guideline statement,⁵ MRI-assessed myocardial fibrosis has begun to assume importance in risk stratifying patients.⁷ Late gadolinium enhancement was also a notable omission from the European Society of Cardiology (ESC) risk prediction model,⁶ which when applied to 35 incurred SD events in one study found that 21 (60%) failed to qualify for an ICD.⁸ This and the absence of other potentially high-risk clinical entities (eg, apical aneurysm) suggested that the available guideline statements^5,6 are outdated with respect to SD prevention by ICDs.

Relief of symptoms in patients with obstructive HCM is primarily accomplished by reducing LVOT obstruction by lifestyle changes and pharmacotherapy. Dehydration, the splanchnic pooling that accompanies a large meal, and alcohol consumption increase LVOT obstruction and should be avoided. β-Blockers are the drug of choice for treatment of symptomatic obstructive HCM and act by favorable negative inotropic and chronotropic effects. β-Blockers reduce LVOT gradient and are particularly effective in reducing provoked gradients such as those associated with exertion and have a class I indication in the 2011 guideline statement, which recommends titrating the dose to a resting heart rate of 60 to 65 bpm.⁵ Verapamil also has a Class I indication for symptomatic patients with HCM who do not respond to β-blockers or have contraindications to these drugs. Caution has been recommended in the use of verapamil in symptomatic patients with very large resting LVOT gradients because sudden hemodynamic collapse has been reported. Verapamil has negative inotropic and chronotropic effects similar to β-blockers. Patients with LVOT obstruction who remain symptomatic despite treatment with β-blockers and/or verapamil can be considered for treatment with disopyramide, a Class IA antiarrhythmic drug with negative inotropic effects as well as anticholinergic side effects that hinder widespread usage. In addition, initiation of disopyramide therapy requires in-hospital cardiac monitoring for QT prolongation and arrhythmias (torsades de pointes). Disopyramide has a Class IIa indication in the 2011 guidelines.⁵

For patients whose symptoms and LVOT obstruction prove refractory to optimal pharmacologic therapy, septal reduction therapies with myectomy or alcohol septal ablation are the currently recommended strategies.^5,9 Dual-chamber pacing, which was widely used 20 years ago, was shown in 3 randomized crossover trials to produce a significant improvement in symptoms and exercise tolerance along with a decrease in LVOT gradients in <50% of patients. This led to a Class III indication for pacing as first-line therapy in drug-refractory patients.⁵ The observation that older patients were a subgroup that benefited most led to a 2011 guideline class IIb recommendation for pacing in patients with obstructive HCM who were poor candidates for septal reduction therapy.⁵ The choice of septal reduction strategy (myectomy or alcohol septal ablation) requires a comprehensive evaluation of clinical symptoms, comorbidities, and hemodynamic, echocardiographic, and angiographic features and should incorporate the wishes of a well-informed patient.¹⁰

The Morrow procedure, a transaortic approach to septal myectomy, was initially adopted as safe and effective after presentation of the outcomes of 83 patients in 1975.¹¹ Failure of this procedure in selected patients and a greater appreciation of the diversity of mitral valve structural abnormalities in HCM by Klues and colleagues^12,13 led to alternative surgical techniques to include a more extensive myectomy,¹⁴ as well as approaches to abnormalities of the mitral valve and papillary muscles^15,16 using intraoperative transesophageal echocardiography monitoring. In patients with other cardiac issues such as atrial fibrillation or obstructive coronary disease, additional procedures may be carried out (maze procedure or coronary bypass). In the current era, the risk of surgery in HCM centers of excellence has decreased significantly, with reported mortality for isolated myectomy ranging from 0.0% to 1.5%,^17-20 with some reports of the additional procedures increasing risk to 2% to 3.4%.^17,21 Although long-term outcomes after myectomy have not been evaluated in a randomized controlled trial, observational studies have almost uniformly reported significant improvements in heart failure symptoms, functional capacity, and survival similar to that of the general population.^2,3,7 Surgical myectomy results in permanent reductions in LVOT obstruction, reduces or abolishes mitral regurgitation, and is associated with long-term survival exceeding that of a comparable group of unoperated patients with LVOT obstruction.³ Surgical myectomy results in excellent long-term outcomes and has a Class IIa indication in the 2011 guideline statement.⁵ However, it is an invasive procedure that requires well-honed surgical skills not widely dispersed, and this has resulted in underutilization, particularly in Europe where its demise was inaccurately reported.²⁰

Alcohol septal ablation (ASA) is a percutaneous catheter-based procedure that was first reported by Sigwart²² in 1995. He had previously noted that balloon occlusion of the first septal perforator artery temporarily reduced the LVOT pressure gradient and correctly surmised that delivery of alcohol would produce infarction of the hypertrophied septum and permanent reduction in LVOT gradient. When performed by skilled operators,^23-27 ASA leads to reductions in peak resting or provoked LVOT gradient in >80% of patients. Treatment of the portion of the hypertrophied septum producing the obstruction, that is, the SAM-septal contact area, leads to immediate at least partial relief of obstruction with further decrease over time as thinning of the septum occurs. Reductions in mitral regurgitation parallel the reduction in LVOT obstruction such that patients with severe obstruction and significant SAM-related mitral regurgitation do well with ASA (see Fig. 49-3). Long-term benefits include reduction in LV end-diastolic pressure, regression of LV hypertrophy, reduced size of the left atrium, less atrial fibrillation, and relief of pulmonary hypertension.^23,26-30 ASA results in significant improvement of heart failure symptoms, peak oxygen consumption, and exercise capacity. Similar to the experience with surgical septal reduction, patients after successful ASA also appear to have long-term survival rates comparable to the non-HCM population.²⁷ The less invasive nature of ASA with prompt return to active lifestyle with continued improvement over time has led to a dramatic increase in ASA worldwide, far exceeding the number of surgical myectomy procedures. ASA limitations include the following: (1) less precise targeting of the anterior basal septum, the SAM-septal contact area removed by the surgeon; (2) the need for permanent pacing in a significant minority of patients; and (3) a septal scar with, as yet, uncertain long-term consequences.

Patient Selection for ASA

Patients selected for ASA must qualify based on clinical, hemodynamic, and anatomic criteria. The 2011 ACC/AHA guideline statement and the European guidelines recommend that ASA be offered only to patients with severe symptoms despite optimal medical therapy (usually New York Heart Association (NYHA) functional class III or IV or other exertional symptoms that interfere with everyday activity or quality of life)^5,9 (Table 49-2). The physician should be convinced that relief of obstruction and subsequent favorable changes in mitral regurgitation, diastolic compliance, and LV hypertrophy will result in significant improvement in symptoms. This assessment may be difficult in the patient with severe obstructive HCM and severe chronic pulmonary disease and/or other comorbidities. Hemodynamic criteria required include dynamic LVOT gradient at rest or with physiologic provocation ≥50 mm Hg associated with SAM of the mitral valve. Dynamic outflow obstruction produces a characteristic “spike and dome” arterial waveform, post-extrasystolic potentiation, and the Brockenbrough sign (see Fig. 49-1). Anatomic features that must be present include basal septal hypertrophy ≥15 mm. ASA is discouraged in patients with septal thickness ≥30 mm due to uncertain effectiveness of ASA and in patients with septal thickness <1.5 mm due to the risk of creating a ventricular septal defect.⁵ Patients with midventricular obstruction, subvalvular membrane, intrinsic mitral valve or subvalvular abnormalities, and malpositioned papillary muscles are not good candidates for ASA. Because ASA induces a right bundle branch block in a majority of patients, a preexisting left bundle branch block results in a high probability of complete heart block. The 2011 guideline statement gives a Class IIa indication for surgical myectomy and class IIa for ASA when surgery is contraindicated or high risk (see Table 49-2). ASA may be selected over myectomy by a well-informed patient, and this is a Class IIb indication. The most recent European guideline statement gave ASA and myectomy equal status as therapeutic options in drug-refractory obstructive HCM.⁹ The 2011 guideline statement indicates that ASA should not be done in patients less than 21 years of age and discouraged in those younger than 40. This recommendation to avoid ASA in younger patients is a result of the more complete relief of obstruction with myectomy, concern regarding the arrhythmic potential of the septal scar produced by ASA, and the paucity of a long-term data at the time the guideline statement was drafted. Since then, longer term follow-up has been completed, and although there remain some concerns,^31-33 several studies have reported favorable outcomes in younger patients after ASA, with survival similar to the age-matched general population and to age-matched HCM patients without obstruction.^34-37