Hypertrophic, restrictive, and infiltrative cardiomyopathies are a diverse group of heart muscle diseases that can culminate in the development of heart failure (HF) with associated risks of sudden death and thromboembolism. Much progress has been made elucidating the molecular pathways involved in these disorders, and the reader is directed to Chapters 68 and 69 of the ninth edition of Braunwald’s Heart Disease for details of natural history and pathophysiology. A contemporary approach to diagnosis and management is presented in this chapter.
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy, with an estimated prevalence of 0.2%. It is defined as left ventricular hypertrophy (LVH) that develops in the absence of excess hemodynamic load (hypertension) or other systemic conditions known to cause increased ventricular wall thickness. Mutations in sarcomere genes cause HCM and are transmitted in an autosomal-dominant fashion. Carriers of pathogenic sarcomere mutations typically do not develop LVH until later in life ( age-dependent penetrance ), and clinical expression may vary dramatically, even within the same family. The general therapeutic considerations for individuals with HCM are symptom management, prevention of sudden death, prevention of thromboembolism, and screening of at-risk family members. The principal pathophysiologic mechanisms of symptoms in HCM are LV outflow tract obstruction with or without mitral regurgitation, diastolic dysfunction, and in a subset, atrial fibrillation.
Management of Left Ventricular Outflow Tract Obstruction
Left ventricular outflow tract obstruction (LVOTO) is caused by Venturi and drag forces, which cause systolic anterior motion (SAM) of the mitral valve and obstruction to the flow through the outflow tract. Mitral regurgitation caused by malapposition of mitral leaflets often accompanies LVOTO. Up to 70% of HCM patients have clinically significant LVOTO (≥30 mm Hg) at rest and/or with provocation by exercise, Valsalva maneuver, or pharmaceuticals. Lifestyle adjustment and medical therapy are usually sufficient to control symptoms related to LVOTO, but about 5% to 10% of patients require nonpharmacologic intervention with either surgical myectomy or alcohol septal ablation (ASA). Patients are advised to avoid medications and situations that worsen obstruction via reduced preload or afterload or increased contractility. Commonly prescribed drugs that worsen LVOTO include vasodilators such as angiotensin-converting enzyme (ACE) inhibitors, diuretics, and digoxin. Culprit recreational activities include alcohol consumption and activities associated with vasodilation and/or dehydration, such as sauna use.
Standard medical therapies for LVOTO are β-blockers and nondihydropyridine calcium channel blockers, such as verapamil and diltiazem, either alone or in combination. Doses of these medications are escalated until symptoms are relieved or limiting side effects develop. Patients who remain symptomatic may derive benefit from the addition of disopyramide, and β-blockers have been shown to reduce the severity of LVOTO and improve angina. Verapamil, and to a lesser extent diltiazem, may also improve symptoms and exercise tolerance, but the vasodilating properties of verapamil may actually contribute to worsening LVOTO in some patients.
Disopyramide, a class I antiarrhythmic drug, reduces LVOTO through its negative inotropic properties. In a multicenter retrospective study of 118 patients with obstructive HCM treated with controlled-release disopyramide (200 to 300 mg twice daily), 66% had a clinical response and avoided surgical myectomy, pacing, or ASA. Clinical responders had a drop in LV outflow tract gradient (from 75 ± 33 to 40 ± 32 mm Hg; P < .001), whereas clinical nonresponders had a more modest hemodynamic benefit (from 75 ± 35 to 63 ± 31 mm Hg). The annual risk of sudden death while taking disopyramide was 0.8%, which was not increased compared with a matched HCM cohort not taking disopyramide. Because disopyramide can increase the QT interval, in-hospital initiation of this medication is advised to allow for continuous electrocardiographic (ECG) monitoring. If the baseline QTc is prolonged, or if the QTc increases by 25%, disopyramide should not be used, nor should it be trialed at a lower dose. Verapamil, diltiazem, or a β-blocker should be prescribed with disopyramide because it can accelerate atrioventricular (AV) nodal conduction. Anticholinergic side effects of disopyramide—such as constipation, dry mouth, and urinary retention—can limit its use, especially in elderly patients. In a multicenter HCM study, 7% of patients discontinued disopyramide because of these side effects.
Patients with significant LVOTO, either resting or provoked, and moderate-to-severe effort intolerance that is refractory to medical therapy should be considered for surgical myectomy. The current surgical approach involves resection of a rectangular section of septal muscle (trough) from the base to midventricle, resulting in increased LV outflow tract area and decreased SAM ( Figure 17-1 ). Typically less than 10 g of muscle tissue is excised, but this should include the area of mitral-septal contact to relieve LVOTO. Unlike the rectangular muscle trough described by Morrow and colleagues, some surgeons advocate extending the myectomy trough toward the apex, where the trough is wider than at the base of the heart. It has become standard practice to perform intraoperative transesophageal echocardiography (TEE) with all myectomies. In a retrospective series, the use of intraoperative TEE has been shown to alter surgical intervention in 9% to 20% of cases, often through the detection of residual obstruction that requires further myectomy.
Mitral regurgitation associated with LVOTO is caused by SAM and incomplete coaptation of anterior and posterior mitral leaflets. This results in posteriorly directed regurgitation, which corresponds in severity to the magnitude of the outflow tract obstruction. Septal myectomy alone—that is, without mitral valve surgery—will effectively resolve mitral regurgitation secondary to LVOTO ( Figure 17-2 ). In contrast, about 10% of HCM patients with mitral regurgitation have structural disease of the mitral apparatus, such as mitral valve prolapse, which results in centrally or anteriorly directed regurgitation. These patients often require mitral valve repair or replacement. Anomalies of the submitral apparatus, including abnormal papillary muscle insertion or orientation, are present in 10% to 20% of patients and may require operative intervention, such as extended myectomy and/or papillary muscle reorientation. Nevertheless, valve replacement is infrequently required to correct anomalies of the mitral apparatus.
Contemporary myectomy at highly experienced referral centers typically results in elimination of LVOTO and improvement in symptoms for the vast majority of patients ( Table 17-1 ). Severe effort intolerance after myectomy is uncommon (<20%) and is associated with advanced age and female gender, not residual LVOTO. Perioperative death is also uncommon (<2%) in the modern era. The postoperative risk of AV block requiring permanent pacing is 5% to 10%. Because most patients will develop left bundle branch block (LBBB) after myectomy, the risk of complete AV block is much higher in patients with preoperative right bundle branch block (RBBB). Late survival after myectomy is good and is similar to age-matched individuals without HCM. Risk factors for cardiovascular events late after myectomy are increased age, concomitant coronary artery disease, female gender, preoperative atrial fibrillation, and atrial enlargement.
|LVOTO (mm Hg, Mean ± SD)||Survival (%)|
|REFERENCE||N||AGE (yr)||BEFORE||AFTER||OPERATIVE MORTALITY (%)||1 yr||3 yr||5 yr||REOPERATION (%)||ppm (%)|
|323||50 ± 14||68 ± 43||17 ± 11||0||99||98||96||3||7.9|
|338 *||47 ± 14||66 ± 32||†||1.5||98||95||83||NR||6|
|289||45 ± 19||67 ± 41||3 ± 8||0.8||98||NR||96||NR||NR|
ASA is a less invasive approach to septal reduction, and it can effectively relieve LVOTO in selected patients ( Table 17-2 ). ASA involves selective delivery of concentrated ethanol (1 to 3 mL) into a septal perforator artery, causing infarction and thinning of the obstructing myocardium. Coronary anatomy is not always suitable to allow ASA, and inappropriate ASA where coronary anatomy is not favorable may be ineffective or may even cause inadvertent infarction of the right ventricle or papillary muscles—with disastrous outcomes. The use of periprocedural contrast echocardiography has been shown to affect 15% to 20% of ASA cases by leading to procedural termination (6%) or target vessel change (11%). Septal thickness should be at least 15 mm to prevent iatrogenic ventricular septal rupture. Patients with midcavitary obstruction do not benefit from ASA.
|LVOTO (mm Hg)|
|REFERENCE||N||AGE (yr)||ETHANOL (mL)||BEFORE||AFTER||PROCEDURAL MORTALITY (%)||IN-HOSPITAL VF/VT (%)||1-YEAR SURVIVAL (%)||PPM (%)|
|138||64 ± 21||1.8 ± 0.5||80 ± 50||10 ± 19||1.4||0.7||93.5||20|
|91||54 ± 15||3.5 ± 1.5||92 ± 25||8 ± 17||2.2||4.4||NA||4|
|329 *||58 ± 15||0.8 ± 0.4||72 ± 43||16 ± 22||0.6||NA||NR||NR|
|629||54 ± 15||2.6 ± 1.0||77 ± 31||26 ± 27||1.0||NA||97||8.2|
|279||59 ± 14||2.2 ± 0.8||58 †||12 †||0.3||2.8||97||20|
Similar to myectomy, ASA results in substantial reductions in LVOTO (see Table 17-2 ) and in symptoms for most patients. In a meta-analysis of 42 studies with 2959 patients undergoing ASA, the resting and provoked gradients were reduced from 65 to 16 mm Hg and from 125 to 32 mm Hg, respectively. Although LVOTO improves immediately after ASA, the maximum benefit usually does not develop until adequate thinning of the infarcted segment has occurred, typically after several weeks. When performed at experienced centers, less than 20% of patients are left with significant LVOTO after ASA. Predictors of long-term procedural failure are operator inexperience, immediate postprocedural LVOTO of 25 mm Hg or higher, and low post-ASA peak creatine kinase. The reduction in LVOTO translates into improved symptoms, as most patients are New York Hospital Association (NYHA) class I or II after ASA. In a multicenter Scandinavian series, the percentage of patients who experienced severe effort intolerance (NYHA class III to IV) was reduced from 94% before ASA to 21% at 1 year follow-up. Persistent symptoms after ASA may reflect persistent LVOTO but are more likely to result from concomitant cardiopulmonary comorbidities. Approximately 2% of patients who undergo ASA will die within 30 days, and 2% to 4% will be resuscitated because of ventricular tachyarrhythmias. Patients who die during or immediately after ASA are often critically ill before the procedure. AV block that requires permanent pacing complicates 10% to 20% of ASA procedures. In addition, RBBB commonly develops afterward; accordingly, patients with preexisting LBBB more commonly require a pacemaker. Coronary artery dissection, pericardial tamponade, and iatrogenic ventricular septal rupture are rare complications of ASA that complicate less than 2% of cases. Late complications of ASA are relatively infrequent, although the associated risk of ventricular arrhythmias and sudden death is debated.
It remains controversial whether myectomy or ASA should be considered the preferred treatment modality for patients with LVOTO and medically refractory symptoms. It is unlikely that any controlled, prospective study will compare the efficacy and safety of surgical myectomy to ASA. As such, comparisons are based on retrospective analyses that are subject to considerable selection bias. Meta-analyses have compared ASA to myectomy and found no significant difference in postintervention NYHA functional class or mortality. The American Heart Association/American College of Cardiology (AHA/ACC) consensus document on HCM recommends surgical myectomy as the preferred therapy for patients with medically refractory obstructive HCM. Nevertheless, ASA far outnumbers myectomy, and institutional practice varies considerably. Ultimately, patient preference is often the major factor driving this decision, and providers should appropriately inform patients of the relative merits of each procedure. Nevertheless, certain patient-specific factors do constitute either absolute or relative indications for myectomy over ASA or vice versa. Patients with a need for concomitant surgery, such as coronary artery bypass grafting (CABG) or mitral valve repair, should undergo myectomy. Surgical myectomy is also preferred for individuals with coronary anatomy unsuitable to ASA, severe hypertrophy (interventricular septum [IVS] >30 mm), papillary muscle anomalies, or unusual patterns of hypertrophy. Likewise, most experts agree that young patients are better served with surgical myectomy. Alternatively, patients with medical comorbidities associated with high cardiac surgical risk should undergo ASA.
Ventricular pacing showed initial promise for reducing LVOTO in small studies. In the Multicenter Pacing Therapy (M-PATHY) study, 44 medically refractory patients with a resting outflow tract gradient of 50 mm Hg or higher underwent implantation of a dual-chamber pacer. In this randomized, double-blind crossover study, pacing did not improve exercise capacity or symptoms. The severity of obstruction was improved after 3 months of pacing (76 ± 32 vs. 48 ± 32 mm Hg; P < .001), but gradient reduction did not correlate with symptom improvement or exercise capacity. Accordingly, implantation of a pacemaker is not recommended as a routine treatment of symptomatic outflow tract obstruction. However, if patients have a pacemaker for another indication (e.g., heart block), a trial of pacing can be considered for refractory symptoms. In this setting, it is advised that AV delay be sufficient to allow AV synchrony while maximizing the amount of ventricular pacing.
Therapies for Nonobstructive Hypertrophic Cardiomyopathy
Patients with nonobstructive HCM may experience significant effort intolerance related to diastolic dysfunction and/or microvascular ischemia. Few therapies have been systematically studied in nonobstructive HCM; however, nondihydropyridine calcium channel blockers (verapamil and diltiazem) and β-blockers are empiric first-line therapies. In nonobstructive HCM, diuretics are used as required without excess risk of hemodynamic compromise; this stands in contrast to the situation of LVOTO, in which obstruction can be acutely worsened by decreased preload. In a small, double-blind crossover study of 16 patients with mild symptoms and predominantly nonobstructive HCM, neither nadolol nor verapamil improved exercise capacity or oxygen consumption compared with placebo. However, a trend was seen toward improved symptoms with drug therapy.
Abnormal myocardial energy utilization is an important feature of HCM that is present early in disease pathogenesis and represents a new therapeutic target. One drug that improves myocardial oxygen utilization and has been shown to improve ejection fraction and quality of life in HF is perhexiline, which was studied in a double-blind, placebo-controlled trial of 46 patients with nonobstructive HCM; it significantly improved NYHA functional classification, symptoms, and exercise capacity. These changes were associated with improved myocardial energetics (as assessed by P magnetic resonance [MR] spectroscopy) and diastolic function (as assessed by radionuclide angiography). Although these results are promising, perhexiline is not approved for use by the U.S. Food and Drug Administration (FDA) because of concerns about hepatotoxicity.
Approximately 5% of patients will develop end-stage HCM, characterized by reduced LV ejection fraction with or without dilated remodeling. Survival is substantially reduced in end-stage HCM, and although medical therapy has not been studied in this population, conventional therapies for HF with reduced ejection fraction are advised —β-blockers, ACE inhibitors, and aldosterone antagonists—as is withdrawal of verapamil, diltiazem, and disopyramide. Consensus guidelines do not yet address the appropriateness of cardiac resynchronization therapy in end-stage HCM.
Cardiac transplantation is an option for patients with refractory HF or intractable arrhythmias. Registry data have shown that transplanted patients have favorable long-term survival but wait longer for transplantation than non-HCM patients. Patients with HCM were not included in the pivotal trials of left ventricular assist devices (LVADs) for advanced HF. The feasibility of LVAD therapy has been shown in a small series of patients with end-stage HCM.
Prevention of Sudden Cardiac Death in Hypertrophic Cardiomyopathy
The leading cause of sudden cardiac death (SCD) in young people is HCM. Ventricular tachyarrhythmias underlie these events and are unpredictable. Nevertheless, SCD affects only a minority of patients with HCM, and in patients diagnosed as adults, overall survival is similar to age-matched individuals without HCM. Patients at risk can be identified through comprehensive evaluation for established risk factors of SCD, which include 1) unexplained syncope, 2) family history of SCD, 3) failure to augment systolic blood pressure of 20 mm Hg or more with exercise, 4) nonsustained ventricular tachycardia (VT), and 5) maximal wall thickness of 30 mm or more. Of these, unexplained syncope and family history of sudden death carry the greatest prognostic value. Multiple risk factors identify patients at highest risk ( Figure 17-3 ). The prognostic implications are unresolved for several emerging risk factors, including end-stage remodeling, extensive delayed enhancement on cardiac magnetic resonance imaging (MRI), genotype, possibly LVOTO, and paced ventricular electrogram fractionation. Programmed ventricular stimulation (electrophysiology [EP] testing) is not predictive and is therefore not recommended for risk stratification. No controlled studies of SCD prevention strategies in HCM have been done, but all patients should be advised to avoid activities perceived to increase the risk of SCD, including competitive sports and high-intensity athletic training. Routine physical fitness, however, is not prohibited. Placement of an implantable cardioverter-defibrillator (ICD) is advised for all patients with a history of resuscitated SCD or sustained VT. ICD therapy is an option for primary prevention of SCD in patients judged to be at high risk based on the presence of one or more established risk factors. Medical therapy is largely unproven for prevention of SCD in HCM. Consensus guidelines recommend amiodarone in patients at high risk of SCD who are not candidates for an ICD. Combined epicardial and endocardial mapping and ablation has also been used in selected HCM patients to treat refractory monomorphic VT.
Management of Atrial Fibrillation in Hypertrophic Cardiomyopathy
Atrial fibrillation (AF) is a common arrhythmia in patients with HCM, with an overall prevalence of about 20%. In some patients, the development of AF may significantly worsen symptoms through loss of AV synchrony and/or increased ventricular rate. A strategy of heart-rate control versus rhythm management has not been specifically tested in HCM, but in selected patients, restoration of sinus rhythm can be beneficial. Both amiodarone and disopyramide have been studied in HCM and have an acceptable safety profile in these patients. Because disopyramide can increase AV nodal conduction and accelerate ventricular response to AF, it should be used in conjunction with verapamil, diltiazem, or a β-blocker. The role of nonpharmacologic therapy for AF, such as a surgical Maze procedure or radiofrequency ablation (RFA), is not well established in HCM.
Based on large cohort studies, patients with HCM have an annual risk of stroke and arterial embolic events of approximately 1%. AF further increases the risk of these events by as much as 18-fold. Conventional strategies of assessing risk for stroke and assigning antithrombotic therapy for AF, such as the CHADS 2 score, were not developed for patients with HCM. Consensus guideline recommendations call for anticoagulation of patients with HCM and either persistent or permanent AF. Anticoagulation for paroxysmal AF should be considered for patients otherwise at increased risk for thromboembolism.
Screening at-Risk Family Members for Hypertrophic Cardiomyopathy
All first-degree family members of patients with HCM should be screened for LVH with transthoracic echocardiography and 12-lead ECG. The presence of mild hypertrophy (IVS ≥13 mm or Z score ≥2 in children) is sufficient to make a diagnosis of overt HCM. In addition, findings on ECG may be nonspecific, particularly increased QRS voltage, but these can serve as supportive or confirmatory findings. Because disease may not develop until later in life, screening should be performed on a longitudinal basis, beginning in childhood and concentrated during adolescence and young adulthood, when development of the overt phenotype is most common. Genetic testing is recommended because it can simplify family evaluations by definitively identifying risk, and it can restrict clinical evaluations except where truly needed. A pathogenic sarcomere mutation can be identified in about 50% of patients with HCM. Complete sequencing of a panel of sarcomere genes should be performed on the proband because pathogenic mutations are typically “private” or unique to a family. If present in the index family member (proband), relatives can be tested for the presence of the same mutation; those who are carriers will require clinical follow-up. The clinical management of asymptomatic mutation carriers who have not (yet) developed LVH is undefined. Abnormal myocardial function can be demonstrated in preclinical mutation carriers, including abnormal diastolic function, increased myocardial fibrosis, and abnormal energetics. Nevertheless, medical therapy is not currently indicated in this population, and proscription from competitive athletics is not mandated.