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Left Ventricular Outflow Tract Obstruction
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Patients with LVOTO should maintain hydration at all times, avoid excessive alcohol consumption, and maintain a healthy weight. Arterial and venous vasodilators should be avoided. Rapid AF is often poorly tolerated in patients with LVOTO and should be promptly managed with cardioversion. Digoxin is contraindicated because of the positive inotropic effects.1
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Medical therapy should be considered the first-line therapy for the relief of symptoms in patients with obstructive HCM. β-Adrenergic blocking agents are usually the drugs of choice.1,4,94,165,166,167,168,169,170 Theoretic actions of β-blockers include decreased heart rate response to exercise, relief of angina by a decrease in myocardial oxygen demand, and improvement in diastolic filling time. Acute hemodynamic studies have shown that β-blocking agents blunt the increase in gradient that occurs with exercise (or isoproterenol), but have little effect on the resting gradient. Clinical studies suggest an improvement in angina, exercise tolerance, and syncope in 60% to 80% of patients. However, only approximately 40% of patients continue to have sustained symptomatic improvement.165,166,171 The dosage of β-blocker should be titrated to symptom relief or to obtain a resting heart rate of < 60 bpm.
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Nondihydropyrine calcium channel blockers—specifically, verapamil and diltiazem—are also of value in the treatment of HCM,66,172,173,174,175,176 particularly if β-blockers are contraindicated or ineffective.1 By preventing calcium influx, they not only decrease inotropy and chronotropy, but also improve abnormal diastolic relaxation.66,175,176,177 Verapamil is used most frequently because of its minimal effect on afterload. Clinical studies have shown a decrease in both basal and provoked gradients during acute drug intervention with verapamil. Verapamil has been shown to improve exercise tolerance by 20% to 30% in short-term follow-up. Calcium channel blockers may improve angina to a greater degree than β-blockers, but sustained symptomatic improvement is seen in < 50% of patients. The dose of verapamil should be titrated up to 480 mg/d to obtain a resting heart rate of 60 bpm.
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A small subset of patients can deteriorate hemodynamically with verapamil, presumably because of a lowering of afterload.178 This deterioration occurs particularly in the presence of severe outflow tract gradients (≥ 100 mm Hg), high diastolic filling pressures, and elevated pulmonary artery systolic pressures.1 Diltiazem has greater vasodilating properties and should be considered when there is intolerance or contraindications for β-blockers or verapamil.1 Dihydropyridine calcium channel blockers should be avoided in patients with LVOTO because these pure vasodilators can increase the severity of the outflow tract by reducing afterload.
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Disopyramide is used to treat patients with obstructive HCM1,4,168,169,170,179,180 by reason of its negative inotropic effect. Concomitant β-blockade may be important to prevent rapid AV node conduction, particularly during exercise or with coexistent AF.1,179 It can also be used together with verapamil. The dose of disopyramide required to produce symptomatic benefit is between 300 to 600 mg/d. The corrected QT interval needs to be monitored at the initiation of disopyramide and dose reduced if > 480 ms.1 The anticholinergic adverse effects of the drug can limit its usefulness in older patients. Contraindications to its use include glaucoma, prostatism, and concomitant medication with QT-prolonging drugs.1
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Septal Reduction Therapy
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For patients who have an LVOTO gradient ≥ 50 mm Hg, moderate-to-severe symptoms (New York Heart Association functional class III-IV), or recurrent exertional syncope despite maximally tolerated drug therapy, other treatment options such as septal myectomy, septal ablation, or dual-chamber pacing should be considered.1,4
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Surgical septal myectomy is the gold standard therapy for patients with obstruction and severe drug-refractory symptoms when performed in experienced surgical centers.1,4,181,182,183,184,185,186,187,188 The procedure consists of a transaortic resection of a small amount of muscle from the proximal to mid-septal region (Morrow procedure). This enlarges the LV outflow tract and significantly decreases or totally abolishes LVOTO in 90% of patients. In patients with concomitant mitral regurgitation secondary to SAM of the mitral valve, mitral regurgitation usually diminishes as a result of the myectomy.1,4,189,190
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A more extensive myectomy procedure is sometimes performed191,192 when there is mid-cavity obstruction. However, follow-up data are more scarce for this more extensive procedure.1 In patients with abnormalities of the papillary muscle, dissection and reduction of the anomalous papillary muscle apparatus may also be performed, as well as mobilization or realignment.193,194
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Mitral valvuloplasty or plication in combination with myectomy is used in some patients with elongated mitral valve leaflets.195,196,197 Mitral valve replacement is generally performed only when there is severe and unrepairable disease of the mitral valve.1 Simultaneous mitral valve surgery is necessary in 11% to 20% of patients.1 Another proposed surgical technique consists of cutting the thickened secondary mitral valve chordae combined with a shallow septal muscular resection.198
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In large-volume centers, the operative mortality for septal myectomy is < 1%,199,200 but the risk is higher (3%-4%) in elderly patients who require other procedures, such as aortic valve replacement, mitral valve repair, or coronary artery bypass grafting. Complications (AV nodal block, ventricular septal defect, and aortic regurgitation) of surgery are uncommon.1,110,201,202,203
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Alcohol septal ablation (ASA) is a procedure in which alcohol is infused in the septal perforator arteries in order to cause necrosis and scarring of the proximal interventricular septum.1,4,204,205,206 The subsequent wall thinning and remodeling of the basal septum results in reduction of the LVOTO (Figs. 59–20 and 59–21).
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Several centers have reported successful short-term outcomes following septal ablation.205,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222 The major complication of ASA is complete heart block, which, with small doses of alcohol and guidance with myocardial contrast echocardiography, occurs in 7% to 20% of patients.1,4,221,222,223,224 Patients are more likely to experience complete heart block if left bundle branch block is present prior to the ablation procedure.1,4,221,222,225,226 Other complications of septal ablation include coronary artery dissection, excessive myocardial infarction from leakage of the alcohol into other coronary arteries, ventricular septal defects, and myocardial perforation. A maximum LV wall thickness < 16 mm at the point of leaflet-septal contact is a risk factor for ventriculoseptal defects in both ASA or myectomy.1 The periprocedural mortality is comparable to myectomy.1,221,222
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Current guidelines1,4 recommend a thorough anatomic and functional evaluation of the septum, mitral valve leaflets, and subvalvular apparatus to guide the choice of invasive septal reduction therapy. ASA may be less effective if extensive septal fibrosis is demonstrated on CMRI and in cases of massive septal hypertrophy. Septal myectomy is preferred in the presence of other abnormalities requiring surgical intervention.
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Dual-Chamber Pacing for Left Ventricular Outflow Obstruction
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Dual-chamber pacing from the right ventricular apex can decrease the outflow tract gradient as a result of alteration of ventricular contraction and a decrease in systolic projection of the basal septum into the LV outflow tract. It may also induce a chronic remodeling effect during continuous pacing with enlargement of the LV cavity and a further decrease in LVOTO.1,2,4,94,227
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Several randomized trials have shown a decrease in outflow tract gradient of 25% to 40% of baseline values, but this was not associated with any improvement in quality of life scores or exercise capacity.228 Nevertheless, dual-chamber pacing may be useful in selected patients with resting or provocable LVOTO ≥ 50 mm Hg, sinus rhythm, and drug-refractory symptoms who have contraindications for ASA or septal myectomy or are at high risk of developing heart block following ASA or septal myectomy.1 Candidates for dual-chamber pacing also include patients who have significant bradycardia so as to facilitate an increased dosage of medication and patients who need an automatic defibrillator as a primary treatment.1
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There are some technical considerations when using pacemaker therapy for treatment of patients with HCM.229,230 Pacing or sensing the atrium, in addition to pacing the ventricle, is necessary to maintain the hemodynamic contribution of atrial contraction. There is an optimal AV delay for maximizing hemodynamic performance (Fig. 59–22).231,232 If the paced AV interval is too short, it may increase left atrial pressure and reduce preload, whereas an overly long AV delay can result in incomplete pre-excitation of the right ventricle with suboptimal reduction in gradient. It is necessary to have the pacemaker tip placed in the apex of the right ventricle to achieve the maximum reduction in gradient, and pacing parameters need to be optimized to achieve maximum pre-excitation of the right ventricular apex with minimal compromise of LV filling.
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Treatment of Nonobstructive Cardiomyopathy
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β-Blockers and calcium channel blockers can been used to improve diastolic filling in symptomatic patients with normal LV ejection fraction and no resting or provoked LVOTO.1,4,94 Diuretics can decrease elevated filling pressures.
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For patients with reduced ejection fraction (< 50%), general guidelines for chronic heart failure apply, including the use of renin-angiotensin-aldosterone system inhibitors and diuretics.1,4 Cardiac transplantation is the only therapy for patients who have severe symptoms and are unresponsive to conventional treatments. Post-transplantation survival is similar or better than for other disease (75% at 5 years; 60% at 10 years).94
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Both β-blockers and calcium channel antagonists are the recommended pharmacologic options for angina, after excluding LVOTO or obstructive epicardial coronary artery disease.1,4
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Prevention of Sudden Cardiac Death
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Individuals with HCM are advised against participation in competitive sports and intense physical activity to reduce their risk of sudden ventricular arrhythmia.1,233,234,235,236 Low-to-moderate levels of aerobic exercise are permitted as part of a healthy lifestyle after careful risk assessment.
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Amiodarone has been shown in retrospective nonrandomized trials to be associated with improved survival in young HCM patients with nonsustained ventricular tachycardia, but there are no randomized trial data to suggest that antiarrhythmic agents in general improve survival in patients with HCM.1,4,152,155,237,238 For this reason, implantation of an implantable cardioverter-defibrillator (ICD) is the most effective and reliable treatment option for protecting patients against SCD.
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Estimation of SCD risk should be a routine part of clinical management. In adolescents and adults, the risk assessment should comprise clinical and family history, 48-hour ambulatory ECG, transthoracic echocardiogram (or CMRI in the case of poor echo windows), and a symptom-limited exercise test. The decision to recommend an ICD to patients is complex and requires individualized discussion of the long-term risks and benefits of the device.1,4
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ICDs are generally indicated in patients with prior cardiac arrest or sustained spontaneous ventricular tachycardia.1,4 Implantation of ICDs for primary prophylaxis is guided by the presence of a small number of clinical characteristics (see Table 59–2).152 One approach is to consider an ICD in patients with more than one risk factor or when an individual risk factor is deemed sufficient by itself to warrant therapy (eg, multiple sudden deaths in a family or frequent unexplained syncope).4,155 Contemporary evidence suggests that this approach is modestly successful in identifying high-risk patients,239 but it also has some limitations; specifically, it estimates relative and not absolute risk; it does not account for the different effect size of individual risk factors; and some risk factors, such as LV wall thickness, are treated as binary variables when they are associated with a continuous increase in risk.152,154 One proposed solution is to consider other clinical features, such as myocardial fibrosis (determined by contrast-enhanced CMRI), LV apical aneurysms, and the inheritance of multiple sarcomere protein gene mutations, as arbiters that can be used to guide ICD therapy in individuals who are at an intermediate risk.4,155 An alternative is to estimate risk using a multivariate prediction tool analogous to that used in other scenarios such as coronary artery disease prevention.1,153 In all cases, decisions on ICDs must balance the likely benefit against the lifelong risk of complications and the impact of an ICD on lifestyle, socioeconomic status, and psychological health.1
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Anticoagulation is recommended for patients with AF and HCM.1,4 Despite the absence of randomized controlled trials, a recent exploratory retrospective analysis showed a reduction in thromboembolic events with vitamin K antagonists.160 The CHA2DS2-VASc score (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or thromboembolism, vascular disease, age 65-74 years, sex category [ie, female sex]) does not correlate well with clinical outcome in patients with HCM and is not recommended to assess thromboembolic risk.1,160 A recent systematic review and meta-analysis showed the feasibility of AF ablation in HCM, but more repeat procedures and antiarrhythmic drugs were needed to prevent recurrence.240
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New Drug Targets and Disease-Modifying Drugs
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The growing number of preclinical carriers identified through genetic testing and family screening has led to increased interest in the development of new therapeutics that can inhibit or attenuate the development of the HCM phenotype.241,242 Potential strategies that are under evaluation include small molecules that interfere with cross-bridge kinetics, manipulation of myofilament calcium sensitivity, modification of calcium cycling/homeostasis (eg, through late-sodium current inhibition), inhibition of fibrosis-promoting pathways and mediators, modification of cardiomyocyte energy metabolism, and genetic therapies such as exon skipping and RNA interference to reduce expression of mutant missense transcripts.43,241,243
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All HCM patients who wish to become pregnant should be given prenatal counseling about the risk of transmission of disease to their offspring (autosomal dominant inheritance pattern with 50% risk for transmission to each child) and the risks associated with pregnancy.1 Patients with HCM usually tolerate pregnancy well if they are not severely symptomatic prior to conception, but should be managed by expert teams throughout.1 Echocardiography is recommended each trimester or in the presence of new symptoms.
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If patients have been on treatment with β-blockers or calcium channel blockers, these drugs should be continued throughout the pregnancy. β-Blockers are also indicated in the presence of new symptoms related to LVOTO,1 with close monitoring of fetal growth. Verapamil, diltiazem, and disopyramide can be used when benefits are judged to outweigh potential risks.1 Low-dose diuretics may be required if pulmonary congestion occurs. Birth should be planned and take place in a high-risk center. Epidural and spinal anesthesia should be used cautiously given the risks of vasodilation and hypotension in the presence of significant LVOTO, but are not contraindicated in current guidelines.1 Cesarean section should be considered in cases of severe LVOTO, preterm labor in patients receiving oral anticoagulant drugs, and severe heart failure symptoms.1