Hypertrophic Cardiomyopathy Treatment & Management

Evaluation usually can be conducted on an outpatient basis. Inpatient studies and surgical treatment also may be necessary. Medical and surgical therapy are used to reduce ventricular contractility or increase ventricular volume, increase ventricular compliance and outflow tract dimensions, and, in the case of obstructive hypertrophic cardiomyopathy (HCM), reduce the pressure gradient across the LV outflow tract. Paramount to any therapy is reduction in the risk of sudden death by identification of these patients early on and effective medical and/or surgical implantation of an automatic defibrillator. ^[11]

Medications include beta blockers, calcium channel blockers, and, rarely, diltiazem, amiodarone, and disopyramide. ^[12] Antitussives may be administered as needed to avoid coughing.

Research shows that stepwise therapy can reduce high blood pressure in patients with HCM. In a study of 115 HCM patients, including 94 with obstructive HCM, stepwise antihypertensive therapy effectively controlled both obstructive HCM symptoms and hypertension. Average systolic pressure in the obstructive HCM group was reduced from 137 to 131 mm Hg, and uncontrolled hypertension was reduced from 56% at the first visit to 37% at the last. ^{[13, 14]}  

Mavacamten, a first-in-class allosteric inhibitor of cardiac myosin, gained approval form the FDA for adults with symptomatic New York Heart Association class II-III obstructive hypertrophic cardiomyopathy (HCM) to improve exercise capacity and symptoms. Mavacamten modulates number of myosin heads that can enter “on actin” (power-generating) states, thus reduces probability of force-producing (systolic) and residual (diastolic) cross-bridge formation. Excess myosin actin cross-bridge formation and dysregulation of the super-relaxed state are mechanistic hallmarks of HCM.

Approval of mavacamten was based on results from the multicenter, phase 3 EXPLORER-HCM trial (n = 251). Of 123 patients randomly assigned to mavacamten, 92 (75%) completed the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline and week 30 and of the 128 patients randomly assigned to placebo 88 (69%) completed the KCCQ at baseline and week 30. At 30 weeks, the change in KCCQ-OS score was greater with mavacamten than placebo (mean score 14.9 vs 5·4 13.7; difference +9.1; p < 0.0001), with similar benefits across all KCCQ subscales. The proportion of patients with a very large change (KCCQ-OS 20 points or more) was 36% in the mavacamten group versus 15% in the placebo group, with an estimated absolute difference of 21%. These gains returned to baseline after treatment was stopped. ^[15]  

Additionally, the EXPLORER long-term extension trial (EXPLORER-LTE) projected mavacamten was associated with an increase of 4.17 additional quality-adjusted life-years compared with placebo (with or without beta-blocker or calcium channel blocker therapies). ^[16]  

Avoid inotropic drugs if possible; also avoid nitrates and sympathomimetic amines, except in those patients with concomitant coronary artery disease. Avoid digitalis, because glycosides are contraindicated except in patients with uncontrolled atrial fibrillation. Cautious use of diuretics should be exercised because of their potential adverse effect on the LV outflow gradient and ventricular volume.

Transfer

Transfer may be required for further diagnostic evaluation and electrophysiologic device or surgical intervention.

Deterrence/prevention

Patients must abstain from highly strenuous competitive athletic activity and highly strenuous physical exertion, such as shoveling snow or lifting very heavy objects, due to the high risk of arrhythmogenic sudden cardiac death. No acceptable medical recommendation deviates from total abstinence from these activities.

Consultations

Consultations may be indicated with the following specialists:

• Cardiologist

• Cardiothoracic surgeon

• Cardiac electrophysiologist

• Geneticist

Diet

No special diet is required. However, the patient should avoid excessive weight gain.

Left ventricular myomectomy

Left ventricular (LV) myomectomy is used for patients with severe symptoms refractory to therapy and an outflow gradient of more than 50 mmHg, either with provocation or with rest. The procedure typically is successful in abolishing the outflow gradient; most patients have symptomatic improvement for at least 5 years.

The reduction in LV outflow gradient may not correlate with a risk reduction for sudden death or overall mortality. Furthermore, the outflow gradient may increase gradually over time and return to the same level as before, requiring a repeat procedure or additional medical therapy.

Patients who have obstructive hypertrophic cardiomyopathy with low resting gradients and latent obstruction may have limiting symptoms similar to patients with more severe resting gradients. In a series of 749 patients undergoing septal myectomy, 249 had minimal gradients at rest but severe outflow tract obstruction with provocation testing. Symptom relief and survival in these patients was similar to that of patients with severe resting outflow obstruction undergoing myectomy. The authors suggest that septal myectomy may be recommended to patients who have severe outflow obstruction only on provocative testing because survival and symptom relief are excellent, suggesting that dynamic obstruction is the major hemodynamic problem and not diastolic dysfunction. ^[17]

In a retrospective study (1998-2010) that evaluated data from the Nationwide Inpatient Sample regarding the results of ventricular septal myectomy in patients with hypertrophic cardiomyopathy (HCM) with refractory LV outflow tract (OT) obstruction, Panaich et al found an overall mortality of 5.9%; there was an association between age and severity of comorbidities with higher rates of complications and mortality. ^[18]

In a prospective observational study (1991-2012) that evaluated the long-term outcomes (8.3 ± 6.1 y) of myectomy combined with anterior mitral leaflet extension in severely symptomatic patients with HCM, Vriesendorp et al reported no operative mortality, with symptomatic relief similar to the general population. ^[19] Cumulative survival rates at 1 year were 98%; 5 years, 92%; 10 years, 86%; and 15 years, 83%. ^[19]

In a systematic review and meta-analysis of 10 studies comprising 1824 patients for evaluating the efficacy and short- and long-term mortality of surgical myectomy (n = 1019) compared with alcohol septal ablation (n = 805}, Singh et al found no significant difference in symptomatic relief between the two procedures, and outcomes were similar for sudden cardiac death and short- and long-term mortality. ^[20]  However, in a more recent study by Cui et al that assessed the long-term mortality of 3859 patients with obstructive HCM who underwent either alcohol septal ablation (n = 585) or septal myectomy (n = 3274), there was an association between alcohol septal ablation and long-term all-cause mortality relative to surgical myectomy, and its impact on survival was independent of other known factors. ^[21] The investigators suggest that the impact may be influenced by unmeasure confounding patient features.

Mitral valve replacement

Mitral valve replacement is reserved for patients with severe mitral regurgitation due to systolic anterior movement of the mitral valve, particularly when mitral regurgitation (large regurgitant fraction) is associated with the development of congestive heart failure or severe pulmonary hypertension.

Pacemaker implantation has been a proposed treatment for patients with hypertrophic cardiomyopathy (HCM). Studies have shown that pacing the right ventricular (RV) apex to maintain atrioventricular synchrony results in a decrease of the left ventricular outflow tract (LVOT) gradient, with symptomatic and quality-of-life improvements. ^{[22, 1]} A Cochrane review suggested that the benefits of pacing are based on physiologic measures and lacks clinically relevant end-points. ^[23]

Transvenous catheter ablation of the septal region has been performed using selective arterial ethanol infusion to destroy myocardial tissue. ^[24] The procedure involves infusing 96% ethanol down the first septal branch of the left anterior descending artery and inducing a therapeutic infarction of the proximal interventricular septal myocardium.

This leads to a remodeling of the septum, which decreases the marked septal thickening characteristic of hypertrophic cardiomyopathy (HCM) and results in a decrease of the gradient across the left ventricular outflow tract (LVOT). In this manner, the procedure is analogous to a surgical myomectomy, in attempting to decrease the amount of septal ventricular myocardium and thereby reducing the LVOT gradient.

The procedure has been used in clinical practice since the early 1990s and the reported results have been excellent, with significant reduction in symptoms, particularly in the incidence of heart failure. ^{[25, 26]} In many centers, it is the surgical procedure of choice for HCM.

Alcohol septal ablation

Alcohol septal ablation offers some advantages over surgical myectomy in that (1) it does not require surgical incision and/or general anesthesia, (2) the recovery time is shorter, and (3) its results lead to less discomfort and greater patient satisfaction than are reported with surgical myectomy. ^{[22, 1]} In addition, older patients who often have multiple comorbidities may better tolerate alcohol septal ablation than septal myectomy, which has high postoperative risks and complications in this patient population. Note that alcohol septal ablation is not indicated for the pediatric population. ^{[22, 1]}

Complications of alcohol septal ablation and comparison to surgical myectomy

The European Society of Cardiology (ESC) indicates that the main nonfatal complication of alcohol septal ablation is atrioventricular block (7-20%); in addition, it is associated with 4-5–fold increased risk for permanent pacemaker, as well as right rather than left bundle branch block, compared to septal myectomy. ^[9] Moreover, although clinical and hemodynamic effects are seen immediately after setpal myectomy, they may be delayed for up to 3 months following alcohol septal ablation.

There appears to be little benefit to alcohol septal ablation in patients whose septal thickness is 30 mm or more (ie, severe HCM), as compared to septal myectomy. ^[9] The septal myectomy treatment approach visually assesses the anatomy of the LVOT and the mitral apparatus, whereas the alcohol septal ablation approach indirectly ablates the septal perforator artery distribution.

Overall, the procedural mortality for both procedures are similar. ^[9]

Sudden cardiac death occurs in approximately 1% of patients with hypertrophic cardiomyopathy (HCM) each year, and pharmacotherapy has not shown protection against sudden cardiac death. ^{[22, 1]} However, high-risk individuals in whom prophylactic therapy may be indicated may potentially benefit from placement of an implantable cardioverter defibrillator (ICD), which can effectively terminate life-threatening ventricular tachyarrhythmias in the setting of HCM. ^{[22, 1]}

Complications associated with ICD in HCM

There is a 4% reported rate of ICD-associated complications (procedural and over the long term) per year. ^{[22, 1, 27]}  Early complications include the possibility of pneumothorax, pericardial effusion, pocket hematoma, acute pocket infection, and/or lead dislodgment. Complications that may arise late include upper extremity deep venous thrombosis, lead dislodgment, infection, a high defibrillation threshold that may require revision of the the lead, and receipt of inappropriate shocks. ^{[22, 1, 27]}

Pediatric patients appear to suffer a higher rate of inappropriate shocks and lead fractures than adults adults do, predominantly owing to the strain placed on the leads as the children grow and are active. ^{[22, 1, 27]}

Although the procedure to place ICDs is generally safe, defective generators have been known to cause death, high-voltage leads with small diameters have a tendency to fracture, and patients with severe hypertrophy or who are receiving amiodarone may need high-energy output generators or epicardial lead systems. ^{[22, 1, 27]}

Heart transplantation is recommended in specific situations for patients with hypertrophic cardiomyopathy (HCM). The 2011 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines indications for heart transplantation include advanced heart disease and New York Heart Association (NYHA) functional class III or IV symptoms that are refractory to all other interventions. ^{[22, 1]} In addition, transplant referral for refractory symptoms does not require a reduced ejection fraction (EF), and heart transplantation is performed in the presence of preserved EF. ^{[22, 1]}

HCM patient outcome after heart transplant is not different from that of other patients with other heart diseases. ^{[22, 1]}

Atrial fibrillation (AF) is common in hypertrophic cardiomyopathy (HCM). During the clinical course of HCM, approximately 25% of patients will experience AF or atrial flutter. AF is diagnosed by electrocardiography (ECG) during an AF episode, on ambulatory Holter monitoring, or on an event monitor. ^{[22, 1]}  AF causes significant worsening of congestive heart failure, especially in patients with left ventricular (LV) outflow tract (OT) obstruction. Amiodarone is most effective in controlling AF recurrence; however, long-term use of this agent is limited due to its side effects. An alternative antiarrhythmic agent to use in this setting is sotalol. 

AF is associated with an increased risk for embolic stroke. Prevalence of AF is 6% and incidence is 0.8% per year. In patients with paroxysmal or chronic AF, prophylactic anticoagulation is recommended. Prior to starting anticoagulation, determine the individual patient's bleeding risk and compliance. The CHADS2 score (C ongestive heart failure, H ypertension, A ge [>65 y = 1 point, >75 y = 2 points], D iabetes, previous Stroke/transient ischemic attack [2 points]) has not been specifically validated in HCM. Anticoagulants to be considered are warfarin or newer oral agents such as dabigatran or rivaroxaban. 

In patients with symptomatic AF that fails antiarrhythmic therapy, pulmonary vein catheter-based ablation (radiofrequency or cryoablation) should be considered.

In general, women with HCM can safely undergo pregnancy and labor with minimal risks. ^{[22, 1]} However, preconception genetic counseling is advised, and it is essential that the expectant mothers receive careful prepregnancy and pregnancy evaluation and functional assessment. Cesarean delivery is usually not required. ^{[22, 1]}

If the patient's HCM is controlled with medical therapy, then such management should be continued with careful maternal-fetal monitoring. In setting of advanced disease (eg, progressive heart failure, severe diastolic dysfunction, ventricular tachycardia, supraventricular tachycardia, marked left ventricular outflow tract obstruction [LVOT]), management with a multidisciplinary team that includes a materal-fetal specialist and cardiologist is crucial. ^{[22, 1]}

Pillarisetti et al reported that predictors of improvement in left ventricular dysfunction in patients with peripartum cardiomyopathy appear to include postpartum diagnosis and white/Hispanic race. ^[28]

Data spanning 2 decades and 160,000 deliveries from an institutional review of pregnant women with hypertrophic cardiomyopathy showed a small number of completed pregnancies (23 completed in 14 patients) and no maternofetal deaths. ^[29] The overall morbidity was 26%, with a 13% incidence of peripartum congestive heart failure. ^[29]

Federal Motor Carrier Safety Administration recommendations

The Federal Motor Carrier Safety Administration (FMCSA) sets medical standards and guidelines for commerical motor vehicle drivers. Current guidelines state that individuals with hypertrophic cardiomyopathy (HCM) should not be certified to drive CMV. However, the Medical Expert Panel (MEP) recommends that the guidelines be changed to reflect the fact that not all individuals with HCM are at risk for sudden incapacitation or death. Specifically, the panel recommends that individuals who meet all the following criteria are at low risk and may be certified to drive ^[30] :

• No history of cardiac arrest
• No spontaneous sustained ventricular tachycardia (VT)
• Normal exercise blood pressure (BP) (eg, no decrease in BP at maximal exercise)
• No nonsustained VT
• No family history or premature sudden death
• No syncope
• Has an left ventricular (LV) septum thickness of less than 30 mm

However, low-risk individuals must be closely monitored for changes in their risk status. ^[30]

Federal Aviation Administration standards

The Federal Aviation Administration (FAA) sets the criteria for aircraft pilots with medical conditions, including cardiovascular diseases. ^[31] Currently, HCM is incompatible with the highest grade aviation license for commercial pilots due to its unpredictable risk for impairment in the cockpit. ^{[32, 33, 34]}

Avoid strenuous exercise. Competitive-level sports should not be permitted if any of the following is present:

• Significant outflow gradient

• Significant ventricular or supraventricular arrhythmia

• Marked LV hypertrophy

• History of sudden death in relatives with hypertrophic cardiomyopathy (HCM)

• Identified malignant genotype

• Young age (< 30 years)

• Abnormal blood pressure response to exercise

• History of syncope, particularly in children

Although avoidance of intense physical exertion is probably appropriate, participation in noncompetitive-level recreational sports activities is not believed to be contraindicated.

Cardiovascular screening before participation in competitive sports appears to reduce the frequency of unexpected sudden death from HCM, although whether large-scale screening of athletes is administratively feasible or cost-effective remains to be determined. ^{[35, 36]}

Sudden death often occurs during exercise, but it also demonstrates a circadian distribution, with clustering of deaths in the morning and early evening.