Medical, surgical and interventional management of hypertrophic cardiomyopathy with obstruction

Current Treatment Options in Cardiovascular Medicine (2012) 14:665–678DOI 10.1007/s11936-012-0206-5

Valvular Heart Disease (AS Desai and PT O'Gara, Section Editors)

Medical, Surgicaland Interventional Managementof Hypertrophic CardiomyopathyWith ObstructionSammy Elmariah, MD, MPHMichael A. Fifer, MD*

Address*Cardiology Division, Department of Medicine, Massachusetts General Hospitaland Harvard Medical School, 55 Fruit Street, GRB-800, Boston,MA 02114, USAEmail: mfifer@partners.org

Published online: 6 September 2012* Springer Science+Business Media, LLC 2012

Keywords Alcohol septal ablation I Atrial fibrillation I Beta blocker I Calcium channel blocker IDisopyramide I Hypertrophic obstructive cardiomyopathy I Pacemaker I Septal myectomy I Septal reductiontherapy I Sudden cardiac death

Opinion statement

Patients with hypertrophic cardiomyopathy (HCM) are classified as having hypertro-phic obstructive cardiomyopathy (HOCM) if a left ventricular outflow tract (LVOT)gradient is present at rest or during provocation, as with Valsalva maneuver or ex-ercise. Management of HCM in general and HOCM in particular encompasses (1) ac-tivity restriction with avoidance of volume depletion, (2) prevention of suddencardiac death, (3) control of symptoms, and (4) screening of relatives. Thosepatients at high risk of sudden cardiac death (SCD) should be offered an implant-able cardioverter-defibrillator (ICD). Pharmacologic treatment of symptoms inpatients with HOCM consists of negative inotropic drugs, namely beta blockers,and disopyramide; a nondihydropyridine calcium channel blocker (CCB), usually ve-rapamil, may be used in patients with noncardiac side-effects of beta blockers.Patients who have a dual-chamber pacemaker (PM) or ICD should undergo a trialof pacing with short atrioventricular (AV) delay. For patients with intolerable symp-toms despite optimal conservative therapy, septal reduction therapy (SRT) shouldbe considered and should be performed by experienced operators in institutionswith multidisciplinary HCM programs. Younger patients with extreme hypertrophyare usually offered septal myectomy, while older patients, and those with importantcomorbidities are usually directed to alcohol septal ablation (ASA). For patients forwhom either therapy is appropriate, there should be a balanced discussion with thepatients of the benefits and risks of the 2 procedures.

IntroductionHCM is a disease characterized by substantial anatom-ic, genetic, and pathophysiologic heterogeneity. Theprevalence of the disease is estimated to be 0.2 %[1]. While HCM is often inherited in an autosomaldominant pattern, there are many patients, includingmost of those with the “elderly” form of the disease[2•], in whom a familial pattern cannot be identified.There are diverse patterns of hypertrophy, includingasymmetric septal, midventricular, apical, free wall,and concentric variants. A subset of patients withHCM has HOCM, characterized by asymmetrical sep-tal hypertrophy, systolic anterior motion (SAM) ofthe mitral valve, an LVOT gradient, and varyingdegrees of mitral regurgitation. The degree of LVOTobstruction varies widely, with a gradient that is per-sistently present at rest in some patients and absentat rest but provocable by stimuli such as Valsalva ma-neuver, exercise, and postextrasystolic potentiation(HOCM with “latent” or “provocable” obstruction)in others [3]. It has recently become apparent that up-right exercise is more sensitive than supine exercise forprovocation of an LVOT gradient [4].

The majority of patients with HCM have a benignclinical course, with few or no symptoms and a nor-mal lifespan [3]. Some patients, however, have sub-stantial and often debilitating symptoms, and someare at relatively high risk of SCD. Symptoms associatedwith HCM are dyspnea, angina, and a disproportion-ate representation of symptoms on the spectrum com-prised of lightheadedness, presyncope, syncope, andSCD. Dyspnea occurs with exertion, and may resultfrom limitation of cardiac output due to low end-

diastolic volume of a noncompliant LV, high pulmo-nary venous pressure due to diastolic dysfunctionand mitral regurgitation, or myocardial ischemia (asan “anginal equivalent”). Angina in the absence of epi-cardial coronary artery disease usually occurs with ex-ertion, and may result from an inability of thecoronary microcirculation to supply the hypertrophiedmyocardium. In HOCM in particular, ischemia mayalso result from high myocardial oxygen demanddue to elevated LV systolic pressure. The spectrumfrom lightheadedness to SCD is often precipitated byphysical exertion, and reflects a complex interplay ofdiastolic dysfunction, LVOT obstruction, myocardialischemia, inappropriate systemic vasodilation, andventricular arrhythmias [5]. Patients with HCM are al-so at increased risk of developing atrial fibrillation(AF) and are at relatively high risk of thromboembolicevents associated with AF [6, 7, 8••].

The management of patients with HOCM may bedifficult given the complexity of the pathophysiologicprocesses inherent to the disease. Randomized clinicaltrials evaluating most therapies for HOCM are lacking,leaving clinicians dependent on clinical experienceand consensus. In 2011, the American College of Car-diology and American Heart Association publishedjoint management guidelines for the diagnosis andtreatment of patients with HCM [8••]. These guide-lines are also largely based on consensus, but providethe best guidance available to date. Here, we will re-view the management strategy for patients withHOCM, highlighting evidence that has emerged overthe past year.

Treatment

& In patients with HOCM, the goals of management are prevention ofSCD, symptom relief, and screening of relatives [5].

& Risk factors for SCD include unexplained syncope, family history of SCDassociated with HCM, ventricular tachycardia, extreme left ventricularhypertrophy (≥30 mm), and subnormal (G20 mmHg) increase in sys-tolic blood pressure during maximum exercise [8••]. Those patients athigh risk of SCD should be offered an implantable cardioverter-defibrillator (ICD). Activity restriction is prescribed for all patients withHCM, independent of anatomic variant and treatment [8••].

666 Valvular Heart Disease (AS Desai and PT O'Gara, Section Editors)

& Pharmacologic management of the symptoms of HOCM consists ofnegative inotropic drugs, namely beta blockers, disopyramide, and,in patients with noncardiac side-effects of beta blockers, a nondihy-dropyridine CCB, usually verapamil [5, 8••]. If a diuretic is necessarybecause of congestive symptoms, it must be administered with caution.

& When pharmacologic management is unsuccessful, mechanicalinterventions, namely septal myectomy, ASA, and pacing with shortAV delay, can be considered (Fig. 1) [8••].

Diet and lifestyle& Avoidance of volume depletion is recommended in order to main-

tain LV end-diastolic volume and to minimize LVOT obstruction.We recommend that patients drink copious water and drinks con-taining electrolytes when exercising.

Pharmacologic treatment

Beta adrenergic antagonistsBeta blockade serves as the mainstay of therapy for patients with HOCM.Beta blockade has the potential to ameliorate or abolish both resting LVOTobstruction and the increase that occurs with exertion; this effect results fromthe negative inotropic action of the drugs and their negative chronotropic

Figure 1. Algorithm for management of symptoms of HOCM.Reproduced with permission from Fifer MA, Vlahakes GJ.Circulation. 2008;117:429–39. AV atrioventicular, HCMhypertrophic cardiomyopathy, LVOT left ventricular outflowtrack, PM pacemaker.

Medical, Surgical and Interventional Management Elmariah and Fifer 667

effect, which prolongs diastolic filling time and consequently increases LVend-diastolic volume. The bulk of data regarding evidence for beta adrenergicblockade have been generated for the nonselective beta blocker propranolol.In one of the earliest studies, propranolol therapy (average dose 462 mg/day)significantly reduced dyspnea, angina, palpitations, dizziness, and syncope[9]. In practice, we generally extrapolate this result to longer-acting, beta1selective blockers such as atenolol and metoprolol.

Standard dosage We titrate dosage for symptom control, to resting heart rate 50–60 beats/min.

Contraindications Severe bronchospastic disease; sinus, or AV node disease without a pace-maker in place; intolerance to the drugs (most often fatigue)

Main drug interactions Combined use with verapamil or diltiazem increases the risk of bradycardiaand AV block.

Main side effects Fatigue, bradycardia, constipation, impotence, depression, alopecia

Special points Limited data suggest less benefit with selective beta blockers.

Cost/cost-effectiveness Several beta blockers are available in generic form and are inexpensive.

Nondihydropyridine calcium channel antagonistsNondihydropyridine CCBs are frequently effective in patients who are intol-erant of beta blockers. Verapamil has been extensively studied in this regard,while there is much less experience with diltiazem, which we do not use forpatients with HCM. As do beta blockers, verapamil reduces heart rate, pro-longing diastolic filling time, and increasing LV end-diastolic volume. Nega-tive inotropy also plays a role in alleviating symptoms of HOCM, althoughthe LVOT gradient may increase if the vasodilator effect of verapamil pre-dominates. Substantial data support the use of verapamil in HOCM in orderto improve exercise tolerance and reduced exertional symptoms. On rare oc-casion however, verapamil may cause hypotension, increased LVOT obstruc-tion, pulmonary edema, and even death [5].

Standard dosage We titrate the dosage for symptom control, to resting heart rate 50–60 beats/min, with careful attention to blood pressure in order to avoid hypotension.We administer verapamil in its extended-release form.

Contraindications Sinus or AV node disease without a pacemaker in place; overt congestiveheart failure; caution in patients with high LVOT gradients

Main drug interactions Combined use with beta blockers increases the risk of bradycardia and AVblock.

Main side effects Bradycardia, hypotension, hepatotoxicity, constipation, edema

Cost/cost-effectiveness Verapamil is available in generic form and is inexpensive.

DisopyramideDisopyramide, a drug formerly used for treatment of atrial and ventriculararrhythmias, has a negative inotropic property mediated by modulation ofsodium-calcium exchange. This action, combined with the vasoconstrictoreffect of the drug, reduces LVOT obstruction in HOCM [10, 11•]. The anti-

668 Valvular Heart Disease (AS Desai and PT O'Gara, Section Editors)

arrhythmic properties of disopyramide provide added benefit for patientswith HOCM and AF or atrial flutter.

Standard dosage 100 to 300 mg twice daily in the controlled-release form with monitoring ofthe corrected QT (QTc) interval

Contraindications Sinus or AV node disease without a pacemaker in place, QTc prolongation,closed angle glaucoma, risk factors for bladder outlet obstruction such asenlarged prostate, difficult-to-control hypertension (since the drug is a va-soconstrictor)

Main drug interactions Drugs with the potential to increase QTc interval

Main side effects QTc prolongation; anticholinergic effects such as dry mouth and gastroin-testinal symptoms

Special points Anticholinergic side effects can be reversed with pyridostigmine, 90 mg dailyin the controlled-release form (Mark V. Sherrid, MD, personal communica-tion).

Cost/cost-effectiveness Disopyramide is available in generic form and is inexpensive.

Interventional procedures& Mechanical therapies available to patients with HOCM who suffer

disabling symptoms despite optimal medical therapy include SRTwith surgical myectomy or ASA, and pacing with short AV delay.

& While it is often stated that SRT should be performed in patients withNew York Heart Association (NYHA) Class III or IV symptoms, thisgrading system is ill-suited to HCM. Regardless of NYHA (or Cana-dian Cardiovascular Society angina) class, patients should undergoSRT if they have symptoms, despite optimal conservative therapy,that interfere substantially enough with their lives that they are wil-ling to assume the morbidity and mortality of invasive management.

& In a recent retrospective study, patients treated with mechanicaltherapies (ASA, septal myectomy, or pacing with short AV delay) hadsimilar HCM-related mortality to those treated medically [12]. Thisfinding reinforces the strategy of reserving mechanical therapies forpatients with refractory symptoms.

& Two meta-analyses compiled non-randomized data comparing clin-ical outcomes after ASA and septal myectomy. Each of these suggestscomparable unadjusted mortality rates with the 2 SRT techniques[13•, 14••]. Adjustment for baseline patient characteristics, however,revealed significantly lower rates of all-cause mortality and SCD withASA than with septal myectomy [14••].

& SRT should be performed by experienced operators within multi-disciplinary HCM programs [8••].

& Factors favoring ASA over septal myectomy include advanced age,comorbid conditions, preexisting right bundle branch block (sincemyectomy usually causes left bundle branch block), and presence ofPM or ICD (which substantially lowers the risk of ASA); those fa-voring myectomy include young age, marked hypertrophy (since it

Medical, Surgical and Interventional Management Elmariah and Fifer 669

may not be feasible to ablate sufficient myocardium with alcohol),need for immediate relief of LVOT obstruction (since septal thinningafter ASA takes place over months), and preexisting left bundlebranch block (since ASA usually causes right bundle branch block).For the many patients for whom either procedure is a reasonableoption, the principle of patient autonomy dictates that patientsshould choose between them after a balanced discussion of the rel-ative benefits and risks of the 2 procedures [15•].

& There are limited data regarding SRT in patients with HCM andmidventricular obstruction [16]. Either ASA or septal myectomy maybe technically feasible in these patients.

Alcohol Septal Ablation

Alcohol septal ablation produces a focal, targeted infarction of the upperinterventricular septum, resulting in an increase in LVOT diameter, areduction in LVOT gradient, regression of the pressure overload com-ponent of LV hypertrophy, and alleviation of symptoms [15•]. In addi-tion, recent studies have identified improvements in LV synchrony,coronary microvascular function, and myocardial energetics [17, 18].Selection criteria for alcohol septal ablation are: (1) symptoms that in-terfere substantially with lifestyle despite optimal medical therapy; (2)septal thickness ≥15–16 mm; (3) LVOT gradient ≥30 mm Hg at rest or≥50 mm Hg on provocation; (4) accessible septal branch(es); and (5)absence of intrinsic abnormality of the mitral valve or other indication forcardiac surgery [ 8••,15•]. Multicenter efforts have provided robust dataregarding short- and medium-term procedural outcomes. These and otherstudies have confirmed the safety of ASA, with in-hospital mortality 0.3%–2 % [19•, 20••]. Approximately 10 %–15 % of patients require implanta-tion of a permanent pacemaker before discharge. Alcohol septal ablation isefficacious, with improvement in symptoms experienced by approximately80%of patients [15•, 19•]. The hemodynamic and symptomatic effects aresustained at medium-term follow-up (2.9±2.6 years) [19•].

Standard procedure The first step in performing ASA is obtaining reliable baseline hemodynamicmeasurements. Special care must be taken to allow for the substantialspontaneous variability that has been noted in gradient measurementswithin a single hemodynamic assessment [21]. Our practice is to withholdpharmacologic agents that lower the LVOT gradient, avoid intravenous flu-ids, and measure gradients using anterograde catheterization of the leftventricle via the trans-septal approach. Because the proximal septal branchessupply the conduction system, AV block is a common effect of alcohol in-jection. All patients without permanent devices therefore receive a temporaryright ventricular pacemaker prior to administration of ethanol. Standardcoronary guiding catheters and guide wires are used to engage the proximalseptal branch(es). A small-caliber over-the-wire balloon catheter is then ad-vanced into the septal perforator and inflated. Myocardial contrast echocar-diography may then be utilized to confirm selection of the appropriate septalbranch. Balloon inflation alone may result in a reduced LVOT gradient byinducing ischemia within the septal territory. The duration of time neededfor the gradient to decrease by 50 % has been shown to correlate with thefinal result of ASA [22]. There is growing interest in the use of both pre- and

670 Valvular Heart Disease (AS Desai and PT O'Gara, Section Editors)

intraprocedural computed tomography to guide septal ablation [23–25].Regardless of technique, the goal is to ablate the portion of septal myocar-dium at which the anterior leaflet of the mitral valve comes into contact withthe septum and at which there is maximal flow acceleration. Upon identi-fication of the optimal septal branch, 0.5–1 ml of anhydrous (996 %) eth-anol is infused, with repeat administration, as needed, in the same or otherbranches for total volume 1–3 ml. Recent studies have indicated that thelikelihood of success of ASA with lower ethanol dosage is similar to that withhigher dosage [26]. Optimal results are often obtained by selecting septalsub-branches for ethanol administration [27]. Procedural success is definedas a reduction of resting LVOT gradient to G10 mm Hg or a 50 % reductionin provocable gradient [15•]. In addition to this standard transfemoral ap-proach, transradial ASA has been shown to be safe and feasible [28]. A noveltransendocardial ethanol injection technique is being explored in an effort tominimize dependence of ASA on septal anatomy [29].

Contraindications Septal thickness G15–16 mm, another indication for cardiac surgery, un-suitable septal branch anatomy

Complications Transient or persistent AV block, ventricular arrhythmias, coronary artery dis-section, cardiac tamponade, access site complications, ventricular septal defect

Special points Because of the incidence of late AV block and risk of late ventriculararrhythmias, we monitor patients in the inpatient setting for 3–6 days. Weuse a flexible screw-in temporary pacemaker lead [30], which we leave inplace for 1 to 6 days, depending on the presence of risk factors for completeheart block [31]. A permanent pacemaker is implanted if complete heartblock persists or arises beyond 24–48 hours after ASA.

Cost/cost-effectiveness Cost is high and includes inpatient hospitalization for at least 3 days. Therehave been no studies of cost-effectiveness.

Surgery

Septal Myectomy

As with ASA, surgical myectomy should be reserved for patients with LVOTobstruction and symptoms refractor to optimal medical therapy. Patientswith low resting gradient (G30 mm Hg) but higher provocable gradientshave symptoms similar to those with severe resting LVOT obstruction [5,8••]. Septal myectomy is effective in relieving symptoms and should beconsidered for such patients [32•]. Survival after surgical myectomy at ahigh-volume center was similar to that of age- and sex-matched controls,and, in contradistinction to survival for patients treated medically, was in-dependent of wall thickness, and LV mass [33]. An important caveat is thatsurgical results obtained at high-volume programsmay not be replicated inlower-volume settings. Furthermore, since septal myectomy does not re-move the possibility of SCD, we recommend continual SCD risk factor as-sessment postoperatively, with ICD placement when indicated [34].

Standard procedure Whereas the initial surgical approach to HOCM consisted solely of trans-aortic resection or simple incision of septal muscle, increased understandingof the pathophysiology of HOCM, and of the involvement of the mitralvalve apparatus has allowed for more complete surgical corrections, andimproved results. Contemporary surgeries for HOCM include extended

Medical, Surgical and Interventional Management Elmariah and Fifer 671

septal resections and partial resection or mobilization of the papillarymuscles. Suturing of the medial- and lateral-most segments of the anteriorleaflet of the mitral valve to the posterior annulus is a novel addition that hasbeen associated with improvement in mitral regurgitation and prevention ofresidual and recurrent LVOT obstruction [35]. Recent evidence suggests thatintraoperative transesophageal echocardiography is technically inadequatefor assessment of LVOT gradients in a substantial proportion of patients(39 %), suggesting that direct intraoperative measurement of outflow gra-dients is warranted [36].

Contraindications Septal thickness G16–18 mm, prohibitively high operative risk

Complications Ventricular septal defect, aortic regurgitation, AV block, in addition tocomplications of cardiac surgery in general. Permanent pacemaker im-plantation for AV block occurs in approximately 5 % of patients.

Cost/cost-effectiveness Very expensive. Cost-effectiveness data not available.

Physical/speech therapy and exercise& Patients with HCM should not engage in intense competitive sports.

This recommendation is supported by evidence that the HCM is re-sponsible for 26 %–39 % of cardiac arrests during long-distancerunning races and that HOCM is a risk factor for unsuccessful re-suscitation [37, 38].

Assistive devices

Pacemaker therapy

The proposed mechanism of right ventricular pacing with short AV delay inHOCM is that pre-excitation of the LV apex results in paradoxical septalmotion, a decrease in ejection velocity, amelioration of SAM, and reductionof the LVOT gradient [5, 8••]. Initial enthusiasm for permanent pacing forHOCMwaned upon the completion of clinical trials suggesting thatmuch ofthe observed benefit was due to placebo effect. Beneficial effects are, however,seen in a minority of patients. Consequently, it is reasonable to attemptpacing for reduction of LVOT obstruction in patients who have had a dual-chamber pacemaker or ICD implanted for a standard indication. Pacingmayalso be considered for the unusual patient with refractory symptoms who isnot a candidate for either formof SRT [8••]. Biventricular pacingmayprovidegreater LV preexcitation and ability to reduce LVOT obstruction. The authorsof a small pilot study of biventricular pacing suggest that alleviation of theLVOT gradientmay be associatedwith LV reverse remodeling andprogressivereduction in LVOT obstruction in the first year after implantation [39].

Usage At present, right ventricular pacing with short AV delay should be reservedfor patients who have a dual-chamber device implanted for a separate in-dication and, rarely, those with symptoms refractory to medical therapy whoare not candidates for SRT.

Cost/cost-effectiveness Minimal cost is associated with mode/setting changes in patients with apreviously implanted device.

672 Valvular Heart Disease (AS Desai and PT O'Gara, Section Editors)

Implantable Cardioverter-Defibrillator

Some patients with HOCM are at particular risk for SCD. Since no drug hasbeen shown to reduce the likelihoodof SCD,we rely on ICD implantation toavert this outcome [8••]. Patients with HCM and a history of SCD due toventricular fibrillation or ventricular tachycardia are at high risk for recurrentSCD and should receive an ICD for secondary prevention [8••]. A familyhistory of sudden cardiac death, unexplained syncope, LV wall thickness≥30 mm, nonsustained ventricular tachycardia, and abnormal blood pres-sure response to exercise have each been associated with increased risk ofSCD in HCM and can justify ICD implantation for primary prevention.Patients receiving ICDs for primary prevention because of a family history ofsudden cardiac death experienced rates of appropriate ICD dischargescomparable to other high-risk patients, confirming that family history is animportant risk factor for suddendeath [40].Devices implanted for secondaryprevention are clearly warranted; there is a need, however, for risk predictionmodels to aid clinical decision making regarding ICD implantation for pri-mary prevention, particularly in light of the potential complications of de-vice implantation, including inappropriate ICD shocks [41••].

Usage ICD implantation is indicated in patients with prior cardiac arrest. ICD im-plantation for primary prevention should be individualized based uponcareful risk assessment and patient preference [8••].

Cost/cost-effectiveness Expensive, but generally thought to be cost-effective in appropriately selectedpatients [42, 43].

Management of atrial fibrillationAtrial fibrillation (AF) is common in HCM, occurring in approximately 20 %of patients, and is responsible for substantial morbidity and mortality. Therisk of thromboembolic events in patients with AF and HCM is high (2.4 %–7.1 %/year) [6], so that anticoagulation is recommended for patients withHCM and AF in the absence of contraindications [6, 8••]. While ventricularrate control may be sufficient to control symptoms, the loss of atrial con-traction is poorly tolerated in some patients with HCM. Rhythm control maybe problematic in patients with HCM because the efficacy and safety of an-tiarrhythmic agents is largely untested.

Anticoagulants& Due to the high risk of thromboembolic events, all patients with HCM

and paroxysmal, persistent, or chronic atrial fibrillation should receivean oral anticoagulant in the absence of contraindications to anticoa-gulation. Dabigatran and rivaroxaban are alternatives to warfarin.

Antiarrhythmic agents& Antiarrhythmic agents must be used with caution in patients with

HCM given the sparseness of clinical efficacy and safety data.& It is prudent to control ventricular rate prior to employing rhythm

control strategies.

Medical, Surgical and Interventional Management Elmariah and Fifer 673

& Amiodarone is the only agent for which efficacy and safety data areavailable for patients with HCM [4, 6].

& Disopyramide is known to be safe in patients with HOCM given itsfrequent use in reducing LVOT obstruction and symptoms [44].However, the safety and efficacy of disopyramide specifically in themanagement of AF in HOCM patients has not been studied.

Radiofrequency ablationLimited data addressing the use of radiofrequency ablation (RFA) for AF inHCMsuggest that procedural and short-term success, and safety are similar to those inpatientswithoutHCM.One study, however suggests thatHCM is a risk factor forrecurrence of AF after multiple RFA procedures [45••]. Current guidelinesconsider RFA a reasonable option (Class IIa) for symptomatic HCM patients inwhom antiarrhythmic agents are ineffective or not tolerated [8••].

Standard procedure The technique of radiofrequency ablation for AF varies based on patientfeatures, but routinely involves the creation of a linear ablation line alongthe roof of the left atrium or mitral isthmus and ablation lesions to isolatethe pulmonary veins via the trans-septal approach.

Contraindications Left atrial thrombus

Complications Cardiac tamponade, pulmonary vein stenosis, stroke, access site complications

Cost/cost-effectiveness Expensive

Emerging therapies& Despite being one of the most common inherited cardiomyopathies,

and the most common cause of sudden death in young people, ourunderstanding of the etiology and pathophysiology of HCM is in-sufficient. A multitude of genetic mutations have been associatedwith HCM, each of which has the potential to identify new pathwaysand therapeutic targets to interrupt disease progression. Consequently,the National Heart, Lung, and Blood Institute of the National Institutesof Health has published a series of research priorities and initiativesdestined to advance the field over the years to come [46].

& Substantial evidence suggests abnormal energy metabolism playsa critical role in the pathophysiology of HCM and the associatedsymptoms. Perhexiline, a metabolic modulator known to im-prove cardiac energetics, was recently found to improve LV dia-stolic dysfunction and increase exercise capacity in patients withHCM [47]. While this novel therapy was tested in patientswithout LVOT obstruction, it may hold promise in patients withHOCM as well.

& A recent small study suggests that sodium-channel blockade may bemore effective in reducing inotropy and enhancing LVdiastolic functionthan inhibition of beta adrenergic receptors and calcium channels. Theinvestigators demonstrated that disopyramide is superior to propran-olol and verapamil in reducing LVOT gradients. In a parallel study arm,

674 Valvular Heart Disease (AS Desai and PT O'Gara, Section Editors)

pilsicainide, a pure sodium channel blocker, is as effective in reducingLV obstruction as disopyramide and cibenzoline, each of which com-bines sodium and calcium channel blockade. All 3 patients whoseLVOT gradients were acutely resistant to disopyramide had reductionsin the gradient with both pilsicainide and cibenzoline [11•].

& Glue septal ablation using cyanoacrylate has been suggested to be asafe and effective approach to reduce septal thickness in patients withseptal collateral vessels to the right coronary artery. The authorssuggest that immediate glue polymerization prevents its transitthrough collateral vessels. Significant reductions in LVOT obstructionwere observed, but long-term durability of this technique has not yetbeen demonstrated [48].

& Because ASA is not feasible in some patients due to unfavorable septalbranch anatomy, some investigators have introduced direct endocardialradiofrequency ablation of septal hypertrophy (ERASH) for the man-agement of HOCM [49, 50]. The procedure has been attempted in bothadults and children, and from both the left and right ventricular sides ofthe interventricular septum. Initial results suggest that ERASH may beeffective and safe in both adults and children. While this technique maybe suitable for patients with anatomy not amenable to ASA, furtherstudy will be required before it emerges as an alternative to ASA inpatients for whom ASA is technically feasible.

DisclosuresNo potential conflicts of interest relevant to this article were reported.

References and Recommended ReadingPapers of particular interest, published recently, have beenhighlighted as:• Of importance•• Of major importance

1. Spirito P, Seidman CE, McKenna WJ, Maron BJ. Themanagement of hypertrophic cardiomyopathy. NEngl J Med. 1997;336:775–85.

2.• Gupta RM, Weiner RB, Baggish AL, Fifer MA. Still akid at heart: hypertrophic cardiomyopathy in theelderly. Circulation. 2011;124:857–63.

This case provides a step-by-step approach to the clinicalmanagement of patients presenting with HOCM and car-diovascular symptoms, highlighting medical managementtechniques, SCD risk stratification, familial screening, andsurgical septal reduction.3. Braunwald E, Brockenbrough EC, Morrow AG. Hy-

pertrophic subaortic stenosis–a broadened concept.Circulation. 1962;26:161–5.

4. Dimitrow PP, Cotrim C, Cheng TO. Importance ofupright posture during exercise in detection ofprovocable left ventricular outflow tract gradient inhypertrophic cardiomyopathy. Am J Cardiol.2011;108:614.

5. Fifer MA, Vlahakes GJ. Management of symptoms inhypertrophic cardiomyopathy. Circulation.2008;117:429–39.

6. Fuster V, Ryden LE, Cannom DS, Crijns HJ, CurtisAB, Ellenbogen KA, et al. 2011 ACCF/AHA/HRS fo-cused updates incorporated into the ACC/AHA/ESC2006 guidelines for the management of patients withatrial fibrillation: a report of the American College ofCardiology Foundation/American Heart Association

Medical, Surgical and Interventional Management Elmariah and Fifer 675

Task Force on practice guidelines. Circulation.2011;123:e269–367.

7. Olivotto I, Cecchi F, Casey SA, Dolara A, Traverse JH,Maron BJ. Impact of atrial fibrillation on the clinicalcourse of hypertrophic cardiomyopathy. Circulation.2001;104:2517–24.

8.•• Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA,Link MS, et al. ACCF/AHA guideline for the diagnosisand treatment of hypertrophic cardiomyopathy: a reportof the American College of Cardiology Foundation/American Heart Association Task Force on PracticeGuidelines. Circulation. 2011;124:e783–831.

These are the first ACCF/AHA practice guidelines for the di-agnosis and management of HCM.9. Frank MJ, Abdulla AM, Canedo MI, Saylors RE.

Long-term medical management of hypertrophicobstructive cardiomyopathy. Am J Cardiol.1978;42:993–1001.

10. Fifer MA, O'Gara PT, McGovern BA, Semigran MJ.Effects of disopyramide on left ventricular diastolicfunction in hypertrophic cardiomyopathy. Am JCardiol. 1994;74:405–8.

11.• Kajimoto K, Imai T, Minami Y, Kasanuki H.Comparison of acute reduction in left ventricularoutflow tract pressure gradient in obstructive hyper-trophic cardiomyopathy by disopyramide versuspilsicainide versus cibenzoline. Am J Cardiol.2010;106:1307–12.

This small (24-patient) but elegant study demonstrated thesuperiority of disopyramide over propranolol and verapamilin reducing LVOT obstruction at rest. In addition, theauthors use the comparative efficacy of disopyramide andcibenzoline (combined sodium and calcium channelblockers), and pilsicainide (a pure sodium channel blocker)in reducing LV outflow gradient to identify sodium channelblockade as a therapeutic target for LVOT gradient reduction.12. Ball W, Ivanov J, Rakowski H, Wigle ED, Linghorne M,

Ralph-Edwards A, et al. Long-term survival in patientswith resting obstructive hypertrophic cardiomyopathycomparison of conservative versus invasive treatment. JAm Coll Cardiol. 2011;58:2313–21.

13.• Agarwal S, Tuzcu EM, Desai MY, Smedira N, Lever HM,Lytle BW, et al. Updatedmeta-analysis of septal alcoholablation versus myectomy for hypertrophic cardiomy-opathy. J Am Coll Cardiol. 2010;55:823–34.

Thismeta-analysis includes12observational studies comparingthe efficacy of surgical myectomy to ASA. The study finds nosignificant difference between the 2 treatment modalities inregard to short- and medium-term mortality and to post-pro-cedure functional status. However, ASA was associated with anhigher risk of the need for permanent pacemaker implantation.14.•• Leonardi RA, Kransdorf EP, Simel DL, Wang A. Meta-

analyses of septal reduction therapies for obstructivehypertrophic cardiomyopathy: comparative rates ofoverall mortality and sudden cardiac death aftertreatment. Circ Cardiovasc Interv. 2010;3:97–104.

This meta-analysis includes observational studies evaluatingclinical outcomes after ASA (19 studies) and/or septal

myectomy (eight studies). Unadjusted rates of all-causemortality and SCD were similar between ASA and septalmyectomy. After adjustment for differences in baseline pa-tient characteristics, however, mortality was lower after ASAthan after myectomy.15.• Fifer MA, Sigwart U. Controversies in cardiovascular

medicine. Hypertrophic obstructive cardiomyopathy:alcohol septal ablation. Eur Heart J. 2011;32:1059–64.

This review article addresses the controversy surroundingASA in addition to highlighting several advances in proce-dural techniques that have increased the safety of ASA andimproved patient outcomes.16. Cecchi F, Olivotto I, Nistri S, Antoniucci D, Yacoub

MH. Midventricular obstruction and clinical deci-sion-making in obstructive hypertrophic cardiomy-opathy. Herz. 2006;31:871–6.

17. Chen J, Nagaraj H, Bhambhani P, Kliner DE, SomanP, Garcia EV, et al. Effect of alcohol septal abla-tion in patients with hypertrophic cardiomyopathyon left-ventricular mechanical dyssynchrony asassessed by phase analysis of gated SPECT myo-cardial perfusion imaging. Int J Cardiovasc Imag-ing. 2011 doi:10.1007/s10554-011-9942-y.

18. Timmer SA, Knaapen P, Germans T, Dijkmans PA,Lubberink M, Ten Berg JM, et al. Effects of alcoholseptal ablation on coronary microvascular functionand myocardial energetics in hypertrophic obstruc-tive cardiomyopathy. Am J Physiol Heart CircPhysiol. 2011;301:H129–37.

19.• Jensen MK, Almaas VM, Jacobsson L, Hansen PR,Havndrup O, Aakhus S, et al. Long-term outcome ofpercutaneous transluminal septal myocardial abla-tion in hypertrophic obstructive cardiomyopathy: aScandinavian multicenter study. Circ CardiovascInterv. 2011;4:256–65.

This multicenter study reports the medium-term outcomesof 313 ASA procedures performed in 279 patients.Improvements in LV outflow obstruction and functionalstatus were sustained over mean follow-up 2.9 years. In ad-dition, 10-year survival after ASA was similar to that of anage- and sex-matched population.20.•• Nagueh SF, Groves BM, Schwartz L, Smith KM, Wang

A, Bach RG, et al. Alcohol septal ablation for thetreatment of hypertrophic obstructive cardiomyopa-thy. A multicenter North American registry. J Am CollCardiol. 2011;58:2322–8.

This large multicenter study including 874 patients whounderwent ASA identified lower ejection fraction at baseline,smaller number of septal arteries injected with ethanol,higher number of ASA procedures per patient, greater septalthickness after ASA, and beta blocker use after ASA as inde-pendent predictors of postprocedural mortality.21. Geske JB, Sorajja P, Ommen SR, Nishimura RA.

Variability of left ventricular outflow tract gradientduring cardiac catheterization in patients withhypertrophic cardiomyopathy. JACC CardiovascInterv. 2011;4:704–9.

676 Valvular Heart Disease (AS Desai and PT O'Gara, Section Editors)

22. Almasood A, Garceau P, Woo A, Rakowski H,Schwartz L, Overgaard CB. Time to significant gra-dient reduction following septal balloon occlusionpredicts the magnitude of final gradient responseduring alcohol septal ablation in patients withhypertrophic obstructive cardiomyopathy. JACCCardiovasc Interv. 2011;4:1030–4.

23. Ghersin E, Soto V, Heldman AW. Multidetectorcomputerized tomography can guide and documentalcohol septal ablation in hypertrophic obstructivecardiomyopathy. Circulation. 2011;123:e5–7.

24. Krishnaswamy A, Tuzcu EM, Kapadia SR. Use ofintraprocedural CT imaging to guide alcohol septalablation of hypertrophic cardiomyopathy in thecardiac catheterization laboratory. Catheter Cardio-vasc Interv. 2011.

25. Spratt JC, Langrish JP. Identifying the target septalperforator prior to alcohol septal ablation in hyper-trophic obstructive cardiomyopathy: a new applica-tion for computed tomography coronaryangiography. Heart. 2011;97:1718–9.

26. Veselka J, Duchonova R, Prochazkova S, PalenickovaJ, Sorajja P, Tesar D. Effects of varying ethanol dosingin percutaneous septal ablation for obstructivehypertrophic cardiomyopathy on early hemody-namic changes. Am J Cardiol. 2005;95:675–8.

27. Fifer MA, Palacios I, Sanborn DMY, Sigwart U.Hypertrophic cardiomyopathy. In: Lanzer P, editor.Catheter-based Cardiovascular Interventions.Springer; In press.

28. Cuisset T, Franceschi F, Prevot S, Ansaldi S, Habib G,Pankert M, et al. Transradial approach and subclavianwired temporary pacemaker to increase safety ofalcohol septal ablation for treatment of obstructivehypertrophic cardiomyopathy: the TRASA trial. ArchCardiovasc Dis. 2011;104:444–9.

29. Guo R, Qian J, Yang Y, Zhu Q, Liu D, Deng C, et al. Anew strategy for septal ablation with transendocar-dial ethanol injection using a multifunctional intra-cardiac echocardiography catheter: a feasibility study incanines. Catheter Cardiovasc Interv. 2011;78:316–23.

30. Sorajja P, Valeti U, Nishimura RA, Ommen SR, RihalCS, Gersh BJ, et al. Outcome of alcohol septal abla-tion for obstructive hypertrophic cardiomyopathy.Circulation. 2008;118:131–9.

31. Chen AA, Palacios IF, Mela T, Yoerger DM, PicardMH, Vlahakes G, et al. Acute predictors of subacutecomplete heart block after alcohol septal ablation forobstructive hypertrophic cardiomyopathy. Am JCardiol. 2006;97:264–9.

32.• Schaff HV, Dearani JA, Ommen SR, Sorajja P,Nishimura RA. Expanding the indications for septalmyectomy in patients with hypertrophic cardiomyop-athy: Results of operation in patients with latent ob-struction. J Thorac Cardiovasc Surg. 2012;143:303–9.

The authors review the results of septal myectomy in 249patients who had latent obstruction with minimal (G30 mm

Hg) resting LVOT gradients. Patients with latent obstructionhad limiting symptoms comparable to those with more se-vere resting gradients and experienced a similar degree ofimprovement in symptoms after myectomy.33. Brown ML, Schaff HV, Dearani JA, Li Z, Nishimura

RA, Ommen SR. Relationship between left ventricularmass, wall thickness, and survival after subaortic septalmyectomy for hypertrophic obstructive cardiomyopa-thy. J Thorac Cardiovasc Surg. 2011;141:439–43.

34. Rothman RD, Sadfiia MA, Lowry PA, Mela T, AbbaraS, O'Callaghan C, et al. Risk stratification for suddencardiac death after septal myectomy. J Card Cases.2011;3:e65–7.

35. Nasseri BA, Stamm C, Siniawski H, Kukucka M,Komoda T, Delmo Walter EM, et al. Combined an-terior mitral valve leaflet retention plasty and septalmyectomy in patients with hypertrophic obstructivecardiomyopathy. Eur J Cardiothorac Surg.2011;40:1515–20.

36. Ashikhmina EA, Schaff HV, Ommen SR, Dearani JA,Nishimura RA, Abel MD. Intraoperative direct mea-surement of left ventricular outflow tract gradients toguide surgical myectomy for hypertrophic cardio-myopathy. J Thorac Cardiovasc Surg. 2011;142:53–9.

37. Kim JH, Malhotra R, Chiampas G, d’Hemecourt P,Troyanos C, Cianca J, et al. Cardiac arrest duringlong-distance running races. N Engl J Med.2012;366:130–40.

38. Maron BJ, Chaitman BR, Ackerman MJ, Bayes deLuna A, Corrado D, Crosson JE, et al. Recommen-dations for physical activity and recreational sportsparticipation for young patients with genetic cardio-vascular diseases. Circulation. 2004;109:2807–16.

39. Berruezo A, Vatasescu R, Mont L, Sitges M, Perez D,Papiashvili G, et al. Biventricular pacing in hyper-trophic obstructive cardiomyopathy: a pilot study.Hear Rhythm. 2011;8:221–7.

40. Bos JM, Maron BJ, Ackerman MJ, Haas TS, Sorajja P,Nishimura RA, et al. Role of family history of suddendeath in risk stratification and prevention of suddendeath with implantable defibrillators in hypertrophiccardiomyopathy. Am J Cardiol. 2010;106:1481–6.

41.•• O'Mahony C, Lambiase PD, Quarta G, Cardona M,Calcagnino M, Tsovolas K, et al. The long-termsurvival and the risks and benefits of implantablecardioverter defibrillators in patients with hypertro-phic cardiomyopathy. Heart. 2012;98:116–25.

This study describes clinical outcomes in 334 patients withHCM and risk of SCD who underwent ICD implantation.Inappropriate shocks and/or implant complications wereseen in 30 % of patients. These results highlight the need foroptimization of patient selection algorithms for ICD im-plantation,and for meticulous ICD programming to mini-mize inappropriate shocks.42. You JJ, Woo A, Ko DT, Cameron DA, Mihailovic A,

Krahn M. Life expectancy gains and cost-effectivenessof implantable cardioverter/defibrillators for the

Medical, Surgical and Interventional Management Elmariah and Fifer 677

primary prevention of sudden cardiac death inpatients with hypertrophic cardiomyopathy. AmHeart J. 2007;154:899–907.

43. Goldenberg I, Moss AJ, Maron BJ, Dick AW, ZarebaW. Cost-effectiveness of implanted defibrillators inyoung people with inherited cardiac arrhythmias.Ann Noninvasive Electrocardiol. 2005;10:67–83.

44. Sherrid MV, Barac I, McKenna WJ, Elliott PM, DickieS, Chojnowska L, et al. Multicenter study of theefficacy and safety of disopyramide in obstructivehypertrophic cardiomyopathy. J Am Coll Cardiol.2005;45:1251–8.

45.•• McCready JW, Smedley T, Lambiase PD, Ahsan SY,Segal OR, Rowland E, et al. Predictors of recurrencefollowing radiofrequency ablation for persistentatrial fibrillation. Europace. 2011;13:355–61.

This position paper from a working group of the NationalHeart, Lung, and Blood Institute identifies research initia-tives that are expected to lead to novel therapeuticapproaches for patients with HCM.46. Force T, Bonow RO, Houser SR, Solaro RJ,

Hershberger RE, Adhikari B, et al. Research priorities

in hypertrophic cardiomyopathy: report of aWorking Group of the National Heart, Lung, andBlood Institute. Circulation. 2010;122:1130–3.

47. Abozguia K, Elliott P, McKenna W, Phan TT,Nallur-Shivu G, Ahmed I, et al. Metabolic modulatorperhexiline corrects energy deficiency and improvesexercise capacity in symptomatic hypertrophiccardiomyopathy. Circulation. 2010;122:1562–9.

48. Oto A, Aytemir K, Okutucu S, Kaya EB, Deniz A,Cil B, et al. Cyanoacrylate for septal ablation inhypertrophic cardiomyopathy. J Interv Cardiol.2011;24:77–84.

49. Lawrenz T, Borchert B, Leuner C, Bartelsmeier M,Reinhardt J, Strunk-Mueller C, et al. Endocardialradiofrequency ablation for hypertrophic obstruc-tive cardiomyopathy: acute results and 6 months'follow-up in 19 patients. J Am Coll Cardiol.2011;57:572–6.

50. Sreeram N, Emmel M, de Giovanni JV. Percutaneousradiofrequency septal reduction for hypertrophicobstructive cardiomyopathy in children. J Am CollCardiol. 2011;58:2501–10.

678 Valvular Heart Disease (AS Desai and PT O'Gara, Section Editors)