Review HCM

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Pathophysiology and Treatment ofHypertrophic Cardiomyopathy

Mark V. Sherrid

All patients with hypertrophic cardiomyopathy(HCM) should have five aspects of care addressed.An attempt should be made to detect the presenceor absence of risk factors for sudden arrhythmicdeath. If the patient appears to be at high risk,discussion of the benefits and risks of ICD areindicated, and many such patients will be im-planted. Symptoms are appraised and treated.Bacterial endocarditis prophylaxis is recommen-ded. Patients are advised to avoid athletic compe-

tition and extremes of physical exertion. Firstdegree family members should be screened withechocardiography and ECG.n 2006 Elsevier Inc. All rights reserved.

Hypertrophic cardiomyopathy (HCM) isviewed as a complex and challengingcardiac disease. Its pathophysiology, diagnosisand treatment span the gamut of cardiologicdisciplines: In pathophysiology one must con-sider left ventricular outflow obstruction, mitral

regurgitation, ischemia, atrial fibrillation, sud-den death, diastolic dysfunction, molecularbiology and genetics. Diagnostic testing withechocardiography, nuclear scintigraphy, stresstesting, catheterization, 24 hour ECG, and MRImay be applied. Treatment may involve theimplanted defibrillator, pharmacologic agents,surgery, transcoronary intervention, or pacing.But, when these lists are examined, one recog-nizes that this is same exact spectrum encoun-tered in more common cardiac diseases. The

challenge in HCM is learning the disease-specificpathophysiology and treatment indications.

Genetics, Pathology, Diagnosis

The inherited nature of HCM was noted as earlyas the modern description of the disease.1

Hypertrophic cardiomyopathy is inherited as anautosomal dominant trait; roughly half ofpatients have another family member withHCM. Unexplained hypertrophy occurs in1:500 in the general population, making it themost common inherited cardiac disorder. Sarco-meric mutations of 10 genes that code formyofilaments or their supporting proteins havebeen identified as a cause of HCM.2-5 In a cohortof referred, unrelated patients with HCM, rough-ly 40% of patients with HCM were found to havesarcomeric mutations. In the remaining 60%,none of the known genotype abnormalities werefound.5 Younger age at diagnosis, marked wallthickness, and a family history of HCM increasethe frequency that a patient will be gene positive.Echocardiographic appearance also appears topredict a high likelihood of sarcomeric-proteinmutation HCM; a reversed septal curvaturecausing a crescent-shaped LV cavity predictsgene-positive patients as compared with thosewith localized subaortic bulge and preservedseptal curvature.6,7 The most common mutationsfound are in the b-myosin heavy chain and inmyosin-binding protein C. Although the bulk ofgenetically determined HCM occurs on 8 genes,many hundreds of HCM-causing mutations are

dispersed over the many loci of these genes. Allof these genes may cause different phenotypesand have different prognoses. Even amongfamilies with the same mutation on a particularloci individuals vary with respect to phenotypeand prognosis. This has markedly delayedgenotype-phenotype correlation. The pathophys-iologic linkage between mutations and hypertro-phy appears to be mediated by mutation-inducedfunctional abnormalities.8

Progress in Cardiovascular Diseases, Vol. 0, No. 0 (August), 2006: pp 1-29 1

From the Hypertrophic Cardiomyopathy Program andEchocardiography Laboratory, Department of Medicine,Division of Cardiology, St. Lukes-Roosevelt HospitalCenter, College of Physicians and Surgeons, ColumbiaUniversity, New York, NY.

Address reprint requests to Mark V. Sherrid, MD, 100010th Avenue 3B-30, New York City, NY 10019.

E-mail: [email protected]/$ - see front matter

n 2006 Elsevier Inc. All rights reserved.

doi:10.1016/j.pcad.2006.08.001


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Many patients have no family history of HCM.

Some of these patients may have sporadicmutations. But many have no genes identified.In these, the responsible genes may not beidentified to date; or some unidentified factormay be causing their hypertrophy.

Hypertrophic cardiomyopathy is diagnosedwhen left ventricular (LV) hypertrophy occursin the absence of a clinical condition that wouldcause the degree of hypertrophy noted.9-14 Wallthickness greater than 14 mm is the criteria weuse for diagnosis. The majority of patients whoreach clinical attention have wall thicknesses

between 20 and 30 mm.14 The location of theabnormal hypertrophy is most often of anteriorseptum, although the posterior septum andanterior wall are frequently hypertrophied aswell. Typical of the heterogeneity of HCM is thathypertrophy can occur in any segment, evenamong relatives known to have the same geno-type. Apical hypertrophy that spares the basilarand mid segments is a variant that occurs morefrequently in East Asian patients with HCM.However, it is a relatively common variant inNorth American and European patients as well,

occurring in 7%.15 This variant generally has abetter prognosis. Truly atypical HCM variantsinclude thickening just of the lateral wall orposterior wall.

Wall thickening is most often assessed by2-dimensional echocardiography. Particular at-tention should be paid to the septum and also tothe thickness of the anterior wall. The anteriorwall is more difficult to visualize clearly than theseptum because of poorer lateral resolution

compared with the axial resolution of echocar-diography systems. Magnetic resonance imagingmay be useful in selected cases.16

On light microscopy individual myocyte hy-pertrophy is noted. Myocardial fiber disarray isthe pathognomonic abnormality. In normals,myocytes are arranged in linear parallel arrays.

Fig 1. Myocardial fiber disarray is the pathognomonicabnormality in hypertrophic cardiomyopathy.

Fig 2. Histopathology from surgical specimens of 3patients with obstructive HCM who underwent surgi-cal septal myectomy for progressive heart failuresymptoms. All 3 patients had intimal and medialhypertrophy of the intramural septal branches withluminal narrowing. Dense perivascular fibrosis ispresent in the middle frame. Top and bottom, hema-toxylin and eosin. Middle, Massons trichrome stain.

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In HCM with fiber disarray, myocytes formchaotic intersecting bundles (see Fig 1). Withelectron microscopy, myofilament disarray isnoted as well. Although fiber disarray is notedin other diseases, the percentage of the myocar-dium occupied by disarray is higher in patientswith HCM.17,18 Fiber disarray is thought to pre-dispose to electrical reentry and sudden death.19

Fibrosis is also a prominent feature on lightmicroscopy. Interstitial and perivascular fibrosismay occupy as much as 14% of the myocardium

in patients who die suddenly.20-23 Fibrosis andhypertrophy decrease LV chamber complianceand cause diastolic dysfunction and exerciseintolerance.24,25 Fibrosis appears to predisposeto complex ventricular arrhythmia.26 Althoughthe epicardial coronary arteries are dilated,narrowings of the intramural penetrating coro-nary arteries are noted, due to arteriolar intimaland medial hyperplasia. These narrowings arethought to contribute to ischemia, well docu-mented in HCM.27-29 Fig 2 shows such narrow-ings in myectomy resections.

Dynamic LV outflow obstruction is an addedburden imposed on top of these already impor-tant pathologic abnormalities. Left ventricularoutflow tract obstruction is an important deter-minant of symptoms11 and is associated withadverse outcome (Fig 3).30 The most commonlocation of obstruction is in the LV outflow tract,caused by systolic anterior motion (SAM) of themitral valve and mitral-septal contact.11,31-33

Fig 4 shows dynamic SAM as it progressesthrough the early moments of systole. Thisphenomenon is caused by a crucial anatomicoverlap between the inflow and outflow portionsof the left ventricle.34,35

Two decades ago, a debate about whether trueobstruction to LV ejection occurred in HCM36

was largely settled by the review of Wigle et al11

Fig 4. Systolic anterior motion of the mitral valve, drawn from apical 5-chamber view, as it proceeds in earlysystole. Reprinted with permission from J Am Coll Cardiol 1993;22:816-825.

Fig 3. Comparison of survival free from HCM-relatedcardiac death, in patients with obstructive and non-obstructive HCM. Patients with obstructive HCM havehigher cardiac mortality. Reprinted with permissionfrom N Engl J Med 2003;348:295-303.

PATHOPHYSIOLOGY AND TREATMENT OF HYPERTROPHIC CARDIOMYOPATHY 3

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published in this journal in 1985. In particular,catheterization demonstration of LVOT gradientsbetween catheters in the aorta and in the body ofthe LV in the inflow tract, via the transseptalapproach, excluded the possibility of catheterentrapment as a cause of gradients.37 Subsequentecho-Doppler demonstration of gradients, andtheir location by pulsed Doppler at the point ofmitral-septal contact, was conclusive. Recentechocardiographic observations highlight thehemodynamic significance of LVOT obstruction.Obstruction causes a mid-systolic drop in LVejection velocities and flow when the gradient isgreater than 60 mm Hg.38,39 This echocardio-graphic pattern has been termed the blobsterclawQ abnormality because of its characteristicappearance (Fig 5). The ejection velocity dropoccurs because instantaneous mid-systolic after-load exceeds contractility. It is the cause of themid-systolic closure of the aortic valve and thepulsus bisfiriens. The sensitivity of the myopathicventricle to the sudden increase in afterload isdemonstrated by the precise, simultaneous tim-ing of the nadir of the LV velocities and the peakof the LVOT gradient. Mid-systolic LVOT ejec-tion flow decreases further after pharmacologic

increase in the gradient by dobutamine.39 Themid-systolic drop disappears with medical elim-ination of the gradient (Fig 5).38,39 The mid-systolic drop in ejection velocity is caused bypremature termination of LV longitudinal con-traction and is a manifestation of systolic dys-function due to afterload mismatch.40

Although SAM with mitral-septal contact isthe most common cause of outflow tractobstruction, other variants occur. An anomalouspapillary muscle may insert directly into thebase of the anterior mitral leaflet, withoutintervening chordae. Here, obstruction occursbecause of systolic apposition of the anteriorpapillary muscle and the septum. This anomalymust be detected before surgery, and thesurgeon advised to its presence, to prevent poorsurgical outcome.41 This sort of mid-ventricularobstruction is different from mid-ventricularobstruction caused by systolic apposition ofthe mid-LV walls.42 Apical HCM with concom-itant mid-LV thickening may progress to causeobstruction in the mid LV, with development ofan apical akinetic chamber that occurs in theabsence of epicardial coronary disease. Theapical akinetic chamber occurs because of apical

Fig 5. Left: Mid-systolic drop in LV ejection velocity in obstructive HCM. Pulsed wave Doppler recording just apicalof the entrance to the LVOT in a patient with severe dynamic obstruction due to SAM and mitral-septal contact.The pulsed wave cursor is 2 cm apical of the tips of the mitral valve leaflets. Long arrow points to the nadir of LVmid-systolic drop in LV ejection flow velocity. This drop in velocity has been called the blobster claw abnormalityQbecause of its characteristic appearance. The drop in velocity is due to the sudden imposition of afterload due tothe mitral-septal contact and the gradient.38,39 Right: pulsed wave Doppler in the same patient, from the sameposition, after pharmacologic relief of obstruction. The mid-systolic drop is no longer present.

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blood trapping, high apical chamber pressures,and supply-demand mismatch at the apex.Severe symptoms may accompany this develop-ment; the akinetic chamber may harbor thrombiand also become a source of monomorphicventricular tachycardia.43

Left ventricular outflow tract obstruction isquantified by measuring the pressure drop, thegradient across the narrowing. This is mostcommonly done with continuous wave Dopplerechocardiography.44 Pulsed Doppler correlationwith the 2-dimensional echocardiogram allowsdetermination of the site of obstruction, whichmust be ascertained in every patient, especially ifintervention is contemplated. Resting obstruc-tion is considered present when a restinggradient of 30 mm Hg is present. Changingpreload and afterload may provoke a gradient byincreasing the overlap between the inflow andoutflow portions of the LV. Patients who have noresting gradient but who have gradients greaterthan 30 mm Hg after maneuvers have latentobstruction, and patients with mild obstructionthat rises above 30 mm Hg after maneuvers haveprovocable obstruction. Typically, Valsalva, ex-ercise, and standing may be used to provokeobstruction and, on occasion, exercise in thepost-prandial state.45 As the main reason forprovoking gradient is to correlate patient symp-

toms with obstruction and to provide a target fortherapy, one should only use physiologic maneu-vers, such as standing or exercise or Valsalva.Dobutamine and amyl nitrite are not physiologicstimuli and should not be used to provokegradient. Also, dobutamine may provoke gra-dients in normals. Clinically, we perform tread-mill stress exercise echocardiography on allpatients with HCM who are able to exercise.An exception would be for patients with restinggradients of more than 150 mm Hg where littleavailable information will be gained.

Cardiac catherization may also demonstratethe severity and location of gradients inobstructed patients.11 During the procedure,gradients may be provoked by Valsalva and theintroduction of premature ventricular beats.

Pathophysiology of SAM

Understanding the hemodynamic mechanism ofSAM is crucial to developing successful treat-

ment strategies. There is agreement about theanatomic features that expose the mitral valve tothe hydrodynamic effect of flow and thuspredispose to SAM. These are the septal bulge,large mitral leaflets that are anteriorly positionedin the LV cavity because of anterior displacementof the papillary muscles, and residual portions ofthe leaflets that extend past the coaptation pointand protrude into the outflow tract.11,41,46-49

Initial reports advanced the hypothesis thatSAM might be caused by a Venturi mechanism, alocal underpressure in the LVOT caused bynarrowing of the outflow tract and rapid earlyejection. An alternate theory is that the mitralvalve is swept into the septum by the pushingforce of flow, referred to as the drag force.31,32,48

Contrasting points favoring the Venturi mecha-nism of SAM vs the flow drag mechanism areshown in Fig 6. Data pertinent to the debateabout the cause of SAM focuses on the geometryof the LV relative to the mitral valve, the velocityof the flow in the LVOT, and the shape of themitral valve. These are admittedly not the sort ofdata cardiologists are usually called on toevaluate, but a brief review may be illuminating.

Systolic anterior motion begins at a time of lowDoppler velocities in the LV. This is not compat-ible with the Venturi mechanism, which posits ahigh-velocity ejection flow pulling the protruding

mitral leaflet toward the septum.32 Systolic

Fig 6. The debate between the Venturi (pulling)mechanism and the flow drag (pushing) mechanismof systolic anterior motion of the mitral valve. Reprin-ted with permission from J Am Coll Cardiol 2000;36:1344-1354.


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anterior motion begins when mean outflow tractvelocity averaged 89 cm/s, a velocity not unlikethose found in normals without SAM.31,32,48

The orientation of the mitral valve relative toejection flow, and its shape, provides additionalevidence relative to this debate. The anteriorposition of the mitral valve puts it into the edgeof the flow stream of LV ejection, subjecting theleaflets to the hemodynamic force of ejectionflow. Left ventricular outflow tract narrowingprovides the substrate for, and is evidence tosupport, both theories. This has been a source ofconfusion in the debate. On the one hand, flow

velocity must increase as it enters the narrowedoutflow tract producing Venturi (lift) forces.Such Venturi forces are necessarily present,although they are a minor contributor becauseof other factors discussed here. On the otherhand, narrowing of the LVOT and the anteriorposition of the coaptation point also places theprotruding leaflet into the edge of the flowstream, subject to the pushing force of flow thatstrikes the undersurface of the leaflet as illus-trated in Fig 7. In normal dogs, without septalhypertrophy, SAM and obstruction may beexperimentally produced by lifting the papillary

Fig 7. Left: The pushing force of flow. Intraventricular flow relative to the mitral valve in the apical 5-chamber view.In obstructive HCM, the mitral leaflet coaptation point is closer to the septum than normal.34 The protruding leafletsextend into the edge of the flowstream and are swept by the pushing force of flow toward the septum. Flow pushesthe underside of the leaflets (arrow). Note that the midseptal bulge redirects flow so that it comes from a relativelylateral and posterior direction; on the 5-chamber view flow comes from bright fieldQ or b1 oclockQ direction. Thiscontributes to the high angle of attack relative to the protruding leaflets. Also note that the posterior leaflet isshielded and separated from outflow tract flow by the cowl of the anterior leaflet. Venturi flow in the outflow tractcannot be lifting the posterior leaflet because there is little or no area of this leaflet exposed to outflow tract flow.

Venturi forces cannot be causing the anterior motion of the posterior leaflet. Right frames: flow strikes theundersurface and lateral aspect of the mitral valve very early in systole, causing SAM in a patient with restinggradient of 54 mm Hg. Top right: 2-dimensional apical 5-chamber view shows the protruding mitral leaflet on thefirst frame in systole that showed mitral coaptation. Arrowhead points to mitral valve. O indicates outflow tract.Bottom right: figure shows the same view of the first systolic frame with color flow. Color flow is seen lateral to theleaflet tips (arrow). These images show the event graphically drawn on the left. Note that color flow velocity is lowon bottom right. On 2-D, the next systolic frames showed fully developed SAM on both views. On color flow, the nextsystolic frames showed aliasing in the outflow tract. The mitral leaflets are medially and anteriorly positioned intothe edge of the flow stream. Low-velocity flow strikes the undersurface of valve leaflets; they are swept toward theseptum by the pushing force of flow. Reprinted with permission from J Am Coll Cardiol 2000;36:1344-1354.

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muscles anteriorly with ligatures exposing thevalve to drag forces.50 Similarly, SAM andobstruction may occur as a complication ofmitral annuloplasty for prolapse when mitralcoaptation is displaced anteriorly by the ring.Consequently, annuloplasty techniques havebeen developed to ensure that postoperativemitral coaptation is posterior in the LV, explic-itly out of the way of the ejection stream anddrag forces.

Orientation

In patients with obstructive HCM there is a highangle of attack of the Doppler ejection flow streamonto the mitral valve leaflets. This orientationprecludes significant Venturi effects and impli-cates drag.31 In the apical 5-chamber view, localflow direction comes from an angle lateral to theprotruding leaflet. The mean angle at time ofmitral coaptation was lateral by 218; mean anglejust before septal contact increased to 458. Dragincreases as systole progresses. As the mitral valveis pushed toward the septum, the angle of attackrelative to flow increases. An analogy is a partlyopened door in a drafty corridor: the draft catchesthe door and sets it in motion; as it presents agreater surface to the wind the forces on itincrease, until it is slammed shut. These events

are shown graphically in Figs 4 and 8-10.A major contributor to the high positive angle

of attack of flow onto the mitral valve is the mid-septal bulge which is the rule in patients withhigh resting gradients, occurring in 92% ofpatients with resting obstruction.11 This occursbecause the midseptal bulge forces the outflow tosweep from a relatively posterior and lateraldirection in the LV, as shown in Fig 6. Whenviewed in the echocardiographic apical 5-cham-ber view, flow comes from bright fieldQ or

b1 oclockQ direction and strikes the undersurface

of the valve from a posterior and lateral directionand with a high angle.31 In contrast, subaorticbasilar septal thickening that just narrows theoutflow tract is uncommon in patients withresting gradients, found in just 12%.11

Shape of the Mitral Valve

The mitral valve resembles other biologic struc-tures with high drag coefficient. The valve has a

sharp anterior edge with no streamlining, andthere is a concavity under the cowl of theprotruding leaflet.47,48,51,52 The mitral valve inobstructive HCM displays increased drag coeffi-cient with increasing velocity of flow due toincreased contractility, an adverse feature similarto other examples in nature.52 Vogel and othershave extensively studied and quantified suchshape reconfiguration with increase in velocity(ibid, pp 113-126).

Other evidence indicating the drag mechanismstems from posterior leaflet SAM. In almost allpatients with SAM and obstruction, the posteriorleaflet moves anteriorly as well, underneath theanterior leaflet.53,54 But the posterior leaflet isseparated from the flow in the LVOT by the cowlof the anterior leaflet as shown in Fig 7. Venturiforces in the LVOT cannot be lifting theposterior leaflet because there is little or no areaof the posterior leaflet that is exposed to LVOTflow. In light of this and the previously men-tioned geometric observations, it i s concludedthat the posterior leaflet is pushed anteriorly.This mechanism is shown in Fig 7. By Occamsrazor, is it likely that the anterior and posteriorleaflets, which share a coaptation plane, havedifferent causes for SAM? It is more reasonablethat the anterior motion ofthe anterior leaflet iscaused by the same force that triggers the

abnormal posterior leaflet motion: both arecaused by flow drag.

Chordal slack plays a permissive role and isnecessary for SAM to occur. Without chordalslack no SAM would occur because the leafletswould be tethered. Systolic anterior motion isanteriorly directed mitral valve prolapse.31 In bothconditions, the mitral valve is often large and ispushed by flow from its normal position, withmitral regurgitation as a result.

Figs 8 and 9 show the sequence of events inlate diastole and early systole in a patient with

severe SAM just before mitral-septal contact.Low-velocity flow is seen behind the mitralvalve, shown as dark blue color flow. No high-velocity flow is seen in the LVOT until the mitralvalve is actually touching the septum and agradient has developed. It is the low-velocityflow behind the valve that pushes it into theseptum, well before any high-velocity flowdevelops in the outflow tract. Fig 10 shows asimilar example.


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Therapeutic Implications of Drag asthe Cause of SAM

Recently, new methods to relieve obstructionhave been developed: revised surgical techni-

ques, alcohol septal ablation (ASA), and dual-chamber pacing. Interventions are not alwayssuccessful and the reason for heterogeneity inresponse is not clear. Understanding the centralrole of flow drag in the pathogenesis of SAM mayprevent treatment failures.55,56

Fig 11 (second panel) shows how inadequatemyectomy resection focused on just the sub-valvular septum, targeted to widen the outflowtract and to reduce Venturi forces, may result inpersistent SAM and obstruction. A limitedmyectomy misses the impact of the mid-ven-tricular septal bulge which redirects LV flow sothat it comes from a relatively posterolateraldirection. This sort of resection results inpersistent SAM and either outflow obstructionor mitral regurgitation because flow still mustcourse around the remaining septal hypertro-phy, and it still catches the mitral valve andpushes it into the septum, and causes mitralregurgitation. To alleviate this sort of residualSAM, Messmer57 and Schoendube et al58 havepopularized the extended myectomy, diagram-matically shown in Fig 11 (third panel). Moreextensive resection redirects flow away from themitral valve precluding drag-induced SAM. Alarge decrease in the angle of attack of flowrelative to the mitral valve has been shown aftersuccessful myectomy; flow is made more parallel

to the mitral valve.59 The myectomy resectionmust be extended far enough down toward the

Fig 8. The pushing force of flow initiates SAM: foursequential zoomed 5-chamber view frames in latediastole and early systole in a patient with obstructiveHCM and resting gradient of 150 mm Hg. The 2D andcolor flow images are acquired simultaneously, on theleft and right, respectively, showing the relation of theflow field and the mitral leaflets. Timing of frames isshown on the ECG below each frame. Top: Latediastolethe widely open mitral leaflets are shown(white arrows) with transmitral diastolic flow appear-ing as red between the leaflets. Second: Diastolic flowis ending. Third: The first frame that showed thebeginning of SAM. The mitral valve is closed (whitearrow). Low-velocity, dark blue flow is seen behindthe mitral valve pushing it into the septum (yellowarrow). Note the absence of high-velocity flow in theoutflow tract. Bottom: Mitral-septal contact hasoccurred and now high-velocity flow due to thegradient appearing in the LV outflow tract. Systolicanterior motion is initiated by the dark blue, low-velocity flow in the third panel that pushes the mitralvalve into the septum, before high-velocity flow hasoccurred in the outflow tract.

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apex to allow flow to track anteriorly alongthe surgically reduced septum away from themitral valve.

Practically, preoperatively, the resectionshould be planned by measuring the distance onthe echocardiogram from the aortic valve to the

Fig 10. The pushing force of flow initiates SAM. Patient has obstructive HCM with resting gradient of 120 mm Hg.Frames depict the relation of flow and the mitral valve very early in systole. Timing of frame is shown on the ECGbelow each frame. Top left: Yellow arrow points to low-velocity blue flow behind the mitral valve anterior leafletthat pushes it into the septum. Top right depicts events slightly later in systole. The yellow arrow points to theblack signal void of the mitral valve. The valve contacts the septum just as the high-velocity aliasing flow begins.Bottom frame shows events later. The black signal void of the mitral valve is again seen in the color flow, but nowfull-fledged gradient, turbulence, and mitral regurgitation has developed.

Fig 9. The pushing force of flow initiates SAM. Enlarged third panel of the previous sequence. Left: Systolicanterior motion is initiated by the dark blue, low-velocity flow that pushes the mitral valve into the septum, beforehigh-velocity flow has occurred in the outflow tract (arrow). Right: The spinnaker is pushed by the wind, whichstrikes its undersurface. Image of Stanley Rosenfeld reproduced by permission, The Rosenfeld Collection, MysticSeaport Museum'.


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far side of the septal bulge, well past the contactpoint of the mitral valve. In our experience, inmost patients with a mid-septal bulge thisdistance is about 4.5 cm. These considerationsalso apply to site selection for percutaneous ASAprocedures. Targeting the basal septum alone isunlikely to completely relieve SAM, obstruction,and mitral regurgitation.

Messmer and Schoendube also have intro-duced freeing bound papillary muscles from the

anterior wall of the LV with sharp dissection ofabnormal connections between the papillarymuscles and the anterior wall .57,58 Thisaddresses the anterior position of the mitralcoaptation point (Fig 11, bottom panel). Afterthis resection, the surgeon sees the mitral valvedrop down into LV cavity. This puts the mitralvalve explicitly out of the outflow stream and itsdrag forces. bThis relieves the obstructive com-ponent of the mitral valve, which is rarely due tothe often cited and never proved Venturi effectbut has its origin rather in pathologic insertion ofsubvalvular apparatusQ.57 With this approach,90% of patients had no postoperative SAM.58

Although extended myectomy addresses the LVhalf of the SAM equation, it does not address theproblem of large redundant mitral leaflets, chord-al slack, and the excess leaflet that extends pastthe coaptation point. With this anatomy, in somepatients, SAM may still persist despite myec-tomy.56 Selected patients with large redundantvalves benefit from attention to the mitral valveanterior leaflet. Such patients have long mitralvalves on echo.46,60 At direct inspection, tractionwith the nerve hook shows excess valveslack.47,55,61 McIntosh et al62 reduced the size ofthe anterior mitral leaflet by a plication line downthe vertical axis of the leaflet. Swistel altered thisapproach by the horizontal plication, shown in

Fig 12. The advantage of this plication is that itnot only decreases the size of the anterior leafletoverall and reduces slack, but it also shortens thevalve in the long axis, reducing the protrudingexcess leaflet.55,61 Another advantage is that itis not difficult to perform. Thus, the operation isindividualized as required by patient anatomy,involving up to 3 components: extended resectionmyectomy, plication of redundant anterior leaflet,and release of the papillary muscles. This ap-proach has been termed the RPR operation:resect-plicate-release.61

A Therapeutic Approach to theComplexity of HCM

All patients with HCM should have 5 aspects oftheir care addressed. An attempt should be madeto detect the presence or absence of risk factorsfor sudden arrhythmic death. If the patientappears to be at high risk, discussion of thebenefits and risks of implantable cardioverter

Fig 11. Surgical separation of left ventricular inflowfrom outflow in obstructive HCM: extended myectomyand papillary muscle mobilization. Top: Line drawingof outflow relative to the mitral valve in early systole.Note the anterior position of the mitral valve coapta-tion. The prominent mid-septal bulge redirects out-flow so that it comes from a relatively posteriordirection, catching the anteriorly positioned mitral

valve and pushing it into the septum. Second: Aftersubaortic septal resection. The subaortic septum hasbeen resected, but only down to the tips of the mitralleaflets. Flow is still redirected by the remainingseptal bulge so that it comes from a posteriordirection. It still catches the mitral valve; SAMpersists, as does obstruction. Third: The septal bulgebelow the mitral leaflet tips has been resected, anextended myectomy. Now, flow tracks more anteriorlyand medially, away from the mitral leaflets Bottom:Mobilization and partial excision of the papillarymuscles is added to extended myectomy. The mitralcoaptation plane is now more posterior, explicitly outof the flow stream. Reprinted with permission from

Ann Thorac Surg 2003;75:620-632.

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defibrillator (ICD) is indicated, and many suchpatients will be implanted. Symptoms of dys-

pnea, angina, syncope, and fatigue are appraisedand treated. Bacterial endocarditis prophylaxis isrecommended.63 Patients are advised to avoidathletic competition and extremes of physicalexertion. First-degree family members should bescreened with echocardiography and ECG.

As a routine, screening for hyperlipidemiashould be performed and there should beaggressive treatment for hyperlipidemia as thecombination of HCM and coronary diseasecauses excess mortality above that seen inHCM alone.64

Risk Factors for Susceptibility toSudden Cardiac Death

Sudden cardiac death (SCD) was a prominentfeature in the modern description of HCM1 and isits most dreaded complication.9,65-72 An initiallyreported incidence of up to 4% per year wasoverestimated in the early HCM literature becauseof referred-patient selection bias. Reports had

come from selected centers where the sickestpatients had been referred.73-75 Community-based, more recent series have shown a yearlyHCM-related mortality of 1.5% per year.73,76-80

Ability to predict which patients with HCMwill experience sudden death has long been aclinical goal. The need for risk stratification hasbecome even more focused since the advent ofSCD prevention with the ICD for both primaryand secondary prevention. The benefit of ICDimplantation in high-risk patients is suddendeath prevention with appropriate shock ratesof 4.5% per year for primary prevention and 11%per year for secondary prevention.67

In patients who have experienced SCD orsustained ventricular tachycardia, the judgmentto implant an ICD for secondary prevention isstraightforward because of subsequent high an-nual rates of recurrent malignant arrhythmia.67,81

Because patients with HCM may present atyoung age, and since the risk period for suddenarrhythmic death may be long and cumulative,decision making about primary prevention maybe difficult. For primary prevention, risk factorsthat are observed to stratify risk for SCD inHCM include massive wall thickening (N30mm),65,66 unexplained syncope,66,71 family his-tory of SCD in a first-degree family memberthe relative dying at age less than 40 years,82

ventricular tachycardia3 or more beats on 24-or 48-hour ECG monitoring,83 inadequateriseor frank dropin blood pressure withexercise in patients younger than 40 years,66,84-86 and resting obstruction gradient of 30 mmHg or more.30 Certain risk factors, that is,nonsustained ventricular tachycardia, are con-sidered to have limited weight, when they occurin isolation.87 Ventricular tachycardia, occur-ring without syncope, in patients older than30 years is not a risk factor for SCD, whereasit is a predictor in young patients younger than

30 years.83

The problem with risk stratification is thateach risk factor has relatively low positivepredictive value for SCD.66,88 Absence of anyrisk factors offers the patient and clinician somemeasure of assurance that the risk of SCD islow.66 The presence of 1 risk factor is verycommon in HCM, whereas sudden death isuncommon. Risk factors may coexist in the samepatient, and when they do, individual risk for

Fig 12. Horizontal plication of the anterior mitralleaflet to reduce leaflet length and leaflet/chordal

slack. Plication is performed by placing three to fourfine mattress sutures of 5-0 polypropylene in ahorizontal rather than longitudinal orientationthrough the fibrotic area of the leaflet. The width ofthe mattress sutures is dictated by the degree ofr edu ndan c y of t h e le af let a n d m obilit y w h enassessed by the nerve hook. This modification moredirectly reduces leaflet-chordal slack and excesslength than a suture line in the longitudinal orienta-tion. Reprinted with permission from Ann ThoracSurg 2003;75:620-632.


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death increases (Fig 13).66 At present, mostclinicians would agree that the presence of 2 riskfactors would be enough to consider implanta-tion of an ICD and would individually tailortherapy depending on age and patient circum-stances. For example, the low incidence of SCDafter myectomy would make the necessity of ICDimplantation debatable for patients undergoing

surgery. Implantation of an ICD in patients with1 risk factor would depend on physician judg-ment and patient choice. There should bediscussion with the patient of the benefits andrisks of the ICD, and the pros and cons ofimplantation, and the reason for the physiciansconsidered recommendation.

To date, genotype analysis has not yet beenfruitful in predicting high risk. Initially, familieswith thin myofilament disease, tropinin, and atropomyosin mutations were thought to be athigher risk. These mutations are uncommon,

occurring in less than 5% of patients. However,recent data indicate that they have no definiteprognostic characteristics.88-91 Because HCMmay be caused by any of the many mutationson each individual gene, a myriad number ofdisease-causing mutations have been discovered.Thus, there is yet limited prognostic informationcollected on individual mutations (although thiswork is ongoing, see http://www.cardiogenomics.org). In addition, there are modifier genes that

may accentuate or attenuate the individualprognostic effect of particular mutations.92,93

Risks of ICD Implantation and

ICD Management in HCMRisks of ICD implantation may be thought of,and communicated to patients, as 4 bIs,Q im-plantation risk, infection, inappropriate shock,and never using the device insurance risk (youbuy the policy but dont die). Implantation risksinclude perforation of the great vessels, lung, andcardiac chambers, and the infrequent need forsurgery to correct perforation. The risk ofimplantation is not just restricted to the initialprocedure, but extends a trail of risk into thepatients future as they require generator replace-

ments roughly every 5 to 7 years and may requirelead removal because of fracture or infection.Lead infection is a dreaded complication becauseit requires removal of infected leads that may befixed in situ at either the right ventricle, rightatrium, or the great veins. Removal of leads hasdeveloped into a specialty of its own, because ofthe need for specialized laser technology and hasa greater than 1% potential for major complica-tions, including death.94 Inappropriate shockoccurs frequently in patients with HCM. Youngpatients may overexert, even if this is proscribed,

and sinus tachycardia may be the incitingarrhythmia, especially if a dose of b-blocker isforgotten. Atrial fibrillation is a frequent compli-cation of HCM, and this arrhythmia rivals sinustachycardia as a cause for inappropriate shock.Because the trigger for device intervention is raterelated, most young patients receiving an ICDshould be maintained on b-blockade.

Young patients with HCM should understandthat having an ICD is analogous to purchasing aterm insurance policy. Although there is a 4%per year chance of appropriate shock andprevention of cardiac death, it is also possiblethat malignant arrhythmia will never occur intheir particular case. They will never need deviceintervention. This group will grow old andcontract another lethal illness, die from it, andnever need the device, despite decades of itssurveillance. After discussing the risks andbenefits of ICD implantation, most patients willdecide to have implantation done.

Families are encountered who have had mul-tiple sudden deaths.82 In these families, it would

Fig 13. Risk of mortality stratified by increasingnumber of risk factors. For each 5-mm increase inmaximum LV wall thickness, the chance of dyingincreases. But even more striking increases in mor-tality depend on the number of additional risk factors

present. Reprinted with permission from Curr ProblCardiol2004;29:239-291, as compiled from the data ofElliott et al.66

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seem prudent to consider ICD implantation for allfirst-degree relatives who are diagnosed withovert HCM. Because of modifier genes andincomplete penetrance, it is not clear at this timewhether relatives with very mild thickening(V14 mm), or genotype-positive family memberswho are completely phenotype-negative with nowall thickening, should be implanted.

Recommendation toAvoid Competition

Athletes who die suddenly on the playing field aremost often found to have structural heart disease.At autopsy, HCM is the most common structuralheart disease found.95 Because of these observa-tions, it is recommended that patients with HCMshould avoid competition and extremes of exer-tion. This recommendation should be discussedwith each patient.96 Moreover, explain also thatexercise would not in any case be expected toimprove the patients cardiac condition, whichmight be a patient-held misconception. Thisrecommendation may be barely relevant inseverely symptomatic patients or in the elderlywho limit themselves. However, in the young, orin asymptomatic middle-aged patients, this rec-ommendation may have profound effect. Athlet-ics and sport occupy a central role in many

patients lifestyles. In some, athletic prowess andsuccess have intoxicating appeal. In some ath-letes, the diagnosis of HCM crushes ambition forfame and fortune.97 The guidelines allow recrea-tional sports activity and specifically allow exer-cise to maintain muscular tone. There is inevitableambiguity in the intensity of activity allowed. Wetry to clarify by pointing out that, in competition,athletes will often push beyond limiting symp-toms to win and this is to be specifically avoided,whether in formal competition or in pickupgames. We also recommend avoiding activities

where syncope would have disastrous effect suchas scuba diving or surfing. We recommend thatpatients not lift more than 40 lb.

In a family with sudden death, there is theappropriate concern that individuals who aregenotype positive might be at risk for SCD ifthey compete in sports, even if they have noclinical signs of HCM. There are no data toguide recommendations here. However, withcurrent knowledge, such genotype-positive, phe-

notype-negative patients might be guided toavoid competition.

Symptoms

Symptoms of dyspnea and exercise intoleranceare related to LV diastolic dysfunction and also toLV outflow tract obstruction when it is present.Reduced exercise tolerance correlates with aninability to increase stroke volume as assessed bycardiopulmonary stress testing.98 In nonob-structed patients, inability to increase strokevolume is due to decreased chamber compliance.When outflow gradients exceed 60 mm Hg, amid-systolic drop in LV ejection velocities andvolumetric flow has been shown, which maycontribute to inability to increase stroke vol-ume.38,39 Moreover, further decrement in flowoccurs after pharmacologic increase in gradientwith dobutamine.39 In addition, dynamic ob-struction is almost invariably associated withmitral regurgitation, a byproduct of SAM.11,99

Grade of mitral regurgitation correlates withposterior leaflet length; it is particularly severewhen the posterior leaflet is not long enough tocover the extent of displacement of the anteriorleaflet, as it is pushed into the septum.100

Chest discomfort of an anginal nature occursfrequently in patients with HCM with and

without obstruction. There is ample evidence ofischemia: pacing-induced myocardial lactate pro-duction and reversible stress-induced scinti-graphic perfusion defects are the most widelystudied manifestations.101 In addition, there isevidence from multiple sources of inadequatevasodilator reserve.102,103 This has pointed toarteriolar narrowing and microvascular dysfunc-tion as the most likely cause for ischemia. Theepicardial coronary arteries are dilated in HCMand overall coronary flow is increased, to providethe hypertrophied myocardium. In contrast, the

arterioles show intimal and medial hyperplasia,resulting in narrowing of these vessels.27 Becauseof dilatation of epicardial vessels, coronary flowvelocity is normal, whereas velocities in thearterioles are double that of the epicardium andalso twice that found in normals or hyper-tensives.28 These data lend credence to impor-tance of arteriolar narrowings as a physiologicallysignificant cause of ischemia. Ischemia maypredict adverse outcome.101 Left ventricular


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outflow tract obstruction exacerbates ischemia,by increasing LV work, and simultaneouslydecreasing aortic diastolic, and thus LV perfusionpressure.104 Surgical relief of obstructiondecreases pacing-induced lactate production.

Syncope is the most multifactorial of HCMsymptoms.105 In any given patient, the clinicalcircumstances of syncope must be considered,although in many cases ambiguity about etiologyprevails. Syncope that occurs without anycircumstantial cause must be considered due toventricular arrhythmia until proven otherwise.Sudden inappropriate vasodilatation due toautonomic dysfunction in the absence of ar-rhythmia also occurs.106 Postexercise syncopemay be due to arrhythmia, obstruction, or aparadoxical fall in blood pressure.107 Inappro-priate vasodilatation after exercise occurs in 25%of patients.84,107 Typical neurally mediatedsyncope occurs in HCM. Circumstances thatmay suggest this etiology are associated gastro-intestinal symptoms.

General fatigue is a common nonspecificcomplaint. When fatigue occurs, it is oftendifficult to distinguish between HCM-relatedfatigue and that induced by b-blockade.

Decrease in dose, or elimination ofb-blockade,may allow differentiation.

Watchful Waiting in Asymptomatic

and Mildly Symptomatic HCMThe prognosis in large community-based pop-ulations of patients with HCM is generallygood.73,77,78 Indeed, survival to old age iscommon with diagnosis of HCM.108 Theseobservations must be considered in the approachto the patient with no or only mild symptoms,New York Heart Association (NYHA) class I orII, who are not deemed to be at high risk forsudden death. In such patients, as no medical,surgical, or interventional therapy has beenshown in randomized trials to improve mortalityor prevent disease progression (such trials havenot been done in HCM), the approach ofwatchful waiting is often appropriate. There isno urgency to begin pharmacologic therapy inasymptomatic patients. In mildly symptomaticobstructed patients, after pharmacologic therapyis begun, there is no urgency to progress rapidlyto myectomy or alcohol ablation. Such patientsmay be treated expectantly, moving deliberately

Fig 14. A schematic summary of the pharmacologic therapy of HCM. Reprinted with permission from Blackwell-Futura.111

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to more aggressive therapies only when symp-toms progress.

Pharmacologic Treatment of

Symptoms

Nonobstructive HCM

In symptomatic nonobstructive HCM (Fig 14),symptoms are due to diastolic dysfunction,impaired relaxation early in diastole, and de-creased chamber compliance in late diastole. Thepathology is small LV volumes, hypertrophy,fiber disarray, and fibrosis. There are few agents

available and they are generally not particularlyeffective in improving severe symptoms due todiastolic dysfunction. No pharmacologic agenthas been consistently shown to improve LVr e la x at i on a n d c h am be r c o mp li a nc e i nHCM.109,110

Hence, treatment options for symptomaticnonobstructive HCM are limited.111 Two treat-ment goals are to improve LV diastolic functionand to improve ischemia. Two classes of agentsare currently used, b-blockade and calciumchannel blockade. Neither class of agents hasbeen shown to improve diastolic chamber com-pliance. Moreover, studies in the catheterization

Fig 15. Verapamil causes an increase in LVEDP, impaired relaxation, and increased early mitral filling velocities.Upper andmiddlepanel:Simultaneous mitralflow velocitiesand LV pressure curvesfrom two patients with coronarydisease before and after intravenous verapamil (0.1 mg/kg). The left panels are the control tracings and the rightpanelsare after verapamil. Note theincreasein LV enddiastolicpressureafterverapamil andthe increase in theearlytrans-mitral velocities. LVEDP=LV end diastolic pressure. Lower panelsRight: transmitral (E) flow velocitiesincrease after verapamil; left: LVEDP increases after verapamil (0.1 mg/kg). Increased early LV filling after verapamilreflects worsened, not improved relaxation. Reprinted with permission from J Am Coll Cardiol1993;21:182-188.


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laboratory have shown that neither intravenousb-blockade nor verapamil improved early dia-stolic relaxation in the hypertrophic left ventri-cle.109,110 The data about the effect of verapamilon early diastolic relaxation are controversial.One source ofconfusion concerns data indicatingan increase in early diastolic peak filling rate asassessed on serial radionuclide ventriculogra-phy.112-114 This had initially been interpreted asan improvement in diastolic function (ie, fastfilling is better) until the work of Nishimuraet al.115 They simultaneously measured LV fillingwith high-fidelity catheters and Doppler echocar-diography, before and after verapamil IV, inpatients with coronary disease115 (Fig 15). In thisrevealing study, LV diastolic pressures rose afterverapamil, s increased, indicating impaired re-laxation, but early transmitral echo Doppler dia-stolic velocities increased. With current knowledgeof diastology, it is now understood that verapamilactually caused worsening, restrictive LV diastolicdysfunction, increasing early velocities because ofincreased left atrial pressure. This paper showedthat in a coronary population that verapamil wasnot lusitropic, and that the faster early fillingvelocities reported in nuclear studies, may actu-ally be detecting worsened diastolic function.

Verapamils positive contribution in the patho-physiology of nonobstructive HCM appears to be

relief ofischemia. Verapamil improves myocardialperfusion as assessed by stress radionuclide perfu-sion imaging116 and may thus improve symptoms.

b-Blockade, and, to a lesser degree, verapamil,may cause chronotropic incompetence inHCM.117 As diastolic dysfunction may limit theexercise-induced increase in stroke volume,patients with HCM often rely on increased heartrate to increase cardiac output. In such patients,pharmacologic limitation of heart rate rise mayimpair exercise capacity.

Whereas disopyramide has been shown to

improve diastolic function in obstructedpatients, by decreasing gradient and systolicload,118,119 it has not been shown to improvediastolic function in nonobstructed patients andshould be avoided in this group, pendingfurther investigation.

For the unusual patient with fluid retention,diuretics may be helpful by relieving dyspnea anduncommon edema. Overdiuresis should beavoided as patients with HCM are often preload

dependent for adequate cardiac output. If patientsinitially present with edema, another diagnosisshould be sought as this is very unusual. Amyloidmay be suspected in this clinical situation,especially if the ECG QRS voltage is low.

In animal models of HCM, aldosterone antag-onism has been shown to improve or preventfibrosis and hypertrophy.120 Similarly, statintherapy has been shown to prevent phenotypein genotype-positive animals.121 As a new desig-nation, these pharmacologic agents may betermed fibrotardive. Clinical trials would seemappropriate for these new approaches as there iscurrently no good pharmacologic treatment foradvanced symptoms in nonobstructive HCM.

Obstructive HCM

Pharmacologic therapy of symptoms in obstruc-tive HCM is succesful in two-thirds of patients(Fig 14). Negatively inotropic drugs improvedynamic LV outflow obstruction by decreasingejection acceleration122 (see Figs 16 and 17).Decreasing ejection acceleration decreases flowvelocities early in systole, decreasing early dragforces on the mitral valve, delaying mitral-septalcontact, and reducing gradient. Delaying theearly trigger of SAM may allow reassertion ofchordal tension by papillary muscle shortening

to provide countertraction to prevent SAM, evencompletely.

b-Blockade is the initial treatment for symp-tomatic obstructed patients.111,123 b-Blockersdecrease the sympathetic-mediated rise in gradi-ent with exercise and improve symptoms. How-ever, b-blockade is not expected to reduceresting gradient124 and less than half of patientshave sustained improvement in symptoms.

For patients with refractory symptoms andgradients after b-blockade, there is regionalvariation in the choice of the next drug trial. In

many centers, the next trial selected is substitu-tion of verapamil for b-blocker.111,125,126

In other centers, disopyramide is added tob-blockade.12,111,119,127-130 Verapamil, a potentcalcium channel blocker, has both negativeinotropic properties but also is a vasodilator. Ithas been shown to decrease gradient andimprove symptoms.131 In a limited number ofpatients, exercise tolerance has been shown toincrease as well.125,126,132

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Fig 16. Top: Comparison of left ventricular pulsed Doppler tracings before treatment (left) and after successfulmedical treatment (right). The sample volume was 2.5 cm apical of mitral valve coaptation point. Before treatment,ejection acceleration was rapid (arrowhead), and velocity peaked in the first half of systole. After treatment,ejection acceleration was slowed (arrowhead), and velocity peaked in the second half of systole. Systolic anteriormitral motion was delayed, and a 96mm Hg gradient was eliminated. Note that although acceleration slowed,peak velocity remained virtually unchanged. This contrast highlights the importance of acceleration and the timingof ejection in successful medical therapy. The velocity calibration is identical in both panels. The scale is 20 cm/sbetween white marks. Bottom: Similar comparison of left ventricular Doppler tracings before treatment (left) andafter successful elimination of gradient (right). After treatment, ejection acceleration was slowed (arrowhead), andvelocity peaked in the second half of systole. Top panels reprinted with permission from Circulation 1998;97:41-47.


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Verapamil is indicated for patients with mildto moderate symptoms and moderate gradients.However, it is not used in patients with severeobstruction and severe symptoms because, onoccasion, vasodilating effects outweigh negative-ly inotropic effects: gradient may rise, andpulmonary edema and death have been reported.In addition, heart block and bradycardia maycomplicate its use.133

Disopyramide is a type I antiarrhythmic drug,with potent negatively inotropic properties; in

normals, it decreases echocardiographic fraction-al shortening by 28%.134 It is a sodium channelblocker and may have calcium channel blockingproperties as well; it is not a vasodilator. Dis-opyramide is generally given to patients who arerefractory to b-blockade and would otherwiserequire intervention with surgical septal myec-tomy or ASA. In a multicenter study, two thirds ofpatients with obstructed HCM treated with dis-opyramide combined with a b-blocker could be

managed medically with amelioration of symp-toms and 50% reduction in LVOT gradient whenfollowed for 3 years. The remaining one third ofpatients could not be managed successfully withdisopyramide and required invasive treatmentsbecause of inadequate symptom and gradientcontrol or vagolytic side effects. There was atrend to lower cardiac mortality and suddendeath. Disopyramide therapy was not proarrhyth-mic in obstructive HCM127 (Figs 18 and 19).

The dose of disopyramide that is most often

successful is 250 mg bid, using the controlledrelease preparation.111 For patients who do notrespond, dose is increased to 300 mg bid.Disopyramide is generally given with an agentwith atrioventricular (AV) nodal blocking prop-erties, to slow exercise heart rate and to slowventricular response, should atrial fibrillationoccur. Although disopyramide has been mostoften used with b-blockade, it may also be usedin conjunction with verapamil.

Fig 17. Explanation of pressure gradient development before and after treatment of obstruction. Before treatment(top tracing), rapid left ventricular acceleration apical of the mitral valve, shown as a horizontal thick arrow,triggers early SAM and early mitral-septal (M-S) contact. Once mitral-septal contact occurs, a narrowed orificedevelops, and a pressure difference results. The pressure difference forces the leaflet against the septum, whichdecreases the orifice size and further increases the pressure difference. An amplifying feedback loop isestablished, shown as a rising spiral. The longer the leaflet is in contact with the septum, the higher the pressuregradient. After treatment (bottom tracing), negative inotropes slow early SAM (shown as a horizontal wavy arrow)and may thereby decrease the force on the mitral leaflet, delaying SAM. Mitral-septal contact occurs later, leavingless time in systole for the feedback loop to narrow the orifice. This reduces the final pressure difference. DelayingSAM may also allow more time for papillary muscle shortening to provide countertraction. In the figure, for clarity,the bbeforeQ arrow is positioned above the bafterQ arrow, although at the beginning of systole they both actuallybegin with a pressure gradient of 0 mm Hg. Reprinted with permission from Circulation 1998;97:41-47.

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Disopyramide does not cause hepatic, renal, orcentral nervous system toxicity. Mild vagolyticside effects, dry mouth, blurred vision, and cons-tipation are common but generally subside. Ifthey prove troubling, the dosage may be re-duced, or controlled-release pyridostigmine maybe added, 180 mg/d (Mestinon Timespan, ICN,Costa Mesa, CA). A more serious vagolytic sideeffect is urinary retention. Disopyramide should

not be given to patients with symptoms ofprostatism. If this proscription is observed,urinary retention is rare. Vagolytic side effectscause discontinuation of disopyramide in 7% ofpatients. Because of its impaired elimination inrenal failure, disopyramide should be adminis-tered in reduced dosage or with serum monitor-ing. We do not administer concomitantamiodarone, sotolol, or other antiarrhythmicwith disopyramide to avoid electrophysiologic

drug interaction and ventricular arrhythmia. Wealso avoid macrolide antibiotics.111,127

Because disopyramide is a type I antiarrhyth-mic, and because proarrhythmia has been ob-served in patients with other heart diseases, wehave admitted patients we begin on disopyramideto the hospital for 3 days of electrocardiographicmonitoring. But this is not the practice of the non-US centers that actively use disopyramide, andthe absence of any significant arrhythmia duringour 3-day admissions would support outpatientinitiation in uncomplicated cases. We routinelyperform ECG surveillance of the QTc interval onall follow-up clinic visits. We will not increasedisopyramide if QTc prolongation has occurredlonger than 525 milliseconds in patient withnormal QRS duration, but QTc prolongation hasnot prompted drug discontinuation.

Fig 18. Top: Kaplan-Meier survival plot for all-causecardiac mortality in disopyramide-treated and non-disopyramide patients. Bottom: Kaplan-Meier survivalplot for sudden cardiac death mortality in disopyr-amide-treated and nondisopyramide patients. Reprin-ted with permission from J Am Coll Cardiol 2005;45:1251-1258.

Fig 19. Top: Response of LV outflow tract gradient todisopyramide in 78 patients treated medically withoutrequirement for major nonpharmacologic intervention(such as surgical septal myectomy, alcohol septalablation, or dual-chamber pacing), and 40 patientswho required invasive intervention. Bottom: Re-sponse of NYHA class to disopyramide in 78 patientstreated medically without requirement for nonphar-macologic intervention (such as surgical septal myec-tomy, alcohol septal ablation, or dual-chamberpacing), and 40 patients who ultimately had suchinterventions. Reprinted with permission from J AmColl Cardiol 2005;45:1251-1258.


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Atrial fibrillation occurs frequently in patientswith HCM in 25% to 30% of older patients, bothwith and without obstruction.135-138 Left atrialdilatation is the most frequent substrate. Theadvent of atrial fibrillation is often marked by adeterioration of symptoms and is a frequent causeof hospitalization. There is a dramatic increase inembolic potential and stroke after the develop-ment of atrial fibrillation.136 This pertains both topatients with paroxysmal atrial fibrillation andalso to the young. Such patients also experiencehigher mortality. Patients with atrial fibrillationshould be anticoagulated with warfarin.136 Amio-darone is an effective antiarrhythmic for preven-tion of recurrence, but because of its long-termtoxicity it is not a good solution for youngerpatients. Such patients may be controlled withsotolol or dofetilide. In selected patients, radio-frequency ablation of the orifices of the pulmo-nary veins prevents recurrence.139

Surgical Septal Myectomy

Myectomy is the treatment of choice for patientswho fail medical therapy.55,61,140-148 Candidatesfor myectomy have persistent disabling symp-toms and gradients of greater than 50 mm Hg atrest or after physiologic provocation. Myectomyhas been successfully performed for 30 years,

and in experienced centers it can be performedwith low surgical mortality, 1%, and is uniformlysuccessful in reducing both gradient and symp-toms. Postoperative survival has been excellentwith series reporting annual cardiac mortality of1% per year.9,13,141,142,145,146 Medications forobstruction may be reduced or stopped postop-eratively. Gradient reduction after surgery isgreater than that observed after ASA.149 Inpatients with paroxysmal atrial fibrillation, amodified intraoperative maze procedure may bedone concomitantly with myectomy in an at-

tempt to prevent postoperative fibrillation. Theopportunity to address atrial fibrillation directly(and the mitral valve) is a benefit of surgery overalcohol ablation. Intraoperative transesophagealechocardiography both before the resection andafter rewarming and weaning from bypassis essential.60,150,151 Imaging is done beforeremoving the canulas. If resting or provocableobstruction persists, or if there is more than mildmitral regurgitation, the patient must be placed

back on bypass and further resection/repair mustbe attempted; if this is not possible, then mitralvalve replacement is rarely required.

Krajcer et al152 introduced the idea that asobstruction is most often caused by SAM of themitral valve, routine mitral valve replacementmight be a logical and successful way to relieveobstruction. However, this approach has themain disadvantage that the patient now has theburden of a life-long prosthetic valve. For theyoung who receive a mechanical prosthesis, thisrequires anticoagulation with warfarin with its1% to 2% per year risk of bleeding. All suchpatients are subject to the risk of prosthetic valvefailure and endocarditis. Because of these dis-advantages, myectomymitral-valve sparingoperations are always preferred.153

The exceptions are for patients with mitralregurgitation due to structural mitral diseaseabove and beyond that caused by SAM: mitralvalvular or annular calcification with restrictedmotion, severe unrepairable mitral prolapse, ordamage from endocarditis. Besides calcification,a clue to the presence of structural mitralregurgitation is a central or anteriorly directedjet. Mitral regurgitation solely from SAM isinvariably posteriorly directed and alwaysimproves after myectomy.

The most common serious complication of

myectomy is complete heart block that occurs in0% to 10% of patients.14,55,148 Ventricular septaldefect has been reported in 0% to 2%. Transientheart block may disappear after the operativeday. As surgical patients invariably are given aleft bundle branch block, patients who have rightbundle branch block preoperatively are at higherrisk for heart block and a pacemaker. Resectiontoo close to the aortic valve may result inventricular septal defect. As this area plays norole in the etiology of SAM, resection hereshould be avoided, in preference for resection

lower down in the mid-septum. Perhaps thelargest morbidity of myectomy stems fromcardiopulmonary bypass and thoracotomy andits associated risk of infection and stroke,especially in the elderly.

Alcohol Septal Ablation

Percutaneous ASA offers the attractive promiseof septal reduction without cardiopulmonary

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bypass and its complications.154-160 After place-ment of a temporary right ventricular pacinglead, a small diameter balloon catheter is placedin a selected left anterior descending (LAD)septal branch, and after inflating the balloon,angiographic contrast is injected to assure thatcontrast does not reflux back into the LAD.154

Diluted echo contrast is then injected duringtransthoracic or transesophageal echocardio-graphic imaging. In 8% of such injections,contrast is seen to flow to structures wherealcohol injection would be disastrous: posteriorLV wall, RV free wall, mitral papillary muscles, orthe entire septum. With this information, theoperator searches for a septal branch that can bedemonstrated to just supply the upper septum,preferably extending past the point of mitralseptal contact.161 One to 3 mL of absolute alcoholis instilled into the septal branch. Optimally, acontrolled myocardial infarction occurs. This isaccompanied by typical chest pain, enzymeelevation, and risk for potential lethal ventriculararrhythmia. The acute gradient reduction of ASAis caused by reduced ejection acceleration fromthe infarct and decreased hemodynamic force onthe mitral valve decreasing SAM in exactly thesame way as negatively inotropic medications.162

After recovery from the infarction, progressivethinning of the septum occurs and flow is

directed away from the mitral valve, actingsynergistically with the persistent infarct-relatedreduction in ejection acceleration.

Temporary right ventricular pacing is fre-quently necessary because of heart block whichproves to be permanent in 7%.161 Almost allpatients develop right bundle branch, so com-plete heart block is more frequent in those withpreprocedure left bundle branch block. Manip-ulation of the LAD is not without risk. Proce-dure-related LAD dissection has been reported.Reflux of alcohol back into the main LAD may

result in massive anterior infarction. Acute andlate progressive mitral regurgitation requiringmitral valve replacement has been reported.163

Of concern is that an anterior infarction andscar are produced by ASA and indeed are itsexplicit goal. There is concern expressed in theliterature that large scar may subject patients toincreased life-long risk of potentially lethalventricular arrhythmia.141 To date, there areno long-term longitudinal studies of consecu-

tively operated patients available to address thisconcern.

Alcohol septal ablation is not as effective assurgical myectomy in reducing gradient andalleviating symptoms.149,164 Another concern isthe perception that because ASA is a relativelyeasy procedure that it might be performed onpatients with mild symptoms, without adequatemedical trial, and by any interventional cardiol-ogist experienced with angioplasty. But obs-tructive HCM is a heterogeneous complex mul-tifaceted disease; among HCM experts, there isthe universal opinion that ASA should only beperformed in centers committed and familiarwith overall HCM care, including myectomy. Itshould not be performed without online expertechocardiographic guidance.

It has been pointed out that the number ofASA procedures that have been performed inthe 10 years since its introduction far out-numbers the number of surgical myectomiesreported in the 30 years it has been performed.As ASA and myectomy have the same indica-tions, there is the perception that ASA is beingapplied to patients who are less symptomaticthan those who previously have been sent forsurgery.141

As with surgery, ASA should be reserved forpatients who are NYHA class III, who have had

no relief of their symptoms with maximalpharmacologic therapy, and who have persis-tently high gradients (z50 mm Hg) at rest orafter physiologic provocation. Maximal phar-macologic therapy should include a trial ofb-blockade combined with disopyramide. Itshould not be used in NYHA class II patients.We reserve it for patients who have comorbidconditions that preclude surgery or for thosewho refuse thoracotomy. In our experience,these circumstances are uncommon (b1 in50 patients with obstruction).

Dual-Chamber Pacing

Dual-chamber pacing with complete ventricularpreexcitation through a short atrioventriculardelay significantly reduces outflow tract gra-dients.165 However, therapeutic effect is oftenincomplete; SAM persists with mean gradients of30 to 55 mm Hg after 3 months of pacing.166,167

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unclear at this time. It must be due to thedyssynchrony caused by the right ventricularpacing, or due to the short AV delay. Onehypothesis is that pacing might cause asynchro-nous or paradoxical septal motion, widening theoutflow tract and decreasing Venturi forces.However, against this notion is that septalparadox is only rarely seen. Jeanrenaud andKappenberger168 did find a modest decrease inregional septal wall motion, but there was nouniform correlation between the magnitude ofdecreased septal motion and percent gradientreduction. Also, as discussed above, a decrease inVenturi forces can only play a minor role in SAMimprovement.32 Therefore, both direct observa-tions and pathophysiology indicate that themechanism by which DDD pacing reduces SAMis more complex than just a widening of theoutflow tract. An alternate hypothesis is thenegative inotropic pathway: LV dyssynchonymay cause decreased LV ejection accelerationand decreases early forces on the mitral valve. Afinal hypothesis is that apical pacing may tensethe mitral subvalvular apparatus sooner than therest of the LV, so that when ejection drag forcesare applied to the mitral valve, excess slack hasalready been mitigated. In all patients, truncationof active transmitral filling (the Doppler A wave)should be avoided by excessive shortening of the

AV delay.169 In our experience, AV delays of60 milliseconds or less are almost invariablyassociated with such shortening. Atrioventricularoptimization with echocardiography is oftenperformed with the goal of gradient reductionby complete electrocardiographic ventricularcapture, without A-wave truncation. Late gradi-ent reduction is often higher than that observedat acute testing.

The benefit of pacing for symptom relief andgradient reduction is less than that observed aftersurgical septal myectomy.170 Initial enthusiasm

for symptom relief by DDD pacing with short AVdelay has been tempered by randomized clinicaltrials.166,167,171-173 Although gradients are re-lieved, overall exercise capacity and symptomrelief vary from patient to patient and benefit isunpredictable. In the M-Pathy randomized trial,a consistent significant treatment effect could beidentified only in elderly patients older than65 years. A significant placebo effect of pacinghas been found.166,172 But Gadler et al174 have

shown that when pacing is withdrawn by blindedinstitution of AAI pacing, there is a dramatic andprompt recrudescence of symptoms, only re-lieved by reinstitution of DDD pacing. Anotherrecent series of pacing for obstruction in patientsolder than 50 years has shown long-termbenefit.175 Despite the observation that somepatients derive benefit, DDD pacing cannot beregarded as a primary treatment modality forgradient reduction in younger and middle agedpatients with HCM because of its unpredictabil-ity and because myectomy is more effective. Asdevice therapy is now common for SCD preven-tion, many obstructed patients may receive aDDD pacemaker as a potentially useful adjunctto their ICD implantation procedure.

Coexisting Hypertension orHyperlipidemia

The prevalence of systemic hypertension in ourHCM clinic is 30%, which is comparable to itsprevalence in the middle-aged population. Thisposes diagnostic and therapeutic problems. It issometimes difficult to assess whether hypertro-phy is primary or due to the hypertension. Thepresence of SAM with obstruction, family mem-bers with HCM, or extreme hypertrophy out ofproportion to mild hypertension suggests that

the hypertrophy is due to primary HCM.Hypertensive HCM is characterized by markedhypertrophy accompanied by LV end diastolicdiameter of less than 42 mm and LV fractionalshortening greater than 45%.176

Vasodilators (angiotensin-converting enzymes,angiotensin receptor blockers, dihydropyridinecalcium antagonists) for hypertension are con-traindicated in obstructive HCM because theyworsen obstruction and symptoms and mayprecipitate syncope. Often, when patients pres-ent for evaluation at HCM centers, their symp-

t om s a re f ou nd t o d at e f ro m t he w ee kvasodilators were started. Symptoms respondalmost immediately to stopping vasodilators.Hypertension in obstructed patients is besttreated by increasing doses of b-blockers orverapamil and sparing use of thiazide diuretics.Clonidine may be used, often given at night toavoid daytime sedation. Rarely, intervention forgradient may be necessary to both controloutflow gradient and allow vasodilator therapy

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of severe hypertension. In patients without aprovocable gradient or after successful surgicalseptal myectomy, angiotensin inhibition orblockade can be safely used.

Concomitant coronary artery disease increasesmortality in HCM and may be overlooked whenconservatively managing HCM.64 There shouldbe a low threshold for coronary angiography inpatients with angina. Hyperlipidemia should betreated aggressively. There is no contraindicationto the use of nicotine patches or bupropion forsmoking cessation in HCM.

Transformation into Hypokinetic LVDysfunction

Less than 5% of patients with HCM progress toLV systolic dysfunction with low ejection frac-tion. Exercise intolerance worsens in thesepatients who may become symptomatic at restand often deteriorate rapidly and die from heartfailure.177 When this transformation occurs,pharmacologic treatment is changed: negativeinotropes are stopped and angiotensin-convert-ing enzyme inhibitors, digoxin, diuretics, andb-blockers are begun. Because of a high risk forsudden arrhythmic death, ICD implantationshould be considered in all of these patients.

Biventricular pacing to improve heart-failuresymptoms is now available for patients withLBBB. Patients with systolic LV dysfunctionshould be referred for transplantation evaluationwhen symptoms progress to NYHA Class 3-4.

Future Research

There is a need for basic understanding of themechanisms that transform a genotype-positiveindividual into a patient with HCM. If these wereunderstood, means to prevent or modify patho-logic hypertrophy might be found even without

correcting the mutation (which would be best).More medications are needed for this conditionfor both palliation of symptoms and preventingdisease progression. In particular, there is noeffective pharmacologic means to prevent fibrosisand improve chamber compliance. For obstruc-tion, long-term study of the benefits and risks ofalcohol ablation must be compiled and comparedto myectomy. Current paradigms for suddendeath risk stratification lack predictive accuracy.

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