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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) is

viewed as a complex and challengingcardiac disease. Its pathophysiology, diagnosis

and treatment span the gamut of cardiologic

disciplines: In pathophysiology one must con-

sider left ventricular outflow obstruction, mitral

regurgitation, ischemia, atrial fibrillation, sud-

den death, diastolic dysfunction, molecular

biology and genetics. Diagnostic testing with

echocardiography, nuclear scintigraphy, stresstesting, catheterization, 24 hour ECG, and MRI

may be applied. Treatment may involve the

implanted 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

Progress in Cardiovascular Diseases, Vol. 0, No. 0 (August), 20

From the Hypertrophic Cardiomyopathy Program andEchocardiography Laboratory, Department of Medicine,

Division of Cardiology, St. Luke’s-Roosevelt Hospital

Center, College of Physicians and Surgeons, ColumbiaUniversity, New York, NY.

Address reprint requests to Mark V. Sherrid, MD, 1000

10th Avenue 3B-30, New York City, NY 10019.

E-mail: msherrid@chpnet.org0033-0620/$ - see front matter

n 2006 Elsevier Inc. All rights reserved.

doi:10.1016/j.pcad.2006.08.001

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

Genetics, Pathology, Diagnosis

The inherited nature of HCM was noted as early

as the modern description of the disease.1

Hypertrophic cardiomyopathy is inherited as an

autosomal dominant trait; roughly half of

patients have another family member with

HCM. Unexplained hypertrophy occurs in

1:500 in the general population, making it the

most common inherited cardiac disorder. Sarco-

meric mutations of 10 genes that code for

myofilaments or their supporting proteins havebeen identified as a cause of HCM.2-5 In a cohort

of referred, unrelated patients with HCM, rough-

ly 40% of patients with HCM were found to have

sarcomeric mutations. In the remaining 60%,

none of the known genotype abnormalities were

found.5 Younger age at diagnosis, marked wall

thickness, and a family history of HCM increase

the frequency that a patient will be gene positive.Echocardiographic appearance also appears to

predict a high likelihood of sarcomeric-protein

mutation HCM; a reversed septal curvature

causing a crescent-shaped LV cavity predicts

gene-positive patients as compared with those

with localized subaortic bulge and preserved

septal curvature.6,7 The most common mutations

found are in the b-myosin heavy chain and inmyosin-binding protein C. Although the bulk of

genetically determined HCM occurs on 8 genes,

many hundreds of HCM-causing mutations are

dispersed over the many loci of these genes. All

of these genes may cause different phenotypes

and have different prognoses. Even among

families with the same mutation on a particular

loci individuals vary with respect to phenotypeand prognosis. This has markedly delayed

genotype-phenotype correlation. The pathophys-

iologic linkage between mutations and hypertro-

phy appears to be mediated by mutation-induced

functional abnormalities.8

06: pp 1-29 1

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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, Masson’s trichrome stain.

MARK V. SHERRID2

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Many patients have no family history of HCM.

Some of these patients may have sporadic

mutations. But many have no genes identified.

In these, the responsible genes may not be

identified to date; or some unidentified factor

may be causing their hypertrophy.Hypertrophic cardiomyopathy is diagnosed

when left ventricular (LV) hypertrophy occurs

in the absence of a clinical condition that would

cause the degree of hypertrophy noted.9-14 Wall

thickness greater than 14 mm is the criteria we

use for diagnosis. The majority of patients who

reach clinical attention have wall thicknesses

between 20 and 30 mm.14 The location of theabnormal hypertrophy is most often of anterior

septum, although the posterior septum and

anterior wall are frequently hypertrophied as

well. Typical of the heterogeneity of HCM is that

hypertrophy can occur in any segment, even

among relatives known to have the same geno-

type. Apical hypertrophy that spares the basilar

and mid segments is a variant that occurs morefrequently in East Asian patients with HCM.

However, it is a relatively common variant in

North American and European patients as well,

occurring in 7%.15 This variant generally has a

better prognosis. Truly atypical HCM variants

include thickening just of the lateral wall or

posterior wall.

Wall thickening is most often assessed by2-dimensional echocardiography. Particular at-

tention should be paid to the septum and also to

the thickness of the anterior wall. The anterior

wall is more difficult to visualize clearly than the

septum because of poorer lateral resolution

compared with the axial resolution of echocar-

diography systems. Magnetic resonance imaging

may be useful in selected cases.16

On light microscopy individual myocyte hy-

pertrophy is noted. Myocardial fiber disarray is

the pathognomonic abnormality. In normals,myocytes are arranged in linear parallel arrays.

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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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In HCM with fiber disarray, myocytes form

chaotic intersecting bundles (see Fig 1). With

electron microscopy, myofilament disarray is

noted as well. Although fiber disarray is noted

in other diseases, the percentage of the myocar-dium occupied by disarray is higher in patients

with HCM.17,18 Fiber disarray is thought to pre-

dispose to electrical reentry and sudden death.19

Fibrosis is also a prominent feature on light

microscopy. Interstitial and perivascular fibrosis

may occupy as much as 14% of the myocardium

Fig 4. Systolic anterior motion of the mitral valve, drawnsystole. Reprinted with permission from J Am Coll Cardiol

in patients who die suddenly.20-23 Fibrosis and

hypertrophy decrease LV chamber compliance

and cause diastolic dysfunction and exercise

intolerance.24,25 Fibrosis appears to predispose

to complex ventricular arrhythmia.26 Although

the epicardial coronary arteries are dilated,narrowings of the intramural penetrating coro-

nary arteries are noted, due to arteriolar intimal

and medial hyperplasia. These narrowings are

thought 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 added

burden imposed on top of these already impor-tant pathologic abnormalities. Left ventricular

outflow tract obstruction is an important deter-

minant of symptoms11 and is associated with

adverse outcome (Fig 3).30 The most common

location of obstruction is in the LV outflow tract,

caused by systolic anterior motion (SAM) of the

mitral valve and mitral-septal contact.11,31-33

Fig 4 shows dynamic SAM as it progressesthrough the early moments of systole. This

phenomenon is caused by a crucial anatomic

overlap between the inflow and outflow portions

of the left ventricle.34,35

Two decades ago, a debate about whether true

obstruction to LV ejection occurred in HCM36

was largely settled by the review of Wigle et al11

from apical 5-chamber view, as it proceeds in early1993;22:816-825.

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MARK V. SHERRID4

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published in this journal in 1985. In particular,

catheterization demonstration of LVOT gradients

between catheters in the aorta and in the body of

the LV in the inflow tract, via the transseptal

approach, excluded the possibility of catheter

entrapment as a cause of gradients.37 Subsequentecho-Doppler demonstration of gradients, and

their location by pulsed Doppler at the point of

mitral-septal contact, was conclusive. Recent

echocardiographic observations highlight the

hemodynamic significance of LVOT obstruction.

Obstruction causes a mid-systolic drop in LV

ejection velocities and flow when the gradient is

greater than 60 mm Hg.38,39 This echocardio-graphic pattern has been termed the blobster

clawQ abnormality because of its characteristic

appearance (Fig 5). The ejection velocity drop

occurs because instantaneous mid-systolic after-

load exceeds contractility. It is the cause of the

mid-systolic closure of the aortic valve and the

pulsus bisfiriens. The sensitivity of the myopathic

ventricle to the sudden increase in afterload isdemonstrated by the precise, simultaneous tim-

ing of the nadir of the LV velocities and the peak

of the LVOT gradient. Mid-systolic LVOT ejec-

tion flow decreases further after pharmacologic

Fig 5. Left: Mid-systolic drop in LV ejection velocity in obstruof the entrance to the LVOT in a patient with severe dynamThe pulsed wave cursor is 2 cm apical of the tips of the mitmid-systolic drop in LV ejection flow velocity. This drop in vbecause of its characteristic appearance. The drop in velocthe mitral-septal contact and the gradient.38,39 Right: pulsposition, after pharmacologic relief of obstruction. The mid

increase in the gradient by dobutamine.39 The

mid-systolic drop disappears with medical elim-

ination of the gradient (Fig 5).38,39 The mid-

systolic drop in ejection velocity is caused by

premature 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 is

the most common cause of outflow tract

obstruction, other variants occur. An anomalous

papillary muscle may insert directly into the

base of the anterior mitral leaflet, without

intervening chordae. Here, obstruction occurs

because of systolic apposition of the anteriorpapillary muscle and the septum. This anomaly

must be detected before surgery, and the

surgeon advised to its presence, to prevent poor

surgical outcome.41 This sort of mid-ventricular

obstruction is different from mid-ventricular

obstruction caused by systolic apposition of

the mid-LV walls.42 Apical HCM with concom-

itant mid-LV thickening may progress to causeobstruction in the mid LV, with development of

an apical akinetic chamber that occurs in the

absence of epicardial coronary disease. The

apical akinetic chamber occurs because of apical

ctive HCM. Pulsed wave Doppler recording just apicalic obstruction due to SAM and mitral-septal contact.ral valve leaflets. Long arrow points to the nadir of LVelocity has been called the blobster claw abnormalityQity is due to the sudden imposition of afterload due toed wave Doppler in the same patient, from the same-systolic drop is no longer present.

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PATHOPHYSIOLOGY AND TREATMENT OF HYPERTROPHIC CARDIOMYOPATHY 5

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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 thrombi

and also become a source of monomorphic

ventricular tachycardia.43

Left ventricular outflow tract obstruction is

quantified by measuring the pressure drop, the

gradient across the narrowing. This is most

commonly done with continuous wave Doppler

echocardiography.44 Pulsed Doppler correlation

with the 2-dimensional echocardiogram allows

determination of the site of obstruction, which

must be ascertained in every patient, especially ifintervention is contemplated. Resting obstruc-

tion is considered present when a resting

gradient of 30 mm Hg is present. Changing

preload and afterload may provoke a gradient by

increasing the overlap between the inflow and

outflow portions of the LV. Patients who have no

resting gradient but who have gradients greater

than 30 mm Hg after maneuvers have latentobstruction, and patients with mild obstruction

that rises above 30 mm Hg after maneuvers have

provocable obstruction. Typically, Valsalva, ex-

ercise, and standing may be used to provoke

obstruction and, on occasion, exercise in the

post-prandial state.45 As the main reason for

provoking 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 physiologic

stimuli and should not be used to provoke

gradient. Also, dobutamine may provoke gra-

dients in normals. Clinically, we perform tread-

mill stress exercise echocardiography on all

patients with HCM who are able to exercise.An exception would be for patients with resting

gradients of more than 150 mm Hg where little

available information will be gained.

Cardiac catherization may also demonstrate

the severity and location of gradients in

obstructed patients.11 During the procedure,

gradients may be provoked by Valsalva and the

introduction of premature ventricular beats.

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.

Pathophysiology of SAM

Understanding the hemodynamic mechanism of

SAM is crucial to developing successful treat-

ment strategies. There is agreement about the

anatomic features that expose the mitral valve to

the hydrodynamic effect of flow and thus

predispose to SAM. These are the septal bulge,

large mitral leaflets that are anteriorly positioned

in the LV cavity because of anterior displacementof the papillary muscles, and residual portions of

the leaflets that extend past the coaptation point

and protrude into the outflow tract.11,41,46-49

Initial reports advanced the hypothesis that

SAM might be caused by a Venturi mechanism, a

local underpressure in the LVOT caused by

narrowing of the outflow tract and rapid early

ejection. An alternate theory is that the mitralvalve is swept into the septum by the pushing

force 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 are

shown in Fig 6. Data pertinent to the debate

about the cause of SAM focuses on the geometry

of the LV relative to the mitral valve, the velocity

of the flow in the LVOT, and the shape of themitral valve. These are admittedly not the sort of

data cardiologists are usually called on to

evaluate, but a brief review may be illuminating.

Systolic anterior motion begins at a time of low

Doppler velocities in the LV. This is not compat-

ible with the Venturi mechanism, which posits a

high-velocity ejection flow pulling the protruding

mitral leaflet toward the septum.32 Systolic

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MARK V. SHERRID6

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anterior motion begins when mean outflow tract

velocity averaged 89 cm/s, a velocity not unlike

those found in normals without SAM.31,32,48

The orientation of the mitral valve relative to

ejection flow, and its shape, provides additional

evidence relative to this debate. The anteriorposition of the mitral valve puts it into the edge

of the flow stream of LV ejection, subjecting the

leaflets to the hemodynamic force of ejection

flow. Left ventricular outflow tract narrowing

provides the substrate for, and is evidence to

support, both theories. This has been a source of

confusion in the debate. On the one hand, flow

Fig 7. Left: The pushing force of flow. Intraventricular flow reIn obstructive HCM, the mitral leaflet coaptation point is closextend into the edge of the flowstream and are swept by thethe underside of the leaflets (arrow). Note that the midseptalateral and posterior direction; on the 5-chamber view flowcontributes to the high angle of attack relative to the protshielded and separated from outflow tract flow by the cowlcannot be lifting the posterior leaflet because there is little oVenturi forces cannot be causing the anterior motion ofundersurface and lateral aspect of the mitral valve very eagradient of 54 mm Hg. Top right: 2-dimensional apical 5-chfirst frame in systole that showed mitral coaptation. ArrowBottom right: figure shows the same view of the first systolicleaflet tips (arrow). These images show the event graphicallon bottom right. On 2-D, the next systolic frames showed fullsystolic frames showed aliasing in the outflow tract. The mithe edge of the flow stream. Low-velocity flow strikes the unseptum by the pushing force of flow. Reprinted with permis

velocity must increase as it enters the narrowed

outflow tract producing Venturi (lift) forces.

Such Venturi forces are necessarily present,

although they are a minor contributor because

of other factors discussed here. On the other

hand, narrowing of the LVOT and the anteriorposition of the coaptation point also places the

protruding leaflet into the edge of the flow

stream, subject to the pushing force of flow that

strikes the undersurface of the leaflet as illus-

trated in Fig 7. In normal dogs, without septal

hypertrophy, SAM and obstruction may be

experimentally produced by lifting the papillary

lative to the mitral valve in the apical 5-chamber view.er to the septum than normal.34 The protruding leafletspushing force of flow toward the septum. Flow pushesl bulge redirects flow so that it comes from a relativelycomes from bright fieldQ or b1 o’clockQ direction. Thisruding leaflets. Also note that the posterior leaflet isof the anterior leaflet. Venturi flow in the outflow tractr no area of this leaflet exposed to outflow tract flow.the posterior leaflet. Right frames: flow strikes therly in systole, causing SAM in a patient with resting

amber view shows the protruding mitral leaflet on thehead points to mitral valve. O indicates outflow tract.

frame with color flow. Color flow is seen lateral to they drawn on the left. Note that color flow velocity is lowy developed SAM on both views. On color flow, the nexttral leaflets are medially and anteriorly positioned intodersurface of valve leaflets; they are swept toward thesion from J Am Coll Cardiol 2000;36:1344-1354.

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PATHOPHYSIOLOGY AND TREATMENT OF HYPERTROPHIC CARDIOMYOPATHY 7

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muscles anteriorly with ligatures exposing the

valve to drag forces.50 Similarly, SAM and

obstruction may occur as a complication of

mitral annuloplasty for prolapse when mitral

coaptation is displaced anteriorly by the ring.

Consequently, annuloplasty techniques havebeen developed to ensure that postoperative

mitral coaptation is posterior in the LV, explic-

itly out of the way of the ejection stream and

drag forces.

Orientation

In patients with obstructive HCM there is a highangle of attack of the Doppler ejection flow stream

onto the mitral valve leaflets. This orientation

precludes significant Venturi effects and impli-

cates drag.31 In the apical 5-chamber view, local

flow direction comes from an angle lateral to the

protruding leaflet. The mean angle at time of

mitral coaptation was lateral by 218; mean angle

just before septal contact increased to 458. Dragincreases as systole progresses. As the mitral valve

is pushed toward the septum, the angle of attack

relative to flow increases. An analogy is a partly

opened door in a drafty corridor: the draft catches

the door and sets it in motion; as it presents a

greater surface to the wind the forces on it

increase, 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 with

high resting gradients, occurring in 92% of

patients with resting obstruction.11 This occurs

because the midseptal bulge forces the outflow to

sweep from a relatively posterior and lateral

direction in the LV, as shown in Fig 6. Whenviewed in the echocardiographic apical 5-cham-

ber view, flow comes from bright fieldQ or

b1 o’clockQ direction and strikes the undersurface

of the valve from a posterior and lateral direction

and with a high angle.31 In contrast, subaortic

basilar septal thickening that just narrows the

outflow tract is uncommon in patients with

resting 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, and

there is a concavity under the cowl of the

protruding leaflet.47,48,51,52 The mitral valve in

obstructive HCM displays increased drag coeffi-

cient with increasing velocity of flow due to

increased contractility, an adverse feature similarto other examples in nature.52 Vogel and others

have extensively studied and quantified such

shape reconfiguration with increase in velocity

(ibid, pp 113-126).

Other evidence indicating the drag mechanism

stems from posterior leaflet SAM. In almost all

patients with SAM and obstruction, the posterior

leaflet moves anteriorly as well, underneath theanterior leaflet.53,54 But the posterior leaflet is

separated from the flow in the LVOT by the cowl

of the anterior leaflet as shown in Fig 7. Venturi

forces in the LVOT cannot be lifting the

posterior leaflet because there is little or no area

of the posterior leaflet that is exposed to LVOT

flow. In light of this and the previously men-

tioned geometric observations, it is concludedthat the posterior leaflet is pushed anteriorly.

This mechanism is shown in Fig 7. By Occam’s

razor, is it likely that the anterior and posterior

leaflets, which share a coaptation plane, have

different causes for SAM? It is more reasonable

that the anterior motion of the anterior leaflet is

caused by the same force that triggers the

abnormal posterior leaflet motion: both arecaused by flow drag.

Chordal slack plays a permissive role and is

necessary for SAM to occur. Without chordal

slack no SAM would occur because the leaflets

would be tethered. Systolic anterior motion is

anteriorly directed mitral valve prolapse.31 In both

conditions, the mitral valve is often large and is

pushed by flow from its normal position, withmitral regurgitation as a result.

Figs 8 and 9 show the sequence of events in

late diastole and early systole in a patient with

severe SAM just before mitral-septal contact.

Low-velocity flow is seen behind the mitral

valve, shown as dark blue color flow. No high-

velocity flow is seen in the LVOT until the mitral

valve is actually touching the septum and agradient has developed. It is the low-velocity

flow behind the valve that pushes it into the

septum, well before any high-velocity flow

develops in the outflow tract. Fig 10 shows a

similar example.

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Therapeutic Implications of Drag asthe Cause of SAM

Recently, new methods to relieve obstruction

have been developed: revised surgical techni-

ques, alcohol septal ablation (ASA), and dual-

chamber pacing. Interventions are not always

successful and the reason for heterogeneity in

response is not clear. Understanding the central

role of flow drag in the pathogenesis of SAM may

prevent treatment failures.55,56

Fig 11 (second panel) shows how inadequate

myectomy resection focused on just the sub-

valvular septum, targeted to widen the outflow

tract and to reduce Venturi forces, may result in

persistent SAM and obstruction. A limited

myectomy misses the impact of the mid-ven-

tricular septal bulge which redirects LV flow so

that it comes from a relatively posterolateraldirection. This sort of resection results in

persistent SAM and either outflow obstruction

or mitral regurgitation because flow still must

course around the remaining septal hypertro-

phy, and it still catches the mitral valve and

pushes it into the septum, and causes mitral

regurgitation. To alleviate this sort of residual

SAM, Messmer57 and Schoendube et al58 havepopularized the extended myectomy, diagram-

matically shown in Fig 11 (third panel). More

extensive resection redirects flow away from the

mitral valve precluding drag-induced SAM. A

large decrease in the angle of attack of flow

relative to the mitral valve has been shown after

successful 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: Latediastole—the 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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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'.

PATHOPHYSIOLOGY AND TREATMENT OF HYPERTROPHIC CARDIOMYOPATHY 9

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apex to allow flow to track anteriorly along

the surgically reduced septum away from the

mitral valve.

Fig 10. The pushing force of flow initiates SAM. Patient hasFrames depict the relation of flow and the mitral valve verybelow each frame. Top left: Yellow arrow points to low-velthat pushes it into the septum. Top right depicts events slblack signal void of the mitral valve. The valve contacts theBottom frame shows events later. The black signal void of tfull-fledged gradient, turbulence, and mitral regurgitation h

Practically, preoperatively, the resection

should be planned by measuring the distance on

the echocardiogram from the aortic valve to the

obstructive HCM with resting gradient of 120 mm Hg.early in systole. Timing of frame is shown on the ECGocity blue flow behind the mitral valve anterior leafletightly later in systole. The yellow arrow points to theseptum just as the high-velocity aliasing flow begins.

he mitral valve is again seen in the color flow, but nowas developed.

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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 mitralvalve 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 fromAnn Thorac Surg 2003;75:620-632.

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far side of the septal bulge, well past the contactpoint of the mitral valve. In our experience, in

most patients with a mid-septal bulge this

distance is about 4.5 cm. These considerations

also apply to site selection for percutaneous ASA

procedures. Targeting the basal septum alone is

unlikely 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 of

abnormal connections between the papillary

muscles and the anterior wall.57,58 This

addresses the anterior position of the mitral

coaptation point (Fig 11, bottom panel). After

this resection, the surgeon sees the mitral valvedrop down into LV cavity. This puts the mitral

valve explicitly out of the outflow stream and its

drag forces. bThis relieves the obstructive com-

ponent of the mitral valve, which is rarely due to

the often cited and never proved Venturi effect

but has its origin rather in pathologic insertion of

subvalvular apparatusQ.57 With this approach,

90% of patients had no postoperative SAM.58

Although extended myectomy addresses the LV

half of the SAM equation, it does not address the

problem of large redundant mitral leaflets, chord-

al slack, and the excess leaflet that extends past

the coaptation point. With this anatomy, in some

patients, SAM may still persist despite myec-

tomy.56 Selected patients with large redundant

valves benefit from attention to the mitral valveanterior leaflet. Such patients have long mitral

valves on echo.46,60 At direct inspection, traction

with the nerve hook shows excess valve

slack.47,55,61 McIntosh et al62 reduced the size of

the anterior mitral leaflet by a plication line down

the vertical axis of the leaflet. Swistel altered this

approach by the horizontal plication, shown in

Fig 12. The advantage of this plication is that itnot only decreases the size of the anterior leaflet

overall and reduces slack, but it also shortens the

valve in the long axis, reducing the protruding

excess leaflet.55,61 Another advantage is that it

is not difficult to perform. Thus, the operation is

individualized as required by patient anatomy,

involving up to 3 components: extended resection

myectomy, 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 made

to detect the presence or absence of risk factors

for sudden arrhythmic death. If the patient

appears to be at high risk, discussion of the

benefits and risks of implantable cardioverter

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Fig 12. Horizontal plication of the anterior mitralleaflet to reduce leaflet length and leaflet/chordalslack. 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 ofredundancy of the leaflet and mobility whenassessed 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.

PATHOPHYSIOLOGY AND TREATMENT OF HYPERTROPHIC CARDIOMYOPATHY 11

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defibrillator (ICD) is indicated, and many such

patients will be implanted. Symptoms of dys-

pnea, angina, syncope, and fatigue are appraised

and treated. Bacterial endocarditis prophylaxis isrecommended.63 Patients are advised to avoid

athletic competition and extremes of physical

exertion. First-degree family members should be

screened with echocardiography and ECG.

As a routine, screening for hyperlipidemia

should be performed and there should be

aggressive treatment for hyperlipidemia as the

combination of HCM and coronary diseasecauses excess mortality above that seen in

HCM alone.64

Risk Factors for Susceptibility toSudden Cardiac Death

Sudden cardiac death (SCD) was a prominent

feature in the modern description of HCM1 and isits most dreaded complication.9,65-72 An initially

reported incidence of up to 4% per year was

overestimated in the early HCM literature because

of referred-patient selection bias. Reports had

come from selected centers where the sickest

patients had been referred.73-75 Community-

based, more recent series have shown a yearly

HCM-related mortality of 1.5% per year.73,76-80

Ability to predict which patients with HCM

will experience sudden death has long been aclinical goal. The need for risk stratification has

become even more focused since the advent of

SCD prevention with the ICD for both primary

and secondary prevention. The benefit of ICD

implantation in high-risk patients is sudden

death prevention with appropriate shock rates

of 4.5% per year for primary prevention and 11%

per year for secondary prevention.67

In patients who have experienced SCD or

sustained ventricular tachycardia, the judgment

to implant an ICD for secondary prevention is

straightforward because of subsequent high an-

nual rates of recurrent malignant arrhythmia.67,81

Because patients with HCM may present at

young age, and since the risk period for sudden

arrhythmic death may be long and cumulative,decision making about primary prevention may

be difficult. For primary prevention, risk factors

that are observed to stratify risk for SCD in

HCM include massive wall thickening (N30

mm),65,66 unexplained syncope,66,71 family his-

tory of SCD in a first-degree family member—

the relative dying at age less than 40 years,82

ventricular tachycardia—3 or more beats on 24-or 48-hour ECG monitoring,83 inadequate

rise—or frank drop—in blood pressure with

exercise in patients younger than 40 years,66,84-

86 and resting obstruction gradient of 30 mm

Hg or more.30 Certain risk factors, that is,

nonsustained ventricular tachycardia, are con-

sidered to have limited weight, when they occur

in isolation.87 Ventricular tachycardia, occur-ring without syncope, in patients older than

30 years is not a risk factor for SCD, whereas

it is a predictor in young patients younger than

30 years.83

The problem with risk stratification is that

each risk factor has relatively low positive

predictive value for SCD.66,88 Absence of any

risk factors offers the patient and clinician somemeasure of assurance that the risk of SCD is

low.66 The presence of 1 risk factor is very

common in HCM, whereas sudden death is

uncommon. Risk factors may coexist in the same

patient, and when they do, individual risk for

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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 factorspresent. Reprinted with permission from Curr ProblCardiol 2004;29:239-291, as compiled from the data ofElliott et al.66

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death increases (Fig 13).66 At present, most

clinicians would agree that the presence of 2 risk

factors would be enough to consider implanta-

tion of an ICD and would individually tailor

therapy depending on age and patient circum-

stances. For example, the low incidence of SCD

after myectomy would make the necessity of ICD

implantation debatable for patients undergoingsurgery. Implantation of an ICD in patients with

1 risk factor would depend on physician judg-

ment and patient choice. There should be

discussion with the patient of the benefits and

risks of the ICD, and the pros and cons of

implantation, and the reason for the physician’s

considered recommendation.

To date, genotype analysis has not yet beenfruitful in predicting high risk. Initially, families

with thin myofilament disease, tropinin, and atropomyosin mutations were thought to be at

higher risk. These mutations are uncommon,

occurring in less than 5% of patients. However,

recent data indicate that they have no definite

prognostic characteristics.88-91 Because HCM

may be caused by any of the many mutationson each individual gene, a myriad number of

disease-causing mutations have been discovered.

Thus, there is yet limited prognostic information

collected on individual mutations (although this

work is ongoing, see http://www.cardiogenomics.

org). In addition, there are modifier genes that

may accentuate or attenuate the individual

prognostic effect of particular mutations.92,93

Risks of ICD Implantation andICD Management in HCM

Risks of ICD implantation may be thought of,

and communicated to patients, as 4 bI’s,Q im-plantation risk, infection, inappropriate shock,and never using the device —insurance risk (youbuy the policy but don’t 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 thepatient’s 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

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PATHOPHYSIOLOGY AND TREATMENT OF HYPERTROPHIC CARDIOMYOPATHY 13

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seem prudent to consider ICD implantation for all

first-degree relatives who are diagnosed with

overt HCM. Because of modifier genes and

incomplete penetrance, it is not clear at this time

whether relatives with very mild thickening

(V14 mm), or genotype-positive family memberswho are completely phenotype-negative with no

wall thickening, should be implanted.

Recommendation toAvoid Competition

Athletes who die suddenly on the playing field are

most often found to have structural heart disease.At autopsy, HCM is the most common structural

heart disease found.95 Because of these observa-

tions, it is recommended that patients with HCM

should avoid competition and extremes of exer-

tion. This recommendation should be discussed

with each patient.96 Moreover, explain also that

exercise would not in any case be expected to

improve the patient’s cardiac condition, whichmight be a patient-held misconception. This

recommendation may be barely relevant in

severely symptomatic patients or in the elderly

who limit themselves. However, in the young, or

in 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 for

fame and fortune.97 The guidelines allow recrea-

tional sports activity and specifically allow exer-

cise to maintain muscular tone. There is inevitable

ambiguity in the intensity of activity allowed. We

try 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 pickup

games. We also recommend avoiding activities

where syncope would have disastrous effect such

as scuba diving or surfing. We recommend that

patients not lift more than 40 lb.

In a family with sudden death, there is the

appropriate concern that individuals who aregenotype positive might be at risk for SCD if

they compete in sports, even if they have no

clinical signs of HCM. There are no data to

guide recommendations here. However, with

current knowledge, such genotype-positive, phe-

notype-negative patients might be guided to

avoid competition.

Symptoms

Symptoms of dyspnea and exercise intoleranceare related to LV diastolic dysfunction and also to

LV outflow tract obstruction when it is present.

Reduced exercise tolerance correlates with an

inability to increase stroke volume as assessed by

cardiopulmonary stress testing.98 In nonob-

structed patients, inability to increase stroke

volume is due to decreased chamber compliance.

When outflow gradients exceed 60 mm Hg, amid-systolic drop in LV ejection velocities and

volumetric flow has been shown, which may

contribute to inability to increase stroke vol-

ume.38,39 Moreover, further decrement in flow

occurs after pharmacologic increase in gradient

with dobutamine.39 In addition, dynamic ob-

struction is almost invariably associated with

mitral regurgitation, a byproduct of SAM.11,99

Grade of mitral regurgitation correlates with

posterior leaflet length; it is particularly severe

when the posterior leaflet is not long enough to

cover the extent of displacement of the anterior

leaflet, as it is pushed into the septum.100

Chest discomfort of an anginal nature occurs

frequently 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 widely

studied manifestations.101 In addition, there is

evidence from multiple sources of inadequate

vasodilator reserve.102,103 This has pointed to

arteriolar narrowing and microvascular dysfunc-

tion as the most likely cause for ischemia. Theepicardial coronary arteries are dilated in HCM

and overall coronary flow is increased, to provide

the hypertrophied myocardium. In contrast, the

arterioles show intimal and medial hyperplasia,

resulting in narrowing of these vessels.27 Because

of dilatation of epicardial vessels, coronary flow

velocity is normal, whereas velocities in the

arterioles 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 physiologically

significant cause of ischemia. Ischemia may

predict adverse outcome.101 Left ventricular

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outflow tract obstruction exacerbates ischemia,

by increasing LV work, and simultaneously

decreasing aortic diastolic, and thus LV perfusion

pressure.104 Surgical relief of obstruction

decreases pacing-induced lactate production.

Syncope is the most multifactorial of HCMsymptoms.105 In any given patient, the clinical

circumstances of syncope must be considered,

although in many cases ambiguity about etiology

prevails. Syncope that occurs without any

circumstantial cause must be considered due to

ventricular arrhythmia until proven otherwise.

Sudden inappropriate vasodilatation due to

autonomic dysfunction in the absence of ar-rhythmia also occurs.106 Postexercise syncope

may be due to arrhythmia, obstruction, or a

paradoxical fall in blood pressure.107 Inappro-

priate vasodilatation after exercise occurs in 25%

of patients.84,107 Typical neurally mediated

syncope occurs in HCM. Circumstances that

may suggest this etiology are associated gastro-

intestinal symptoms.General fatigue is a common nonspecific

complaint. When fatigue occurs, it is often

difficult to distinguish between HCM-related

fatigue and that induced by b-blockade.

Fig 14. A schematic summary of the pharmacologic therapFutura.111

Decrease in dose, or elimination of b-blockade,

may allow differentiation.

Watchful Waiting in Asymptomaticand Mildly Symptomatic HCM

The prognosis in large community-based pop-

ulations of patients with HCM is generally

good.73,77,78 Indeed, survival to old age is

common with diagnosis of HCM.108 These

observations must be considered in the approach

to the patient with no or only mild symptoms,

New York Heart Association (NYHA) class I or

II, who are not deemed to be at high risk forsudden death. In such patients, as no medical,

surgical, or interventional therapy has been

shown in randomized trials to improve mortality

or prevent disease progression (such trials have

not been done in HCM), the approach of

watchful waiting is often appropriate. There is

no urgency to begin pharmacologic therapy in

asymptomatic patients. In mildly symptomaticobstructed patients, after pharmacologic therapy

is begun, there is no urgency to progress rapidly

to myectomy or alcohol ablation. Such patients

may be treated expectantly, moving deliberately

y of HCM. Reprinted with permission from Blackwell-

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PATHOPHYSIOLOGY AND TREATMENT OF HYPERTROPHIC CARDIOMYOPATHY 15

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to more aggressive therapies only when symp-

toms progress.

Pharmacologic Treatment ofSymptoms

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. The

pathology is small LV volumes, hypertrophy,

fiber disarray, and fibrosis. There are few agents

Fig 15. Verapamil causes an increase in LVEDP, impairedUpper and middle panel: Simultaneous mitral flow velocities adisease before and after intravenous verapamil (0.1 mg/kg)panels are after verapamil. Note the increase in LV end diastotrans-mitral velocities. LVEDP=LV end diastolic pressure.increase after verapamil; left: LVEDP increases after verapamreflects worsened, not improved relaxation. Reprinted with

available and they are generally not particularly

effective in improving severe symptoms due to

diastolic dysfunction. No pharmacologic agent

has been consistently shown to improve LV

relaxation and chamber compliance in

HCM.109,110

Hence, treatment options for symptomatic

nonobstructive HCM are limited.111 Two treat-

ment goals are to improve LV diastolic function

and to improve ischemia. Two classes of agents

are currently used, b-blockade and calcium

channel blockade. Neither class of agents has

been shown to improve diastolic chamber com-

pliance. Moreover, studies in the catheterization

relaxation, and increased early mitral filling velocities.nd LV pressure curves from two patients with coronary

. The left panels are the control tracings and the rightlic pressure after verapamil and the increase in the earlyLower panels—Right: transmitral (E) flow velocitiesil (0.1 mg/kg). Increased early LV filling after verapamil

permission from J Am Coll Cardiol 1993;21:182-188.

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laboratory have shown that neither intravenous

b-blockade nor verapamil improved early dia-

stolic relaxation in the hypertrophic left ventri-

cle.109,110 The data about the effect of verapamil

on early diastolic relaxation are controversial.

One source of confusion concerns data indicatingan increase in early diastolic peak filling rate as

assessed on serial radionuclide ventriculogra-

phy.112-114 This had initially been interpreted as

an improvement in diastolic function (ie, fast

filling is better) until the work of Nishimura

et al.115 They simultaneously measured LV filling

with high-fidelity catheters and Doppler echocar-

diography, before and after verapamil IV, inpatients with coronary disease115 (Fig 15). In this

revealing study, LV diastolic pressures rose after

verapamil, s increased, indicating impaired re-

laxation, but early transmitral echo Doppler dia-

stolic velocities increased. With current knowledge

of diastology, it is now understood that verapamil

actually caused worsening, restrictive LV diastolic

dysfunction, increasing early velocities because ofincreased left atrial pressure. This paper showed

that in a coronary population that verapamil was

not lusitropic, and that the faster early filling

velocities reported in nuclear studies, may actu-

ally be detecting worsened diastolic function.

Verapamil’s positive contribution in the patho-

physiology of nonobstructive HCM appears to be

relief of ischemia. 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 in

HCM.117 As diastolic dysfunction may limit the

exercise-induced increase in stroke volume,

patients with HCM often rely on increased heart

rate to increase cardiac output. In such patients,pharmacologic limitation of heart rate rise may

impair exercise capacity.

Whereas disopyramide has been shown to

improve diastolic function in obstructed

patients, by decreasing gradient and systolic

load,118,119 it has not been shown to improve

diastolic function in nonobstructed patients and

should be avoided in this group, pendingfurther investigation.

For the unusual patient with fluid retention,

diuretics may be helpful by relieving dyspnea and

uncommon edema. Overdiuresis should be

avoided as patients with HCM are often preload

dependent for adequate cardiac output. If patients

initially present with edema, another diagnosis

should be sought as this is very unusual. Amyloid

may 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 prevent

fibrosis and hypertrophy.120 Similarly, statin

therapy has been shown to prevent phenotype

in genotype-positive animals.121 As a new desig-

nation, these pharmacologic agents may be

termed fibrotardive. Clinical trials would seem

appropriate for these new approaches as there is

currently 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 improve

dynamic LV outflow obstruction by decreasingejection acceleration122 (see Figs 16 and 17).

Decreasing ejection acceleration decreases flow

velocities early in systole, decreasing early drag

forces on the mitral valve, delaying mitral-septal

contact, and reducing gradient. Delaying the

early trigger of SAM may allow reassertion of

chordal 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-Blockers

decrease the sympathetic-mediated rise in gradi-

ent with exercise and improve symptoms. How-

ever, b-blockade is not expected to reduce

resting gradient124 and less than half of patients

have sustained improvement in symptoms.For patients with refractory symptoms and

gradients after b-blockade, there is regional

variation 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 to

b-blockade.12,111,119,127-130 Verapamil, a potent

calcium channel blocker, has both negativeinotropic properties but also is a vasodilator. It

has been shown to decrease gradient and

improve symptoms.131 In a limited number of

patients, exercise tolerance has been shown to

increase 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 96–mm 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.

PATHOPHYSIOLOGY AND TREATMENT OF HYPERTROPHIC CARDIOMYOPATHY 17

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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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Verapamil is indicated for patients with mild

to moderate symptoms and moderate gradients.

However, it is not used in patients with severe

obstruction and severe symptoms because, on

occasion, vasodilating effects outweigh negative-

ly inotropic effects: gradient may rise, and

pulmonary 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 channel

blocker and may have calcium channel blocking

properties as well; it is not a vasodilator. Dis-

opyramide is generally given to patients who arerefractory to b-blockade and would otherwise

require intervention with surgical septal myec-

tomy or ASA. In a multicenter study, two thirds of

patients 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 when

followed for 3 years. The remaining one third of

patients could not be managed successfully with

disopyramide and required invasive treatments

because of inadequate symptom and gradient

control or vagolytic side effects. There was a

trend 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 controlled

release preparation.111 For patients who do not

respond, dose is increased to 300 mg bid.

Disopyramide is generally given with an agent

with atrioventricular (AV) nodal blocking prop-erties, to slow exercise heart rate and to slow

ventricular response, should atrial fibrillation

occur. Although disopyramide has been most

often used with b-blockade, it may also be used

in conjunction with verapamil.

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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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Disopyramide does not cause hepatic, renal, or

central nervous system toxicity. Mild vagolytic

side effects, dry mouth, blurred vision, and cons-

tipation are common but generally subside. If

they prove troubling, the dosage may be re-duced, or controlled-release pyridostigmine may

be added, 180 mg/d (Mestinon Timespan, ICN,

Costa Mesa, CA). A more serious vagolytic side

effect is urinary retention. Disopyramide should

not be given to patients with symptoms of

prostatism. If this proscription is observed,

urinary retention is rare. Vagolytic side effects

cause discontinuation of disopyramide in 7% ofpatients. Because of its impaired elimination in

renal failure, disopyramide should be adminis-

tered in reduced dosage or with serum monitor-

ing. We do not administer concomitant

amiodarone, sotolol, or other antiarrhythmic

with disopyramide to avoid electrophysiologic

drug interaction and ventricular arrhythmia. We

also 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, we

have admitted patients we begin on disopyramideto the hospital for 3 days of electrocardiographic

monitoring. But this is not the practice of the non-

US centers that actively use disopyramide, and

the absence of any significant arrhythmia during

our 3-day admissions would support outpatient

initiation in uncomplicated cases. We routinely

perform ECG surveillance of the QTc interval on

all follow-up clinic visits. We will not increasedisopyramide if QTc prolongation has occurred

longer than 525 milliseconds in patient with

normal QRS duration, but QTc prolongation has

not prompted drug discontinuation.

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Atrial fibrillation occurs frequently in patients

with HCM in 25% to 30% of older patients, both

with and without obstruction.135-138 Left atrial

dilatation is the most frequent substrate. The

advent of atrial fibrillation is often marked by a

deterioration of symptoms and is a frequent causeof hospitalization. There is a dramatic increase in

embolic potential and stroke after the develop-

ment of atrial fibrillation.136 This pertains both to

patients with paroxysmal atrial fibrillation and

also to the young. Such patients also experience

higher mortality. Patients with atrial fibrillation

should be anticoagulated with warfarin.136 Amio-

darone is an effective antiarrhythmic for preven-tion of recurrence, but because of its long-term

toxicity it is not a good solution for younger

patients. Such patients may be controlled with

sotolol 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 patients

who fail medical therapy.55,61,140-148 Candidates

for myectomy have persistent disabling symp-

toms and gradients of greater than 50 mm Hg at

rest or after physiologic provocation. Myectomy

has been successfully performed for 30 years,

and in experienced centers it can be performedwith low surgical mortality, 1%, and is uniformly

successful in reducing both gradient and symp-

toms. Postoperative survival has been excellent

with series reporting annual cardiac mortality of

1% per year.9,13,141,142,145,146 Medications for

obstruction may be reduced or stopped postop-

eratively. Gradient reduction after surgery is

greater than that observed after ASA.149 Inpatients with paroxysmal atrial fibrillation, a

modified intraoperative maze procedure may be

done concomitantly with myectomy in an at-

tempt to prevent postoperative fibrillation. The

opportunity to address atrial fibrillation directly

(and the mitral valve) is a benefit of surgery over

alcohol ablation. Intraoperative transesophageal

echocardiography both before the resection andafter rewarming and weaning from bypass

is essential.60,150,151 Imaging is done before

removing the canulas. If resting or provocable

obstruction persists, or if there is more than mild

mitral regurgitation, the patient must be placed

back on bypass and further resection/repair must

be attempted; if this is not possible, then mitral

valve replacement is rarely required.

Krajcer et al152 introduced the idea that as

obstruction is most often caused by SAM of the

mitral valve, routine mitral valve replacementmight be a logical and successful way to relieve

obstruction. However, this approach has the

main disadvantage that the patient now has the

burden of a life-long prosthetic valve. For the

young who receive a mechanical prosthesis, this

requires anticoagulation with warfarin with its

1% to 2% per year risk of bleeding. All such

patients are subject to the risk of prosthetic valvefailure and endocarditis. Because of these dis-

advantages, myectomy–mitral-valve sparing

operations are always preferred.153

The exceptions are for patients with mitral

regurgitation due to structural mitral disease

above and beyond that caused by SAM: mitral

valvular or annular calcification with restricted

motion, severe unrepairable mitral prolapse, ordamage from endocarditis. Besides calcification,

a clue to the presence of structural mitral

regurgitation is a central or anteriorly directed

jet. Mitral regurgitation solely from SAM is

invariably posteriorly directed and always

improves after myectomy.

The most common serious complication of

myectomy is complete heart block that occurs in0% to 10% of patients.14,55,148 Ventricular septal

defect has been reported in 0% to 2%. Transient

heart block may disappear after the operative

day. As surgical patients invariably are given a

left bundle branch block, patients who have right

bundle branch block preoperatively are at higher

risk for heart block and a pacemaker. Resection

too close to the aortic valve may result inventricular septal defect. As this area plays no

role in the etiology of SAM, resection here

should be avoided, in preference for resection

lower down in the mid-septum. Perhaps the

largest morbidity of myectomy stems from

cardiopulmonary bypass and thoracotomy and

its associated risk of infection and stroke,

especially in the elderly.

Alcohol Septal Ablation

Percutaneous ASA offers the attractive promise

of septal reduction without cardiopulmonary

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PATHOPHYSIOLOGY AND TREATMENT OF HYPERTROPHIC CARDIOMYOPATHY 21

ARTICLE IN PRESS

bypass and its complications.154-160 After place-

ment of a temporary right ventricular pacing

lead, a small diameter balloon catheter is placed

in 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 during

transthoracic or transesophageal echocardio-

graphic imaging. In 8% of such injections,

contrast is seen to flow to structures where

alcohol injection would be disastrous: posterior

LV wall, RV free wall, mitral papillary muscles, or

the entire septum. With this information, theoperator searches for a septal branch that can be

demonstrated to just supply the upper septum,

preferably extending past the point of mitral

septal contact.161 One to 3 mL of absolute alcohol

is instilled into the septal branch. Optimally, a

controlled myocardial infarction occurs. This is

accompanied by typical chest pain, enzyme

elevation, and risk for potential lethal ventriculararrhythmia. The acute gradient reduction of ASA

is caused by reduced ejection acceleration from

the infarct and decreased hemodynamic force on

the mitral valve decreasing SAM in exactly the

same way as negatively inotropic medications.162

After recovery from the infarction, progressive

thinning of the septum occurs and flow is

directed away from the mitral valve, actingsynergistically with the persistent infarct-related

reduction in ejection acceleration.

Temporary right ventricular pacing is fre-

quently necessary because of heart block which

proves to be permanent in 7%.161 Almost all

patients develop right bundle branch, so com-

plete heart block is more frequent in those with

preprocedure 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 and

late progressive mitral regurgitation requiring

mitral valve replacement has been reported.163

Of concern is that an anterior infarction and

scar are produced by ASA and indeed are itsexplicit goal. There is concern expressed in the

literature that large scar may subject patients to

increased life-long risk of potentially lethal

ventricular arrhythmia.141 To date, there are

no long-term longitudinal studies of consecu-

tively operated patients available to address this

concern.

Alcohol septal ablation is not as effective as

surgical myectomy in reducing gradient and

alleviating symptoms.149,164 Another concern is

the perception that because ASA is a relativelyeasy procedure that it might be performed on

patients with mild symptoms, without adequate

medical 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 is

the universal opinion that ASA should only be

performed in centers committed and familiarwith overall HCM care, including myectomy. It

should not be performed without online expert

echocardiographic guidance.

It has been pointed out that the number of

ASA procedures that have been performed in

the 10 years since its introduction far out-

numbers the number of surgical myectomies

reported in the 30 years it has been performed.As ASA and myectomy have the same indica-

tions, there is the perception that ASA is being

applied to patients who are less symptomatic

than those who previously have been sent for

surgery.141

As with surgery, ASA should be reserved for

patients 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 or

after physiologic provocation. Maximal phar-

macologic therapy should include a trial of

b-blockade combined with disopyramide. It

should not be used in NYHA class II patients.

We reserve it for patients who have comorbid

conditions that preclude surgery or for thosewho refuse thoracotomy. In our experience,

these circumstances are uncommon (b1 in

50 patients with obstruction).

Dual-Chamber Pacing

Dual-chamber pacing with complete ventricular

preexcitation through a short atrioventriculardelay significantly reduces outflow tract gra-

dients.165 However, therapeutic effect is often

incomplete; SAM persists with mean gradients of

30 to 55 mm Hg after 3 months of pacing.166,167

The mechanism by which pacing benefits SAM is

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MARK V. SHERRID22

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unclear at this time. It must be due to the

dyssynchrony caused by the right ventricular

pacing, or due to the short AV delay. One

hypothesis is that pacing might cause asynchro-

nous or paradoxical septal motion, widening the

outflow tract and decreasing Venturi forces.However, against this notion is that septal

paradox is only rarely seen. Jeanrenaud and

Kappenberger168 did find a modest decrease in

regional septal wall motion, but there was no

uniform correlation between the magnitude of

decreased septal motion and percent gradient

reduction. Also, as discussed above, a decrease in

Venturi forces can only play a minor role in SAMimprovement.32 Therefore, both direct observa-

tions and pathophysiology indicate that the

mechanism by which DDD pacing reduces SAM

is more complex than just a widening of the

outflow tract. An alternate hypothesis is the

negative inotropic pathway: LV dyssynchony

may cause decreased LV ejection acceleration

and decreases early forces on the mitral valve. Afinal hypothesis is that apical pacing may tense

the mitral subvalvular apparatus sooner than the

rest of the LV, so that when ejection drag forces

are applied to the mitral valve, excess slack has

already been mitigated. In all patients, truncation

of 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 invariably

associated with such shortening. Atrioventricular

optimization with echocardiography is often

performed with the goal of gradient reduction

by complete electrocardiographic ventricular

capture, without A-wave truncation. Late gradi-

ent reduction is often higher than that observed

at acute testing.The benefit of pacing for symptom relief and

gradient reduction is less than that observed after

surgical septal myectomy.170 Initial enthusiasm

for symptom relief by DDD pacing with short AV

delay has been tempered by randomized clinical

trials.166,167,171-173 Although gradients are re-

lieved, overall exercise capacity and symptom

relief vary from patient to patient and benefit isunpredictable. In the M-Pathy randomized trial,

a consistent significant treatment effect could be

identified only in elderly patients older than

65 years. A significant placebo effect of pacing

has been found.166,172 But Gadler et al174 have

shown that when pacing is withdrawn by blinded

institution of AAI pacing, there is a dramatic and

prompt recrudescence of symptoms, only re-

lieved by reinstitution of DDD pacing. Another

recent series of pacing for obstruction in patients

older than 50 years has shown long-termbenefit.175 Despite the observation that some

patients derive benefit, DDD pacing cannot be

regarded as a primary treatment modality for

gradient reduction in younger and middle aged

patients with HCM because of its unpredictabil-

ity and because myectomy is more effective. As

device therapy is now common for SCD preven-

tion, many obstructed patients may receive aDDD pacemaker as a potentially useful adjunct

to their ICD implantation procedure.

Coexisting Hypertension orHyperlipidemia

The prevalence of systemic hypertension in our

HCM clinic is 30%, which is comparable to itsprevalence in the middle-aged population. This

poses diagnostic and therapeutic problems. It is

sometimes difficult to assess whether hypertro-

phy is primary or due to the hypertension. The

presence of SAM with obstruction, family mem-

bers with HCM, or extreme hypertrophy out of

proportion to mild hypertension suggests that

the hypertrophy is due to primary HCM.Hypertensive HCM is characterized by marked

hypertrophy accompanied by LV end diastolic

diameter of less than 42 mm and LV fractional

shortening greater than 45%.176

Vasodilators (angiotensin-converting enzymes,

angiotensin receptor blockers, dihydropyridine

calcium antagonists) for hypertension are con-

traindicated in obstructive HCM because theyworsen obstruction and symptoms and may

precipitate syncope. Often, when patients pres-

ent for evaluation at HCM centers, their symp-

toms are found to date from the week

vasodilators were started. Symptoms respond

almost immediately to stopping vasodilators.

Hypertension in obstructed patients is best

treated by increasing doses of b-blockers orverapamil and sparing use of thiazide diuretics.

Clonidine may be used, often given at night to

avoid daytime sedation. Rarely, intervention for

gradient may be necessary to both control

outflow gradient and allow vasodilator therapy

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PATHOPHYSIOLOGY AND TREATMENT OF HYPERTROPHIC CARDIOMYOPATHY 23

ARTICLE IN PRESS

of severe hypertension. In patients without a

provocable gradient or after successful surgical

septal myectomy, angiotensin inhibition or

blockade can be safely used.

Concomitant coronary artery disease increases

mortality in HCM and may be overlooked whenconservatively managing HCM.64 There should

be a low threshold for coronary angiography in

patients with angina. Hyperlipidemia should be

treated aggressively. There is no contraindication

to the use of nicotine patches or bupropion for

smoking cessation in HCM.

Transformation into Hypokinetic LVDysfunction

Less than 5% of patients with HCM progress to

LV systolic dysfunction with low ejection frac-tion. Exercise intolerance worsens in these

patients who may become symptomatic at rest

and often deteriorate rapidly and die from heart

failure.177 When this transformation occurs,

pharmacologic treatment is changed: negative

inotropes are stopped and angiotensin-convert-

ing enzyme inhibitors, digoxin, diuretics, and

b-blockers are begun. Because of a high risk forsudden arrhythmic death, ICD implantation

should be considered in all of these patients.

Biventricular pacing to improve heart-failure

symptoms is now available for patients with

LBBB. Patients with systolic LV dysfunction

should be referred for transplantation evaluation

when symptoms progress to NYHA Class 3-4.

Future Research

There is a need for basic understanding of the

mechanisms that transform a genotype-positive

individual 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 condition

for both palliation of symptoms and preventing

disease progression. In particular, there is no

effective pharmacologic means to prevent fibrosis

and improve chamber compliance. For obstruc-tion, long-term study of the benefits and risks of

alcohol ablation must be compiled and compared

to myectomy. Current paradigms for sudden

death risk stratification lack predictive accuracy.

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