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(Circulation. 1995;92:1680-1692.)
© 1995 American Heart Association, Inc.

Articles

Hypertrophic Cardiomyopathy

Clinical Spectrum and Treatment

E. Douglas Wigle, MD; Harry Rakowski, MD; Brian P. Kimball, MD; William G. Williams, MD

From the Divisions of Cardiology and Cardiovascular Surgery and the Center for Cardiovascular Research, the Toronto Hospital, General Division, University of Toronto, Ontario, Canada.

Key Words: cardiomyopathy • cardiovascular diseases • myocardium • physiology • ventricles

	Introduction

Top Introduction Definition and Pathology Pathophysiology Clinical Spectrum Treatment HCM in the Elderly... Summary References

 
Although the pathology of HCM was described by two French pathologists in the mid 19th century^{1 2} and by a German pathologist in the early 20th century,³ it remained for the virtually simultaneous reports of Brock⁴ and Teare,⁵ some 37 years ago, to bring modern attention to this fascinating entity. Subsequent to these surgical⁴ and pathological⁵ observations, there has been an almost exponential growth in the number of research reports and in our knowledge of HCM, and a number of extensive reviews have been published.^{6 7 8 9 10 11} The growth in our knowledge of HCM parallels the development of various investigative techniques available to cardiology. Thus, the 1960s and 1970s were the clinical,^{12 13 14 15 16} hemodynamic,^{17 18 19 20 21 22 23 24 25 26 27 28 29} and angiographic^{30 31 32 33} era that focused mainly on obstructive HCM. The 1970s through the 1990s saw the various imaging modalities (echo-Doppler,^{34 35 36 37 38 39 40 41 42 43 44 45 46 47 48} nuclear,^{49 50 51 52 53 54} magnetic resonance,^{55 56 57 58} and positron emission tomography^{59 60} ) enhance our understanding of the systolic and diastolic abnormalities as well as the significance of myocardial ischemia in HCM. At the same time, electrophysiological techniques defined the spectrum of atrial and ventricular arrhythmias that are such an important feature of this disease.^{61 62 63 64 65}

More recently, the results of molecular genetic studies have resulted in a quantum leap in our basic knowledge and understanding of the mendelian dominant inheritance of HCM and have far-reaching prognostic and clinical implications.^{66 67 68 69 70 71 72 73 74 75 76 77 78 79 80} HCM is now described as a heterogeneous disease of the sarcomere,^{77 78} in that at least 34 missense mutations have been described in the ß-myosin heavy chain gene (chromosome 14q11-q12),^{66 67 68 69 70 71 72 75 76} 7 mutations have been described in cardiac troponin-T (chromosome 1),^{74 77 79} and 2 mutations in -tropomyosin (chromosome 15q2).^{77 78} Another locus has been found on chromosome 11p13-q13,⁷³ and familial HCM with Wolff-Parkinson-White syndrome maps to a locus on chromosome 7q3.⁸⁰ The hypertrophy in HCM may be compensatory in response to the abnormalities induced by these mutations. This belief is supported by the upregulation of genes commonly observed in compensatory hypertrophy, ie, atrial and brain natriuretic peptides and angiotensin-converting enzyme.^{81 82 83 84 85 86} These molecular genetic studies are already having important clinical implications in that some mutations carry a benign prognosis,^{69 77} whereas others, possibly interacting with angiotensin-converting enzyme genotypes,^{85 86} have increased penetrance, early onset of manifestations, and a bad prognosis,^{69 77 79} thus explaining the malignant family history noted by some authors.⁸⁷

	Definition and Pathology

Top Introduction Definition and Pathology Pathophysiology Clinical Spectrum Treatment HCM in the Elderly... Summary References

 
Just as the inheritance of HCM is heterogeneous, so are the phenotypic manifestations, even in a single family cohort with the same molecular genetic defect⁷⁶ (Figs 1 through 3; Table 1). HCM may be defined as LV and/or RV hypertrophy of unknown cause that is usually, but not always, asymmetrical and associated with microscopic evidence of myocardial fiber disarray.^{7 8 9} Ventricular septal hypertrophy^{5 16} (Fig 1) is by far the most common type of asymmetrical hypertrophy, with midventricular^{8 88 89 90 91} (Fig 2), apical^{56 57 58 92 93 94} (Fig 3), and the rarer types⁴² of asymmetrical hypertrophy being far less common (Table 1). The extent of hypertrophy at any given site can vary greatly and bears importantly on the manifestations of the disease.⁸

View larger version (99K): [in this window] [in a new window]   Figure 1. Ventricular septal hypertrophy. Longitudinal section of the heart from a 32-year-old woman with subaortic obstructive HCM who died suddenly while on propranolol therapy. Hemodynamic investigation had confirmed the presence of subaortic obstruction, as well as mitral regurgitation that was partially due to an abnormal mitral valve (insertion of an anomalous papillary muscle [arrow] onto the ventricular surface of the anterior mitral leaflet). Note the asymmetric hypertrophy with a grossly thickened ventricular septum and a narrowed outflow tract between the upper septum and the anterior mitral leaflet, which is very thickened and fibrosed from repeated mitral leaflet–septal contact. There was microscopic evidence of extensive myocardial fiber disarray involving both the septum and the free wall of the left ventricle. From Wigle et al8 with permission.

View larger version (71K): [in this window] [in a new window]   Figure 2. Midventricular hypertrophy. Cross-sectional slices of the heart from a patient who in life was shown, by hemodynamic, angiographic, and echocardiographic techniques, to have midventricular obstruction. The site of the obstruction was at the level of the papillary muscles, where there was massive hypertrophy (second slice from left). The slice at left is from the base of the heart, and the two slices at the right are from the apex. The apex of the left ventricle was the site of extensive myocardial infarction and aneurysm formation that was evidenced in life by a dyskinetic apical chamber on angiography and by persistent ST segment elevation in leads V4 to V6 on the ECG. The coronary arteries revealed no significant luminal narrowings. The patient died of intractable ventricular arrhythmias. From Wigle et al8 with permission.

View larger version (91K): [in this window] [in a new window]   Figure 3. Apical hypertrophy. Magnetic resonance spin-echo images from a patient with apical HCM. A, Long-axis four-chamber slice demonstrates localized LV hypertrophy, involving the apical anterior and inferior walls, and the true apex (arrows). Note the characteristic spade-shaped left ventricular cavity at end diastole, described by Japanese authors92 93 and caused by the anterior and inferior wall apical hypertrophy. B, Short-axis basal slice showing normal LV wall thickness. C, Short-axis apical slice demonstrating circumferential apical hypertrophy. Recently, a non–spade-shaped variety of apical HCM has been described, again by Japanese authors,56 and in these cases, the anterior and inferior apical walls are not involved as they are in A, but rather the septal and lateral walls are involved, and this can only be picked up by short-axis MRI scanning, as seen in C. From Webb et al57 with permission.

View this table: [in this window] [in a new window]   Table 1. Types of HCM and Approximate Incidence1

	Pathophysiology

Top Introduction Definition and Pathology Pathophysiology Clinical Spectrum Treatment HCM in the Elderly... Summary References

 
The following is a description of the clinically important pathophysiological features of HCM that bear upon the clinical spectrum and treatment.

Obstruction to LV Outflow
Subaortic Obstruction
The pathology of the subaortic obstruction in HCM is shown in Fig 1. The pathophysiology of the obstruction and mitral regurgitation in subaortic obstructive HCM is shown in Fig 4, and the transesophageal echocardiographic–color Doppler appearance of these features⁴⁸ is shown in Fig 5. It is believed that the narrow LV outflow tract, caused by the ventricular septal hypertrophy and the anterior displacement of the papillary muscles^{38 95} and mitral leaflets,^{36 39 45 95 96 97} is important to the development of the obstruction, as is the fact that the mitral leaflets are elongated^{45 48 95 96 97} and coapt in the body of the leaflets,^{45 48 95} rather than at their tips, as is normal.⁴⁵ That part of the anterior leaflet distal to the coaptation point is subjected to Venturi²⁹ and/or drag^{8 36 98 99} forces, resulting in systolic anterior motion^{34 45 48} and subsequent mitral leaflet–septal contact,⁸ causing the subaortic obstruction^{34 35 36 37 38 39 40 41} (Figs 4 and 5). The systolic anterior motion of the anterior mitral leaflet also results in a failure of coaptation of the mitral leaflets,⁴⁸ and it is through this funnel-shaped interleaflet gap that the mitral regurgitation is directed posteriorly into the left atrium⁴⁸ (Figs 4 and 5).

View larger version (37K): [in this window] [in a new window]   Figure 4. Diagram of pathophysiology of the obstruction to outflow and mitral regurgitation in subaortic obstructive HCM. Early systole (left): The left ventricular outflow tract is narrowed by the ventricular septal hypertrophy and the anterior displacement of the papillary muscles38 39 and the mitral leaflets.36 39 45 95 96 97 The point of coaptation of the elongated mitral leaflets occurs in the body of the leaflets, rather than at the tips, as is normal.45 48 95 That part of the anterior leaflet beyond the coaptation point45 48 is carried anteriorly and superiorly (systolic anterior motion, arrow) by Venturi29 and/or drag35 36 98 99 forces and results in mitral leaflet–septal contact, causing the subaortic obstruction (indicated by the converging and diverging lines, right). Mitral leaflet–septal contact (right): The systolic anterior motion of the anterior leaflet results in a failure of coaptation of the mitral leaflets48 and the onset of mitral regurgitation, which is directed posteriorly into the left atrium, through the funnel-shaped interleaflet gap. The length and mobility of the posterior leaflet may also affect the size of this gap, and hence the degree of mitral regurgitation.102 A, B, C, and D indicate Doppler velocity recordings throughout systole in the ascending aorta103 (A) (flow toward transducer), at level of mitral leaflet–septal contact46 (B), in left atrium (C), and near apex of LV (D). In B, C, and D, flow is away from the transducer. Reduced forward flow in the presence of the obstruction is indicated by the shape of the aortic velocity waveform103 (A) and the smaller aortic arrow. Peak velocities recorded at B correlate accurately with the simultaneously measured pressure gradient,46 whereas late-peaking velocities at D do not. AO indicates aorta; MV, mitral valve. Adapted from Wigle10 with permission.

View larger version (0K): [in this window] [in a new window]   Figure 5. Intraoperative transesophageal echocardiogram (frontal long-axis plane) before (top) and after (bottom) myectomy. Upper left, Two-dimensional systolic frame demonstrating anterior leaflet–septal contact with failure of mitral leaflet coaptation. Upper right, same frame with Doppler color flow imaging demonstrating turbulent LV outflow as a result of the subaortic obstruction and a large jet of posteriorly directed mitral regurgitation arising from the gap between the two leaflets. Lower left, two-dimensional systolic frame demonstrating a widened LV outflow tract and abolition of systolic anterior motion following myectomy. Lower right, same frame with Doppler color flow imaging demonstrating nonturbulent LV outflow with a marked reduction in the severity of the mitral regurgitation, which is now reflected only by a small residual central jet. From Grigg et al48 with permission.

The onset of the pressure gradient is virtually simultaneous with the onset of mitral leaflet–septal contact.^{40 41} The time of onset and duration of mitral leaflet–septal contact in systole determines the magnitude of the pressure gradient^{8 40 41} and the degree of prolongation of the LV ejection time^{8 40 41 100 101} ; ie, the pressure gradient and ejection time become progressively greater as the time of mitral leaflet–septal contact occurs earlier in systole.

When there is no additional mitral valve abnormality other than systolic anterior motion, there is a direct relation between the magnitude of the pressure gradient and the degree of mitral regurgitation.^{8 26 27} The fact that there is leaflet coaptation in early systole and that systolic anterior motion results in a failure of coaptation of the leaflets by midsystole⁴⁸ explains the mid- to late-systolic timing of the mitral regurgitation in subaortic obstructive HCM. It also explains the eject/obstruct/leak sequence of events in systole, described from cineangiographic observations, in which there is rapid early ejection into the aorta, followed by the radiolucent line indicating the subaortic obstruction, followed by mid- to late-systolic mitral regurgitation.^{8 32} Thus, the time of onset and duration of mitral leaflet–septal contact determines not only the magnitude of the pressure gradient and the degree of prolongation of the LV ejection time but also the degree of mitral regurgitation and the volume of blood ejected from the left ventricle in the presence of obstruction.⁸

In about 20% of patients with subaortic obstruction in HCM, the mitral regurgitation is to a variable extent independent of the systolic anterior motion,^{8 27} in which case, other abnormalities of the mitral valve are present, such as anomalous papillary muscle attachment to the anterior leaflet^{8 27 104} (Fig 1), mitral valve prolapse,¹⁰⁵ extensive anterior leaflet fibrosis due to repeated mitral leaflet–septal contact^{8 97} (Fig 1), mitral annular calcification, or other rarer abnormalities. These independent abnormalities of the mitral valve at times cause pansystolic mitral regurgitation, which is often anteriorly or centrally directed into the left atrium and is quite different from the late-onset, posteriorly directed mitral regurgitation that is the result of anterior mitral leaflet systolic anterior motion.⁴⁸

Although several exercise studies with subjects in the supine position have reported no increase in gradient during exercise, but only afterward,^{6 106} a recent study reported a 50% increase in gradient during supine exercise, as well as revealing latent obstruction in 30% of patients who had no obstruction at rest.¹⁰⁷ Even more significant is the fact that on upright bicycle exercise, the magnitude of the pressure gradient almost doubled.¹⁰⁸ These observations are very much in keeping with the factors known to affect the severity of the obstruction^{6 8 9} (LV contractility, afterload, and preload) and suggest caution in the interpretation of exercise studies involving patients with or without obstruction under control conditions unless the presence and magnitude of the obstruction during exercise are known. The increased gradient on upright exercise is also very much in keeping with the severity of symptoms observed in some patients with subaortic obstructive HCM on exertion and the ease with which symptoms may sometimes occur with minor exercise after the upright posture is assumed or postprandially.¹⁰⁹

Midventricular Obstruction
The pathology of midventricular obstruction is depicted in Fig 2, which clearly demonstrates that the obstruction is at the papillary muscle level.^{8 88 89 90 91} Apical myocardial infarction in the presence of large normal coronary arteries is not uncommon with midventricular obstruction,^{8 90 91} as is the case in apical HCM.⁵⁷ The syndrome of midventricular obstruction with apical infarction may evolve by two mechanisms: (1) apical infarction may occur in the presence of midventricular obstruction or (2) apical infarction may occur in severe apical HCM with cavity obliteration up to the midventricular level, in which case the noninfarcted proximal part of the apical hypertrophy at the midventricular level results in the midventricular obstruction.^{8 90 91} The severity of the midventricular obstruction is affected by LV contractility, afterload, and preload, as is the case with subaortic obstruction.⁸ Angiographically, midventricular obstruction is best recognized in the right anterior oblique LV cineangiogram,^{88 89 90 91} in contrast to the subaortic obstruction, whose dynamics are best appreciated in the left anterior oblique LV cineangiogram with cranial angulation.^{8 32} The size of the obstructed apical chamber in midventricular obstruction may vary considerably, but it is always smaller than the amount of the LV cavity that is obstructed in the subaortic obstruction (Fig 6). In contrast to the subaortic obstruction in HCM, mitral regurgitation is not a feature of midventricular obstruction. There are a number of other differences between these two forms of obstructive HCM⁸ (Fig 6).

View larger version (27K): [in this window] [in a new window]   Figure 6. Diagram showing LV inflow tract pressure concept.25 In subaortic obstructive HCM, all LV pressures proximal to the outflow tract obstruction caused by mitral leaflet–septal contact (arrow) are elevated, including the inflow tract pressure, just inside the mitral valve. In cavity obliteration and midventricular obstruction, the pressure at the apex of the LV is elevated, but the inflow tract pressure is not. Note that the amount of the LV cavity that is obstructed in subaortic obstructive HCM is greater than in midventricular obstruction (see text). AO indicates aorta. Adapted from Wigle10 with permission.

Systolic Dysfunction
LV systolic function in HCM is usually normal to supranormal, with a high ejection fraction, in both obstructive and nonobstructive forms of the disease. Late in the disease, however, impaired systolic function of both the LV and RV caused by myocardial fibrosis has been recognized with increased frequency (end-stage HCM).^{110 111 112 113} The fibrosis^{114 115} may occur as the result of fibrous transformation of the loose intercellular connective tissue that is interspersed between areas of myocardial fiber disarray^{5 8} or as a result of myocardial ischemia and infarction due to small-vessel disease^{112 116} or rarely, as a result of concomitant atherosclerotic coronary artery disease. This myocardial fibrosis results in wall thinning, loss of outflow obstruction, incoordinate and impaired systolic function with reduced ejection fraction, and increased end-systolic volume.^{110 111 112 113} There is moderate ventricular dilatation, but this is usually less than in typical dilated cardiomyopathy.

Diastolic Dysfunction
Initially, diastolic dysfunction in HCM was felt to be due to decreased ventricular compliance (increased chamber stiffness),^{13 16} but with enhanced understanding of diastole,^{117 118 119} it has become evident that impaired relaxation is the more important cause of diastolic dysfunction in HCM.^{8 120} Fig 7 depicts the way that HCM can affect ventricular diastolic filling.⁸ Chamber stiffness is increased (compliance decreased) by virtue of the increase in muscle mass, decrease in ventricular volume, and increase in muscle stiffness caused by myocardial fibrosis. This increased chamber stiffness results in an increased diastolic pressure with respect to volume (increased dP/dv), ie, the diastolic pressure-volume curve is shifted upward and to the left.¹²¹

View larger version (22K): [in this window] [in a new window]   Figure 7. Diagram indicating the mechanisms by which chamber stiffness is increased and relaxation is impaired in HCM. In some patients with extensive hypertrophy, increased restoring forces may act to improve relaxation during isovolumic relaxation, whereas the degree of pericardial constraint and ventricular interaction may be decreased by the extent of septal hypertrophy8 (see text). Adapted from Wigle et al8 with permission.

Ventricular relaxation is related to certain hemodynamic loads (both systolic and diastolic), to inactivation (the reuptake of calcium by the sarcoplasmic reticulum), and to the degree of nonuniformity of load and inactivation in space and time.^{117 118 119} Normally, relaxation is load dependent.^{117 118} In HCM, relaxation may be impaired by the systolic contraction load (the obstruction to outflow⁸ ) and perhaps more importantly, by the reduced relaxation loads (ventricular filling and coronary filling loads^{117 118 119} ) (Fig 7). Inactivation may be impaired by the increased myoplasmic calcium that has been reported in HCM.^{122 123} This alone would impair relaxation, but diminished inactivation would also reduce the load dependence of relaxation,^{117 118 119} and the loads are already reduced⁸ (the double-edged sword effect of impaired inactivation^{117 118 119} ). Finally, there is ample evidence that nonuniformity contributes to the impaired relaxation in HCM.^{124 125 126} Thus, all three factors that regulate ventricular relaxation are altered in HCM in a way that would impair relaxation.

Impaired relaxation in HCM results in a reduced rate and volume of filling during the rapid filling period of diastole, with a resultant compensatory increase in atrial systolic filling, which results in a loud and often palpable fourth heart sound.* Patients with HCM and impaired relaxation, including patients with apical HCM,⁵⁷ develop progressive LA enlargement and atrial fibrillation, which results in severe hemodynamic deterioration because of the importance of atrial systole in the presence of impaired relaxation.^{8 10 49 50 51 120 127} Late in the evolution of diastolic dysfunction, a restrictive type of diastolic filling defect may become evident⁴⁴ in which a high atrial pressure results in an increased rate and volume of filling during the rapid filling period (loud third heart sound^{10 120} ) with reduced filling during atrial systole.⁴⁴

Myocardial Ischemia
Myocardial ischemia has been repeatedly demonstrated in both obstructive and nonobstructive HCM by means of fixed and reversible thallium perfusion defects^{52 53 54} ; by measurement of myocardial lactate production, particularly during rapid atrial pacing^{129 130 131} ; and by positron emission tomography.^{59 60} Although the exact cause of the ischemia is in some doubt, it may be related to small-vessel disease with decreased vasodilator capacity.^{116 129} Other factors that could cause or contribute to ischemia are septal perforator artery compression,⁸ myocardial bridging,⁸ decreased coronary perfusion pressure,¹²⁹ obstruction to LV outflow,^{8 30} and decreased capillary myocardial fiber ratio. Impaired relaxation of the myocardium during the isovolumic and rapid filling periods could impair coronary filling and result in ischemia.⁸ On the other hand, myocardial ischemia could act to impair relaxation by a number of mechanisms. Indeed, a vicious cycle may exist in HCM that relates diminished coronary perfusion and myocardial ischemia with impaired diastolic relaxation and vice versa.⁸

	Clinical Spectrum

Top Introduction Definition and Pathology Pathophysiology Clinical Spectrum Treatment HCM in the Elderly... Summary References

 
As a result of the above considerations, it is customary to classify HCM hemodynamically as in Table 2. In obstructive HCM, the subaortic or midventricular obstruction may be latent (provocable), labile (spontaneously variable), or persistent (obstruction at rest). In nonobstructive HCM, there is no systolic obstruction at rest or on provocation.⁸

View this table: [in this window] [in a new window]   Table 2. Hemodynamic Classification of HCM

Symptoms
Patients with obstructive HCM typically complain of dyspnea, angina, and presyncope and/or syncope on exertion. The severity of symptoms on upright exertion does not necessarily correlate with the magnitude of the obstructive pressure gradient measured in the supine position, which is understandable, particularly when the lability of the obstruction is taken into account.^{6 8 9 107 108} In our experience, patients with nonobstructive HCM present with these symptoms less frequently, and usually the symptoms are milder.⁸ Congestive heart failure is rarely seen in HCM in normal sinus rhythm, but it may be seen with severe obstruction to outflow or severe systolic and/or diastolic dysfunction, and of course it is common in the presence of atrial fibrillation.

Physical Examination
RV involvement in HCM may be detected by a prominent A wave in the jugular venous pulse and rarely by a right-sided fourth heart sound, reflecting RV diastolic dysfunction, and by a systolic ejection murmur along the left sternal border, reflecting subpulmonic or midventricular obstruction to RV outflow.^{8 16}

LV involvement is reflected by a variably displaced and forceful LV impulse and a left-sided fourth heart sound that is often palpable,^{13 16} reflecting impaired LV relaxation.^{10 49 120} Patients with nonobstructive HCM have either no murmur or a faint grade 1/6 systolic murmur at the cardiac apex that does not increase significantly with provocation.⁸ In patients with latent subaortic obstruction, the murmur at the apex is usually grade 1/6 to 2/6 in intensity and increases to grade 3/6 with appropriate provocation,⁸ such as amyl nitrite inhalation,¹⁸ assuming the upright posture, or the Valsalva maneuver.⁶ In patients with subaortic obstructive HCM at rest, the murmur at or just medial to the apex is grade 3/6 to 4/6 in intensity, with radiation to the left sternal border, reflecting the obstruction, and to the axilla, reflecting the mitral regurgitation. In addition to the louder murmur, there is an intriguing constellation of physical signs in subaortic obstructive HCM not seen in nonobstructive HCM. These include a bifid arterial pulse,¹³² a double systolic or triple apex beat,¹³³ reversed splitting of the second heart sound, a mitral diastolic inflow murmur due to mitral regurgitation,⁸ and rarely a mitral leaflet–septal contact sound.⁸

Patients with midventricular obstruction also have an apical systolic murmur, although it is usually softer (grade 2/6 to 3/6) than with subaortic obstruction. A bifid arterial pulse, double systolic beat, and triple apex beat are not characteristic of midventricular obstruction, and a mitral leaflet–septal contact sound is never found. If the obstruction is severe, there may be reversed splitting of the second heart sound. In midventricular obstruction, there is at times a very distinctive, long, mitral diastolic murmur caused by the midventricular narrowing and asynchronous relaxation.

Clinical Course
The clinical course of HCM is very variable (some would say unpredictable). Although the rate of progression of the disease is believed to be more rapid in children, adolescents (particularly during the teenage growth years⁴³ ), and young adults, rapid progression may also be encountered in the adult population of patients. The best predictor of outcome may turn out to be the nature of the molecular genetic defect^{69 77 79} ; at present, the risk factors for sudden death are considered to be young age,^{134 135 136 137 138} syncope,^{135 137 138 139} a malignant family history,⁸⁷ myocardial ischemia (particularly in the young),⁵⁴ sustained ventricular tachycardia on electrophysiological testing,⁶³ and ventricular tachycardia on ambulatory monitoring.^{61 62} More recent studies suggest that ventricular tachycardia on ambulatory monitoring is more benign¹⁴⁰ unless associated with altered consciousness or sustained ventricular tachycardia on electrophysiological testing.⁶³ The fact that unexplained syncope and cardiac arrest in obstructive HCM can be satisfactorily managed by alleviation or abolition of the obstruction by dual-chamber pacing¹⁴¹ or myectomy¹⁴² suggests that outflow obstruction is also a risk factor for sudden death.

Syncope in HCM may be related to atrial or ventricular tachyarrhythmias or bradyarrhythmias,¹³⁹ heart block,¹³⁹ obstruction to LV outflow,¹⁴³ diastolic dysfunction, altered baroreflex mechanisms,^{144 145} and myocardial ischemia.⁵⁴ Unfortunately, many studies concerned with syncope in HCM do not distinguish whether it occurred at rest or on exertion, and the presumption is that it was arrhythmic in origin. In our experience, presyncope and syncope on exertion are encountered most frequently in patients with obstructive HCM, and at times the degree of exertion required to bring on profound presyncope or syncope may be minimal.

The annual mortality in HCM referral centers is said to be 4% to 6% in children and 3% to 4% in adults.^{138 146} However, recent studies from a community-based experience¹⁴⁷ as well as from a tertiary referral center¹⁴⁸ have indicated an annual mortality of 1%. HCM is the most common cause of unexplained sudden death in otherwise apparently healthy competitive athletes.¹⁴⁹

Laboratory Investigation
Patients referred with suspected HCM should have an ECG, a chest x-ray, and a transthoracic echo/Doppler examination on the initial visit.

The ECG in HCM may be normal with mild degrees of hypertrophy or show LV hypertrophy and strain in the presence of extensive hypertrophy.⁸ Abnormal Q waves, which may mimic myocardial infarction and which at times reflect septal hypertrophy,¹⁵⁰ are a feature of the ECG in HCM, as is the giant T-negativity syndrome typical of apical HCM.^{92 93} Apical infarction may also be reflected in the ECG,⁵⁷ and the ECG may be abnormal in HCM when echocardiography reveals no evidence of LV hypertrophy.¹⁵¹

The chest x-ray may be normal or show LV or LA and/or RA enlargement with or without vascular redistribution in the lungs. The aorta is typically small. A bulge on the left heart border, between the LA appendage and LV apex, may reflect anterolateral wall extension of anteroseptal hypertrophy.¹³³

Transthoracic echo/Doppler examination in HCM is undoubtedly the most important form of laboratory investigation. These combined techniques can determine the location and extent of hypertrophy,^{8 42 152} systolic^{111 112 113} and diastolic function,^{44 46 47} the presence and degree of systolic anterior motion,^{34 35 36 37 38 39 40 41} the severity of the subaortic and/or midventricular obstruction,^{35 36 39 40 41 46 47} the direction and degree of mitral regurgitation,^{46 47 48} the presence of additional mitral valve abnormalities,^{104 105} and LA size. Transesophageal echo/Doppler studies are valuable in defining additional mitral valve abnormalities and the level of outflow obstruction and are used intraoperatively in planning, guiding, and assessing the results of surgical intervention.^{48 153}

Nuclear angiography is very valuable in HCM to assess both systolic and diastolic ventricular function.^{49 50 51} Stress thallium studies^{52 53 54} and positron emission tomography^{59 60} are important for detecting evidence of myocardial ischemia or infarction.

Magnetic resonance imaging is of particular value in HCM when two-dimensional echocardiography is unable to document the site and extent of hypertrophy, especially in apical HCM^{55 56 57 58} (Fig 3).

Heart catheterization and angiography in HCM are usually reserved for diagnostic problems, when surgery or dual-chamber pacing is being considered in either type of obstructive HCM, and in the investigation of end-stage HCM in regard to the possibility of cardiac transplantation. The diagnostic accuracy of echo/Doppler studies has dramatically lessened the need for invasive investigation in HCM.

Electrophysiological investigation has traditionally used ambulatory monitoring for detection and assessment of treatment of all arrhythmias in HCM, particularly ventricular arrhythmias.^{61 62 63 140} More recently, invasive electrophysiological studies have been used extensively in some centers to provoke arrhythmias as a guide to prog-nosis and therapy.⁶³

Genetic screening for HCM is prognostically important and undoubtedly will become more common once all the molecular genetic defects are defined and screening procedures simplified.

	Treatment

Top Introduction Definition and Pathology Pathophysiology Clinical Spectrum Treatment HCM in the Elderly... Summary References

 
The treatment of HCM should be based on the patient's symptoms and on whether the patient has obstructive or nonobstructive disease. The presence of other pathophysiological abnormalities, such as myocardial ischemia, impaired systolic and/or diastolic function, arrhythmias, syncope, and a history of cardiac arrest, should also be taken into consideration. The role of treatment for the asymptomatic patient has not been clearly defined, and the decision to treat or not to treat any given patient should be based on the presence or absence of a malignant family history, the nature of the molecular genetic defect if known, and the severity of the pathophysiological abnormalities present.

Obstructive HCM
The treatment of subaortic and midventricular obstructive HCM is basically the same, although the effects of medical, pacemaker, and surgical therapy have been much better documented in subaortic obstructive HCM.

Medical Therapy
In obstructive HCM, negative inotropic agents (ß-blockers,^{154 155 156 157 158 159 160 161 162} calcium antagonists,^{49 50 163 164 165 166 167 168} and disopyramide^{8 169 170 171 172} ) have been used to decrease the degree of outflow obstruction. In our experience, ß-blockers are especially effective in latent obstruction and to some extent in mild resting obstruction but tend to be less effective in the more severe degrees of obstruction,^{8 159} although others have reported more favorable results.^{154 155 156 158 160} The negative inotropic properties of calcium antagonists, particularly verapamil, usually lessen the obstruction,^{163 164 165 166 167 168} but unpredictably, the vasodilating properties of these drugs may increase the obstruction, with resultant death due to intensified obstruction, cardiogenic shock, and pulmonary edema.¹⁶⁷ It is for this reason that we have avoided the use of calcium antagonists, particularly those with potent vasodilating properties, in obstructive HCM.⁸ The negative inotropic effect of the type 1A antiarrhythmic agent disopyramide has been demonstrated to decrease or abolish the obstruction when given intravenously^{8 169 170 172} or in oral doses up to 600 to 800 mg/d.^{8 169 171} This drug has the disadvantage of having a number of anticholinergic side effects, and in a significant percentage of patients, the initial clinical and hemodynamic benefits decrease with time. Despite these problems, at present, it is our drug of choice in treating symptomatic obstructive HCM.⁸ If the resting heart rate is >70 beats per minute, we would add a ß-blocker to slow the rate to 60 to 65 beats per minute.⁸

Pacemaker Therapy
Dual-chamber (DDD) pacing has been recognized for almost 20 years to decrease the subaortic pressure gradient in HCM, but only recently has it been extensively studied and used.^{173 174 175 176 177 178 179} The mechanism by which the gradient is decreased is uncertain but may be related to decreased (or paradoxical) septal motion,^{177 178} late activation at the base of the septum with RV apical pacing,¹⁸⁰ or decreased LV contractility.¹⁷⁸ There is a progressive reduction in the gradient with time¹⁷⁸ and a short-term persistence of pacing effect in normal sinus rhythm,¹⁷⁷ suggesting the possibility of LV remodeling or a mechanical memory effect. Acute studies reveal impairment of both systolic and diastolic function, possibly related to asynchronous contraction and relaxation.^{181 182} To be successful, there must be complete ventricular capture, which requires optimization of the AV delay.^{177 178 179} This is readily accomplished in patients with a PR interval of 120 to 180 ms, but when the PR interval is shorter, a very short AV delay (50 to 60 ms) is frequently required for complete ventricular capture.¹⁸³ This often results in significant diastolic dysfunction with a loss of effective LA function. It is in this group of patients that drugs (ß-blockers, calcium antagonists) must be given to prolong the PR interval or AV nodal ablation is required to avoid the deleterious effects of a very short AV delay.¹⁸³ To have complete ventricular capture at all times (which is required for successful therapy), there should be separate programming of the paced and sensed AV delay and an autoadaptive function to shorten AV delay with increased heart rates.¹⁸⁴

There are now numerous reports of significant symptomatic improvement with dual-chamber pacing in patients with obstructive HCM refractory to medical therapy.^{176 177 178 183} Thus, dual-chamber pacing in obstructive HCM represents a viable alternative to myectomy surgery, particularly if a low-risk and effective surgical program is not readily available.¹⁷⁹ Dual-chamber pacing may have a particular role to play in elderly patients, in whom the PR interval tends to be longer and who are unresponsive to medical therapy, yet have severe symptomatic obstruction and are often poor candidates for open-heart surgery. It is important to note, however, that not all patients with obstructive HCM respond favorably to dual-chamber pacing and that the long-term effects of this treatment modality are currently unknown.

Surgical Therapy
Myectomy surgery for symptomatic obstructive HCM that is unresponsive to medical therapy has been carried out successfully for more than three decades.^{185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201} In our experience, successful surgery (total relief of the obstruction at rest and on provocation) provides far more hemodynamic and symptomatic benefits for severely symptomatic patients than any form of medical therapy currently available.^{8 188 196 200} The occurrence of atrial fibrillation is also an indication for myectomy, in that abolition of the obstruction and the concomitant mitral regurgitation can result in a decrease in LA size in younger patients, which is the most effective form of antiarrhythmic therapy for these individuals.^{8 202 203} Similarly, patients with obstructive HCM who have suffered unexplained syncope or cardiac arrest have been managed successfully by myectomy alone.¹⁴² Although the annual mortality of obstructive HCM has been reported to be 3% to 4%,¹⁴⁶ several large surgical series have reported postoperative annual mortality rates of 1% to 2%.^{191 192 193 196 199 200}

Several centers have carried out mitral valve replacement as either the primary surgical intervention²⁰¹ or in a significant percentage of their patient population.¹⁹⁵ This procedure removes the offending mitral leaflets but condemns the patient to a low-profile mechanical prosthesis and lifelong anticoagulants. We have rarely replaced a mitral valve in these patients, and only when there is a significant independent abnormality of the mitral valve, causing severe mitral regurgitation, that is not related to the systolic anterior motion.^{8 159 188 189 196 200} A number of centers have reported mortality rates of <2% for the myectomy operation alone, with somewhat higher mortality rates when combined with valve replacement or bypass surgery.^{193 196 197 199 200} Myectomy thins the ventricular septum and widens the outflow tract, which results in abolition of the systolic anterior motion, with resultant relief of the outflow obstruction and the concomitant mitral regurgitation.^{8 10} LV end-diastolic and LA pressures decrease,¹⁸⁸ with a resultant decrease in LA size in patients <45 years of age.^{8 203}

Dual-Chamber Pacing Versus Myectomy
Thus far, there has been no direct comparison between these two treatment modalities, both of which appear to be superior to medical therapy. In the absence of experienced, effective, and low-risk surgery, dual-chamber pacing is a viable alternative, but it does not appear to totally abolish the obstruction as effectively as successful surgery.^{177 178 179} In addition, the long-term effects of pacemaker therapy in obstructive HCM are unknown. We continue to offer the myectomy operation to symptomatic patients who are refractory to medical therapy, because of the presence of an experienced, effective, and low-risk surgical program,^{196 200} but we are also assessing the effects of dual-chamber pacing where appropriate.

Nonobstructive HCM
Normal Systolic Function
Calcium antagonists are the preferred therapy for nonobstructive HCM with normal systolic function and impaired relaxation and/or myocardial ischemia.^{49 50 51 54 163 164 165 166 167 168} If calcium antagonists are not tolerated, slowing of the heart rate with ß-adrenergic blockers will act to relieve ischemia and will allow more time for relaxation during diastole.

Impaired Systolic Function
Table 3 contrasts the diametrically opposite therapy for nonobstructive HCM with impaired systolic function (end-stage HCM) versus therapy for obstructive HCM. In the latter, digitalis, afterload reduction, and diuretics are contraindicated because they could worsen the obstruction and negative inotropes are indicated to lessen the obstruction. In nonobstructive HCM with impaired systolic function and no outflow obstruction, digitalis, afterload reduction, and diuretics are indicated and negative inotropes contraindicated to improve systolic function (Table 3). In obstructive HCM, dual-chamber pacing or myectomy surgery is indicated in patients refractory to medical therapy. In nonobstructive HCM with impaired systolic function, pacemaker therapy is indicated only for electrophysiological reasons, and transplantation is the only surgical treatment that is appropriate.

View this table: [in this window] [in a new window]   Table 3. Treatment of Obstructive HCM Versus Nonobstructive HCM With Impaired Systolic Function (End-Stage HCM)

Arrhythmias
Atrial Fibrillation
Atrial fibrillation in the vast majority of cases of HCM is related to an increase in LA size (usually >50 mm).^{8 202} Obstructive HCM with concomitant mitral regurgitation is the most common cause of increased LA size and atrial fibrillation,^{8 39 203} but both systolic and diastolic dysfunction may also lead to significant LA enlargement and atrial arrhythmias.⁵⁷ The onset of atrial fibrillation in both obstructive and nonobstructive HCM may result in cardiac failure, syncope, and systemic emboli.⁸ Management is similar to that in other cardiac diseases with this arrhythmia and includes pharmacological and electrical cardioversion, therapy for congestive heart failure, and anticoagulation. Amiodarone is the most effective pharmacological agent to restore and maintain normal sinus rhythm in HCM,²⁰⁴ but because of its side effects and the fact that we are usually dealing with a young patient population, we have tended to use other antiarrhythmic agents, such as sotalol, first. Patients with obstructive HCM and atrial fibrillation are candidates for myectomy to reduce LA size and thereby restore normal sinus rhythm by this mechanism.^{8 203}

Ventricular Tachycardia and Fibrillation
There is no universally accepted therapy for ventricular tachycardia and/or fibrillation in patients with HCM.¹³⁸ Patients with obstructive HCM and unexplained syncope, cardiac arrest, and ventricular tachycardia and/or fibrillation have been treated successfully by dual-chamber pacing¹⁴¹ or myectomy¹⁴² alone. Alternatively, these interventions could be combined with amiodarone therapy or an AICD.⁶³ Patients with nonobstructive HCM and a history of cardiac arrest or unexplained syncope may undergo electrophysiological testing and be treated with amiodarone or an AICD if test findings are positive.⁶³ Younger HCM patients who have a history of cardiac arrest and/or syncope but who are electrophysiologically negative should undergo stress thallium testing for myocardial ischemia, which, if present, should be treated with calcium antagonists or ß-blockers, with or without amiodarone or an AICD.⁵⁴ Cardiac transplantation has been performed in a few patients with life-threatening refractory ventricular tachycardia or fibrillation.

	HCM in the Elderly

Top Introduction Definition and Pathology Pathophysiology Clinical Spectrum Treatment HCM in the Elderly... Summary References

 
It is important to recognize that older patients with or without a past history of hypertension may present with a clinical picture resembling that seen in genetically determined HCM, including obstruction to outflow.^{205 206 207 208 209} In some of these older patients, the disease may be more related to hypertensive hypertrophy²⁰⁵ or to age-related changes such as a sigmoid septum²⁰⁶ and/or mitral annular calcification,²⁰⁷ rather than to HCM per se. The principles of treatment for these patients are the same as for HCM.

	Summary

Top Introduction Definition and Pathology Pathophysiology Clinical Spectrum Treatment HCM in the Elderly... Summary References

 
HCM is a heterogeneous disease genotypically, phenotypically, pathophysiologically, clinically, and therapeutically. In decisions on the management of these patients, it is important to recognize this heterogeneity and to direct therapy at the predominant abnormalities.

	Selected Abbreviations and Acronyms

 

AICD = automatic implantable cardioverter/defibrillator AV = atrioventricular HCM = hypertrophic cardiomyopathy LA = left atrial LV = left ventricular RV = right ventricular

	Acknowledgments

 
The authors wish to thank Sharon Tribble for her excellent technical assistance in preparing the manuscript.

	Footnotes

 
Reprint requests to E. Douglas Wigle, MD, 12-217 Eaton North, Toronto General Hospital, 200 Elizabeth St, Toronto, Ontario, Canada, M5G 2C4.

¹ References 10, 44, 46, 47, 49-51, 120, 127, 128

Received November 28, 1994; revision received May 31, 1995; accepted June 13, 1995.

	References

Top Introduction Definition and Pathology Pathophysiology Clinical Spectrum Treatment HCM in the Elderly... Summary References

 

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