This primary heart disease is due to disorders of sarcomeric proteins of the heart muscle, showing a cellular disarray of myofibrils (fibers of the heart muscle) on histologic, microscopic examination ( fig. 40b ).

This cellular disarray leads to hypertrophy of the left ventricle (increase thickness of the walls of the left ventricle), especially the interventricular septum (IVS ), which is the muscular partition between the right and left ventricles ( fig. 39a, fig. 39b, fig. 39c, fig. 39d, fig. 39f, fig. 39g, fig. 40a).

There is also evidence to show that structural abnormalities of the mitral valve are characteristic of many patients with this disease, including increased size of the valve due to elongation and abnormal insertion of the papillary muscle into the anterior mitral leaflet ( figure 40c ).

In 25% of cases, the increase in size of IVS causes obstruction of left ventricle (LV) outflow tract into the aorta (leading to the disease called hypertrophic obstructive cardiomyopathy (HOCM). The obstruction occurs when the anterior leaflet of the mitral valve (MV) opposes the hypertrophic IVS through systolic anterior motion (SAM), causing a pressure gradient between the LV outflow tract and the area above the aortic valve ( fig.39i, fig.40c, fig.40d).

1. Genetically transmitted as autosomal dominant pattern of inheritance in majority of cases.

2. Remainder of cases: sporadic gene mutations.

Presentation includes the following:

1. Sudden death in 6% of children and young adults, and 1% in adults 45-60 years of age.

2. Symptoms include: dyspnea, paroxysmal nocturnal (sudden shortness of breath at night), chest pain, presyncope, syncope (fainting), fatigue, palpitations.

Physical Examination reveals a harsh systolic murmur ( figure 39k ) best heard along the left sternal border of the chest and the apex below the the left nipple. The most common form includes diffuse hypertrophy of the IVS and anterolateral free LV wall (70-75%) ( see: fig. 39a, fig. 39b, fig. 39f, fig. 39g, fig. 40a, fig. 40b, fig. 40f ).

Diagnostic tests include:

1) EKG showing LV hypertrophy (LVH)

2) Holter monitoring may reveal the folowing abnormalities: PVC's (extra or premature ectopic heart beats from the ventricles), supraventricular tachycardia ( PSVT, see figure 2 and figure 3b,), sustained and nonsustained ventricular tachycardia (VT, see: fig.6, fig.7, fig.8, fig.9a, fig.9b, fig.10, fig. 11, fig.12, fig.13, fig.61) and atrial fibrillation (see: figure 5a, figure 5b, figure 14 ).

3) Echocardiogram showing asymmetric IVS hypertrophy ( figure39i ), MR ( mitral regurgitation, figure 39j-a and figure 39j-b ) and increased pressure gradients between the LV outflow tract and the ascending aorta by Doppler color studies, often described as a dagger-shaped signal on continuous wave Doppler studies (see figure 40a and figure 40f).

4) Exercise EKG testing in controlled circumstances.

5) Cardiac catherterization to verify pressure gradient between the left ventricular outflow tract and the ascending aorta.

6) magnetic resonance imaging (MRI)

7) tests for abnormal genes on chromosomes 1, 3, 11, 12, 14, 15, and 19

Course

Hypertrophic cardiomyopathy accounts for 36% of deaths in athletes younger than 35 (most common cause of sudden death in this age group). Most sudden deaths are due to ventricular fibrillation (VF) or ventricular tachycardia (VT) (see fig. 61). These patients should avoid competitive sports because of high risk of sudden death during physical exertion.

Evaluation

Electrophysiology studies have been used to identify the above referred to cardiac arrhythmias, which may lead to sudden death. In those with sustained ventricular arrhythmias, placement of an automatic implantable cardioverter defibrillator is justified (see fig. 61).

Efficacy of placement in patients where syncopal episodes are not caused by ventricular arrhythmia is less well established.

Betablockers, calcium channel blockers, and amiodarone may relieve symptoms, but do not prevent sudden death.

Prophylaxis against infection of the heart valves with outflow tract obstruction is indicated.

Nitrates and ace inhibitors (heart medications) are contraindicated.

Surgical resection (myectomy) has been done in 5% of those with IVS obstruction with gradients of 50mm or more.

Successful surgical myectomy can significantly reduce or abolish the degree of MR due to SAM without the requirement for concomitant mitral valve surgery in all patients without independent mitral valve disease. For patients without independent mitral valve disease, there is a relationship between the LVOT gradient and MR jet area (table 1, table 2, fig. 39h below).

Figure 39h

The relationship between the LVOT gradient and the mitral regurgitation jet area. LVOT left ventricular outflow tract.

LVOT = left ventricular outflow tract;MAC mitral annular calcification; MRJA mitral regurgitation jet area; MV = mitral valve; MVP mitral valve prolapse; PG peak gradient.

Values are expressed as mean ± SD.
<0.001 by analysis of variance and pairwise testing.
LVOT = left ventricular outflow tract, MR = mitral regurgitation.

(Yu,E.R.C.MD,and others,Mitral Regurgitation in Hypertrophic Obstructive Cardiomyopahy:Relationship to Obstruction and Relief With Myectomy,Journal of the American College of Cardiology, Vol.36, No.7,2000, PP.2219-2224 ).

Also, replacement of the mitral valve with a low profile prosthetic valve to relieve obstruction may be indicated, especially with concomitant mitral valve disease, but exposes patients to the inherent risk of prosthetic valves and anticoagulant therapy. Some of these patients may be relieved with only myectomy.

SURGICAL TREATMENT

Operation is regarded as the standard treatment for those HCM patients with obstruction to left ventricular outflow under basal conditions (gradient approximately 50 mmHg), and severe drug-refractory symptoms. Therefore surgery is performed to relieve incapacitating symptoms and subaortic obstruction by normalizing the markedly increased systolic intraventricular pressures. General agreement is lacking, however, as to whether symptomatic patients with marked outflow gradients- which are present solely or predominantly under provokable conditions such as exercise or with maneuvers in the catheterization laboratory (e.g., isoproterenol infusion, amyl nitrite inhalation, or Valsalva maneuver) - are appropriate operative candidates.

Ventricular septal myotomy-myectomy (Morrow operation) ( Fig. 39l ) is the surgical procedure of choice; a small amount of muscle is removed from the basal anterior septum (usually about 2 to 6 g) through an aortotomy. However, mitral valve replacement has been employed in selected patients when the operative site for muscular resection in the basal anterior portion of the septum is relatively thin (i.e., approximately 18 mm) or when the distribution of septal hypertrophy is atypical.

Occasionally, patients have outflow obstruction from a mechanism other than mitral valve systolic anterior motion. For example, anomalous papillary muscle insertion directly into anterior mitral leaflet without the interposition of the chordae tendineae ( Fig. 39m ) producing muscular mid-ventricular obstruction should always be contemplated prior to surgery, since the operative strategy may require a more extensive myectomy or possibly mitral valve replacement. Suture plication of the anterior mitral leaflet (in combination with myotomy-myectomy) has also been introduced in patients judged to have a greatly enlarged mitral valve, so as to reduce the likelihood that mitral valve systolic anterior motion will persist postoperatively.

Intraoperative 2D echocardiography is an important guide to mapping the distribution and magnitude of septal hypertrophy and determining how the muscle resection should be tailored to the distribution of septal hypertrophy in the individual patient to achieve the desired hemodynamic result and avoid iatrogenic complications such as ventricular septal defect. Transesophageal echocardiography may also be useful in assessing morphologic and functional abnormalities during surgery, particularly of the mitral valve.
Results from a number of North American and European centers employing septal myotomy-myectomy over the past 40 years, in about 2000 patients, have demonstrated salutary hemodynamic as well as symptomatic effects. Operative mortality at the most experienced centers has improved over the past several years and is presently less than 1 to 2 percent. Older patients with associated cardiac lesions, such as coronary artery disease requiring bypass grafting, may be at greater operative risk.

Several important effects of operation have been defined in patients with HCM. First, in more than 90 percent )f patients, myotomy-myectomy (or mitral valve replacement) abolishes or substantially reduces the basal subaortic gradient and mitral valve systolic anterior motion without importantly compromising left ventricular function; this consequence of surgery appears to be permanent, with no evidence that the gradient recurs postoperatively or that spontaneous growth of septal musculature recurs in the area of the resection. Second, the reduction in left ventricular systolic pressure is associated with a significant and persistent improvement in symptoms and exercise capacity in 70 percent of patients approximately 5 years after operation as well as with a demonstrable increase in myocardial oxygen consumption and improvement in lactate metabolism.

In a minority of patients, even after surgical relief of outflow obstruction, symptoms may nevertheless return (presumably due to persistently impaired left ventricular filling or ischemia, atrial fibrillation, or conduction abnormalities), and premature cardiac death can still ensue many years postoperatively. Traditionally, surgery has not been recommended for asymptomatic (or mildly symptomatic) patients with outflow obstruction since, in addition to the operative risk, definitive evidence is lacking that prophylactic relief of outflow obstruction prolongs survival, diminishes risk for sudden death, or mediates the development of symptoms.

ALTERNATIVES TO SURGERY

Dual-Chamber Pacing

Although the septal myotomy-myectomy operation is the first therapeutic option for severely limited patients without obstructive HCM, perhaps the major limitation of surgery is the restricted availability of surgeons with the necessary experience to readily afford patients with low operative mortality and a high expectation of hemodynamic and symptomatic success with myotomy-myectomy. In addition, some patients are not ideal surgical candidates, either due to advanced age, insufficient personal motivation, or a limiting medical disability unrelated to HCM. Therefore it is a reasonable aspiration to develop and pursue alternatives to operation for this small but important subgroup of patients. However, proper patient selection for such procedures is a paramount consideration.

Over the past several years there has been some interest in the application of permanent dual-chamber pacing, as an alternative to operative intervention, for severely symptomatic patients with obstructive HCM who are refractory to drug therapy. Observational and uncontrolled studies have reported pacing to be associated with reduction in outflow gradient and amelioration of symptoms in many patients over relatively short time periods. However, this reported symptomatic benefit has not been consistently accompanied by improved exercise tolerance documented by objective parameters (e.g., treadmill exercise duration and measured oxygen consumption). Randomized, double-blind, crossover pacing studies have shown that the subjectively perceived symptomatic improvement reported by patients is largely due to a placebo effect. In addition, the effect of pacing on outflow gradient and symptoms is variable and reduction in obstruction is often much more modest than that achieved with surgery.

Other laboratory catheterization studies report dual-chamber pacing to have deleterious effects on left ventricular systolic and diastolic function. For these reasons and because the underlying HCM disease process and the risk for sudden death do not appear to be altered by permanent dual-chamber pacing, this potential treatment modality cannot be regarded as a primary treatment for HCM .
However, there may well be a therapeutic role br certain subsets of patients with this disease. In one randomized study, those patients approximately 65 years old showed the most convincing benefit from pacing.

Alcohol Septal Ablation

A second, recently introduced potential alternative to surgery is alcohol septal ablation, in which about 2 ml of alcohol is injected directly into the first septal perforator coronary artery for the purpose of producing an MI, septal thinning, and reduced mitral valve systolic anterior motion. This procedure is intended to mimic the morphologic and functional consequences of ventricular septal myotomy-myectomy. At present the septal ablation technique is associated with a risk similar to that of surgery but is capable of producing a substantial reduction in the basal gradient. As yet, there is little objective substantiation for the improvement in symptoms reported by many patients over short-term follow-up. This is of particular importance in assessing symptomatic and functional changes for a disease in which pathophysiology is complex and symptoms are variable, often difficult to assess by history, and subject to a placebo effect.

As is the case with pacing, alcohol ablation should not be regarded as a primary treatment for the disease or one capable of reducing the risk of sudden death. Indeed, there is concern that this intervention could paradoxically increase the future long-term risk for life-threatening ventricular tachyarrhythmias and sudden death-a risk directly attributable to the intramyocardial scar produced by alcohol ablation (which is not present following myotomy-myectomy) in a patient population that already harbors an arrhythmogenic subrate and often a particularly long period of risk.

Maron,B.J.,HYPERTROPHIC CARDIOMYOPATHY,HURST'S THE HEART,10th Ed.,PP.1967-1983.

The family should be screened for HCM.

Advances in Understanding Hypertrophic Cardiomyopathy

SAIDI MOHIDDIN
LAMEH FANANAPAZIR
National Heart, Lung, and Blood Institute

The single most common cause of sudden death in otherwise healthy young people, the disease is inherited by at least one in 1,000 to one in 500 of the general population. Nine genes are implicated; continued research can be expected to uncover others, along with modifying factors that offer hope of inducing regression. New interventions are being tested for value in addressing symptoms and risk of death.

Everyone has read of the sudden, unforeseen death of an apparently healthy young person--sometimes a well-known athlete who collapses during a workout or game. The death is often described in the press as "inexplicable." Hypertrophic cardiomyopathy (HCM) is the likeliest explanation. It is in fact the single most common cause of sudden death in otherwise healthy young people.

HCM is a complex disease. However, the past decade has brought significant advances in the understanding of its molecular basis. Fundamentally, HCM is a genetic disease with autosomal dominant inheritance occurring in at least one in 1,000 to one in 500 of the general population. The disease is often undiagnosed and would be even more prevalent were asymptomatic cases routinely recognized. Usually, it develops during adolescence, with progressive myocardial hypertrophy during the period of rapid body growth, but it may be present in childhood or even before birth. The hypertrophy, which affects predominantly the left ventricle, is usually more marked than in any other cardiac disease. It represents hypertrophy and hyperplasia of several cell types, including cardiac myocytes, fibroblasts, and smooth muscle cells, along with excessive collagen and matrix deposition in the extracellular space. The normal parallel arrangement of myocytes is often disturbed. Hypertrophy is often accompanied by dynamic left-ventricular outflow obstruction, diastolic abnormalities, and myocardial ischemia. Thus, patients may complain of dyspnea, chest discomfort, light-headedness, presyncope, syncope, tiredness, or palpitations, with symptoms often induced by exertion, dehydration, or sudden changes in body posture, or following a large meal.

Progressive hypertrophy after age 20 is uncommon, but initial diagnosis even in old age is not. In fact, clinical findings may be unremarkable. Alternatively, the arterial pulse may be bifid with a sharp upstroke, and on auscultation a third or fourth heart sound and a systolic murmur (often intensified by the Valsalva maneuver) may be heard. The electrocardiogram is often abnormal. Diagnosis is made by echocardiography, following identification of a hypertrophied left ventricle (in adults, a left ventricular wall thickness of at least 13 mm; in athletes, 15 mm) inexplicable except by HCM. Left-ventricular obstruction and mitral regurgitation may also be seen at echocardiography. Evaluative methods such as exercise stress testing and Holter monitoring may reveal myocardial ischemia or arrhythmias.

In all phenotypic respects, and in the risk of sudden death, HCM can be extremely varied, even among patients from a single family who share the same HCM-causing mutation. There is also a striking genotypic variance, in that several mutations in each of nine genes have thus far been shown to cause HCM. These genes code for protein components of the myocardium's contractile unit, the sarcomere. Collectively, they account for perhaps no more than half of all cases, so several unidentified genes may also be involved. Certain noncardiac clinical features present in several families suggest that nonsarcomeric genes may cause the disease. The emerging question is what the genetic basis of HCM implies for diagnosis and management.

Mutations and Sarcomere Malfunction

A complete etiologic explanation for HCM would consist of a causal chain beginning with a specific mutation and ending with the various manifestations of the disease. Such an account is beyond current understanding, but study of abnormalities identified at the molecular level will greatly assist in determining the mechanisms linking genetic cause and phenotypic effect. Very generally, a mutant gene codes for a defective protein with an altered biomolecular function that interferes with normal cardiac physiology. The phenotypic consequences are a direct or indirect result of this altered function. For the nine genes known to cause HCM, the process originates in the sarcomere.

A myocyte is composed of sarcomeres arranged in series and in parallel. In turn, each sarcomere consists of a thick filament paralleling a thin filament (Figure 1 in text or Fig. 40h on website). The thin filament is anchored to a dense transverse band known as the Z-line. Interaction between the filaments results in their relative motion, shortening the sarcomere and creating a contractile force that acts at the Z-line to cause contraction of the entire muscle cell. In molecular terms, the thick filament is composed principally of the polymerized tails of numerous beta-myosin heavy chains, which are intertwined in pairs, while the thin filament consists chiefly of polymerized actin, which forms from actin monomers in a fashion resembling two stacks of coins gradually twisting around each other.

Figure.1 (Figure 40h)
Click for enlargement

Interaction between myosin and actin is the molecular basis of contraction. Each beta-myosin has a head hinged to its long tail; in pairs, the heads extend away from the heavy chain, oriented toward the thin filament, and are therefore referred to as cross-bridges. Each head can bind actin and the intracellular fuel ATP; the head also carries two proteins, the essential and regulatory light chains of myosin, which are thought to have a modulatory effect. The myosin-binding site on actin is in the groove between the "stacks of coins." In the resting state, the site is occupied by alpha-tropomyosin, which inhibits actin-myosin interaction. Three other proteins, troponins C, I, and T, are also components of the thin filament. The muscle cell's electrical depolarization results in calcium influx. Binding of calcium to troponin C induces a conformational change in alpha-tropomyosin, exposing the myosin-binding site on filamentous actin. The beta-myosin head can thus bind to actin. The head can also hydrolyze its bound ATP, which dissociates, causing a conformational change in the head that exerts directional force on the thin filament. On binding the next ATP, the head dissociates and beta-myosin returns to its former conformation. If ATP and calcium remain available, the process can continue, with progressive translocation of the thin filament relative to the thick filament. Several other proteins have important roles. Myosin-binding protein C is crucial for normal development of the sarcomere and also regulates ATP hydrolysis by myosin. Titin contributes to the passive elasticity of the myocyte and may act as a sensor of the degree of myocyte stretch.

Within each of the nine genes known to cause HCM--the genes encoding beta-myosin, the essential and regulatory light chains, cardiac actin, alpha-tropomyosin, troponins C, I, and T, and titin--several HCM-related mutations have been identified. Most are missense mutations, permitting the biosynthesis of a full-size protein with a substitute amino acid at one or another position. For beta-myosin, almost all of the described missense mutations are in the molecule's head or neck. The Arg403Gln mutation is at the actin-binding site. It is a notably malignant genetic defect, causing HCM in nearly all who have inherited it, along with about 50% mortality by age 50 in the absence of treatment. Other HCM-related beta-myosin mutations are in other functional domains of the molecule, including the ATP-binding region and the light-chain interfaces. Since HCM has an autosomal dominant pattern of inheritance, HCM hearts have not only a mutant gene but also a normal copy of the same gene. Incorporation of the mutated protein into the heart's sarcomeres nonetheless interferes with the normal function of the contractile apparatus. This dominant negative gene effect contrasts with the carrier status of autosomal recessive conditions, in which the normal gene product can compensate for a missing or dysfunctional mutant gene product.

It seems likely that, in one way or another, all sarcomeric gene mutations associated with HCM impair the function of the sarcomere as a molecular motor. This view is supported by in vitro assays of the stiffness of normal and HCM myocardial samples (a parameter proportional to the strength of actin-myosin interaction), and by quantifying the ability of beta-myosin to translocate actin. In the translocation test, myosin is bound by its tail to a glass slide, leaving the head free to interact with filamentous actin. For several different mutations, translocation velocity is altered; in some cases, such as the alpha-tropomyosin mutation Val95Ala, the velocity is depressed, but for two essential light chain mutations, the velocity is increased. This type of evidence, now obtained for several mutations in several genes, supports the belief that different mutations have distinctive functional consequences.

HCM-causing actin mutations have also provided insight into the pathogenesis of cardiomyopathy. We have recently identified five actin mutations in HCM patients. Three mutations were de novo, present in patients but not in their parents, and were therefore responsible for apparently sporadic HCM. One was found in a 10-year-old with marked ST segment depression and recurrent polymorphic ventricular tachycardia. Another two actin mutations had already been found to cause a dilated cardiomyopathy (DCM), in which left-ventricular walls are thinned and systolic function deteriorates. Some 20% to 30% of DCM cases are hereditary, with X-linked, autosomal dominant, and autosomal recessive inheritance patterns all described. It is hypothesized that mutations interfering with force generation between beta-myosin and actin cause HCM, whereas those that interfere with force transmission from actin to the Z-line result in DCM.

It should be added that several cardiac sarcomeric genes--beta-myosin heavy chain, the essential and regulatory light chains, and alpha-tropomyosin--are also expressed in skeletal muscle. In some beta-myosin mutations, a skeletal myopathy develops that resembles central core disease, in which mitochondria are absent from the core of many slow muscle fibers. Light-chain mutations have been associated with a skeletal myopathy involving ragged red fibers similar to those seen in mitochondrial myopathies.

Accounting for Gross Changes

Several distinct heart morphologies have been described in HCM (Figure 40g or Fig. 2 in text). These include asymmetric septal hypertrophy (ASH), which affects mainly the interventricular septum; reversed ASH, affecting the left ventricular free wall; idiopathic hypertrophic subaortic stenosis (IHSS), in which proximal septal hypertrophy obstructs left-ventricular outflow; apical (also called Japanese) HCM; midcavity obstructive HCM, in which hypertrophic papillary muscles abut in systole, obstructing the midcavity of the left ventricle; and biventricular hypertrophy, which may result in outflow obstruction. Although patients sharing the same mutation may have markedly varying phenotypes, genotype strongly influences morphology. For example, midcavity HCM is frequently a result of mutations in the essential or regulatory light chain (or the Leu908Val mutation of beta-myosin, in the domain that binds light chains). An unusual apical meshwork of myocardial tissue has been linked to a cardiac actin mutation.

Fig. 40g (Fig. 2)

Currently, the most acceptable etiologic hypothesis for HCM is that hypertrophy develops as a compensatory response to sarcomeric dysfunction. The response is maladaptive, resulting in the mature HCM phenotype. Myocytes are known to react to excessive mechanical loads with a hypertrophic response involving altered patterns of gene expression and the release of autocrine growth factors such as angiotensin II. In hypertension, high ventricular systolic pressures stimulate such a response. In HCM, normal systolic pressures may be sensed by abnormal myocytes as an excessive load, initiating an analogous hypertrophy. In the short term, an increased left-ventricular wall thickness and a reduced ventricular cavity size will lessen the magnitude of wall tension required for systolic contraction. Indeed, most HCM patients exhibit hyperdynamic left-ventricular contraction and a supranormal ejection fraction. These appearances are deceptive; ventricular systolic and diastolic volumes are smaller than normal, and the high ejection fraction reflects not only lower wall stresses but also reduced stroke volume.

Persistent stimuli to maintain hypertrophy and promote maladaptive cardiac remodeling may arise from regional differences in left-ventricular contractility and from myocardial ischemia. In HCM, the causes of myocardial ischemia are incompletely understood. But since the epicardial coronary vessels tend to be enlarged and to exhibit rapid blood flow, it seems likely that myocardial ischemia has more distal explanations. These may include an excess oxygen demand by the hypertrophic, hyperdynamic myocardium and abnormal intramyocardial arterioles narrowed or blocked by endothelial and smooth muscle cell hyperplasia. Eventually, myocardial necrosis and fibrosis may impair both diastolic and systolic function and lead to cardiac failure and arrhythmia.

Since the severity of left ventricular hypertrophy often differs significantly among patients who share the same HCM-related mutation--some family members with the mutation may even remain unaffected--it appears likely that other genetic factors modify the expression of the disease. Several possible factors are under study, including polymorphisms in genes that affect cellular hyperplasia or hypertrophy. Polymorphisms in the gene for angiotensin-converting enzyme (ACE) are known to affect the rate of production of angiotensin II. The clinical significance of such variation--and the implications for therapy--remain to be established. We are currently conducting a randomized, double-blind, placebo-controlled study of the possible therapeutic value of ACE or angiotensin II inhibition. Patients with nonobstructive HCM receive ACE inhibitors, angiotensin II inhibitors, or placebo and are examined at six months for changes in left-ventricular hypertrophy, systolic and diastolic function, myocardial ischemia, and electrophysiologic characteristics. Manipulation of factors affecting expression of HCM-causing mutations may offer an opportunity for intervening in the disease's development and prognosis.

Evaluation and Risk Stratification

Despite significant advances in the understanding of the molecular basis of HCM and its management, risk evaluation and prevention of sudden death in HCM remain limited. In efforts to identify risk factors amenable to therapy, HCM patients have been followed after clinical workup, Holter monitoring, exercise myocardial scintigraphy, radionuclide angiography, hemodynamic studies, and electrophysiologic evaluation. Several risk factors have indeed been found, including a history of cardiac arrest or syncope, a family history of sudden death of two or more family members, sustained ventricular tachycardia induced during electrophysiologic testing, particular genetic mutations, abnormal blood pressure responses during exercise, and (in children) myocardial ischemia.

In about 5% to 10% of HCM patients, myocardial necrosis and fibrosis result in thinning of the hypertrophic myocardium, leading to cardiac failure. These patients may be at risk of sudden death. In almost 10% of HCM patients, atrial fibrillation develops, with a risk of hemodynamic and thromboembolic consequences (i.e., formation of atrial thrombi, with peripheral or cerebral embolization). A poorly compliant left ventricle has greater dependence on atrial systole for efficient diastolic filling. During atrial fibrillation, a loss of atrial transport, in combination with poor left-ventricular compliance, impairs filling and depresses cardiac output, causing hypotension and pulmonary edema. Lastly, about 20% to 30% of HCM patients exhibit short runs of nonsustained monomorphic ventricular tachycardia during one to three days of Holter monitoring. Ventricular arrhythmias are frequent causes of cardiac arrest and sudden death. In particular, nonsustained ventricular tachycardia may predict adverse outcome in HCM patients with symptoms of impaired consciousness.

Overall, the findings suggest that asymptomatic adults discovered to have HCM may not require risk evaluation or intervention (Figure 40i), provided that the family has no history of sudden death and the patient has no special need for risk stratification, such as being an airplane pilot. Asymptomatic children and adolescents may require more aggressive evaluation and management, in view of the likelihood of rapid disease progression and the risk of sudden death in adolescence. (The risk of HCM sudden death during childhood is about 5% per year, compared with an annual mortality of 1% to 2% in adults.) For children and symptomatic adults, especially those with episodes of impaired consciousness, workup may include 48-hour Holter monitoring, exercise myocardial thallium scintigraphy, and cardiac catheterization with electrophysiologic study (to evaluate left-ventricular obstruction, arrhythmias, and their hemodynamic consequences)

Figure 3:Evaluation and /intervention inHypertrophic Cardiomyopathy

In collaboration with researchers at Johns Hopkins University, we have recently evaluated the prognostic value of an electrocardiographic parameter, QT-interval variability. In all, 36 HCM patients with one or another of seven beta-myosin mutations were compared with 26 age- and sex-matched healthy controls. All subjects underwent Holter monitoring, from which an algorithm identified the heart rate and QT interval for each cardiac cycle. The mean QT interval and heart rate (and variance) were similar in HCM patients and controls. Normally, the QT interval is dynamically related to heart rate, so that at faster heart rates the QT interval shortens. When this relation was examined, HCM patients showed a significant decrease in the association. The finding can also be described as an excessive QT lability or a loosened coherence. QT lability was greatest, and coherence with heart rate lowest, in patients with Arg403Gln, the beta-myosin mutation associated with especially high mortality. Studies had already shown that patients with HCM caused by Arg403Gln are notably susceptible to myocardial ischemia and sudden death.

Clinical Implications of Genetic Discoveries

Since HCM is inherited, it becomes important to examine the families of identified patients. First-degree relatives (each of whom shares a 50% chance of having the HCM-associated genetic defect) should be clinically evaluated by methods such as echocardiography and electrocardiography, preferably at a center familiar with HCM so that even mild manifestations are recognized. For children, we suggest echocardiography at age four or five, with repeat studies at four- or five-year intervals as the child advances into and through adolescence. Following diagnosis, it may be necessary to characterize the disease phenotype more completely, for which invasive investigations may be indicated. At this point, patients may benefit from referral to specialized centers (such as our own).

Currently, genetic testing of patients' relatives, and even of patients themselves, has logistical difficulties. If the specific mutation responsible for HCM in a given family is known, a test can easily detect its presence or absence in individual family members. If the mutation is not known, each of the nine genes known to cause HCM would have to be screened for mutations. The process is laborious, has not yet been automated, and has a detection rate of approximately 85%. Current methods rely on the polymerase chain reaction to amplify each coding region, or exon, of all nine genes, and on electrophoresis or DNA sequencing to identify abnormalities. Currently identified mutations, however, account for no more than half of all cases of HCM, allowing less than a 50% likelihood of a positive finding. Even then, clinical correlates with prognostic significance have been determined for only a few of the known mutations. A patient therefore has little chance of having a mutation whose implications are fully described.

For genetic testing of hitherto unaffected relatives of an HCM patient, further considerations arise. Not all persons with an HCM genotype will have HCM. Indeed, in families where the mutation has low penetrance, the cardiac phenotype may skip one or more generations. Prenatal genetic diagnosis may nonetheless force parents (one of whom may have experienced considerable problems with HCM) to make difficult decisions. Additionally, anxiety may follow the determination of a risk-related genotype, and improper dissemination of such information may affect employability and insurability. Counseling before testing must include careful consideration of the risks as well as benefits of genetic diagnosis.

For all the aforementioned reasons, genetic diagnosis of HCM is not yet a routine component of clinical assessment. However, the clinical correlates of specific mutations will be appreciated only if genetic diagnoses are made more frequently. Furthermore, the accuracy of screening family members at risk of HCM is greatly enhanced if the causative mutation is known. Recent advances in analytic methods such as DNA chip technology are expected to facilitate large-scale mutation detection. In HCM as in many other genetic diseases, the basic hurdle is that any of a large number of different mutations in a large number of different genes may be causative. A clinically applicable mutation detection method must therefore be not only reliable and rapid but also able to "interrogate" a large number of DNA sequences.

DNA chips are silicon wafers with short DNA segments (oligonucleotides) adsorbed onto their surface, which thus becomes a grid of several thousand patches, each holding a different oligonucleotide. The sequence of each oligonucleotide is designed to be chemically complimentary to a sequence of interest in human DNA. After incubation with human DNA preparations, only oligonucleotides that encountered their complement become double-stranded and are thereby detected. The chips are currently used principally to quantify gene expression in one or another tissue. Knowledge of patterns of gene expression in HCM hearts, as compared with normal hearts, is expected to increase greatly our understanding of mechanisms of hypertrophy and heart failure and of responses to various therapies at a molecular level. The knowledge may also suggest candidate genetic causes of HCM. Furthermore, the chip technology lends itself to mutation detection. If a chip's oligonucleotides are designed to be complimentary to both normal and mutated gene sequences, the absence of normal sequences and the presence of abnormal ones can be readily identified. DNA chip technology may satisfy most requirements for clinical applicability, but several practical difficulties remain to be overcome, and rigorous testing must be conducted, before this technique can be routinely used.

Technological issues aside, genetic studies in HCM remain, for now, in the service of research. Efforts to identify novel molecular causes of HCM rely principally on two approaches. Candidate gene analysis requires the researcher to hypothesize that a certain gene or class of genes may cause HCM. The candidate genes are then screened for mutations in HCM patients. By contrast, genetic linkage analysis is a statistical approach to mutation detection. This method becomes usefully powerful only in families where several members (usually more than eight) are affected. The analysis takes advantage of several hundred markers, each at a known chromosomal location. Informative markers are spans of nucleic acid with a high frequency of variability in any human population, allowing a given variant to be followed through generations of a family. Markers are not causes of HCM, but since all patients in a family affected by HCM will have inherited the genetic cause from a common ancestor, the patients are likely to have coinherited markers in close proximity to the disease-causing gene. The positions of these markers identify the approximate chromosomal location of the disease-causing gene. This area can then be scrutinized in detail.

An important goal of our current efforts in linkage analysis is to discover nonsarcomeric genes that cause HCM--genes whose normal functions may be important clues for understanding how the disease develops. To this end, we have been analyzing large families with unusual disease presentations. In one such family, HCM is accompanied by sensorineural hearing impairment, in another by skeletal abnormalities that include short metacarpals, and in a third by an accessory atrioventricular conduction pathway (much as in Wolff-Parkinson-White syndrome).

Current and Novel Interventions

Management decisions (see Figure 40i; Fig.3 in text) are dominated by the need to address two problems: disabling symptoms and risk of sudden death. In HCM, unlike other cardiac disorders, the two are not well correlated. Patients may have severe chest pain, shortness of breath, palpitations, tiredness, or light-headedness but not die of HCM. On the other hand, patients with no symptoms may die suddenly. Interventions show the same dichotomy, in that they may address risk of death without substantially relieving symptoms or relieve symptoms without affecting risk of death.

Interventions that aim to improve prognosis include implanted defibrillators for ventricular arrhythmias, anticoagulants for atrial fibrillation, and ACE inhibitors (or, failing that, heart transplantation) for cardiac failure. Interventions addressing symptoms include a range of options for obstructive HCM. Dynamic obstruction of left-ventricular outflow occurs in about a third of HCM patients. Typically, the hyperdynamic left ventricle and narrowed outflow tract increase the systolic velocity of blood. The high velocity pulls a mitral valve leaflet anteriorly, toward the interventricular septum, resulting in outflow obstruction (and almost always mitral regurgitation).

First-line treatment is pharmacologic, with negative inotropes (beta-blockers and verapamil), disopyramide, and judicious doses of a diuretic for heart failure. If disabling symptoms continue, patients have traditionally been referred for cardiac surgery. Surgical options include myotomy and myectomy (Morrow procedure) or mitral valve replacement. In myotomy and myectomy, enough muscle must be removed from the septum to sufficiently widen the outflow tract. Operative mortality depends on surgical experience and is about 2% to 5%. Additionally, about 5% of patients require a permanent pacemaker due to heart block. A prosthetic mitral valve eliminates systolic anterior motion and left-ventricular outflow obstruction, but the patient requires life-long anticoagulant therapy and is subject to risk of prosthetic malfunction.

Two novel nonsurgical alternatives are being evaluated: dual-chamber pacing and percutaneous transluminal septal ablation (PTSA). At the right ventricular apex, successful pacing induces a paradoxic motion of the interventricular septum away from the mitral valve, reducing left-ventricular obstruction. The full benefits may appear gradually, so that after three to six months of pacing, ventricular outflow pressure gradients are reduced by an average of about 50%. Over longer periods, cardiac hypertrophy may regress. Accurate pacemaker programming and lead placement are critically important for optimal results.

In PTSA, a controlled mini-infarct is produced in a target volume of septal myocardium. The interventional cardiologist begins by identifying the septal perforator branch (or branches) of the left anterior descending artery responsible for perfusing the myocardial region where the anterior mitral leaflet contacts the septum. After several precautions are taken, this septal area is ablated by an infusion of ethanol through an angioplasty catheter. Preliminary studies have reported improved symptoms and a 70% reduction in ventricular pressure gradients. The procedure is usually well tolerated but has been complicated by conduction abnormalities requiring pacemaker implantation and by ventricular arrhythmias and death. Long-term results are not yet known. At the NIH, we are comparing dual-chamber pacing with PTSA for patients with obstructive HCM and severe, drug-refractory symptoms who otherwise would be candidates for myotomy and myectomy. Thirty-five patients will be recruited into each of the study's two arms (pacing or ablation), for evaluation at six months. Important aspects of this study include assessment of propensity to arrhythmia before and after therapy and to cardiac remodeling following PTSA.

Conclusion

So far, nine HCM-related genes have been identified, and in each of them several mutations have been described, for a total of about 100 mutations. Although patients sharing the same mutation may have markedly different clinical pictures, genotype strongly determines disease expression--not only its cardiac morphology but also its penetrance and prognosis. Even the mechanism of sudden death appears to be strongly related to genotype. To the extent that each mutation creates a variant clinical picture, we therefore confront a variety of genetic diseases whose clinical correlates, including outcome, have not yet been thoroughly worked out. To further increase the complexity, the genes found to date account for approximately half of all HCM cases.

For the individual patient, it is currently more important to evaluate the disease by its clinical manifestations than by its genetic basis. Nevertheless, continued research will not only improve our understanding of the function of the known genes but can also be expected to uncover novel molecular causes of familial cardiomyopathies, along with factors that modify the resulting phenotype. Understanding these modifying factors may offer our best hope of inducing regression. In the interim, novel interventions are being tested for their value in lessening symptoms and addressing the risk of death.