קרדיומיופטיה היפרטרופית

לקיציס שלום! אני סטודנטית לרפואה ואני לומדת קרדיולוגיה , העתיד שלי הוא להיות קרדיולוגית רק התחלתי ללמוד את זה כרגע אנחנו עושים עבודה , כל פעם על נושא אחר בלב. כרגע הגענו למחלה הנקראת קדיומיופטיה היפטרופית אני יודעת קצת על המחלה אם תוכל בבקשה להרחיב לי אודה לך מאוד קראתי שלמחלה אין כלל תסמינים , האם זה נכון? וקרדיולוג אחד שהתייעצתי איתו אמר שזוהי מחלה התפתחותית הצצתי בכמה פורום שכתבת בקשר למחלה זו שזוהי מחלת שריר הלב מילדה? אז איך זה שיש לה התפתחות? ואיך זה שלא מגלים אותה עוד טרם הלידה? האם היא תורשתית? והיא עלולה לגרום למוות פתאומי לפי מה שקראתי תודה רבה לך קציס בברכה שירז

על המחלה הזאת אפשר לכתוב ספרים שלמים - לא זה הפורום הנכון ללמוד על מחלות. אני מציע לך שתקראי את הפרק בספר כלשהו אפילו בספר לרפואה פנימית (כמובן עדיף ספר קרדיולוגיה) תודה

תודה אבל אם רק תוכל לענות לי על שאלות קטנות וספצפיות האם המחלה היא מולדת? האם היא יכולה להתפתח בגיל מסויים? האם יש למחלה תסמינים? (לפי מה שהבנתי החולה לא סובל כלל מתסמינים) האם זאת מחלה מסוכנת? הבנתי שזאת מחלה שיכולה להיות תורשתית האם היא פוגעת גם בצעירים? זהו אלה הן כל השאלות תודה מקרב לב !!! שירז

הי שירז, להלן הפרק על קרדיומיופתיה היפרטרופית מתוך התנ"ך של קרדיולוגיה (Heart Disease by Eugene Braunwald) אם את מחפשת חומר תמציתי יותר תקראי בהריסון. בברכה, היפוקמפוס. HYPERTROPHIC CARDIOMYOPATHY Although first described over a century ago, the unique features of HCM were not studied systematically until the late 1950s.148, 149, 150, 151, 152, 153, 154 The characteristic finding was inappropriate myocardial hypertrophy that occurred in the absence of an obvious cause for the hypertrophy (e.g., aortic stenosis or systemic hypertension), often predominantly involving the interventricular septum of a nondilated left ventricle that showed hyperdynamic systolic function (Fig. 48&#8211;7; see also Fig. 48&#8211;13).152, 153 A distinctive clinical feature was soon recognized in some patients with HCM&#8212;a dynamic pressure gradient in the subaortic area that divided the left ventricle into a high-pressure apical region and a lower-pressure subaortic region (Fig. 48&#8211;8). Although subsequent studies have shown that only a minority of patients (perhaps a fourth)155 demonstrate this outflow gradient, its unique features attracted much attention and led to a myriad of terms (more than 75) used to describe the disease (among the more popular terms were idiopathic hypertrophic subaortic stenosis [IHSS] and muscular subaortic stenosis).156 The term hypertrophic cardiomyopathy (HCM) is now preferred because most patients do not have an outflow gradient or &#8220;stenosis&#8221; of the left ventricular outflow tract.153 Because hypertrophy typically occurs in the absence of a pressure gradient, the characteristic distinguishing feature of HCM is myocardial hypertrophy that is out of proportion to the hemodynamic load. Pathology MACROSCOPIC EXAMINATION. This typically discloses a marked increase in myocardial mass, and the ventricular cavities are small (see Fig. 48&#8211;7 A).157, 158 The left ventricle is usually more involved in the hypertrophic process than is the right. The atria are dilated and often hypertrophied, reflecting the high resistance to filling of the ventricles caused by diastolic dysfunction and the effects of atrioventricular valve regurgitation. The pattern and extent of left ventricular hypertrophy in HCM vary greatly from patient to patient, and a characteristic feature is heterogeneity in the amount of hypertrophy evident in different regions of the left ventricle.153, 157, 158 A feature found in most patients with HCM is disproportionate involvement of the interventricular septum and anterolateral wall compared with the posterior segment of the free wall of the left ventricle.153, 157 When hypertrophy is largely localized to the anterior septum, the process has been called asymmetrical septal hypertrophy (ASH). A wide variety of other patterns of hypertrophy may be seen, and about 30 percent of patients show only localized and relatively mild hypertrophy in a single region of the ventricle.153 The differentiation of the &#8220;physiological&#8221; hypertrophy that occurs in some highly trained male athletes from that seen in HCM may be difficult; athletes may demonstrate left ventricular wall thicknesses up to 16 mm in the absence of HCM (normal <12 mm).159 Additional features that may permit differentiation of the two are the abnormal response of Doppler ultrasound-derived indices of diastolic function in response to isometric handgrip and the identification of HCM in a relative.153, 160 Some patients with HCM have substantial hypertrophy in unusual locations, such as the posterior portion of the septum, the posterobasal free wall, and the midventricular level.157 The degree of hypertrophy is dynamic in most patients; although prominent hypertrophy may be found in infants, the typical patient develops hypertrophy during adolescence.153 Development of the morphological features of HCM is unusual after the age of about 18 years,153 although when it occurs it is seen especially with a mutation of cardiac myosin-binding protein C (where hypertrophy may occur at any time during adult life).161, 162 There usually is an inverse relationship between the extent of hypertrophy in HCM and age. Whether this is due to premature death of younger patients with greater hypertrophy or progressive reduction in the extent of hypertrophy is unknown.153, 157 Other morphological abnormalities include enlargement and elongation of the mitral valve leaflets and anomalous papillary muscle insertion directly into the anterior mitral valve leaflet.153 APICAL HCM. A variant with predominant involvement of the apex is common in Japan and is estimated to represent a fourth of Japanese HCM patients.163 In other parts of the world, apical HCM is much less common. Typical features include a characteristic spadelike configuration of the left ventricle during angiographic study (although some patients with this variant do not demonstrate this abnormality),164 giant negative T waves in the precordial ECG leads, the absence of an intraventricular pressure gradient, mild symptoms, and a generally benign course (Fig. 48&#8211;9).157, 165 HCM may on occasion present in the elderly and often demonstrates unique features, including an especially small left ventricular cavity but with relatively mild hypertrophy.166 Other findings include marked anterior displacement of the mitral valve, extensive submitral (annular) calcification in some patients, a left ventricular outflow gradient, and the late appearance of severe and progressive symptoms.167 Gross cardiac morphological features similar to those in HCM may be seen in infants of diabetic mothers and in patients with hyperparathyroidism, neurofibromatosis, generalized lipodystrophy, lentiginosis, pheochromocytoma, Friedreich ataxia, and Noonan syndrome.168 Rarely, the findings may be simulated by amyloid, glycogen storage disease, or tumor involvement of the septum.169 HISTOLOGY. Microscopic findings in HCM are distinctive, with myocardial hypertrophy and gross disorganization of the muscle bundles resulting in a characteristic whorled pattern; abnormalities are found in the cell-to-cell arrangement (disarray) (see Fig. 48&#8211;7 B) and disorganization of the myofibrillar architecture within a given cell.157 (See CD Figure 900.) (See CD Figure 901.) (See CD Figure 902.) (See CD Figure 903.) Fibrosis is usually prominent and may be extensive enough to produce grossly visible scars. Foci of disorganized cells are often interspersed between areas of hypertrophied but otherwise normal-appearing muscle cells. Interstitial (matrix) connective tissue elements are increased.157 Disarray in HCM patients is found in grossly hypertrophied myocardial segments as well as relatively normal segments.170 Although abnormally arranged cardiac muscle cells initially were considered specific for HCM, it is now recognized that they may be found in a variety of acquired and congenital heart conditions. 157 What is unique about the disarray in HCM is its ubiquity and frequency. Almost all HCM patients have some degree of disarray, and most have involvement of 5 percent or more of the myocardium; in general, a fourth or more of the myocardium demonstrates disarray.153 In contrast, disarray in non-HCM patients (when it occurs) usually involves only about 1 percent of the myocardium.157 Abnormal intramural coronary arteries, with a reduction in the size of the lumen and thickening of the vessel wall, are common in HCM, occurring in more than 80 percent of patients.155, 157 (See CD Figure 904.) The prominence of abnormal intramural coronary arteries in areas of extensive myocardial fibrosis is consistent with the hypothesis that these abnormalities may be responsible for the development of myocardial ischemia.153 Etiology GENETICS OF HYPERTROPHIC CARDIOMYOPATHY (see also Chap. 56 ). Familial HCM occurs as an autosomal dominant mendelian-inherited disease at least 50 percent of the time.166, 171, 172 It is thought that some if not all of the sporadic forms of the disease are due to spontaneous mutations.171, 173 At least eight different genes, all encoding sarcomeric polypeptides, are associated with HCM (Fig. 48&#8211;10). Over 125 different mutations have been discovered thus far. It is clear that not all of the genetic defects have been identified yet.172 Most of the mutations are of the missense type. Familial HCM thus is a genetically heterogeneous disease (i.e., it can be caused by genetic defects at more than one locus).174 However, the genetic heterogeneity does not appear to explain the clinical variability. The genetic basis of HCM was first reported in 1989 by Seidman and her collaborators, who reported the existence of a disease gene located on chromosome 14q11-12.175 Subsequently they found this to be the gene encoding for beta cardiac myosin heavy chain (MHC). Sequencing of this gene in one family with HCM revealed that the abnormality was caused by a gene duplication in which the alpha and beta MHC genes were fused and present in an extra copy. In the second family, there was a point mutation in the beta MHC sequence that altered the myosin's arginine to glutamine. Both of these mutations affect the polypeptides crucial to the structure of myofibrils and might be responsible for the myocyte and myofibrillar disarray characteristic of familial HCM. Other disease loci that have been identified include chromosome 1g3 (encoding troponin T); chromosome 19p13 (encoding troponin I); chromosome 15q2 (encoding alpha-tropomyosin); chromosome 11p11 (encoding myosin-binding protein C); chromosomes 3p21 and 12q23 (encoding essential and regulatory myosin light chains); and chromosome 15q11-14 (encoding actin).166, 172, 176, 176a There is an (as yet) unidentified mutation on chromosome 7q3 that has been found in a large Irish family with HCM and the Wolff-Parkinson-White syndrome.177 It is estimated that about 30 percent of familial HCM is due to mutations of the cardiac MHC gene, 15 percent is caused by mutations of the cardiac troponin T gene, less than 3 percent is due to mutations of the tropomyosin gene, and the remainder is due to mutations of other genes.178 It now appears that HCM is genetically transmitted in most patients as an autosomal dominant trait with disease loci on one of at least eight different chromosomes (chromosomes 1, 3, 7, 11, 12, 14, 15, and 19).166 The cause of HCM in the remainder of patients is unknown. Morphological evidence of the disease is found in about one fourth of the first-degree relatives of a patient with HCM; in many of the relatives the disease is milder than in the propositus, the degree of hypertrophy is less and is more localized, and outflow gradients usually are lacking. Symptoms often are absent or minimal, and the disease is detected only by echocardiography. Thus, there is wide variation in the phenotypical expression of a specific mutation of a given gene, with variability in clinical symptoms and the degree as well as time course of appearance of hypertrophy.179, 180, 181 Of particular interest are mutations of the troponin T gene that typically result in only modest (or no) hypertrophy but indicate a poor prognosis and a high risk of sudden death (although at least one mutation has a favorable prognosis).166, 178, 182 Conversely, certain genes and mutations are associated with more favorable prognoses (Fig. 48&#8211;11).183, 184 In some patients with an abnormal gene and no echocardiographic evidence of HCM, the ECG is abnormal. Therefore, otherwise unexplained abnormalities of the ECG in first-degree relatives of patients with HCM may be indicative of a carrier or preclinical state. Unfortunately, genetic testing is not yet easily available for routine clinical use and remains largely a research tool. Pathophysiology SYSTOLE. Since the initial descriptions of HCM, the feature that has attracted the greatest attention is the dynamic pressure gradient across the left ventricular outflow tract (Figs. 48&#8211;8 and 48&#8211;12). Although this pressure gradient was initially attributed to a muscular sphincter action in the subaortic region or was believed by some to be an artifact,156 it is now considered to be related to further narrowing of an already small outflow tract (narrowed by the prominent septal hypertrophy and possibly abnormal location of the mitral valve) by systolic anterior motion of often elongated mitral valve leaflets against the hypertrophied septum.154, 157 (See CD Figure 905.) (See CD Figure 906.) There continues to be considerable controversy about the cause and significance of the outflow gradient.156, 185 Central to the disagreement is whether there is true obstruction to left ventricular ejection or whether the pressure gradient is simply the consequence of vigorous ventricular emptying. Most now favor the view that a true mechanical impediment to left ventricular ejection occurs when outflow gradients are present and is the result of distal portions of the mitral valve apparatus moving anteriorly across the outflow tract and contacting the ventricular septum in mid systole.153 It is likely that the mitral valve is displaced anteriorly because of Venturi effects and as a result of the increased ejection velocities produced by the abnormal left ventricular outflow tract orientation and geometry.185 DIASTOLE. Most patients with HCM demonstrate abnormalities of diastolic function (see Chap. 15) at rest or with stress, whether or not a pressure gradient is present and whether or not they are symptomatic.160, 186 These abnormalities of global diastolic filling are largely independent of the extent and distribution of myocardial hypertrophy; patients with mild and apparently localized hypertrophy may demonstrate prominent diastolic dysfunction, suggesting that the myopathic process occurs in ventricular regions that are not macroscopically hypertrophied.163 Others have found that diastolic filling varies in different regions of the left ventricle and is influenced by the thickness of the septum.187 Diastolic dysfunction in turn leads to increased filling pressure despite a normal or small left ventricular cavity and appears to result from abnormalities of left ventricular relaxation and distensibility. Early diastolic filling is impaired when relaxation is prolonged, perhaps related to abnormal calcium kinetics, subendocardial ischemia, or the abnormal loading conditions found in HCM.188 Late diastolic filling is altered when left ventricular distensibility is impaired; as a consequence, filling pressures rise. HCM may cause abnormal distensibility of the ventricle because of fibrosis or cellular disorganization.189 (See CD Figure 907.) MYOCARDIAL ISCHEMIA. Myocardial ischemia is common and multifactorial in HCM (Table 48&#8211;6).190 Major causes include impaired vasodilator reserve (perhaps related to the thickened and narrowed small intramural coronary arteries found in HCM)191; increased oxygen demand, especially in patients with outflow gradients; and elevated filling pressures with resultant subendocardial ischemia.157, 190, 192, 193, 194 In children, compression of intramyocardial segments of the left anterior descending coronary artery (so-called myocardial bridge) may predispose to myocardial ischemia and sudden death.195 Clinical Manifestations SYMPTOMS. The majority of patients with HCM are asymptomatic or only mildly symptomatic152 and often are identified during screening of relatives of a patient with HCM. Unfortunately, the first clinical manifestation of the disease in such individuals may be sudden death. The disease is identified most often in adults in their 30s and 40s; it occurs more often than is commonly suspected in elderly patients. The condition has been observed at necropsy in stillborns and both clinically and pathologically in octogenarians. The importance of recognizing this disorder in children at the earliest possible time is highlighted by the higher mortality rate in younger patients; death is often sudden and unexpected. When HCM is first diagnosed in older patients, several features are distinctive and are in contrast to findings in younger patients: generally mild degrees of left ventricular hypertrophy; frequent demonstration of outflow gradients; and appearance of marked symptoms late in life (typically after age 55).167 A particularly high index of suspicion of this condition must be maintained to make the clinical diagnosis in the elderly because their symptoms may easily be confused with those due to coronary artery or aortic valve disease. Because syncope and sudden death have been associated with competitive sports and severe exertion in patients with HCM, it is important to diagnose this condition so that these activities may be proscribed. The disease is slightly more common in men, although women may be more likely to be severely disabled and may initially present at a younger age than men.196 The clinical picture varies considerably, ranging from the asymptomatic relative of a patient with recognized HCM who has a slightly abnormal echocardiogram but no other overt manifestation of the disease to the patient with incapacitating symptoms. A general relationship exists between the extent of hypertrophy and the severity of symptoms, but the relationship is not absolute, and some patients have severe symptoms with only mild and apparently localized hypertrophy, and vice versa.157 A complex interaction occurs between left ventricular hypertrophy, the left ventricular pressure gradient, diastolic dysfunction, and myocardial ischemia, which accounts for the great variability in symptoms from patient to patient. The most common symptom is dyspnea, occurring in up to 90 percent of symptomatic patients, which is largely a consequence of the elevated left ventricular diastolic (and therefore left atrial and pulmonary venous) pressure, which results principally from impaired ventricular filling owing to diastolic dysfunction.157 Angina pectoris (found in about three fourths of symptomatic patients), fatigue, presyncope, and syncope are also common. Palpitations, paroxysmal nocturnal dyspnea, overt congestive heart failure, and dizziness are found less frequently, although severe congestive heart failure culminating in death may be seen. Exertion tends to exacerbate many of the symptoms.197 A variety of mechanisms may contribute to the production of angina pectoris (see Table 48&#8211;6). It is at least in part the result of an imbalance between oxygen supply and demand as a consequence of the greatly increased myocardial mass. Abnormalities of the small coronary arteries may contribute to myocardial ischemia, particularly during exertion, and perhaps 20 percent of older patients with HCM may have concurrent atheromatous obstructive coronary artery disease. Transmural infarction may occur in the absence of narrowing of the extramural coronary arteries.157 Impaired diastolic relaxation may produce subendocardial ischemia as a result of prolonged maintenance of wall tension with a concomitant slower-than-normal decrease in the impedance to coronary blood flow. Syncope may result from inadequate cardiac output with exertion or from cardiac arrhythmias. It occurs most commonly in young patients with small left ventricular chamber size and evidence of ventricular tachycardia on ambulatory monitoring.198 Near-syncopal (&#8220;graying out&#8221;) spells that occur in the erect posture and that can be relieved by immediately lying down are common. However, in contrast to valvular aortic stenosis, syncope or near-syncope may not be an ominous finding in adult patients with HCM; some patients have a history of such episodes dating back many years without clinical deterioration.152 In children and adolescents, however, presyncope and syncope identify patients at increased risk of sudden death (see Natural History). PHYSICAL EXAMINATION. This may be normal in asymptomatic patients without gradients, particularly those with the apical variant of HCM, save for a left ventricular lift and a loud S4, but findings are usually prominent in patients with a left ventricular outflow tract pressure gradient. The apical precordial impulse is often displaced laterally and is usually abnormally forceful and diffuse.196 Because of decreased left ventricular compliance, a prominent presystolic epical impulse that results from forceful atrial systole often is present. This may result in a double apical impulse as a result of the prominent a wave.154 A more characteristic but less frequently recognized abnormality is a triple apical beat, the third impulse consisting of a late systolic bulge that occurs when the heart is almost empty and is performing near-isometric contraction.196 The jugular venous pulse may demonstrate a prominent a wave, reflecting diminished right ventricular compliance secondary to massive hypertrophy of the ventricular septum.159 The carotid pulse typically rises briskly and then declines in midsystole as the gradient develops, followed by a secondary rise.196 This may be appreciated on physical examination but can be demonstrated more clearly by means of indirect carotid pulse tracings. (See CD Figure 908.) (See CD Figure 909.) (See CD Figure 910.) (See CD Figure 911.) (See CD Figure 912.) Auscultation. The S1 is normal and is often preceded by an S4 that corresponds to the apical presystolic impulse.196 The S2 usually is normally split. In some patients, however, it is narrowly split and in others, particularly those with severe outflow gradients, paradoxical splitting may be noted.154 An S3 may be present but does not have the same ominous significance as in patients with valvular aortic stenosis. Systolic ejection sounds relating to rapid acceleration of blood flow may be found on occasion. The auscultatory hallmark of HCM associated with an outflow gradient is a systolic murmur that typically is harsh and crescendo-decrescendo in configuration (Fig. 4&#8211;46); it usually commences well after S1 and is best heard between the apex and the left sternal border.196 It often radiates well to the lower sternal border, the axillae, and base of the heart but not into the neck vessels. In patients with large gradients, the murmur usually reflects both left ventricular outflow tract turbulence and concomitant mitral regurgitation.154 Accordingly, the murmur is often more holosystolic and blowing at the apex and in the axillae (due to mitral regurgitation) and midsystolic and harsher along the lower sternal border (due to turbulent flow across the narrowed outflow tract).196 The systolic murmur is labile in intensity and duration, and a variety of maneuvers may be used to augment or suppress it (Table 48&#8211;7). 154 A diastolic rumbling murmur, reflecting increased transmitral flow, may occur in patients with marked mitral regurgitation. The murmur of aortic regurgitation is observed in about 10 percent of patients, although mild aortic regurgitation can be demonstrated by Doppler echocardiography in one third.199 It may develop after operation to correct the outflow gradient or following infective endocarditis. Differentiation from Valvular Aortic Stenosis. It is important to emphasize the features of physical examination that permit differentiation of HCM from fixed orifice obstruction, most commonly due to valvular aortic stenosis (see Chap. 46). The character of the carotid pulse and features of the murmur are most useful in this regard. Because there is obstruction to left ventricular emptying from the beginning of systole with fixed valvular stenosis, the carotid upstroke is slowed and of low amplitude (pulsus parvus et tardus).200 With HCM, initial ejection of blood from the left ventricle is actually enhanced, and therefore the arterial upstroke is brisk. The murmur of HCM, as opposed to that of aortic stenosis, can be reliably identified by its increase with the Valsalva maneuver and during standing from a squatting position, and its decrease during squatting from a standing position, passive leg elevation, and hand grip (see Table 48&#8211;7).196 Other features that may be helpful but are of considerably less significance are the location of the murmur (it radiates along the carotid arteries in valvular aortic stenosis but not in HCM) and the location of the systolic thrill when present (most prominent in the second right intercostal space in valvular aortic stenosis and in the fourth interspace along the left sternal border in HCM). ELECTROCARDIOGRAM. This is usually abnormal in HCM201 and invariably so in symptomatic patients with left ventricular outflow tract gradients.157 Entirely normal ECGs are seen in only 15 to 25 percent of patients and usually are found in the presence of only localized left ventricular hypertrophy.202 The most common abnormalities are ST segment and T wave abnormalities, followed by evidence of left ventricular hypertrophy, with QRS complexes that are tallest in the midprecordial leads.157 Progressive ECG evidence of hypertrophy may develop over time. Giant negative T waves in the midprecordial leads of Japanese patients are characteristic of HCM involving the apex203, but such a pattern in whites may be found with HCM involving segments other than the apex. Prominent Q waves are relatively common, occurring in 20 to 50 percent of patients. The Q wave abnormalities often involve the inferior (II, III, aVF) and/or precordial (V2&#8211;V6) leads. The cause of the Q waves remains unestablished; although they do not correlate simply with the degree of septal hypertrophy,157 they may relate to the balance of electrical forces emanating from the left versus the right ventricle.154 A variety of other ECG abnormalities may occur, including abnormal electrical axis (usually left-axis deviation) and P wave abnormalities (usually left atrial abnormality). Accessory atrioventricular pathways have been found in HCM, although they are uncommon.204 Clinically significant abnormalities of atrioventricular conduction are uncommon but may cause syncope.205 ARRHYTHMIAS. Although hemodynamic or ischemic mechanisms may play roles in the death of patients with HCM (particularly the young),206 many deaths, particularly those that are known to have been sudden, likely are due to an arrhythmia.207, 208 Because of the systolic and diastolic abnormalities in this disorder, rhythm disturbances are less well tolerated. Ventricular arrhythmias are common in patients with HCM, occurring in more than three fourths of patients undergoing continuous ambulatory ECG monitoring. Runs of nonsustained ventricular tachycardia are found in about one fourth of patients with HCM, although sustained monomorphic tachycardia is uncommon.207 In some it is a harbinger of subsequent sudden death; however, its overall predictive value in identifying patients at high risk for sudden death is limited. Treadmill testing may expose arrhythmias that are not present at rest, although continuous ambulatory monitoring is superior in detecting repetitive ventricular tachyarrhythmias. Supraventricular tachycardia may be found in one fourth to one half of patients.207 Atrial fibrillation occurs in about 10 percent of patients (often those with no gradient and mild hypertrophy), and the resultant loss of the atrial contribution to the filling of a hypertrophied, stiff ventricle may result in clinical deterioration.157, 209 Treatment is often effective in controlling symptoms and restoring sinus rhythm; if this is done, long-term survival usually is not jeopardized.210 The signal-averaged ECG has not proved to be helpful in identifying patients at increased risk of sustained or lethal ventricular arrhythmia, although additional studies are necessary.211 Reduced heart rate variability on ambulatory monitor recordings, a predictor of increased sudden death risk after myocardial infarction, appears to be less useful in risk stratification in HCM patients.212 ELECTROPHYSIOLOGICAL TESTING. The role of electrophysiological studies in identifying HCM patients at increased risk of sudden death is controversial; despite earlier enthusiasm, it is now generally believed that it is of limited predictive value.152, 157 These studies may identify a variety of abnormalities in HCM patients; they induce polymorphic ventricular tachycardia in many patients with HCM, but such a response is generally believed to be nonspecific and does not identify high-risk patients.152 Unfortunately, unlike its utility in ischemic heart disease, the predictive value of the more typical inducible sustained ventricular arrhythmias during electrophysiological testing is low in HCM. Aggressive stimulation protocols are required to induce a sustained arrhythmia in high-risk HCM patients, often resulting in arrhythmias in low-risk patients as well.208 Tilt-table testing has not been particularly useful in identifying the cause of syncope in HCM; neurally mediated syncope is uncommon in this setting and true positive tests are uncommon, but false-positive tests are frequent and significantly limit the usefulness of the test.213 CHEST ROENTGENOGRAM. The findings on radiographic examination are variable; the cardiac silhouette may range from normal to markedly increased, and in most cases of apparent &#8220;cardiomegaly&#8221; the enlarged cardiac silhouette is the result of left ventricular hypertrophy and/or left atrial enlargement.157 Left atrial enlargement is observed frequently, especially when significant mitral regurgitation is present.154 Aortic root enlargement and valvular calcification are not seen unless associated diseases are present, although calcification of the mitral annulus is common in HCM. ECHOCARDIOGRAPHY. Because echocardiography combines the attributes of high resolution and no known risk, it has been widely used in the evaluation of HCM. It is useful in the study of patients with suspected HCM and also in the screening of relatives of HCM patients. The echocardiogram is of value in identifying and quantifying morphological features (i.e., distribution of septal hypertrophy), functional aspects (e.g., hypercontractile left ventricle), and (when combined with Doppler recordings) hemodynamic findings (e.g., magnitude of outflow gradient). (See Figs. 7&#8211;99, 7&#8211;100, and 7&#8211;101.) Left Ventricular Hypertrophy. The cardinal echocardiographic feature of HCM is left ventricular hypertrophy. Although the characteristic feature is hypertrophy of the septum and anterolateral free wall, the echocardiogram is useful in identifying involvement of other left ventricular locations, including portions of the free wall and the apex.157, 170, 214 Considerable variability exists in the degree and pattern of hypertrophy; in most patients, there is variation in the extent of hypertrophy from one left ventricular region to another.157 Maximal hypertrophy of the septum often occurs midway between the base and apex of the left ventricle. The finding of a thickened septum that is at least 1.3 to 1.5 times the thickness of the posterior wall when measured in diastole just before atrial systole has been the time-honored criterion for the diagnosis of ASH. The septum not only is relatively thicker than the posterior wall but is typically at least 15 mm in thickness (normal 11 mm). Although the average wall thickness detected on echocardiography is about 20 mm (i.e., almost twice normal), there is great variation, ranging from very mild hypertrophy (13 to 15 mm) to massive hypertrophy (50 mm).159 An unusual echocardiographic pattern consisting of a ground-glass appearance has been noted in portions of the hypertrophied myocardium in some patients with HCM. Even when abnormalities are not apparent on visual inspection, quantitative texture analysis often identifies them in both nonhypertrophied (but presumably abnormal) and hypertrophied regions of the ventricle and can be used to distinguish HCM patients from those with secondary hypertrophy.215 It has been speculated that this pattern may be related to the abnormal cellular architecture and myocardial fibrosis that has been noted in pathological studies.216 Outflow Tract Obstruction. A second echocardiographic feature often found in HCM in addition to left ventricular hypertrophy is narrowing of the left ventricular outflow tract, which is formed by the interventricular septum anteriorly and the anterior leaflet of the mitral valve posteriorly. (See CD Figure 913.) The mitral valve leaflets are abnormally large and elongated and are associated with abnormal left ventricular outflow tract geometry that culminates in the production of a pressure gradient.214, 217, 218 This abnormal geometry is causally related to the mitral regurgitation that accompanies an outflow gradient; the degree of mitral regurgitation correlates with the extent of anterior and posterior leaflet malcoaptation.219 When HCM is associated with a pressure gradient, there is abnormal systolic anterior motion of the anterior leaflet, and occasionally the posterior leaflet of the mitral valve.214 A close relationship exists between the degree of systolic anterior motion and the magnitude of the outflow gradient. Prolonged interventricular septal contact of the mitral apparatus is limited to HCM with resting pressure gradients, and a close temporal relationship exists between the onset of the pressure gradient and the onset of septal apposition of the mitral apparatus. MECHANISMS OF SYSTOLIC ANTERIOR MOTION. Three explanations have been offered for systolic anterior motion: (1) the mitral valve is pulled against the septum by contraction of abnormally oriented papillary muscles and elongated leaflets220; (2) the mitral valve is pushed against the septum (perhaps by the left ventricular posterior wall) because of its abnormal position in the outflow tract; and (3) the mitral valve is drawn toward the septum because of the lower pressure that occurs as blood is ejected at a high velocity through a narrowed outflow tract (Venturi effect).221 In a minority of cases (less than 15 percent), one or both papillary muscles insert anomalously directly into the anterior mitral leaflet, causing a long area of midventricular narrowing that results in an intraventricular pressure gradient. (See CD Figure 914.) Systolic anterior motion of the mitral valve and dynamic left ventricular gradients are not pathognomonic of HCM but may be found in a variety of other conditions, including hypercontractile states, left ventricular hypertrophy, transposition of the great arteries, and infiltration of the septum. Even mild degrees of left ventricular hypertrophy may be associated with systolic anterior motion and outflow gradients, particularly under conditions of enhanced sympathetic tone. In many cases in conditions other than HCM, systolic anterior motion is due to buckling of the chordae tendineae rather than to movement of the anterior mitral valve leaflet as occurs in HCM (although the chordae tendineae and papillary muscles may contribute to systolic anterior motion in HCM). (See CD Figure 915.) Other Echocardiographic Findings. The following may be present: (1) a small left ventricular cavity; (2) reduced septal motion and thickening during systole, particularly of the upper septum (presumably because of the disarray of the myofibrillar architecture and abnormal contractile function)222; (3) normal or increased motion of the posterior wall; (4) a reduced rate of closure of the mitral valve in mid diastole secondary to a decrease in left ventricular compliance or abnormal transmittal diastolic flow; (5) mitral valve prolapse; and (6) partial systolic closure or, more commonly, coarse systolic fluttering of the aortic valve related to turbulent blood flow in the outflow tract. MRI studies have shown that regional left ventricular function and the degree of local hypertrophy are inversely related and the hypertrophied septum typically is hypokinetic.222, 223 The echocardiographic findings that accompany a left ventricular outflow tract gradient (systolic anterior motion and aortic valve partial closure) may be quite labile, and provocative measures such as the Valsalva maneuver, pharmacologically induced vasodilatation with amyl nitrite, stimulation of contractility with isoproterenol, or an induced premature ventricular contraction may be required to precipitate the findings.150, 224 Abnormalities of diastolic function (see Chap. 15) may be demonstrated by echocardiography and Doppler recordings in about 80 percent of patients with HCM, independent of the presence or absence of a systolic pressure gradient.157 Because the septum typically is hypokinetic, the rate of left ventricular filling is determined primarily by the rate of free wall thinning. Little relationship exists between the extent of hypertrophy and the severity of abnormalities of diastolic function. Doppler ultrasonography has confirmed the virtual ubiquity of mitral regurgitation when an outflow pressure gradient is present157 and has accurately measured the magnitude of the outflow tract gradient.155 Doppler color flow imaging reveals mitral regurgitation, most prominent in late systole, accompanying the appearance of turbulent flow in the left ventricular outflow tract. Recordings from the left ventricular outflow tract support the concept that true obstruction to flow occurs and accounts for the pressure gradient.155 RADIONUCLIDE SCANNING. Thallium-201 myocardial imaging, particularly when tomographic imaging (single-photon emission computed tomography [SPECT]) is performed (see Chap. 9), permits direct determination of the relative thicknesses of the septum and free wall and may be of particular value when technical constraints limit the reliability of echocardiographic evaluation in a given patient with presumed HCM. Reversible thallium defects, presumably indicative of ischemia, are common findings in HCM in the absence of obstructive coronary artery disease.225 They are common in adult patients with HCM and in those young patients with a history of sudden death or syncope, suggesting that myocardial ischemia is an important factor and probably a mechanism of demise in younger patients.226 Fixed defects, probably indicative of myocardial scarring, occur primarily in patients with impaired systolic function. Gated radionuclide ventriculography with blood pool labeling permits the evaluation of not only the size but also the motion of the septum and left ventricle. As with the echocardiogram, abnormal diastolic filling of the ventricle has been observed in patients with HCM (both with and without gradients) by computer analysis of the blood pool scan.227 Because of the ease and availability of transthoracic and transesophageal echocardiography, this technique is not widely used in the evaluation of HCM. (See CD Figure 916.) Hemodynamics and Angiography CARDIAC CATHETERIZATION. Heart catheterization is not required for the diagnosis of HCM, because noninvasive evaluation almost always suffices; it is reserved for situations where concomitant coronary artery disease is a consideration, or when invasive modalities of therapy (e.g., pacemaker, surgery) are being considered.154 It discloses diminished diastolic left ventricular compliance and in some patients a systolic pressure gradient within the body of the left ventricle (see Fig. 48&#8211;8), which is separated from a subaortic chamber by the thickened septum and the anterior leaflet of the mitral valve that abuts the septum (see Fig. 48&#8211;12).155 (See CD Figure 917.) The pressure gradient may be quite labile and may vary between 0 and 175 mm Hg in the same patient under different conditions (see later). The arterial pressure tracing may demonstrate a &#8220;spike and dome&#8221; configuration similar to the carotid pulse recording.155 As a consequence of diminished left ventricular compliance, the mean and particularly the a wave in the left atrial pressure pulse and the left ventricular end-diastolic pressures are usually elevated. Artifactual outflow gradients may occur if the left ventricular catheter becomes entrapped in the trabeculae of a markedly hypertrophied left ventricle.156 Proper technique and choice of catheters with side holes should clarify the mechanism of such gradients. Cardiac output may be depressed in patients with long-standing severe gradients, but in the majority of patients it is normal; occasionally it is elevated. (See CD Table 97.) Hemodynamic abnormalities in HCM are not limited to the left side of the heart. Approximately one fourth of patients demonstrate pulmonary hypertension, which is usually mild but in some cases may be moderate to severe. This is due (at least in part) to elevated mean left atrial pressures as a consequence of diminished left ventricular compliance. A pressure gradient in the right ventricular outflow tract occurs in approximately 15 percent of patients who have obstruction to left ventricular outflow196, 228 and appears to result from markedly hypertrophied right ventricular tissue.229 Right atrial and right ventricular end-diastolic pressures may be slightly elevated. LABILITY OF GRADIENT. A feature characteristic of HCM is the variability and lability of the left ventricular outflow gradient (see Table 48&#8211;7).149, 150, 230 A given patient may demonstrate a large outflow gradient on one occasion but have none at another time. In some patients without a resting gradient, it may be temporarily provoked. Three basic mechanisms are involved in the production of dynamic gradients, all of which act by reducing ventricular volume and presumably accentuate the apposition of the anterior mitral leaflet against the septum150: (1) increased contractility, (2) decreased preload, and (3) decreased afterload. In a minority of patients with HCM, the gradient is midventricular and may be intensified by increased contractility, which exerts a direct muscular sphincter action.154, 155 The stimuli that provoke or intensify left ventricular outflow tract gradients in HCM generally improve myocardial performance in normal subjects and in patients with most other forms of heart disease. Conversely, reductions in contractility or increases in preload or afterload, which increase left ventricular dimensions, reduce or abolish the left ventricular outflow gradient. (See CD Figure 918.) (See CD Figure 919.) Alterations in the magnitude of the gradient are reflected by changes in the findings on physical examination, noninvasive tests, and left-sided heart catheterization. This dynamic characteristic of HCM distinguishes it from the discrete forms of obstruction to ventricular outflow. An increase in the gradient usually results in a louder murmur, a longer ejection period with a more characteristic spike and dome configuration in the carotid pulse, and more flagrant echocardiographic evidence of systolic anterior motion of the anterior mitral leaflet. In some patients, the intensity of the murmur may not track with the gradient, perhaps because in many cases the murmur reflects mitral regurgitation (at least in part).154 A number of bedside procedures may be useful in the evaluation of suspected HCM.154 Perhaps the most helpful is sudden standing from a squatting position. Squatting results in an increase in venous return and an increase in aortic pressure, which increases ventricular volume, diminishing the gradient and decreasing the intensity of the murmur. Sudden standing has the opposite effects and results in accentuation of the gradient and the murmur. VALSALVA MANEUVER. This is another useful bedside technique for eliciting or exacerbating the gradient. After a transient increase in arterial pressure that usually lasts for four or five cardiac cycles after the onset of the strain and coincident with an increase in heart rate, the arterial systolic and pulse pressures and ventricular volume decline and the gradient (and murmur) increases. After release of the strain, a compensatory overshoot of arterial pressure and venous return with cardiac slowing occur, all of which increase ventricular volume and reduce the magnitude of the gradient and the murmur. Occasional patients may show paradoxical attenuation of the systolic murmur despite an increase in the pressure gradient, presumably related to a critical reduction in stroke volume. Inhalation of amyl nitrite also intensifies the murmur and the abnormality of the arterial pulse. The murmur of HCM is attenuated by passive leg elevation, hand grip, and sudden squatting from a standing position. Postextrasystolic Changes. One of the most potent stimuli for enhancing the gradient is postextrasystolic potentiation (see Chap. 14), which may occur after a spontaneous premature contraction or be induced by mechanical stimulation with a catheter.231 The resultant increase in contractility in the beat after the extrasystole is so marked that it outweighs the otherwise salutary effect of increased ventricular filling caused by the compensatory pause and produces an increase in the gradient and often of the murmur as well. A characteristic change often occurs in the directly recorded arterial pressure tracing, which, in addition to displaying a more marked spike and dome configuration, exhibits a pulse pressure that fails to increase as expected or actually decreases (the so-called Brockenbrough-Braunwald phenomenon) (see Fig. 48&#8211;12). This is one of the more reliable signs of dynamic obstruction of the left ventricular outflow tract. In some patients, the postextrasystolic murmur is attenuated despite an increase in the outflow gradient, apparently because in this setting the murmur (a hybrid of outflow tract turbulence and mitral regurgitation) is mirroring to a greater degree changes in the severity of mitral regurgitation rather than changes in the outflow tract gradient. POSITIVE INOTROPIC AGENTS. Digitalis glycosides and the beta-adrenoceptor agonist isoproterenol augment the gradient because they increase myocardial contractility, whereas nitroglycerin and amyl nitrite exaggerate the gradient by decreasing arterial pressure and ventricular volume. The ingestion of alcoholic beverages may exacerbate the outflow pressure gradient by producing systemic vasodilatation.232 Hypovolemia (as a result of hemorrhage or overly aggressive diuresis) may also provoke overt obstruction to left ventricular outflow. The intensity of the murmur and the left ventricular outflow gradient may be decreased by beta-adrenoceptor blockade, although the effect of the latter is often not dramatic and is of greatest hemodynamic benefit in protecting against the increase in the gradient that may be provoked by exercise. In most patients the severity of mitral regurgitation and the intensity of the apical blowing regurgitant murmur vary with the degree of obstruction of left ventricular outflow. ANGIOGRAPHY. Left ventriculography shows a hypertrophied ventricle; when an outflow gradient is present, the anterior leaflet of the mitral valve moves anteriorly during systole and encroaches on the outflow tract. Associated with this motion of the leaflet is mitral regurgitation, which is a constant finding in patients with gradients. The left ventricular cavity is often small, and systolic ejection is typically vigorous, resulting in virtual obliteration of the cavity at end systole (Fig. 48&#8211;13), although the apparent hypercontractile state may relate more to reduced afterload (low end-systolic wall stress) than to enhanced inotropy. (See CD Figure 920.) The papillary muscles are often prominent and may fill the left ventricular cavity in late systole. In patients with apical involvement, the extensive hypertrophy may convey a spadelike configuration to the left ventricular angiogram.165 It may be helpful to supplement angiographic evaluation of the left ventricle with simultaneous right ventriculography in a cranially angulated left anterior oblique projection to obtain optimal visualization of the size, shape, and configuration of the interventricular septum. The left septal surface either is flat or bulges into the left ventricular cavity at its mid or lower portion, in contrast to the normal findings of the septum curving toward the right ventricle. In patients older than 45 years of age, obstructive coronary artery disease may be present, although the symptoms of ischemic pain are indistinguishable from those of patients with normal coronary angiograms and HCM. The left anterior descending and septal perforator coronary arteries may demonstrate phasic narrowing and associated abnormalities of flow during systole.233 Natural History The clinical course in HCM is varied; in many patients symptoms are absent or mild, remain stable, and in some instances improve over a period of 5 to 10 years. The annual mortality is about 3 percent in adults seen in large referral centers234 but probably is closer to 1 percent when all patients with HCM are included.235, 236, 237 The risk of sudden death is higher in children, perhaps as high as 6 percent per year.171 Clinical deterioration (aside from sudden death) usually is slow. Although symptoms are unrelated to the severity or even the presence of a gradient,157 the percentage of severely symptomatic patients does increase with age. The onset of atrial fibrillation may lead to an increase in symptoms, although counterintuitively often it appears to be well tolerated.210 Conversion to sinus rhythm by pharmacological or electrical cardioversion should be attempted, although maintenance of sinus rhythm may be difficult.157 Patients who develop atrial fibrillation ordinarily are started on long-term therapy with oral anticoagulants. Progression of HCM to left ventricular dilatation and dysfunction without a gradient (i.e., DCM) occurs in 10 to 15 percent of patients.157, 238 It appears to result, at least in part, from wall thinning and scar formation as a consequence of myocardial ischemia caused by small vessel coronary artery disease and abnormal coronary vasodilator reserve (Fig. 48&#8211;14).157 It is more likely to occur in patients with marked septal hypertrophy and generally is associated with a poor prognosis. The extent of left ventricular hypertrophy in adults usually remains stable over time, although a majority of children demonstrate increasing degrees of hypertrophy (often considerable) and many adults demonstrate a very gradual degree of regression of hypertrophy over time (Fig. 48&#8211;15).239 In some children, the findings of HCM may develop despite a previous normal echocardiogram; this is not common in adults, but it may be seen in particular with the cardiac myosin-binding protein C mutation.161, 166 Its occurrence emphasizes that a single normal echocardiogram does not exclude HCM in a child or adolescent; cellular disarray and the attendant risk of sudden death may be present even in the absence of left ventricular hypertrophy. A marker for the later appearance of clinical HCM may be an initially abnormal ECG demonstrating increased QRS voltage. SUDDEN DEATH. Death is most often sudden in HCM and may occur in previously asymptomatic patients, in individuals who were unaware they had the disease, and in patients with an otherwise stable course (Fig. 48&#8211;16). There is great difficulty in identifying those patients at particular risk of sudden death240, 240a; nevertheless, the features that most reliably identify high-risk patients include young age (< 30 years) at diagnosis, a family history of HCM with sudden death (so-called malignant family history), an abnormal blood pressure response to exercise (presumably related to subendocardial ischemia241), and genetic abnormalities associated with increased prevalence of sudden death.152, 234, 242, 242a The presence or severity of an outflow tract gradient, the degree of functional limitation, and symptoms in general do not correlate with the risk of death.208, 234 A history of syncope is ominous in children but less so in adults. In the latter, nonsustained ventricular tachycardia (NSVT) on 48-hour electrocardiographic monitoring has some predictive value for subsequent sudden death, although most patients (more than 75 percent) with NSVT do not die suddenly.243 The absence of NSVT is a stronger predictor of a good prognosis than is the presence of NSVT of a bad one.207 It is presumed, but not established, that sudden death is due to a ventricular arrhythmia, although atrial arrhythmias may play a role in sensitizing the heart so that ventricular arrhythmias appear subsequently.242 Despite the difficulty in identifying patients at high risk of sudden death, the absence of a variety of characteristics (including the absence of severe symptoms, malignant family history, NSVT, marked hypertrophy, marked left atrial dilatation, and abnormal blood pressure response to exercise) identifies a low-risk group who require little in the way of routine therapy.152, 244 Although avoidance of intense physical exertion is probably appropriate, participation in recreational sports activities is not believed to be contraindicated.152 Children. The mechanism of death may be different in children with HCM, because spontaneous ventricular arrhythmias and inducibility on electrophysiological testing are much less common. It is thought that ischemia may play a prominent role in these patients.226, 245, 246 Hemodynamic mechanisms may also be involved, because younger patients are more likely to demonstrate abnormal changes in peripheral vascular resistance in response to exercise.247 Sudden death often occurs during exercise but also demonstrates a circadian distribution, with clustering of deaths in the morning and early evening.248 Competitive Sports. Guidelines for participation in competitive sports have been developed; strenuous exertion should probably be proscribed in all patients with HCM whether or not symptoms are prominent, especially if high-risk clinical characteristics are present. Unsuspected HCM is the most common abnormality found at autopsy in young competitive athletes who die suddenly. Cardiovascular screening before participation in competitive sports appears to reduce the frequency of unexpected sudden death from HCM,142 although whether large-scale screening of athletes is administratively feasible or cost effective is another matter.249 Why some athletes with HCM die suddenly and others are able to continue to compete without limitation or death is not known.250 It has been speculated that the extent and severity of myocardial disarray may play an important role in determining prognosis, although this is not a finding that is ordinarily or easily obtainable in a living patient! Patients with marked hypertrophy are at increased risk.251 Sudden death is unlikely, however, in asymptomatic or mildly symptomatic patients with mild hypertrophy.252 Bradyarrhythmias and disease of the atrioventricular conduction system may also play a role in sudden death. Management Management of patients with HCM is directed toward alleviation of symptoms, prevention of complications, and reduction in the risk of death (Fig. 48&#8211;17). Whether asymptomatic patients should receive drug therapy is not established because no adequate controlled studies are available.152, 157 Digitalis glycosides should generally be avoided unless atrial fibrillation or systolic dysfunction develops. Diuretics were previously thought to be contraindicated to avoid precipitating or worsening the outflow gradient. More recent experience indicates that cautious use of diuretics often helps reduce symptoms of pulmonary congestion, particularly when they are combined with beta-adrenergic blockers or calcium antagonists.154, 253 Beta-adrenergic agonists may improve diastolic filling but should not be used because they may produce ischemia and usually worsen the outflow gradient. The vast majority of patients with HCM require only medical management; invasive interventions are needed in only 5 to 10 percent of patients, and then only in those patients with outflow gradients who remain severely symptomatic despite optimal medical therapy.152 BETA-ADRENOCEPTOR BLOCKERS. These drugs are the mainstay of medical therapy of HCM. With their use, angina, dyspnea, and presyncope may all be improved. In patients with resting or provocable gradients beta-adrenoceptor blockade may prevent the increase in outflow obstruction that accompanies exertion, although resting gradients are largely unchanged.152 The drugs reduce the determinants of myocardial oxygen consumption and thus angina pectoris and perhaps exert an antiarrhythmic action as well. Angina pectoris generally responds more favorably to treatment with a beta-adrenoceptor blocker than does dyspnea. It has been suggested that beta-adrenoceptor blockade may prevent sudden death, and accordingly some use prophylactic beta-adrenoceptor blockade therapy in asymptomatic patients. However, its efficacy for this purpose has not been established.155, 171 Beta-adrenoceptor blockade also blunts the heart's chronotropic response, thus limiting the demand for increased myocardial oxygen delivery. Beta-adrenoceptor blockade previously was thought to have a beneficial effect on diastolic ventricular filling, but it now appears that any benefit is simply the consequence of a slower heart rate.155 The overall clinical response to beta-adrenoceptor blockade is variable, and only about one third to two thirds of patients experience symptomatic improvement.155 One small blinded trial of beta-adrenoceptor blocker therapy found that nadolol improved symptoms more than placebo or a calcium antagonist but did not improve exercise capacity.254 If beta-adrenoceptor blockers are discontinued, they probably should be withdrawn slowly to avoid rebound adrenergic hypersensitivity. CALCIUM ANTAGONISTS. These are an alternative to beta-adrenoceptor blockade in the management of HCM; most of the experience has been with verapamil, with more limited use of nifedipine, diltiazem, and amlodipine.155, 157 No clear consensus exists as to whether therapy should be initiated first with a beta-adrenoceptor blocker or a calcium antagonist, although verapamil often is effective in improving symptoms in patients who have failed beta-adrenoceptor blockade.157 Exercise performance in particular may be improved when patients are changed from a beta-adrenoceptor blocker to verapamil. Both the hypercontractile systolic function and the abnormalities of diastolic filling may be related to abnormal calcium kinetics, and drugs that block the inward transport of calcium across the myocardial cell membrane may be able to rectify both abnormalities. Verapamil has been the most widely used calcium antagonist in this condition.157 Its use was suggested, at least in part, by the observation that it produces a protective and beneficial effect in the hereditary cardiomyopathy of the Syrian hamster, a condition marked by intracellular calcium overload in which propranolol is ineffective.255 Although the vasodilator effects of verapamil should not be helpful in HCM, it appears that by depressing myocardial contractility, verapamil can decrease the left ventricular outflow gradient when given intravenously or orally. Perhaps more important from a symptomatic point of view, verapamil improves diastolic filling in HCM, at least in part by reducing asynchronous regional diastolic performance.155, 157 It also improves regional myocardial blood flow in some patients, which may contribute to the improvement in diastolic behavior.256 Verapamil appears to improve diastolic filling by improving relaxation rather than by changing left ventricular diastolic stiffness; at any given diastolic volume, filling pressure is reduced. Although variable clinical responses have been reported with verapamil, about two thirds or more of patients show increased exercise capacity and an improved symptomatic status. Sustained symptomatic improvement has been noted with the long-term administration of verapamil in ambulatory patients, although important adverse effects, including sudden death, have been observed in a small fraction of patients so treated.152 Complications with verapamil include suppression of sinus node automaticity and inhibition of atrioventricular conduction, vasodilatation, and negative inotropic effects. These side effects may culminate in hypotension, pulmonary edema, and death; antiarrhythmic agents, especially quinidine, may exacerbate the deleterious hemodynamic effects of verapamil. Because of these adverse effects, it has been suggested that verapamil should not be used, or should be used only with extreme caution, in patients with high left ventricular filling pressure or symptoms of paroxysmal nocturnal dyspnea or orthopnea.152 Unfortunately, these are usually the patients in greatest need of therapy. Nifedipine has also been used in HCM, and it may have theoretical advantages over verapamil because it causes less depression of atrioventricular conduction. This may be counteracted by its more potent vasodilator action. Its effect on diastolic function have been inconsistent.155 Nifedipine may alleviate the chest pain in HCM patients. Combined administration of nifedipine and propranolol may be of benefit in some patients, particularly those with outflow gradients. However, it should be recognized that the potent vasodilator effects of nifedipine may lead to systemic hypotension and an increase in the outflow gradient,152 and in high doses it may depress left ventricular function. Diltiazem has also shown beneficial effects in HCM, producing improved diastolic function, although like verapamil and nifedipine it has caused an increase in the outflow gradient and a worrisome elevation of pulmonary capillary pressure.155, 257 The combination of a beta-adrenoceptor blocker and a calcium antagonist may be effective in patients responding inadequately to monotherapy, although there are only anecdotal reports of the superiority of combination therapy.152, 258 OTHER DRUGS. Disopyramide, an antiarrhythmic drug that alters calcium kinetics, has produced symptomatic improvement and abolition of the pressure gradient in patients with HCM, presumably as a consequence of depression of left ventricular systolic performance as well as a peripheral vasoconstrictor effect.259 It does not appear to have significant effects on diastolic function,259 although this issue has not been entirely resolved.260 Long-term experience with disopyramide is limited, particularly in asymptomatic patients and those without outflow gradients, although the initial benefits appear to decrease with time.152 Beta-adrenoceptor blockers, calcium antagonists, and the conventional antiarrhythmic agents do not appear to suppress serious ventricular arrhythmias or reduce the frequency of supraventricular arrhythmias. However, amiodarone is effective in the treatment of both supraventricular and ventricular tachyarrhythmias in HCM.243 Although there is some belief that amiodarone improves prognosis in HCM, only limited and inconclusive data are available.152, 153, 261 Amiodarone may also improve symptoms and exercise capacity, although its putative beneficial effects on diastolic ventricular function are controversial. 155 Experience with sotalol, although limited, has been generally favorable; in addition to its antiarrhythmic effects on supraventricular and ventricular arrhythmias, its beta-adrenoceptor blocking effects are beneficial.262 We do not favor empirical use of amiodarone (or other antiarrhythmic agents for that matter) in unselected HCM patients, and we worry about possible proarrhythmic effects and potential toxicity, including sudden death.213, 214, 236 Strenuous exercise should be avoided because of the risk of sudden death; almost half of deaths in HCM occur during or just after strenuous physical activity.263 Even though many individuals with subclinical HCM exercise vigorously, the threat of sudden death is sufficiently real that competitive sports are proscribed in patients with marked hypertrophy or other factors believed to be associated with increased risk (see Figs. 48&#8211;16 and 48&#8211;17). Atrial fibrillation should usually be pharmacologically or electrically converted because of the hemodynamic consequences of the loss of the atrial contribution to ventricular filling in this disorder. Anticoagulants should be given to patients with chronic atrial fibrillation when no contraindication exists. Infective endocarditis may occur in about 5 percent of patients but appears to be limited to those with an outflow gradient; accordingly, appropriate antibiotic prophylaxis is indicated in this group.157, 264 The infection usually occurs on the aortic valve or mitral apparatus, on the endocardium, or at the site of the contact lesion on the septum; thus, chronic endocardial trauma may provide a nidus for subsequent infection. DEVICES AND SEPTAL ABLATION. Insertion of a dual-chamber DDD pacemaker may be useful in

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