Ischemia results from a number of factors: 1. Impaired vasodilator reserve

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1 Hypertrophic Cardiomyopathy (HCM) February 24, 2018 Henry Green, MD, FACC, FACP Clinical Professor of Medicine, Wayne State University Definition Hypertrophic cardiomyopathy is defined as myocardial hypertrophy without an identifiable cause. One third of patients have no outflow tract obstruction. Hypertrophy may involve the septum, mid-ventricle or apex. In some patients, the right ventricle may be similarly involved. There may also be right ventricular outflow tract obstruction. Incidence It occurs in about 1 in 500 adults. Being autosomal dominant, it is familial and favors neither sex The onset is usually in late adolescence or early adulthood, rarely during childhood. Sometimes its onset is in the elderly. It is the commonest cause of sudden death in young athletes. Pathophysiology The interventricular septum shows greater hypertrophy than the parietal wall. The left ventricular cavity is typically small. The thickened septum was originally thought to bring about the outflow tract obstruction. It was finally realized that systolic anterior motion (SAM) of the mitral valve is the cause. 23. It is usually the anterior leaflet, but sometimes the posterior leaflet. This not only encroaches on the outflow tract, but also results in mitral regurgitation. Midcavity obstruction may occur without SAM due to muscular apposition or an anomalous papillary muscle. 24 In 1/3 of these patients outflow tract obstruction is labile, rather than fixed. It may become apparent or increase with interventions that reduce ventricular volume (such as dehydration) or increase contractility (such as administration of an inotropic drug, exercise, the strain phase of a Valsalva maneuver, or following a ventricular extrasystole). Another 1/3 of patients have fixed obstruction, while the remainder do not have obstruction. The peak systolic gradient is the measure of interest. Some patients have a subaortic membrane that results in outflow tract obstruction. It is most reliably identifies by contrast echocardiogram or cardiac MRI. Secondary mitral regurgitation commonly occurs as a result of the left ventricular outflow tract obstruction as well as distortion of the mitral leaflets. The hypertrophy may involve the midcavity region, which in turn can result in an apical aneurysm. This confers a greater risk for ventricular arrhuythmias and thromboembolism. 29 Systole is characteristically hyperdynamic. However, the hypertrophy often results in impaired diastolic filling of the ventricle. It also results in a mismatch of myocardial mass to coronary blood flow. The ejection fraction is typically normal or increased. 30 Ischemia results from a number of factors: 1. Impaired vasodilator reserve 1

2 2. Increased oxygen demand 3. Abnormalities of the coronary arteries (wall thickening, narrow lumens) 4. Systolic compression of the arteries (e.g. myocardial bridging) Syncope may result from any of these or a combination: 1. Hypotension 2. Complete heart block 3. Sinus node dysfunction 4. Ventricular tachycardia 5. Left ventricular outflow tract obstruction 6. Abnormal vascular reflexes 7. Rapid supraventricular tachycardia Histologically there is disarray and hypertrophy of the myocytes and interstitial fibrosis. It is likely that this contributes to the arrhythmogenic milieu. The coronary arteries exhibit hypertrophy or hyperplasia of the media. Over a dozen genetic aberrations have been discovered, which may eventually become the diagnostic investigation of choice. Some mutations are more malignant than others. Some individuals are genotypically positive but phenotypically negative. That is, they harbor the disease-causing sarcomere mutation, but do not have left ventricular hypertrophy. These patients can unpredictably develop hypertrophic cardiomyopathy at any age, usually between 12 and 20 years. 25 Nevertheless, genetic testing has limitations, as the correlation between genotype and development of disease has not been consistent. Penetrance is variable. One advantage of genetic testing is that it can lead to recognition of phenocopies of HCM (see below). False diagnosis of HOCM can have many adverse consequences. 28 Clinical findings Presentation Symptoms may include angina, palpitation, dyspnea, orthopnea or nocturnal dyspnea. Fatigue may be present. Myocardial ischemia may occur. Syncope and presyncope occur in some, often with exertion. Patients may describe gray-outs that are relieved by lying down. Symptoms are accentuated by anything that accelerates heart rate or decreases preload. Sudden death occurs in 0.5-2% of cases and may be the initial presentation. One should determine whether there is a family history of HCM or of sudden death. Physical findings The neck veins may show a prominent a wave. The carotid pulse may be bifid with a spike and dome configuration. An atrial gallop is present. Following an extrasystole, the pulse amplitude is diminished. The second sound may be paradoxically split if there is outflow tract obstruction. The apical impulse is hyperdynamic and may be double or triple. A harsh crescendo-decrescendo murmur is present at the left sternal border. Unlike aortic stenosis, it does not radiate to the neck. There is no ejection click. Anything that decreases 2

3 ventricular volume raises the gradient and causes the murmur to become louder, and viceversa. The murmur is louder with Valsalva straining or upon standing. The opposite happens with the murmur of valvular aortic stenosis. The murmur of hypertrophic cardiomyopathy softens with squatting or upon release of Valsalva maneuver, whereas that of aortic stenosis becomes louder. Both become softer with isometric hand grip. Administration of amyl nitrite or nitroglycerine increases the loudness of the murmur, while phenylephrine decreases it. If a murmur is not heard, the patient should be reexamined during or immediately after exercise. There may also be a pansystolic murmur due to mitral regurgitation as well as a left atrial gallop. With the beat that follows an extrasystole, both aortic valvular stenosis and hypertrophic cardiomyopathy murmurs are louder, but the latter is enhanced more. If mitral regurgitation is severe, there may be a diastolic rumble due to increased flow across the mitral valve. Some patients also have mild aortic regurgitation. Electrocardiogram The ECG is abnormal in 75-95% of patients. It may show inferolateral q waves, right or left atrial enlargement, left axis deviation, large negative precordial T waves, or preexcitation. In some, the ECG may be normal. Echocardiographic findings Hypertrophic obstructive cardiomyopathy may be diagnosed in the adult when the end diastolic left ventricular wall thickness is >13 mm. in the absence of other causes of left ventricular hypertrophy. 30 The diagnosis is more difficult in patients who have concomitant disorders, such has hypertension or aortic stenosis. In children, the criterion is based on age, sex and size. The left ventricular cavity is small. Systolic anterior motion of the mitral valve is typically present. Mitral regurgitation is common. The ejection fraction is usually normal. The aortic valve closes prematurely. A transesophageal echocardiogram can be helpful when a transthoracic study is inconclusive. There is an aortic outflow tract gradient, which increases with the Valsalva maneuver, following an extrasystole,with exercise or with administration of amyl nitrite. Another method of demonstrating a dynamic increase in gradient is to do an echocardiogram in the standing position. Dobutamine administration is no longer recommended for this purpose. Stress echocardiography is also useful in risk assessment. In borderline cases, certain echocardiographic or MRI findings are suspicious, such as blood-filled crypts, elongated mitral valve leaflets, diastolic dysfunction or myocardial scarring. 25 Cardiac magnetic resonance imaging (CMRI) This has been found to provide superior images to echocardiography in institutions where the technique has been perfected. It also shows areas of fibrosis in half of these patients. CMRI may also help to differentiate hypertrophic cardiomyopathy from other conditions that simulate it on echocardiogram (see below). 15 3

4 Cardiac CT This can be used in patients in whom CMRI is contraindicated and the echocardiogram does not give satisfactory imaging. Stress myocardial perfusion imaging This can be used to detect coronary artery disease. However there may be fixed or reversible perfusion defects even without epicardial coronary artery disease. Cardiac catheterization (obstructive hypertrophic cardiomyopathy) There is a subaortic or mid-ventricular gradient. The aortic pressure tracing shows a spikeand-dome configuration. Right and left ventricular end-diastolic pressures and pulmonary capillary wedge pressures are elevated. It is also indicated in patients who have survived a cardiac arrest. From a purely diagnostic standpoint, cardiac catheterization is usually not required. However coronary angiography is indicated in patients who have chest pain and risk factors for coronary artery disease, or those who have a positive stress perfusion study. Alternatively, CT tomography can be performed. 48-Hour Holter Recording This should be done every 6-12 months to detect arrhythmias, including atrial fibrillation and ventricular tachycardia. If none are detected, and there is still suspicion of a significant arrhythmia, an implantable loop recorder can be used. Genetic testing of the proband can be useful in screening relatives, as previously stated. Prognosis Hypertrophic cardiomyopathy is frequently well tolerated; most patients have a normal life expectancy. In others, it may remain silent for years, and later become symptomatic. Its course is variable and unpredictable. While the annual mortality rate is less than 1%, it is the commonest cause of sudden death among athletes. The mechanism is ventricular fibrillation. Heart failure may develop secondary to the left ventricular outflow tract obstruction and diastolic dysfunction. It can also occur in "burned out" hypertrophic cardiomyopathy, with reduced ejection fraction. Atrial fibrillation occurs in 25% of patients with outflow tract obstruction. It can aggravate heart failure or result in thromboembolism. 30 Risk stratification Maron 21 recommended that any of the following risk factors justifies implantation of a defibrillator: 1. Family history of sudden cardiac death due to hypertrophic cardiomyopathy. The family member need not be a first degree relative. Or more than one family member who experienced sudden cardiac death. 2. Thick (>30 mm) ventricular septum 3. Repetitive non-sustained ventricular tachycardia on ambulatory monitoring. Preferably the recording should be longer than 24 hours (e.g. 6 days). The significance is judged on a case-by-case basis, taking into account the pattern and frequency of the 4

5 arrhythmia. Some authors regard three or more consecutive ventricular extrasystoles at a rate of 120 or more as significant. 4. Hypotensive blood pressure response to exercise (either a drop of 20 mm below base line, or failure to rise above base line). This can be done using a treadmill with the Bruce protocol, to the maximum predicted heart rate. In addition, minimally symptomatic or asymptomatic patients who achieve 85% or less of their predicted exercise capacity had a 12% risk of adverse events, compared 1% among those who achieved 100% of their predicted exercise capacity Otherwise unexplained syncope. 6. Causal mutations 7. Cardiac MRI showing late gadolinium enhancement involving 15% or more of the left ventricle 21 The risk of sudden death is proportional to the degree of fibrosis. 8. Resuscitated cardiac arrest A high peak outflow tract gradient (e.g. 30 mm at rest) confers a 5% risk of death. Other proposed risk factors include left atrial enlargement. Onset of the disease at a young age is thought by some to be a risk factor. Evidence of myocardial ischemia is another possible risk factor. Electrophysiologic testing has not been helpful in risk stratification. 31 Recent guidelines 22,23 acknowledge that these are risk factors, and do consider them as class I or II recommendations, but do not specifically state that they always indicate the need for a defibrillator. Such findings should be used in conjunction with clinical judgment. However it is likely that any one of the above risk factors would justify an implantable defibrillator. 26 A risk score, the HCM Risk-SCD formula, is offered in the European guidelines (reference 22, p33). It can be downloaded from The absence of the above risk factors, including fibrosis, does not guarantee immunity from sudden death. Spirito et al found the incidence to be 1% per year in a series of over 650 patients who had no apparent risk factors and mild or no symptoms. 17,19 Patients should be reevaluated every1-2 years, or whenever there is a change in clinical status. 18,23 Treatment Activity allowance Hypertrophic cardiomyopathy itself disqualifies an individual from competitive sports, even after septal reduction therapy or implantation of a defibrillator. The same applies to patients who do not have outflow tract obstruction. Less intense activities, such as golf, bowling, recreational running and nautilus weight room exercises are allowed. Aerobic exercises are preferred over isometric ones. However, none of these recommendations is backed by evidence-based studies. Hot, cold or humid environments are also to be avoided. Patients should aoid dehydration and rapid postural changes, especially after meals. Genotypically positive but phenotypically negative patients can engage in competitive sports, but must be screened periodically for the development of hypertrophic cardiomyopathy. 25 5

6 Current guidelines consider patients with hypertrophic cardiomyopathy to be disqualified from certain occupations, such as a commercial airline pilot or a commercial motor vehicle operator. Medical therapy If the patient has a significant gradient (either spontaneous or inducible), beta-blockers are usually the first choice. The target resting heart rate is 60 beats per minute. Disopyramide may be added if obstruction persists, in which case the QT interval should be monitored. It should be initiated in the hospital, and should be given with a beta blocker, because of the risk of accelerated AV conduction if the patient develops atrial fibrillation. Diuretics may be used with caution if congestive symptoms continue. Endocarditis prophylaxis is currently a matter of contention, but some experts recommend it. Good oral hygiene is important. 29,30,32 If beta-blockers are not effective or not tolerated, verapamil can be started at a low dose and titrated up to 480 mg/da for symptoms of angina or dyspnea. Diltiazem is also effective, but either of them can cause pulmonary edema if the outflow tract gradient is 100 mm. or there is pulmonary hypertension. They are also contraindicated if there is preexcitation, conduction disorders or hypotension. They should be started in the hospital. 1, 14,21 Caution is recommended in patients who have high gradients, heart failure or sinus bradycardia. 23 Beta-blockers relieve angina and dyspnea, even in patients without obstruction. They should be used with caution if there is sinus bradycardia or severe conduction disease. Carvedilol and labetalol, which have alpha-blocking properties, should probably not be used. In non-obstructive hypertrophy, verapamil can also be helpful, and diuretics may be used carefully if there is congestion. Nitrites should only be used with caution. Dihydropyridine calcium channel blockers should be avoided if there is outflow tract obstruction. 12 The patient may present with a picture that resembles a myocardial infarction with hypotension, pulmonary edema and suspicious ECG. In such cases, vasodilators and inotropes should be avoided. Beta-blockers and vasoconstrictors (such as phenylephrine or norepinephrine) would be the drugs of choice. 22 If there is pulmonary congestion, diuretics may be used with caution. The minimum effective dose should be employed, and the patient should be monitored for hypotension, hypovolemia and intensification of the outflow tract gradient. 30 A few patients with non-obstructive hypertrophic cardiomyopathy develop systolic ventricular dysfunction and severe heart failure. These patients benefit from afterload reduction with ACE inhibitors, ARB s, diuretics, digitalis, beta-blockers and spironolactone. This is in contrast to patients with obstruction, in whom inotropes and vasodilators are contraindicated. Such patients should also be investigated for other causes 6

7 of systolic dysfunction, such as coronary artery disease. They would not be candidates for negative inotropic therapy, such as calcium channel blockers or disopyramide. 23 Atrial fibrillation develops in about 25% of these patients. Some patients tolerate it, but it can cause serious hemodynamic deterioration. It often results in embolic strokes or other systemic emboli. 21, 22 Anticoagulation with warfarin or one of the newer oral anticoagulants is indicated regardless of the CHA 2 DS 2 VASc score. Even a single short episode of paroxysmal atrial fibrillation is an indication for anticoagulation. Closure of the left atrial appendage is also a possible option. Rate control can be achieved with a beta blocker or a nonhydropyridine calcium channel blocker (provided pre-excitation is not present). Digoxin is not a good choice. Cardioversion is worthwhile. IC drugs should not be used. Amiodarone or sotalol are the preferred drugs. Ablation of the left atrial appendage could also be considered. In patients in whom myectomy is planned, a surgical maze procedure is reasonable. Conversion to sinus rhythm does not guarantee freedom from emboli. 23 Comorbidities that promote coronary artery disease should be addressed, including diabetes, hypertension, hyperlipidemia and obesity. Low-intensity aerobic exercise is recommended. Pregnancy is associated with a number of physiologic changes that can impact the risk of hypertrophic cardiomyopathy, including increased plasma volume, reduced systemic vascular resistance and a hypercoagulable state. Most women with hypertrophic cardiomyopathy tolerate pregnancy well, but there is increased risk to both the mother and the fetus, particularly if the mother has severe symptoms or if the peak gradient is 50 mm. or more. Beta-blockers should be continued, and calcium blockers may be used. Disopyramide usually should be avoided, if possible. The fetal heart rate should be monitored. Vaginal delivery is usually preferred. Surgical treatment Septal myectomy or myotomy is effective if medical therapy fails. An accepted indication is class III or IV NYHA symptoms plus a gradient of 50 mm. despite medical therapy, or class II symptoms with a gradient of 50 mm. and moderate to severe SAM-related mitral regurgitation. 22 It is the procedure of choice if there is concomitant valvular or coronary artery disease. 12 The procedure will correct mitral regurgitation if it is due to SAM, as it is in 95% of cases. Other patients may require mitral valve repair. Complications are rare in experienced centers, and include heart block, aortic regurgitation or septal defects. There is improvement in hypertrophy and cardiac remodeling. Some patients may require cardiac transplantation. 21 Septal reduction therapy is not recommended in asymptomatic patients, regardless of the gradient. The success rate is >99%and the surgical mortality is <1% in expert hands. 29 Long-term survival is similar to that of the general population. Nevertheless, the patient should still be evaluated for the risk of sudden death. 23 7

8 Alcohol septal ablation Percutaneous alcohol septal ablation reduces basal septal thickness and motion, thus relieving obstruction. 100% alcohol is infused into a carefully selected septal perforator artery, thus creating an infarct. The target is the area of contact between the hyperterophied septum and the anterior leaflet of the mitral valve. This usually results in reduction of the gradient and improvement of symptoms in >90% of patients. Over time, it reduces hypertrophy and improves remodeling and diastolic dysfunction. Left atrial pressure and pulmonary hypertension decrease. It does not always relieve systolic anterior motion or mitral regurgitation. In one study, 78% of the patients still had systolic anterior motion after ablation. As a result, they had less reduction in gradient as well as residual mitral regurgitation. 5 The overall success rate is somewhat less than that of myectomy. Patients treated with alcohol ablation required pacemakers more often than those having surgical myectomy. Patients with pre-existing left bundle branch block are at greatest risk. Other complications include large myocardial infarction, ventricular septal defect, pulmonary embolism, stroke, sustained ventricular tachycardia, intractable ventricular fibrillation, and myocardial perforation. In some, there can be early recurrence of outflow tract obstruction, which resolves in 6-12 months. The procedural mortality in experienced centers is <1%. Major complications occur in <2%. 29 It is inadvisable to use alcohol septal ablation if the septal thickness is 30 mm. It is also inappropriate if the patient requires additional cardiac surgery (valvular, bypass grafting). It is not recommended for patients under the age of 21 and is discouraged in those less than 40 years old who would be candidates for myectomy. 23 In addition, Maron has repeatedly expressed concern over creating an infarct in a patient that already has a substrate for cardiac arrhythmias. While there is some evidence that this occurs, this issue remains unsettled. 29 Alcohol septal ablation probably should be reserved for patients who are not good surgical candidates. Pacemaker therapy This modality has generally not proven to be very effective, either in terms of reducing the gradient or improving symptoms. However it may be considered (Class IIb recommendation) in patients who do not respond to medical therapy or who have significant comorbidities. The exact mechanism of improvement is unknown. Implantable defibrillators An ICD is the preferred method of protection for patients with high-risk hypertrophic cardiomyopathy. Followup Patients with hypertrophic cardiomyopathy should undergo annual reassessment of their risk profiles. This should include Holter monitoring and exercise testing Management of complications Dehydration can cause hemodynamic compromise in patients with hypertrophic cardiomyopathy. If hypotension occurs, positive inotropic drugs should not be given, as they will increase the outflow tract gradient. Hypotension should be managed with fluids 8

9 and a vasoconstrictor, such as phenylephrine. Administration of a beta-blocker should also reduce the gradient. Familial considerations While sometimes sporadic, hypertrophic cardiomyopathy is often familial. The disorder may not become apparent until mid or late life. First-degree relatives of the patient should be screened for hypertrophic cardiomyopathy with electrocardiograms and echocardiography. This should be repeated every months in younger relatives, and every five years in older ones. Genetic screening is also valuable, as it may detect phenotypically negative subjects who may later develop the disease. They too should be screened at the same intervals, as the possibility of developing hypertrophic cardiomyopathy is unpredictable. When genetic testing is negative or equivocal, there may still be warning signs on echocardiogram or CMR, such as elongated mitral leaflets, diastolic dysfunction or bloodfilled crypts. If there is a family history of sudden death, stress testing and Holter monitoring should also be done. 12,21,23,27 Differential diagnosis of hypertrophic cardiomyopathy: phenocopies Athlete s heart Athlete s heart, a benign or physiologic adaptation of the heart to intense exercise, may be difficult to distinguish from hypertrophic cardiomyopathy. At times, cardiac catheterization is warranted. Maron 3 offers useful methods of making this distinction: Echocardiogram: Athlete s heart usually shows only mild increase in left ventricular wall thickness, which typically is uniform. In hypertrophic cardiomyopathy, the thickening is greater, but there can be overlap between the two conditions. Hypertrophic cardiomyopathy usually is not uniform, showing greater involvement of the anterior septum. Most patients with hypertrophic cardiomyopathy have small left ventricular end diastolic dimension (<45 mm), whereas the athlete usually does not (>55 mm). Again, there is overlap between the two conditions. The left ventricular filling pattern is normal in athlete s heart, but usually not in hypertrophic cardiomyopathy. Left atrial enlargement favors hypertrophic cardiomyopathy. Systolic anterior motion of the mitral valve, of course, indicates the obstructive form of the disease. Tissue Doppler or speckle Doppler imaging can show diastolic dysfunction, providing evidence of hypertrophic cardiomyopathy. Cardiac magnetic resonance imaging with late gadolinium enhancement: Demonstration of myocardial fibrosis supports a diagnosis of hypertrophic cardiomyopathy. Electrocardiogram: Bizarre ECG patterns tend to favor hypertrophic cardiomyopathy. Very high voltage, deep Q waves, or deep negative T waves may be found. However, there is also wide variation in the ECG of athlete s heart. Nevertheless, a patient with a normal echocardiogram and a markedly abnormal ECG s may develop cardiomyopathy 9

10 years later. 9 In addition, in a study of 114 asymptomatic subjects with known hypertrophic cardiomyopathy, Rowin et al found that 10% had normal ECG s. 13 Female gender: Women rarely develop athlete s heart. The presence of hypertrophy with a borderline cavity size in a female is likely to represent cardiomyopathy. Family history: A family history of hypertrophic cardiomyopathy favors that diagnosis. Genetic testing is helpful as well. Trial of deconditioning: Another helpful approach is to have the subject refrain from athletic activity for 3 months. In athlete's heart, the wall thickness should regress at least 2 mm., while it will not change in the case of hypertrophic cardiomyopathy. Fabry disease Fabry disease is very uncommon, occurring in about 1 in 50,000 males. A small percentage of patients diagnosed with hypertrophic cardiomyopathy have been found to have this condition. It is an x-linked deficiency of lysosomal α-galactosidase A. Classically, it involves the kidneys, brain, skin, heart, and eyes. Angiokeratoses develop, typically in the bathing trunk area. There may be anhidrosis. Corneal and lenticular opacities can occur. Infiltration of the myocardium with glycosphingolipids results in left ventricular hypertrophy. This is usually concentric and lacks outflow tract obstruction. The cardiac valves may also be infiltrated, as may the conduction system. The hypertrophy is often indistinguishable from true hypertrophic cardiomyopathy. When the onset of the disease occurs later in life, manifestations may be limited to the heart or kidneys. Female carriers may also present in this way. Measurement of the plasma α-galactosidase A is a method of screening, and appears to be effective in either sex. Family testing should follow, as there is effective treatment for this otherwise devastating disease. 7,8 Left ventricular noncompaction This condition is characterized by excessive trabeculation in the left ventricle. Patients are at risk for thromboembolism and sudden cardiac death. It may simulate hypertrophic cardiomyopathy on echocardiogram. The incidence is less than 1: LAMP2 cardiomyopathy 11 This is another infiltrative disease that mimics hypertrophic cardiomyopathy. It is sexlinked, affecting primarily young males. Symptoms may include chest pain or syncope. Atrial fibrillation may occur. Various electrocardiographic changes may occur, such as preexcitation, high voltage, or deep negative T waves. The echocardiogram shows diffuse, marked left ventricular hypertrophy. There can be septal hypertrophy as well as left ventricular outflow tract obstruction due to systolic anterior motion of the mitral valve. Genetic testing is required for diagnosis. It is highly lethal, death occurring from heart failure or ventricular fibrillation. The treatment is heart transplantation. 10

11 PRKAG2 mutation This is a glycogen storage disease that also mimics hypertrophic cardiomyopathy. It is associated with conduction defects and pre-excitation. Paroxysmal or sustained atrial fibrillation may occur. The disease may present in childhood. Amyloid heart disease Amyloid heart disease may resemble hypertrophic cardiomyopathy on echocardiogram, but is usually associated with a low-voltage electrocardiogram. The myocardium often exhibits a sparkling appearance on echocardiogram. Many other conditions can be confused with hypertrophic cardiomyopathy, such as Pompe disease and other storage diseases, Noonan syndrome and others. Often they are associated with stigmata, which should be a clue that one is not dealing with hypertrophic cardiomyopathy. 23 References 1. Nishimura RA and Holmes DR. Hypertrophic obstructive cardiomyopathy. N Engl J Med 2004;350: Friedewald VE et al. The Editor s Roundtable: Sudden cardiac death in athletes. Am J Card 2007;100: Maron et al. Task Force I: Preparticipation screening and diagnosis of cardiovascular disease in athletes. J Am Coll Cardiol 2005;45: Cannon RO. Assesing risk in hypertrophic cardiomyopathy. N Engl J Med 2003;349: Delling FN et al. Frequency and mechanism of persistent systolic anterior motion and mitral regurgitation after septal ablation in obstructive hypertrophic cardiomyopathy. Am J Card 2007;100: Maron et al. American College of Cardiology/European Society of Cardiology Clinical Expert Consensus Document on Hypertrophic Cardiomyopathy. J Am Coll Cardiol 2003;42: Monserrat L et al. Prevalence of Fabry disease in a cohort of 508 unrelated patients with hypertrophic cardiomyopathy. JACC 2007;50: Ackerman MJ and Landstrom AP. Detection of subclinical Fabry disease in patients with hypertrophic cardiomyopathy. JACC 2007;50: Pelliccia A et al. Outcomes in athletes with marked ECG repolarization abnormalities. N Engl J Med 2008; 358: McLeod CJ et al. Outcome of patients with hypertrophic cardiomyopathy and a normal electrocardiogram. J am Coll Cardiol 2009;54: Maron BJ et al. Clinical outcome and phenotypic expression in LAMP2 cardiomyopathy. JAMA 2009;301: Marian AJ. Contemporary treatment of hypertrophic cardiomyopathy. Texas Heart Institute Journal 2010; 36: Rowin EJ et al. Significance of false negative electrocardiograms in participation screening of athletes for hypertrophic cardiomyopathy. Am J Cardiol 2012; 110:

12 14. Nistri S et al. Beta blockers for prevention of exercise-induced left ventricular outflow tract obstruction in patients with hypertrophic cardiomyopathy. Am J Cardiol 2012; 110: Maron MS. Clinical utility of cardiovascular magnetic resonance in hypertrophic cardiomyopathy. Journal of Cardiovascular Magnetic Resonance 2012; 14: Alyson K-H et al. Overlapping phenotypes: left ventricular noncompaction and hypertrophic cardiomyopathy. Circulation 2009; 119:e Spirito P et al. Risk of sudden death and outcome in patients with hypertrophic cardiomyopathy with benign presentation and without risk factors. Am J Card 2014; 113: Elliot PM et al ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy. Eur Heart J 2014; 35: Chan RH et al. Prognostic value of quantitative contrast-enhanced cardiovascular magnetic resonance for the evaluation of sudden death risk in patients with hypertrophic cardiomyopathy. Circulation 2014; 130: Desai MYet al. Exercise echocardiography in asymptomatic HCM. J Am Coll Cardiol Cardiovascular Imaging 2014; 7: Maron BJ. Recognition of hypertrophic cardiomyopathy as a contemporary, relatively common, and treatable disease. Am J Cardiol 2014; 113: Elliott PM et al Guidelines on diagnosis and management of hypertrophic cardiomyopathy. Eur Heart J 2014;do1: /eurheart/eu Gersh BJ et al.2011 ACCF/AHA Guideline for the diagnosis and treatment of hypertrophic cardiomyopathy. J Am Coll Cardiol 2011; 58:e Maron BJ. The 50-year history, controversy, and clinical implications of left ventricular outflow tract obstruction in hypertrophic cardiomyopathy. J Am Coll Cardiol 2009; 54: Maron BJ et al. Eligibility and disqualification recommendations for athletes with cardiovascular abnormalities. J Am Coll Cardiol 2015; 66: Maron BJ et al. Prevention of sudden cardiac death implantable cardioverter-defibrillators in children and adolescents with hypertrophic cardiomyopathy. J Am Coll Cardiol 2013; 61: Maron BJ et al. Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities. J Am Coll Cardiol 2015; 66: Manrai AK et al. Genetic Misdiagnoses and the Potential for Health Disparities. N Engl J Med 2016; 375: Nishimura RA et al. Hypertrophic obstructive cardiomyopathy. Circ Res 2017; 121: Marian AJ and Braunwald E. Hypertrophic cardiomyopathy. Circ Res 2017; 121: Al-Khatib SM et al AHA/ACC/HRS guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death; executive summary. J Am Coll Cardiol 2017; doi: /j.jacc Sims JR et al. Clinical, radiographic and microbiologic features of infective endocarditis in patients with hypertrophic cardiomyopathy. Am J Card 2018; 121: