Myocardial Disease

Hypertrophic Cardiomyopathy

Clinical Presentation

Hypertrophic cardiomyopathy (HCM) is a common autosomal dominant heritable disorder related to mutations in the genes that predominantly encode sarcomeric proteins. It is characterized by the presence of increased left ventricular (LV) wall thickness in the absence of loading conditions or other underlying causes. HCM affects approximately 1 in 500 persons. Most patients with HCM remain asymptomatic and have normal life expectancy; however, certain subsets of patients are more likely to develop symptomatic disease and are at risk for sudden cardiac death (SCD).

The diagnosis of HCM often results from the evaluation of a heart murmur or abnormal electrocardiogram. Symptomatic individuals usually present with signs and symptoms of heart failure or arrhythmias. HCM may be identified within all age groups. In the United States, most index cases present within the third to fourth decade of life.

Symptoms of heart failure may be associated with abnormal LV filling (diastolic dysfunction) or dynamic left ventricular outflow tract (LVOT) obstruction. Diastolic dysfunction is multifactorial, involving increased chamber stiffness related to hypertrophy, progressive fibrosis, and myocardial ischemia due to mismatch of coronary flow and LV mass. Dynamic LVOT obstruction, characterized by asymmetric LV hypertrophy with prominent interventricular septal thickening, is the most classic form of HCM. During ventricular systole, anterior motion of the mitral valve results in early to midsystolic obstruction of the LVOT and subsequent mitral regurgitation related to leaflet malcoaptation (“eject-obstruct-leak” triad). Patients with dynamic obstruction may develop dyspnea, presyncope, or syncope during periods of increased ventricular contractility (exercise) or with decreases in ventricular preload or afterload, all of which may worsen the degree of obstruction.

Arrhythmias may manifest as palpitations, syncope, atrial fibrillation, or SCD. Atrial fibrillation is common in patients with HCM, and risk increases with age. During atrial fibrillation with rapid ventricular response, diastolic filling periods shorten, worsening diastolic dysfunction; reduced LV filling may exacerbate the LVOT gradient. In some cases, SCD may be the initial presentation of HCM.

Evaluation

Physical examination may be normal in patients without LVOT obstruction. The most common finding related to LVOT obstruction is a cardiac murmur, and dynamic maneuvers during examination are helpful in differentiating HCM from fixed valvular obstruction (Table 26).

Twelve-lead electrocardiography (ECG) is useful in the evaluation of HCM and reveals abnormal findings in 75% to 95% of affected persons. The most common ECG abnormalities include increased QRS voltage, evidence of left atrial enlargement, LV conduction abnormalities, pathologic Q waves, and significant repolarization abnormalities (Figure 26); however, there is substantial interpersonal variability in the degree of abnormalities.

The clinical diagnosis of HCM is most commonly established by transthoracic echocardiography (TTE). Echocardiography demonstrates the magnitude and distribution of hypertrophy, reveals the presence and degree of dynamic LVOT obstruction and mitral regurgitation, and characterizes diastolic LV filling. Doppler echocardiography is the modality of choice for quantifying the LVOT gradient in patients suspected of having HCM. For patients with inconclusive findings on echocardiography, cardiac magnetic resonance (CMR) imaging is indicated to clarify the diagnosis (Figure 27). For patients with HCM and resting LVOT gradient less than 50 mm Hg, provocative maneuvers (Valsalva, squatting) are recommended to establish the diagnosis. If provocative maneuvers fail to elicit an outflow gradient in symptomatic patients, exercise echocardiography is recommended.

Upon initial diagnosis of HCM, 24to 48-hour ambulatory ECG monitoring should be performed to evaluate for arrhythmias. The presence of nonsustained ventricular tachycardia identifies patients at higher risk for SCD. Treadmill exercise stress testing is reasonable to determine functional status and to provide prognostic information as part of the initial evaluation.

Evaluation for CAD is important in patients with HCM who develop chest discomfort. In patients with a low clinical likelihood of CAD, coronary CT angiography or nuclear myocardial perfusion imaging stress testing is reasonable for risk stratification. In patients at intermediate to high risk for CAD with chest discomfort, coronary angiography is indicated.

HCM must be differentiated from other conditions that may present with increased ventricular wall thickness (Table 27). Particularly challenging is the differentiation of HCM from hypertensive heart disease and from the normal and compensatory changes in LV wall thickness seen in competitive athletes. In patients with hypertension, the likelihood of concomitant HCM is increased if LV wall thickness is greater than 25 mm or if dynamic LVOT obstruction is present. In athletes, LV cavity dilatation and normal diastolic filling favor normal physiologic changes, whereas unusual or asymmetric patterns of hypertrophy on echocardiography favor HCM. A brief period of deconditioning demonstrating a decrease in wall thickness favors the athletic heart. When the diagnosis remains unclear, CMR imaging with gadolinium contrast may help with differentiation.

Risk Stratification

Patients with HCM have an annual incidence of cardiovascular death of 1% to 2%, predominantly related to fatal arrhythmia and heart failure. Most arrhythmic deaths are caused by ventricular fibrillation, and all patients with HCM, regardless of the presence of obstruction, should undergo risk assessment for SCD risk factors at the time of diagnosis and every 1 to 2 years. Prevention with the use of an implantable cardioverter-defibrillator (ICD) is effective in appropriately selected high-risk patients. In patients with one or more established risk factors (Table 28), primary prevention with an ICD is reasonable. For patients with HCM who are not otherwise identified as high risk for SCD, or in whom a decision to proceed with ICD placement remains uncertain, CMR imaging is beneficial to assess for maximum LV wall thickness, ejection fraction, LV apical aneurysm, and extent of myocardial fibrosis with late gadolinium enhancement (LGE). LGE is associated with increased risk for ventricular arrhythmias. In patients with indeterminate risk for SCD, LGE quantification can serve as an aid in decision making regarding ICD placement. Patients who have experienced SCD or sustained ventricular tachycardia have an annual recurrent event rate of 10% and should receive an ICD for secondary prevention.

Management

In patients with HCM who have overweight or obesity, therapeutic lifestyle interventions are recommended to possibly lower the risk for developing LVOT obstruction, heart failure, and atrial fibrillation. Patients with symptoms of sleep-disordered breathing should be formally evaluated, including with a sleep study.

In patients with obstructive symptoms, such as dyspnea or syncope/near-syncope, lifestyle modification and medical therapy form the basis of management. Patients should be advised to avoid dehydration, excessive alcohol intake, and situational exposures that may result in vasodilation and decreased preload (for example, saunas, hot tubs) because these may provoke greater LVOT obstruction. For most patients with HCM, mildto moderate-intensity recreational exercise is beneficial if done for the purpose of leisure (with or without systematic training) and without the purpose to excel or compete against others. Medical therapy should be initiated with nonvasodilating β-blockers titrated to maximum tolerance; carvedilol, labetalol, and nebivolol should be avoided. Verapamil or diltiazem may be used in patients in whom β-blockers are not tolerated or are contraindicated. For patients with persistent symptoms, adding disopyramide, a class IA antiarrhythmic drug with potent negative inotropic activity, to one of the other drugs is a recommended option. Diuretics must be used cautiously and only if symptoms of dyspnea cannot be managed with other therapy. Because of their propensity to exacerbate LVOT obstruction, nitrates and phosphodiesterase type 5 inhibitors should not be used concomitantly.

Invasive treatment of obstruction with open surgical septal myectomy or catheter-based alcohol septal ablation should be considered in patients who have moderate to severe symptoms of obstruction despite maximal medical therapy with a residual resting or provocable LVOT gradient of 50 mm Hg or greater, or in patients with recurrent syncope not related to arrhythmia. Although both surgical myectomy and alcohol septal ablation reduce the LVOT gradient and symptoms related to LVOT obstruction, appropriate patient selection for each procedure is controversial. Surgical myectomy is associated with a higher likelihood of complete symptom relief and lower rate for repeat procedures, and it may be associated with decreased risk for significant ventricular arrhythmias. Alcohol septal ablation carries a significant risk for atrioventricular block requiring pacemaker implantation, which is higher in older patients. Decisions regarding therapy must be individualized. Septal myectomy is favored in young patients, whereas alcohol septal ablation may be more appropriate for older patients with several comorbid conditions who have increased surgical risk. Outcomes with either procedure are best when the procedure is performed in a center with significant experience in the management of HCM. Surgical myectomy is associated with low operative mortality (0.4%) in such centers.

Atrial fibrillation should be managed with rate control and anticoagulation, irrespective of the patient's CHA2DS2-VASc score. Direct oral anticoagulants are preferred to warfarin. Low-molecular-weight heparin or warfarin (maximum dose <5 mg/d) is recommended for pregnant women with HCM and atrial fibrillation. Anticoagulation is also recommended in patients with subclinical atrial fibrillation of more than 24 hours' duration detected by ambulatory monitoring. Patients with HCM and atrial fibrillation often remain symptomatic despite rate control, and rhythm control in conjunction with anticoagulation should be considered early (see Arrhythmias). Digoxin should be avoided in patients with atrial fibrillation because the positive inotropic effects may worsen the LVOT gradient.

A small percentage of patients (<5%) will progress to end-stage HCM, manifesting as dilated cardiomyopathy with systolic dysfunction. These patients would appropriately be treated as would those with systolic heart failure (see Heart Failure).

Surveillance

ECG should be performed every 1 to 2 years in asymptomatic patients with HCM to screen for changes in rhythm or conduction. Patients should also undergo 24to 48-hour ambulatory ECG monitoring at diagnosis and every 1 to 2 years thereafter in asymptomatic patients and with the development of symptoms that suggest arrhythmia, such as palpitations or syncope.

Repeat TTE is recommended with any change in clinical status or new cardiac event. In asymptomatic patients, TTE is recommended every 1 to 2 years to assess for mitral regurgitation and changes in LV hypertrophy, function, and degree of obstruction. Although most patients with HCM demonstrate normal LV function, a decrease in LV systolic function is associated with worse outcomes, including death.

Role of Genetic Testing and Counseling

Patients known or suspected to have HCM should undergo an evaluation of familial inheritance with a three-generation family history and receive genetic counseling. Genetic testing is recommended in patients who meet the clinical definition of HCM to aid screening of family members. First-degree relatives of patients with HCM should undergo evaluation with ECG and echocardiography and be offered genetic testing if a sarcomeric mutation is identified in the proband. A known sarcomeric mutation may be identified in up to 60% of patients with a family history of HCM; the incidence is lower (20%–30%) in isolated cases. The absence of an identified sarcomeric mutation in the index case does not exclude the diagnosis of HCM. Genetic testing may disclose genotype-positive persons who do not express clinical features of HCM (phenotype-negative), and these persons should be followed with clinical examination and serial echocardiography (Table 29). In the absence of a pathogenic mutation in the index case, ongoing clinical screening of first-degree family members is not indicated. The use of genetic testing in the assessment of SCD risk and need for ICD placement is uncertain.

Restrictive Cardiomyopathy

Clinical Presentation and Evaluation

Restrictive cardiomyopathy (RCM) is a rare disorder characterized by abnormally stiff, noncompliant ventricles. RCM was once considered idiopathic; however, increasing evidence suggests that gene mutations in sarcomeric proteins and abnormalities in desmin, an intermediate filament that regulates sarcomere architecture, play an important role in familial and sporadic cases. The sarcomeric protein gene mutations of RCM are similar to or the same as those linked to HCM, raising the possibility that these disorders represent different phenotypic expressions of the same heritable defect.

RCM is characterized histologically by patchy interstitial fibrosis and myocyte disarray, which are also seen in HCM. With increasing interstitial fibrosis, the ventricles stiffen, resulting in increased pressure during normal diastolic filling. Patients may present at any age, usually with symptoms of dyspnea, peripheral edema, and exercise intolerance. Hepatomegaly and ascites may also be present late in the disease course.

The diagnosis of RCM should be suspected in patients when echocardiography demonstrates biatrial enlargement and severe diastolic dysfunction in the setting of normal ventricular size, wall thickness, and systolic function. There is usually evidence of significant pulmonary hypertension, and tricuspid and mitral valve regurgitation are commonly present. Patients with these findings should be referred to a cardiologist for further evaluation.

Primary RCM must be differentiated from other conditions that may present with restrictive physiology. These include fibrosis related to radiation and eosinophilic diseases as well as hemochromatosis, in which wall thickness is typically normal. A complete blood count with manual differential and transferrin saturation are reasonable as part of the evaluation. Infiltrative diseases with increased wall thickness may share restrictive physiology but are considered separate entities. When low ECG voltage accompanies increased wall thickness on echocardiogram, amyloidosis should be considered. Serum protein electrophoresis/urine protein electrophoresis and free light-chain analysis may help identify immunoglobulin light-chain amyloidosis, and technetium-99m cardiac imaging may help identify transthyretin amyloidosis. CMR imaging with gadolinium contrast may help identify and differentiate RCM from other myocardial diseases with restrictive physiology. When the diagnosis remains unclear, endomyocardial biopsy is reasonable to establish a diagnosis.

Differentiating Restrictive Cardiomyopathy from Constrictive Pericarditis

Patients with constrictive pericarditis and RCM present with similar symptoms and findings on echocardiography. Differentiating between these two disorders is essential because specific therapies, including surgical pericardiectomy, may relieve symptoms and prolong life in patients with constriction. In patients with previous cardiac surgery, pericarditis, or chest irradiation, constrictive pericarditis should be strongly considered.

On physical examination, patients with constriction and patients with RCM both demonstrate increased jugular venous pressure. Increase in the height of the jugular waveform during inspiration (Kussmaul sign) has been associated more commonly with constriction. Both RCM and constrictive pericarditis may be associated with a diastolic sound. An S3 gallop is often present in RCM, whereas a pericardial knock can be heard in constrictive pericarditis. Differentiating between these sounds may be very difficult (see Pericardial Disease).

A multimodality approach, including both noninvasive imaging and invasive hemodynamic evaluation, may be required to distinguish RCM from constrictive pericarditis. Clues to the presence of constrictive pericarditis include pericardial calcification on chest radiography or CT, pericardial thickening on CT or CMR imaging, or a B-type natriuretic peptide level below 100 pg/mL (100 ng/L) (usually ≥400 pg/mL [400 ng/L] in patients with RCM). A hallmark feature of constrictive pericarditis is ventricular interdependence, in which total cardiac volume is limited by the rigid pericardium. With ventricular interdependence, increased filling of the right or left ventricle can occur only with reciprocal decreased filling of the other ventricle. Ventricular interdependence may be demonstrated by Doppler echocardiography, CMR imaging, or invasive hemodynamic evaluation; it is not present in patients with RCM.

Management

There is no specific medical therapy for RCM. Loop diuretics are usually necessary for relief of congestive symptoms, especially in late-stage disease. However, patients with RCM require relatively high filling pressures to maintain cardiac output, and balancing relief of congestion with adequate cardiac output is often challenging. Even small changes in volume may lead to hypoperfusion of the kidneys; therefore, volume status should be monitored carefully.

Atrial fibrillation is a common complication due to left atrial dilatation and elevated pressure. It is poorly tolerated in patients with RCM because of increased heart rate and reduced ventricular filling. Anticoagulation and rate control are indicated, and rhythm control should be considered early in symptomatic patients. Digoxin should be used with caution because it indirectly increases intracellular calcium, which may affect diastolic relaxation.

Survival is poor in patients with RCM, with a 5-year mortality rate of 36% and a 10-year mortality rate of 63%. Cardiovascular mortality is predominantly related to progressive heart failure and arrhythmias. Cardiac transplantation may be considered in selected individuals who remain symptomatic despite maximal therapy. There is no accepted indication for ICD placement for primary prevention in patients with RCM who have preserved systolic function.

Cardiac Tumors

Most cardiac tumors are metastatic. Neoplasms with the highest metastatic potential are melanoma, malignant thymoma, and germ cell tumors. Common tumors with an intermediate risk for cardiac involvement include carcinoma of the lung, stomach, and colon. Therapy is directed at systemic treatment of the underlying neoplasm, with cardiac surgery reserved for patients with obstructive symptoms.

Primary cardiac tumors, which are exceedingly rare, are benign in two thirds of patients. Of the benign tumors, nearly 50% are atrial myxomas. Myxomas may occur in either atria but are most commonly attached to the fossa ovalis within the left atrium (Figure 28). Myxomas are usually solitary and discovered at a mean age of 50 years, often after a systemic embolic event. When tumors are multiple, recurrent, or discovered at a young age, they may indicate the Carney complex, which includes the LAMB (lentigines, atrial myxoma, blue nevi) syndrome and the NAME (nevi, atrial myxoma, myxoid neurofibromas, and ephelides) syndrome. The Carney complex is associated with mutations of the PRKAR1A gene, which may function as a tumor suppressor gene. Patients with a myxoma may present with constitutional symptoms related to interleukin production, embolic phenomena from tumor fragmentation, or symptoms referable to intracardiac obstruction (dyspnea, syncope). When mitral valvular obstruction is present, auscultatory findings are similar to those of mitral stenosis; however, findings may vary with position or be associated with an early diastolic sound, known as the tumor plop. Surgical removal is indicated to prevent embolic events, as is subsequent surveillance echocardiography for detection of recurrence.

Papillary fibroelastomas usually occur on the surface of the aortic and mitral valves and are commonly discovered in the eighth decade of life. Although most papillary fibroelastomas do not cause symptoms, they may be associated with stroke, transient ischemic attack, and, rarely, coronary embolization with infarction. On echocardiography, these tumors often have a heterogeneous globular shape or a mobile frond-like appearance. Patients with embolic symptoms are treated surgically. There are currently no randomized data comparing surgical therapy with antithrombotic or antiplatelet therapy to prevent embolic events.

Angiosarcomas are the most common primary malignant tumor. Angiosarcomas typically arise in the right atrium and are often associated with pericardial effusion (Figure 29). Dyspnea and chest pain are common presenting symptoms. Angiosarcomas are highly vascular tumors, and CT or CMR imaging with contrast may help differentiate an angiosarcoma from a right atrial myxoma. When complete surgical extirpation is possible, survival remains less than 2 years for most patients. With incomplete resection, survival is generally less than 10 months.