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Myocardial Disease VI lt aVL w 1 lil aVF V3 tIGURE 37. ECGinapatientwithapical hypertrophiccardiomyopathy. lncreasedORSvoltageandmarkedrepolarizationabnormalities,especiallyinleadsV2throughV5, are present. symptomatic patients, exercise echocardiography is recom- hypertensive heart disease and from the normal and compensa mended. ln patients with inconclusive echocardiographic tory changes in LV wall thickness seen in competitive athletes findings, cardiac magnetic resonance (CMR) imaging is indi- (athlete heart). In patients with hypertension, the likelihood of cated to clarify the diagnosis. concomitant HCM is increased if LV wall thickness is greater than Upon initial diagnosis of HCM, 24 to 48 hour ambula 18 mm and nonconcentric and dynamic LVOT obstruction is tory ECG monitoring should be performed to evaluate for present. In athletes, LV cavity dilatation and normal diastolic fill arrhy.thmias. The presence of nonsustained ventricular tachy ing on echocardiography favor normal physiologic changes, cardia indicates higher risk for SCD. Exercise stress testing is whereas unusual or asymmetric pattems of hypertrophy favor j

symptomatic patients, exercise echocardiography is recom- hypertensive heart disease and from the normal and compensa mended. ln patients with inconclusive echocardiographic tory changes in LV wall thickness seen in competitive athletes findings, cardiac magnetic resonance (CMR) imaging is indi- (athlete heart). In patients with hypertension, the likelihood of cated to clarify the diagnosis. concomitant HCM is increased if LV wall thickness is greater than Upon initial diagnosis of HCM, 24 to 48 hour ambula 18 mm and nonconcentric and dynamic LVOT obstruction is tory ECG monitoring should be performed to evaluate for present. In athletes, LV cavity dilatation and normal diastolic fill arrhy.thmias. The presence of nonsustained ventricular tachy ing on echocardiography favor normal physiologic changes, cardia indicates higher risk for SCD. Exercise stress testing is whereas unusual or asymmetric pattems of hypertrophy favor j reasonable to determine lunctional status and to provide prog HCM. A decrease in wall thickness after a brielperiod of decon- nostic information as part of the initial evaluation. ditioning favors athlete heart. When the diagnosis remains HCM must be differentiated flrom other conditions associ unclear, CMR imaging with gadolinium contrast may help with ated with increased ventricular wall thickness (Table 28). differentiation. Particularly challenging is the diflerentiation of HCM from Risk Stratification TABLE 28. Conditions With lncreased Left Ventricular Patients with HCM have an annual risk for death of 1',{,, pri- WallThickness marily related to fatal arrhythmia and heart failure. Most Condition Clinical Features arrhythmic deaths are caused by ventricular fibrillation, and Hypertension Elevated blood pressure all patients with HCM, regardless of the presence of obstruc tion, should undergo assessment for SCD risk factors at the Athlete heart No hypertension; normal or supranormal exercise capacity time of diagnosis and every I to 2 years. Major risk factors for Amyloidosis SCD are listed in Table 29. Heartfailure, low voltage on ECG, possible neuropathy and/or nephropathy; usually An implantable cardioverter defibrillator (lCD) is effec older patients tive in preventing SCD in appropriately selected high risk Fabry disease Male predominance (X-linked), neuropathic patients. Patients with previous SCD or sustained ventricular pain, kidney dysfunction, telangiectasias, tachycardia have an annual recurrence rate of l0'1, and should angiokeratomas; typically young patients receive an ICD for secondary prevention. In patients with one Friedreich ataxia Ataxia, scoliosis, pes cavus, visual and or more established risk factors, primary prevention with hearing impairment an ICD is reasonable. For patients with HCM who are not

reasonable to determine lunctional status and to provide prog HCM. A decrease in wall thickness after a brielperiod of decon- nostic information as part of the initial evaluation. ditioning favors athlete heart. When the diagnosis remains HCM must be differentiated flrom other conditions associ unclear, CMR imaging with gadolinium contrast may help with ated with increased ventricular wall thickness (Table 28). differentiation. Particularly challenging is the diflerentiation of HCM from Risk Stratification TABLE 28. Conditions With lncreased Left Ventricular Patients with HCM have an annual risk for death of 1',{,, pri- WallThickness marily related to fatal arrhythmia and heart failure. Most Condition Clinical Features arrhythmic deaths are caused by ventricular fibrillation, and Hypertension Elevated blood pressure all patients with HCM, regardless of the presence of obstruc tion, should undergo assessment for SCD risk factors at the Athlete heart No hypertension; normal or supranormal exercise capacity time of diagnosis and every I to 2 years. Major risk factors for Amyloidosis SCD are listed in Table 29. Heartfailure, low voltage on ECG, possible neuropathy and/or nephropathy; usually An implantable cardioverter defibrillator (lCD) is effec older patients tive in preventing SCD in appropriately selected high risk Fabry disease Male predominance (X-linked), neuropathic patients. Patients with previous SCD or sustained ventricular pain, kidney dysfunction, telangiectasias, tachycardia have an annual recurrence rate of l0'1, and should angiokeratomas; typically young patients receive an ICD for secondary prevention. In patients with one Friedreich ataxia Ataxia, scoliosis, pes cavus, visual and or more established risk factors, primary prevention with hearing impairment an ICD is reasonable. For patients with HCM who are not 7A

Myocardial Disease with peak gradient of 59 mm Hg. LA = left atrium; LV = left ventricle. otherwise identified as high risk for SCD or in whom a myocardial fibrosis with late gadolinium enhancement (LGE). decision to proceed with ICD placement remains uncefiain, LGE is associated with increased risk for ventricular arrhlth CMR imaging is beneficial to assess for maximum LV wall mias; in patients with indeterminate risk for SCD, LGE quan thickness, ejection fraction, LV apical aneurysm, and extent of tification of 15'7, or more can serve as a risk modifier in decision making regarding ICD placement.

otherwise identified as high risk for SCD or in whom a myocardial fibrosis with late gadolinium enhancement (LGE). decision to proceed with ICD placement remains uncefiain, LGE is associated with increased risk for ventricular arrhlth CMR imaging is beneficial to assess for maximum LV wall mias; in patients with indeterminate risk for SCD, LGE quan thickness, ejection fraction, LV apical aneurysm, and extent of tification of 15'7, or more can serve as a risk modifier in decision making regarding ICD placement. TABLU 29" Major Risk Factors for Sudden Cardiac Death in Patients With HCM" Management Management of HCM includes lifestyle modification; treat Sudden death in a first-degree relative or close relative age (50 y ment of symptoms referable to LVOT obstruction, heart failure, and atrial fibrillation; and potentially ICD therapy. LV wall thickness >30 mm In patients with HCM who have overweight or obesity, >1 Episode of syncope thought to be arrhythmic in nature therapeutic lifesSzle interventions should be implemented to LV apical aneurysm achieve weight loss and potentially decrease the risk for LVOT LVEF <50% obstruction, heart failure, and atrial fibrillation. Patients with HCM = hypertrophic cardiomyopathy; LV = left ventricular; LVEF = left ventricular symptoms of sleep disordered breathing should be formally ejection fraction. evaluated, including with a sleep study. "For adults with one or more malor risk factors, it is reasonable to offer an Patients with HCM should be advised to avoid dehydra implantable cardioverteLdefibrillator (ciass 2a recommendation). tion, excessive alcohol intake, and exposures that may cause lnformation from Ommen SR, N,4ital S, Burke MA, et al; Writing Committee Members. 2020 AHA/ACC guideline {or the diagnosis and treatment of patients vasodilation and decreased preload (e.g., saunas, hot tubs) with hypertrophic cardiomyopathy: a report of the American College of because these situations may provoke greater LVOT obstruc Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulatioo.2020:1 42:e558-e63 1 . IPMID: 332 1 593 1 ] doi:1 0.1 1 61 / tion. Mild- to moderate intensity recreational exercise is ben crR 0000000000000937 eficial for most patients with HCM. Athletes with HCM should

TABLU 29" Major Risk Factors for Sudden Cardiac Death in Patients With HCM" Management Management of HCM includes lifestyle modification; treat Sudden death in a first-degree relative or close relative age (50 y ment of symptoms referable to LVOT obstruction, heart failure, and atrial fibrillation; and potentially ICD therapy. LV wall thickness >30 mm In patients with HCM who have overweight or obesity, >1 Episode of syncope thought to be arrhythmic in nature therapeutic lifesSzle interventions should be implemented to LV apical aneurysm achieve weight loss and potentially decrease the risk for LVOT LVEF <50% obstruction, heart failure, and atrial fibrillation. Patients with HCM = hypertrophic cardiomyopathy; LV = left ventricular; LVEF = left ventricular symptoms of sleep disordered breathing should be formally ejection fraction. evaluated, including with a sleep study. "For adults with one or more malor risk factors, it is reasonable to offer an Patients with HCM should be advised to avoid dehydra implantable cardioverteLdefibrillator (ciass 2a recommendation). tion, excessive alcohol intake, and exposures that may cause lnformation from Ommen SR, N,4ital S, Burke MA, et al; Writing Committee Members. 2020 AHA/ACC guideline {or the diagnosis and treatment of patients vasodilation and decreased preload (e.g., saunas, hot tubs) with hypertrophic cardiomyopathy: a report of the American College of because these situations may provoke greater LVOT obstruc Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulatioo.2020:1 42:e558-e63 1 . IPMID: 332 1 593 1 ] doi:1 0.1 1 61 / tion. Mild- to moderate intensity recreational exercise is ben crR 0000000000000937 eficial for most patients with HCM. Athletes with HCM should 79

Myocardial Disease undergo a comprehensive evaluation and be engaged in shared Surveillance discussion of potential risks of sports participation. An ECG should be obtained every 1 to 2 years in asymptomatic In symptomatic patients, nonvasodilating p blockers patients with HCM to screen for changes in rhythm or conduc should be initiated. with titration to effectiveness or maxi tion. Patients should also undergo 24 lo 48 hour ambulatory mum tolerance. Carvedilol, labetalol, and nebivolol should be ECG monitoring at diagnosis and every I to 2 years thereafter avoided. Alternatively, verapamil or diltiazem may be used in if asymptomatic or with the development of symptoms that patients in whom p blockers are contraindicated or not toler suggest arrhyhmia, such as palpitations or syncope. ated. For patients with LVOT obstruction and persistent symp Repeat TTE is recommended with any change in clinical toms, adding disopyramide. a class IA antiarrhyhmic drug status or new cardiac event. In asymptomatic patients. TTE is with potent negative inotropic activity, to one of the other recommended every 1 to 2 years to assess for mitral regurgita drugs is a recommended option. Diuretics must be used cau tion and changes in LV hypertrophy. function, and degree of tiously and only if symptoms of dyspnea cannot be managed obstruction. Although most patients with HCM have normal with other therapy. Because oftheir propensity to exacerbate LV function, a decrease in LV systolic function is associated LVOT obstruction, nitrates and phosphodiesterase 5 inhibitors with worse outcomes, including death. should not be used concomitantly. Invasive treatment of obstruction with surgical septal Role of Genetic Testing and Counseling myectomy or catheter based alcohol septal ablation is recom Patients known or suspected to have HCM should undergo an mended in patients with severe obstructive symptoms refrac evaluation ol familial inheritance with a three-generation tory to maximal medical therapy and a resting or provoked family history and receive genetic counseling. Genetic testing LVOT gradient of 50 mm Hg or greater. Although both surgical is recommended in patients who meet the clinical definition myectomy and alcohol septal ablation reduce the LVOT gradi of HCM to aid screening of family members, but results must ent and obstructive symptoms, appropriate patient selection be interpreted carefully. A pathogenic sarcomeric mutation for each procedure is controversial. Surgical myectomy is asso may be identified in up to 60%, of patients with a family his ciated with a higher likelihood of complete symptom resolu tory of HCM; the incidence is lower (2o'X, 3O'X') in isolated tion, greater obstruction reliel and a lower rate of repeat cases. procedures. Alcohol septal ablation carries a higher risk for First degree relatives of patients with HCM should atrioventricular block requiring pacemaker implantation; this undergo screening with ECG and echocardiography. ln first risk is higher in older patients. Decisions regarding therapy degree relatives, ECG and cardiac imaging should be per must be individualized. Septal myectomy is favored in young formed every 1 to 2 years in children and adolescents and every patients and in patients with associated cardiac disease requir 3 to 5 years in adults or with a change in clinical status. ing surgical treatment, whereas alcohol septal ablation may be Alternatively, genetic testing should be offered to first degree more appropriate for patients with comorbid conditions and family members if a causative sarcomeric mutation is identi increased surgical risk. Outcomes with either procedure are fied in the index case. Genetic testing may identi$r genotype best when the procedure is performed in a center with exper positive persons who do not express phenotypic features of tise in HCM management. Surgical myectomy is associated HCM, and these persons should be followed with clinical with low operative mortality (O.a'2,) in such centers. examinations at the same intervals described. The absence of Atrial fibrillation should be managed with rate control and an identified sarcomeric mutation does not exclude HCM in anticoagulation, regardless of the patient's CHATDS, VASc score. the index patient, and first degree relatives should continue Direct oral anticoagulants are considered first line anticoagulant clinical screening. Genorype negative relatives in families therapy, with warfarin as a second line option. Low molecular with genotlpe positive HCM do not require ongoing clinical weight heparin or warfarin (maximum dose <5 mg/day) is rec screening. The use of genetic testing in the assessment of SCD ommended for pregnant women with HCM and atrial fibrillation. risk and need for ICD placement is uncertain. Anticoagulation is also recommended in patients with an epi- TEY POIXT' sode of subclinical atrial fibrillation of more than 24 hours'dura tion detected by ambulatory monitoring. Patients with HCM and . Doppler echocardiography, at rest and with provoca- concomitant atrial fibrillation often remain symptomatic despite tion, is the modality of choice for quantification of the rate control, and rhl.thm control in conjunction with anticoagu left ventricular outflow tract gradient in patients sus- pected of having obstructive hypertrophic cardiomyo lation should be considered early (see Arrhythmias). Digoxin should be avoided in patients with atrial fibrillation because the PathY. positive inotropic effects may worsen the LVOT gradient. o Patients with hlpertrophic cardiomyopathy who have Fewer than 5'1, of patients progress to end stage HCM, experienced sudden cardiac death or sustained ventricu manifesting as dilated cardiomyopathy with systolic dysfunc lar tachycardia or who have major risk factors should tion. For patients with HCM who develop systolic dysfunction receive an implantable cardioverter-defibrillator for (LVEF <50'7,), guideline-directed therapy is recommended (see preventionofsuddencardiacdeath. (Continued) Heart Failure).

undergo a comprehensive evaluation and be engaged in shared Surveillance discussion of potential risks of sports participation. An ECG should be obtained every 1 to 2 years in asymptomatic In symptomatic patients, nonvasodilating p blockers patients with HCM to screen for changes in rhythm or conduc should be initiated. with titration to effectiveness or maxi tion. Patients should also undergo 24 lo 48 hour ambulatory mum tolerance. Carvedilol, labetalol, and nebivolol should be ECG monitoring at diagnosis and every I to 2 years thereafter avoided. Alternatively, verapamil or diltiazem may be used in if asymptomatic or with the development of symptoms that patients in whom p blockers are contraindicated or not toler suggest arrhyhmia, such as palpitations or syncope. ated. For patients with LVOT obstruction and persistent symp Repeat TTE is recommended with any change in clinical toms, adding disopyramide. a class IA antiarrhyhmic drug status or new cardiac event. In asymptomatic patients. TTE is with potent negative inotropic activity, to one of the other recommended every 1 to 2 years to assess for mitral regurgita drugs is a recommended option. Diuretics must be used cau tion and changes in LV hypertrophy. function, and degree of tiously and only if symptoms of dyspnea cannot be managed obstruction. Although most patients with HCM have normal with other therapy. Because oftheir propensity to exacerbate LV function, a decrease in LV systolic function is associated LVOT obstruction, nitrates and phosphodiesterase 5 inhibitors with worse outcomes, including death. should not be used concomitantly. Invasive treatment of obstruction with surgical septal Role of Genetic Testing and Counseling myectomy or catheter based alcohol septal ablation is recom Patients known or suspected to have HCM should undergo an mended in patients with severe obstructive symptoms refrac evaluation ol familial inheritance with a three-generation tory to maximal medical therapy and a resting or provoked family history and receive genetic counseling. Genetic testing LVOT gradient of 50 mm Hg or greater. Although both surgical is recommended in patients who meet the clinical definition myectomy and alcohol septal ablation reduce the LVOT gradi of HCM to aid screening of family members, but results must ent and obstructive symptoms, appropriate patient selection be interpreted carefully. A pathogenic sarcomeric mutation for each procedure is controversial. Surgical myectomy is asso may be identified in up to 60%, of patients with a family his ciated with a higher likelihood of complete symptom resolu tory of HCM; the incidence is lower (2o'X, 3O'X') in isolated tion, greater obstruction reliel and a lower rate of repeat cases. procedures. Alcohol septal ablation carries a higher risk for First degree relatives of patients with HCM should atrioventricular block requiring pacemaker implantation; this undergo screening with ECG and echocardiography. ln first risk is higher in older patients. Decisions regarding therapy degree relatives, ECG and cardiac imaging should be per must be individualized. Septal myectomy is favored in young formed every 1 to 2 years in children and adolescents and every patients and in patients with associated cardiac disease requir 3 to 5 years in adults or with a change in clinical status. ing surgical treatment, whereas alcohol septal ablation may be Alternatively, genetic testing should be offered to first degree more appropriate for patients with comorbid conditions and family members if a causative sarcomeric mutation is identi increased surgical risk. Outcomes with either procedure are fied in the index case. Genetic testing may identi$r genotype best when the procedure is performed in a center with exper positive persons who do not express phenotypic features of tise in HCM management. Surgical myectomy is associated HCM, and these persons should be followed with clinical with low operative mortality (O.a'2,) in such centers. examinations at the same intervals described. The absence of Atrial fibrillation should be managed with rate control and an identified sarcomeric mutation does not exclude HCM in anticoagulation, regardless of the patient's CHATDS, VASc score. the index patient, and first degree relatives should continue Direct oral anticoagulants are considered first line anticoagulant clinical screening. Genorype negative relatives in families therapy, with warfarin as a second line option. Low molecular with genotlpe positive HCM do not require ongoing clinical weight heparin or warfarin (maximum dose <5 mg/day) is rec screening. The use of genetic testing in the assessment of SCD ommended for pregnant women with HCM and atrial fibrillation. risk and need for ICD placement is uncertain. Anticoagulation is also recommended in patients with an epi- TEY POIXT' sode of subclinical atrial fibrillation of more than 24 hours'dura tion detected by ambulatory monitoring. Patients with HCM and . Doppler echocardiography, at rest and with provoca- concomitant atrial fibrillation often remain symptomatic despite tion, is the modality of choice for quantification of the rate control, and rhl.thm control in conjunction with anticoagu left ventricular outflow tract gradient in patients sus- pected of having obstructive hypertrophic cardiomyo lation should be considered early (see Arrhythmias). Digoxin should be avoided in patients with atrial fibrillation because the PathY. positive inotropic effects may worsen the LVOT gradient. o Patients with hlpertrophic cardiomyopathy who have Fewer than 5'1, of patients progress to end stage HCM, experienced sudden cardiac death or sustained ventricu manifesting as dilated cardiomyopathy with systolic dysfunc lar tachycardia or who have major risk factors should tion. For patients with HCM who develop systolic dysfunction receive an implantable cardioverter-defibrillator for (LVEF <50'7,), guideline-directed therapy is recommended (see preventionofsuddencardiacdeath. (Continued) Heart Failure). 80

Myocardial Disease l(EY P0lllIS kominued) . In patients with hypertrophic cardiomyopathy who have symptoms of left ventricular outflow tract obstruc tion, nonvasodilating B blockers are first line therapy. . Transthoracic echocardiography should be performed every 1to 2 years in asymptomatic patients with hyper- trophic cardiomyopathy to assess for mitral regurgitation and changes in left ventricular hypertrophy, function, and degree of obstruction. HVC o Genetic testing is not indicated in first-degree relatives of patients with hypertrophic cardiomyopathy unless a path ogenic genetic variant is identified in the index patient.

l(EY P0lllIS kominued) . In patients with hypertrophic cardiomyopathy who have symptoms of left ventricular outflow tract obstruc tion, nonvasodilating B blockers are first line therapy. . Transthoracic echocardiography should be performed every 1to 2 years in asymptomatic patients with hyper- trophic cardiomyopathy to assess for mitral regurgitation and changes in left ventricular hypertrophy, function, and degree of obstruction. HVC o Genetic testing is not indicated in first-degree relatives of patients with hypertrophic cardiomyopathy unless a path ogenic genetic variant is identified in the index patient. tIGURE 39. 99m-Technetium pyrophosphate scan in a patientwith hereditary Cardiac Amyloidosis transthyretin cardiac amyloidosis. Cardiac uptake of the radiotracer is denser than bone uptake at both t hour(toppanel) and 3 hours (bottom pahel\. Cardiac amyloidosis results from deposition of misfolded pro teins within the myocardium, leading to restrictive physiologr biopsy is diagnostic but unnecessary in the presence of extra- and heart failure symptoms. There are two major forms-light cardiac amyloidosis with abnormalities on CMR imaging. chain amyloid (AL) amyloidosis and transthyretin amyloid Treatment is directed toward the hematologic malignancy. (AITR) amyloidosis (Table 3O). Cardiac amyloidosis is sug Cardiac transplantation can be considered selectively. gested by increased wall thickness on echocardiogram accom Hereditary ATTR (h-ATTR) amyloidosis results from a panied by a low voltage ECG; however, these findings are not genetic mutation in the TTR gene, most commonly Val122lle, diagnostic. CMR imaging is highly sensitive and specific for which occurs in 3.4"/,, of Black persons Iiving in the United cardiac amyloidosis, but it does not distinguish betvveen types. States. Wild-type ATTR (wt ATTR) amyloidosis is an aging AL amyloidosis is a multiorgan disease associated with linked process that may be responsible for up to 10% to 15'2, of plasma cell dyscrasias. The diagnosis is based on the presence cases ofheart failure in the elderly. In addition to heart failure, of an amyloid-related systemic syndrome; amyloid deposits ATTR amyloidosis may cause sensory and autonomic neuropa on fat pad aspiration, bone marrow biopsy, or organ biopsy; thy and carpal tunnel syndrome. In the setting of abnormal abnormal serum immunoglobulin light chains; and monoclo- CMR imaging results, 99m technetium pyrophosphate scin nal gammopathy (see MKSAP 19 Hematologr). Endomyocardial tigraphy of the heart may be diagnostic (Figure 39). Tafamidis,

tIGURE 39. 99m-Technetium pyrophosphate scan in a patientwith hereditary Cardiac Amyloidosis transthyretin cardiac amyloidosis. Cardiac uptake of the radiotracer is denser than bone uptake at both t hour(toppanel) and 3 hours (bottom pahel\. Cardiac amyloidosis results from deposition of misfolded pro teins within the myocardium, leading to restrictive physiologr biopsy is diagnostic but unnecessary in the presence of extra- and heart failure symptoms. There are two major forms-light cardiac amyloidosis with abnormalities on CMR imaging. chain amyloid (AL) amyloidosis and transthyretin amyloid Treatment is directed toward the hematologic malignancy. (AITR) amyloidosis (Table 3O). Cardiac amyloidosis is sug Cardiac transplantation can be considered selectively. gested by increased wall thickness on echocardiogram accom Hereditary ATTR (h-ATTR) amyloidosis results from a panied by a low voltage ECG; however, these findings are not genetic mutation in the TTR gene, most commonly Val122lle, diagnostic. CMR imaging is highly sensitive and specific for which occurs in 3.4"/,, of Black persons Iiving in the United cardiac amyloidosis, but it does not distinguish betvveen types. States. Wild-type ATTR (wt ATTR) amyloidosis is an aging AL amyloidosis is a multiorgan disease associated with linked process that may be responsible for up to 10% to 15'2, of plasma cell dyscrasias. The diagnosis is based on the presence cases ofheart failure in the elderly. In addition to heart failure, of an amyloid-related systemic syndrome; amyloid deposits ATTR amyloidosis may cause sensory and autonomic neuropa on fat pad aspiration, bone marrow biopsy, or organ biopsy; thy and carpal tunnel syndrome. In the setting of abnormal abnormal serum immunoglobulin light chains; and monoclo- CMR imaging results, 99m technetium pyrophosphate scin nal gammopathy (see MKSAP 19 Hematologr). Endomyocardial tigraphy of the heart may be diagnostic (Figure 39). Tafamidis, TABLE 30. Subtypes of Cardiac Amyloidosis Subtype Demographics Clinical Manifestations Diagnostic Tests Therapy AL [Yl = F, age 40-80 y Nephrotic syndrome, Analysis for clonal plasma Treatment of plasma cell cardiomyopathy, cell dyscrasias with SPEP dyscrasias h e patosp le n om eg a ly, and UPEP neuropathy, carpal tunnel Cardiac transplantation in Serum and urine selected cases syndrome, bleeding immunofixation diathesis, periorbital purpura, macroglossia Serum FLC testing Bone marrow biopsy CMR imaging with LGE Endomyocardial biopsy or other tissue biopsy ATTR h-ATTR: M >> F, Cardiomyopathy, ca rpal CMR imaging with LGE Tafamidis t age 55-75 y tunnel syndrome, spinal Techneti u m pyrophosphate Diflunisal (off label) stenosis, neuropathy wt-ATTR: M >>> F scintigraphy Patisiran ( neuropathy) age 65-95 y Endomyocardial biopsy (controversial) lnotersen (neu ropathy) Liver or heart-liver Genetic testing transplantation

TABLE 30. Subtypes of Cardiac Amyloidosis Subtype Demographics Clinical Manifestations Diagnostic Tests Therapy AL [Yl = F, age 40-80 y Nephrotic syndrome, Analysis for clonal plasma Treatment of plasma cell cardiomyopathy, cell dyscrasias with SPEP dyscrasias h e patosp le n om eg a ly, and UPEP neuropathy, carpal tunnel Cardiac transplantation in Serum and urine selected cases syndrome, bleeding immunofixation diathesis, periorbital purpura, macroglossia Serum FLC testing Bone marrow biopsy CMR imaging with LGE Endomyocardial biopsy or other tissue biopsy ATTR h-ATTR: M >> F, Cardiomyopathy, ca rpal CMR imaging with LGE Tafamidis t age 55-75 y tunnel syndrome, spinal Techneti u m pyrophosphate Diflunisal (off label) stenosis, neuropathy wt-ATTR: M >>> F scintigraphy Patisiran ( neuropathy) age 65-95 y Endomyocardial biopsy (controversial) lnotersen (neu ropathy) Liver or heart-liver Genetic testing transplantation AL=amyloidlightchain;ATTR=amyloidtransthyretin;CMR=cardiacmagneticresonance;F=females;FLC=freelightchain;hATTR=hereditaryamyloidtransthyretn; LGE = late gadolinium enhancement; Ny' = males; SPEP = serum protein electrophoresis; UPEP = urine protein electrophoresis; wt ATTR = wild'type amyloid transthyretin.

AL=amyloidlightchain;ATTR=amyloidtransthyretin;CMR=cardiacmagneticresonance;F=females;FLC=freelightchain;hATTR=hereditaryamyloidtransthyretn; LGE = late gadolinium enhancement; Ny' = males; SPEP = serum protein electrophoresis; UPEP = urine protein electrophoresis; wt ATTR = wild'type amyloid transthyretin. 81

Myocardial Disease a protein stabilizer, is an FDA approved therapy that reduces Differentiating Restrictive Cardiomyopathy mortality and cardiovascular hospitalization in patients with From Constrictive Pericarditis ATTR cardiac amyloidosis. Patisiran and inotersen, which RCM and constrictive pericarditis present with similar symp- reduce hepatic production of transthyretin, are indicated for toms and echocardiographic findings. Differentiating between ATTR polyneuropathy and may have benefit for ATTR cardio the two disorders is essential because surgical pericardiectomy myopathy. Liver or combined heart liver transplantation may may relieve symptoms and prolong life in patients with con be considered for patients with h ATTR amyloidosis. striction. In patients with previous cardiac surgery pericardi ftY P0txrs tis, or chest irradiation, constrictive pericarditis should be strongly considered. o Cardiac amyloidosis is suggested by heart failure with On physical examination, patients with RCM or con t restrictive physiologr, increased wall thickness, and low striction demonstrate elevated central venous pressure. ECG voltage. Increase in the height of the jugular venous waveform during . Light chain amyloidosis is a multisystem disease for inspiration (Kussmaul sign) is more commonly associated which treatment is directed toward underlying plasma with constriction. Both RCM and constrictive pericarditis cell dyscrasias. may be associated with a diastolic sound an S, gallop in . Hereditary transthyretin amyloidosis causes heart fail- RCM and a pericardial knock in constrictive pericarditis. ure and sensory and autonomic neuropathy; treatment Differentiating between these sounds may be dilficult (see with tafamidis, a protein stabilizer, reduces mortality. Pericardial Disease). A multimodality approach. including noninvasive imag ing and invasive hemodynamic evaluation, may be required to Restrictive Ca rd iomyopathy distinguish RCM lrom constrictive pericarditis. Clues to the Clinical Presentation and Evaluation presence of constrictive pericarditis include pericardial calci Restrictive cardiomyopathy (RCM) is a rare disorder charac- fication on chest radiography or CT, pericardial thickening on terized by abnormally stiff, noncompliant ventricles. RCM CT or CMR imaging, and a B type natriuretic peptide level was once considered idiopathic; however, increasing evidence below 100 pg/ml (100 ng/L) (usually >400 pgrml [400 ngi L] suggests that gene mutations in sarcomeric proteins and in RCM). A hallmark feature of constrictive pericarditis is ven abnormalities in desmin, an intermediate filament that regu- tricular interdependence, whereby total cardiac volume is lates sarcomeric architecture, play an important role in famil limited by the rigid pericardium. With ventricular interde ial and sporadic cases. The sarcomeric gene mutations of RCM pendence. increased filling ol the right or left ventricle can are similar to or the same as those linked to HCM, raising the occur only with reciprocal decreased filling of the other ven possibility that these disorders represent different phenotypic tricle. Ventricular interdependence may be demonstrated by expressions of the same heritable defect. Histologically, RCM Doppler echocardiography, CMR imaging, or invasive hemo is characterized by patchy interstitial fibrosis and myocyte dynamic evaluation in patients with constriction; however. it disarray, which are also seen in HCM. With increasing inter is not present in patients with RCM. stitial fibrosis, the ventricles stiffen, resulting in increased pressure during normal diastolic fi1ling. Management Patients with RCM can present at any age, usually with dysp There are no medical therapies specifically for RCM. Loop diu nea, peripheral edema, and exercise intolerance. Hepatomegaly retics are usually necessary for relief of congestive symptoms. and ascites may be present late in the disease course. RCM should especially in late stage disease. However, patients with RCM be suspected when echocardiognphy reveals biatrial enlarge require relatively high filling pressures to maintain cardiac ment and severe diastolic dysfunction in the setting of normal output, and balancing relief of congestion with adequate car ventricular size, wall thickness, and systolic function. Pulmonary diac output is often challenging. Volume status should be hypertension is commonly present, as are tricuspid and mitral monitored carefully, because even small changes in volume valve regurgitation. may lead to renal hypoperfusion. Primary RCM must be differentiated from other condi- Atrial fibrillation is common in patients with RCM and is tions involving restrictive physiologr. These include conditions poorly tolerated because of increased heart rate and reduced in which wall thickness is typically normal (radiation induced ventricular filling. Anticoagulation and rate control are indi fibrosis, eosinophilic diseases, hemochromatosis) as well as cated. and rhythm control should be considered early in infiltrative diseases with increased wall thickness (see Cardiac symptomatic patients. Amyloidosis). A complete blood count with manual differen Survival is poor in patients with RCM. r.r'ith a 5 year mor tial, serum ferritin, and transferrin saturation are reasonable tality rate of 36'7, and a l0 year mortality rate of 63'X,. Cardio as part of the evaluation. CMR imaging with gadolinium con vascular mortality is predominantly related to progressive trast may help distinguish between conditions. When the heart failure and arrhythmias. Cardiac transplantation may be diagnosis remains unclear, endomyocardial biopsy is reason- considered in select patients who remain symptomatic despite able for establishing a diagnosis. maximal therapy. There is no accepted indication for primary

a protein stabilizer, is an FDA approved therapy that reduces Differentiating Restrictive Cardiomyopathy mortality and cardiovascular hospitalization in patients with From Constrictive Pericarditis ATTR cardiac amyloidosis. Patisiran and inotersen, which RCM and constrictive pericarditis present with similar symp- reduce hepatic production of transthyretin, are indicated for toms and echocardiographic findings. Differentiating between ATTR polyneuropathy and may have benefit for ATTR cardio the two disorders is essential because surgical pericardiectomy myopathy. Liver or combined heart liver transplantation may may relieve symptoms and prolong life in patients with con be considered for patients with h ATTR amyloidosis. striction. In patients with previous cardiac surgery pericardi ftY P0txrs tis, or chest irradiation, constrictive pericarditis should be strongly considered. o Cardiac amyloidosis is suggested by heart failure with On physical examination, patients with RCM or con t restrictive physiologr, increased wall thickness, and low striction demonstrate elevated central venous pressure. ECG voltage. Increase in the height of the jugular venous waveform during . Light chain amyloidosis is a multisystem disease for inspiration (Kussmaul sign) is more commonly associated which treatment is directed toward underlying plasma with constriction. Both RCM and constrictive pericarditis cell dyscrasias. may be associated with a diastolic sound an S, gallop in . Hereditary transthyretin amyloidosis causes heart fail- RCM and a pericardial knock in constrictive pericarditis. ure and sensory and autonomic neuropathy; treatment Differentiating between these sounds may be dilficult (see with tafamidis, a protein stabilizer, reduces mortality. Pericardial Disease). A multimodality approach. including noninvasive imag ing and invasive hemodynamic evaluation, may be required to Restrictive Ca rd iomyopathy distinguish RCM lrom constrictive pericarditis. Clues to the Clinical Presentation and Evaluation presence of constrictive pericarditis include pericardial calci Restrictive cardiomyopathy (RCM) is a rare disorder charac- fication on chest radiography or CT, pericardial thickening on terized by abnormally stiff, noncompliant ventricles. RCM CT or CMR imaging, and a B type natriuretic peptide level was once considered idiopathic; however, increasing evidence below 100 pg/ml (100 ng/L) (usually >400 pgrml [400 ngi L] suggests that gene mutations in sarcomeric proteins and in RCM). A hallmark feature of constrictive pericarditis is ven abnormalities in desmin, an intermediate filament that regu- tricular interdependence, whereby total cardiac volume is lates sarcomeric architecture, play an important role in famil limited by the rigid pericardium. With ventricular interde ial and sporadic cases. The sarcomeric gene mutations of RCM pendence. increased filling ol the right or left ventricle can are similar to or the same as those linked to HCM, raising the occur only with reciprocal decreased filling of the other ven possibility that these disorders represent different phenotypic tricle. Ventricular interdependence may be demonstrated by expressions of the same heritable defect. Histologically, RCM Doppler echocardiography, CMR imaging, or invasive hemo is characterized by patchy interstitial fibrosis and myocyte dynamic evaluation in patients with constriction; however. it disarray, which are also seen in HCM. With increasing inter is not present in patients with RCM. stitial fibrosis, the ventricles stiffen, resulting in increased pressure during normal diastolic fi1ling. Management Patients with RCM can present at any age, usually with dysp There are no medical therapies specifically for RCM. Loop diu nea, peripheral edema, and exercise intolerance. Hepatomegaly retics are usually necessary for relief of congestive symptoms. and ascites may be present late in the disease course. RCM should especially in late stage disease. However, patients with RCM be suspected when echocardiognphy reveals biatrial enlarge require relatively high filling pressures to maintain cardiac ment and severe diastolic dysfunction in the setting of normal output, and balancing relief of congestion with adequate car ventricular size, wall thickness, and systolic function. Pulmonary diac output is often challenging. Volume status should be hypertension is commonly present, as are tricuspid and mitral monitored carefully, because even small changes in volume valve regurgitation. may lead to renal hypoperfusion. Primary RCM must be differentiated from other condi- Atrial fibrillation is common in patients with RCM and is tions involving restrictive physiologr. These include conditions poorly tolerated because of increased heart rate and reduced in which wall thickness is typically normal (radiation induced ventricular filling. Anticoagulation and rate control are indi fibrosis, eosinophilic diseases, hemochromatosis) as well as cated. and rhythm control should be considered early in infiltrative diseases with increased wall thickness (see Cardiac symptomatic patients. Amyloidosis). A complete blood count with manual differen Survival is poor in patients with RCM. r.r'ith a 5 year mor tial, serum ferritin, and transferrin saturation are reasonable tality rate of 36'7, and a l0 year mortality rate of 63'X,. Cardio as part of the evaluation. CMR imaging with gadolinium con vascular mortality is predominantly related to progressive trast may help distinguish between conditions. When the heart failure and arrhythmias. Cardiac transplantation may be diagnosis remains unclear, endomyocardial biopsy is reason- considered in select patients who remain symptomatic despite able for establishing a diagnosis. maximal therapy. There is no accepted indication for primary 82

Myocardial Disease prevention ICD placement in patients with RCM who have preserved systol ic function. xtY torf,rs . Restrictive cardiomyopathy should be suspected when echocardiography reveals biatrial enlargement and severe diastolic dysfunction in the setting of normal ventricular size, wall thickness, and systolic function. o Differentiating between restrictive cardiomyopathy and constrictive pericarditis is essential because surgical pericardiectomy may relieve symptoms and prolong life in patients with constriction.

xtY torf,rs . Restrictive cardiomyopathy should be suspected when echocardiography reveals biatrial enlargement and severe diastolic dysfunction in the setting of normal ventricular size, wall thickness, and systolic function. o Differentiating between restrictive cardiomyopathy and constrictive pericarditis is essential because surgical pericardiectomy may relieve symptoms and prolong life in patients with constriction. Cardiac Tumors Most cardiac tumors are metastatic. Neoplasms with the high est 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. Nearly 50'X, of primary cardiac tumors are atrial mlxomas. Myxomas may occur in either atrium but are most commonly attached to the fossa ovalis within the left atrium (Figure 4O). Myxomas are usually soli tary and discovered at a mean age of 50 years, often after a systemic embolic event. Patients with a mlxoma may present with constitutional symptoms related to interleukin produc- tion, embolic phenomena from tumor fragmentation, or symptoms referable to intracardiac obstruction (dyspnea, syn cope). When mitral valve obstruction is present, auscultatory findings are similar to those of mitral stenosis; however, find ings 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 surveil- lance 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 ollife. Although most papillary fibroelasto mas do not cause symptoms, they may be associated with stroke, transient ischemic attack, and, rarely, coronary embo lization with infarction. On echocardiogram, these tumors often have a heterogeneous globular shape or a mobile frond- like appearance. Patients with embolic symptoms are treated surgically. There are 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 tlGU RE 40. 4,Transthoracic echocardiogram during diastole demonstrating a are often associated with pericardial effusion (Figure 41). left atrial myxoma originating from the interatrial septum and prolapsing across the Dyspnea and chest pain are common presenting symptoms. mitral valve (MV) into the left ventricle (LV). B, Parasternal long'axis view. ( Excised Angiosarcomas are highly vascular tumors, and CT or CMR myxoma with portion of the lossa ovalis (arow). LA = left atriu m; RA = rig ht atriu m; imaging with contrast may help differentiate an angiosarcoma RV= rightventricle.

Cardiac Tumors Most cardiac tumors are metastatic. Neoplasms with the high est 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. Nearly 50'X, of primary cardiac tumors are atrial mlxomas. Myxomas may occur in either atrium but are most commonly attached to the fossa ovalis within the left atrium (Figure 4O). Myxomas are usually soli tary and discovered at a mean age of 50 years, often after a systemic embolic event. Patients with a mlxoma may present with constitutional symptoms related to interleukin produc- tion, embolic phenomena from tumor fragmentation, or symptoms referable to intracardiac obstruction (dyspnea, syn cope). When mitral valve obstruction is present, auscultatory findings are similar to those of mitral stenosis; however, find ings 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 surveil- lance 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 ollife. Although most papillary fibroelasto mas do not cause symptoms, they may be associated with stroke, transient ischemic attack, and, rarely, coronary embo lization with infarction. On echocardiogram, these tumors often have a heterogeneous globular shape or a mobile frond- like appearance. Patients with embolic symptoms are treated surgically. There are 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 tlGU RE 40. 4,Transthoracic echocardiogram during diastole demonstrating a are often associated with pericardial effusion (Figure 41). left atrial myxoma originating from the interatrial septum and prolapsing across the Dyspnea and chest pain are common presenting symptoms. mitral valve (MV) into the left ventricle (LV). B, Parasternal long'axis view. ( Excised Angiosarcomas are highly vascular tumors, and CT or CMR myxoma with portion of the lossa ovalis (arow). LA = left atriu m; RA = rig ht atriu m; imaging with contrast may help differentiate an angiosarcoma RV= rightventricle. 83