Current Diagnostic and Treatment Strategies for Specific Dilated Cardiomyopathies: A Scientific Statement From the American Heart Association

HomeCirculationVol. 134, No. 23Current Diagnostic and Treatment Strategies for Specific Dilated Cardiomyopathies: A Scientific Statement From the American Heart Association Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBCurrent Diagnostic and Treatment Strategies for Specific Dilated Cardiomyopathies: A Scientific Statement From the American Heart Association Biykem Bozkurt, MD, PhD, FAHA, Chair, Monica Colvin, MD, FAHA, Jennifer Cook, MD, FAHA, Leslie T. Cooper, MD, FAHA, Anita Deswal, MD, MPH, FAHA, Gregg C. Fonarow, MD, FAHA, Gary S. Francis, MD, FAHA, Daniel Lenihan, MD, Eldrin F. Lewis, MD, FAHA, Dennis M. McNamara, MD, Elfriede Pahl, MD, FAHA, Ramachandran S. Vasan, MD, FAHA, Kumudha Ramasubbu, MD, Kismet Rasmusson, DNP, FAHA, Jeffrey A. Towbin, MD, FAHA and Clyde Yancy, MD, FAHAOn behalf of the American Heart Association Committee on Heart Failure and Transplantation of the Council on Clinical Cardiology; Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Epidemiology and Prevention; and Council on Quality of Care and Outcomes Research Biykem BozkurtBiykem Bozkurt Search for more papers by this author , Monica ColvinMonica Colvin Search for more papers by this author , Jennifer CookJennifer Cook Search for more papers by this author , Leslie T. CooperLeslie T. Cooper Search for more papers by this author , Anita DeswalAnita Deswal Search for more papers by this author , Gregg C. FonarowGregg C. Fonarow Search for more papers by this author , Gary S. FrancisGary S. Francis Search for more papers by this author , Daniel LenihanDaniel Lenihan Search for more papers by this author , Eldrin F. LewisEldrin F. Lewis Search for more papers by this author , Dennis M. McNamaraDennis M. McNamara Search for more papers by this author , Elfriede PahlElfriede Pahl Search for more papers by this author , Ramachandran S. VasanRamachandran S. Vasan Search for more papers by this author , Kumudha RamasubbuKumudha Ramasubbu Search for more papers by this author , Kismet RasmussonKismet Rasmusson Search for more papers by this author , Jeffrey A. TowbinJeffrey A. Towbin Search for more papers by this author and Clyde YancyClyde Yancy Search for more papers by this author and On behalf of the American Heart Association Committee on Heart Failure and Transplantation of the Council on Clinical Cardiology; Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Epidemiology and Prevention; and Council on Quality of Care and Outcomes Research Originally published3 Nov 2016https://doi.org/10.1161/CIR.0000000000000455Circulation. 2016;134:e579–e646is corrected byCorrection to: Current Diagnostic and Treatment Strategies for Specific Dilated Cardiomyopathies: A Scientific Statement From the American Heart AssociationOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2016: Previous Version 1 IntroductionThe intent of this American Heart Association (AHA) scientific statement is to summarize our current understanding of dilated cardiomyopathies. There is special emphasis on recent developments in diagnostic approaches and therapies for specific cardiomyopathies. Recommendations in this document are based on published studies, published practice guidelines from the American College of Cardiology (ACC)/AHA1 and other organizations,2,3 and the multidisciplinary expertise of the writing group. Existing evidence in epidemiology, classification, diagnosis, and management of specific cardiomyopathies is usually derived from nonrandomized observational studies, registries, case reports, or expert opinion based on clinical experience, not large-scale randomized clinical trials or systematic reviews. Therefore, in this document, rather than using the standard ACC/AHA classification schema of recommendations and level of evidence,4 we have included key management strategies at the end of each section and categorized our recommendations according to the level of consensus. Although the format of our recommendations might resemble the ACC/AHA classification of recommendations used in the ACC/AHA practice guidelines, because of the preponderance of expert opinion or level of evidence C evidence in our document, we elected to use different terminology to provide a distinction from the practice guidelines, in which stronger levels and quality of evidence with randomized clinical trials or meta-analyses are usually present.4 The levels of evidence follow the AHA and ACC methods of classifying the level of certainty of the treatment effect.4Definition of Dilated CardiomyopathyThe term dilated cardiomyopathy (DCM) refers to a spectrum of heterogeneous myocardial disorders that are characterized by ventricular dilation and depressed myocardial performance in the absence of hypertension, valvular, congenital, or ischemic heart disease.5In clinical practice, the pathogenesis of heart failure (HF) has often been placed into 2 categories: ischemic and nonischemic cardiomyopathy. The term nonischemic cardiomyopathy has been interchangeably used with DCM. Although this approach might be practical, it fails to recognize that nonischemic cardiomyopathy can include cardiomyopathies caused by volume or pressure overload (such as hypertension or valvular heart disease) that are not conventionally accepted under the definition of DCM.1,5 Again, in general practice and clinical research trials, the term ischemic cardiomyopathy is defined as cardiomyopathy caused by ischemic heart disease. Current use of ischemic cardiomyopathy terminology implies ventricular dilation and depressed myocardial contractility caused by ischemia or infarction.Classification of CardiomyopathiesThe first classification on this topic categorized cardiomyopathies as heart muscle diseases with dilated (DCM), hypertrophic, restrictive, arrhythmogenic right ventricular (ARVC), or nonclassifiable cardiomyopathy in 1980.5 Subsequently, the World Health Organization/International Society and Federation of Cardiology classification in 1996 added inflammatory and viral cardiomyopathies as new and distinct entities.5 With the development of molecular genetics, new classification schemes based on genomics such as the classification proposed by the AHA ensued,6 which divided cardiomyopathies into 2 major groups based on predominant organ involvement. Primary cardiomyopathies (ie, genetic, nongenetic, and acquired) were defined as those solely or predominantly confined to heart muscle. Secondary cardiomyopathies had myocardial involvement as part of a large number and variety of generalized systemic (multiorgan) disorders, including systemic diseases such as amyloidosis, hemochromatosis, sarcoidosis, autoimmune/collagen vascular diseases, toxins, cancer therapy, and endocrine disorders such as diabetes mellitus.6 The European Society of Cardiology (ESC) Working Group on Myocardial and Pericardial Diseases took a different approach based on a clinically oriented classification in which heart muscle disorders were grouped into specific morphological and functional phenotypes, including hypertrophic cardiomyopathies, DCM, ARVC, restrictive cardiomyopathies, and unclassified cardiomyopathies. Each phenotype was then subclassified into familial and nonfamilial forms.7 Most recently, the MOGE(S) nosology system was developed, which incorporates the morphofunctional phenotype (M), organ(s) involvement (O), genetic inheritance pattern (G), etiologic annotation (E) including genetic defect or underlying disease/substrate, and the functional status (S) of the disease using both the ACC/AHA HF stages and New York Heart Association (NYHA) functional class. This nomenclature is endorsed by the World Heart Federation, is supported by an Internet-assisted application, and assists in the description of cardiomyopathy in symptomatic or asymptomatic patients and family members in the context of genetic testing.8,9Classifications of cardiomyopathies that mix anatomic designations (ie, hypertrophic and dilated) with functional ones (ie, restrictive) can be quite challenging and have failed to satisfy the purposes of all users.1 Confusion can arise because the same disease could appear in 2 categories (ie, hypertrophic and restrictive); there could be heterogeneity of clinical expression in different phenotypes, and some diseases do not have a uniformly static expression but evolve as a consequence of remodeling from one category to another during their natural clinical course (eg, hypertrophic cardiomyopathy, amyloid, and other infiltrative conditions can progress from a nondilated, often hyperdynamic state to a dilated form). The most recent MOGE(S) classification provides flexibility for such potential transitions between morphofunctional types, involvement of different cardiac structures and organs, progression of symptomatology and functional status, and the addition of different causes such as genetic defects that might be discovered throughout the lifetime of a patient or affected families.6,9 In this scientific statement, our aim is to target appropriate diagnostic and treatment strategies that prevent development and progression of HF in patients with specific cardiomyopathies, not necessarily to reexamine new classification strategies for cardiomyopathies.Epidemiology and Natural History of DCMDetermining the incidence and prevalence of DCMs has been quite challenging because of geographic variations, patient selection, and changes in the diagnostic criteria. For example, the incidence of idiopathic DCM, which is defined as a cardiomyopathy when the exact cause remains initially unknown, doubled from 3.9 per 100 000 person-years between 1975 and 1979 to 7.9 per 100 000 person-years between1980 and 1984 in Olmsted County, MN.10 Around the same time, the incidence of clinical and postmortem diagnosed cases remained 5 per 100 000 per year in Sweden, where the autopsy rates were 90%.11 The prevalence of cardiomyopathy in underdeveloped and tropical countries is considerably higher than in developed countries. In the United States, the age-adjusted prevalence of DCM has been reported to be ≈36 cases per 100 000 population or 1:2500.12,13 The prevalence of DCM in Japan is reportedly lower (17/100 000),14 and in Africa15 and Latin America, it is higher than that of the US population. As populations go through epidemiological and socioeconomic transitions and healthcare modifications, the prevalence of DCM could continue to change.In most multicenter randomized trials in HF, ≈30% to 40% of the enrolled patients have nonischemic HF. According to ADHERE (Acute Decompensated Heart Failure National Registry), 47% of the patients admitted to the hospital with HF had nonischemic cardiomyopathy.16 This number might not accurately reflect the true prevalence of nonischemic DCM, because a significant proportion of these patients will have HF caused by hypertension or valvular heart disease. With the inclusion of the pediatric population and the worldwide spectrum of causes of DCMs, the prevalence of nonischemic DCMs is thought to exceed that of ischemic DCMs.DCM can occur at any age but most commonly occurs in the third or fourth decade of life. Advancing age is an independent risk factor for mortality in DCM.17,18 Interestingly, with advances in pharmacological and device treatment, the prognosis of HF and DCM has improved significantly in the adult population,19 even among the elderly.20 The improvement in survival has been associated with the use of angiotensin-converting enzyme (ACE) inhibitors and β-blockers.19 Compared with whites, blacks have almost a 3-fold increase in risk for developing DCM, which is not explained solely by the confounding variables of hypertension or social or economic factors.21 Moreover, blacks have an ≈1.5- to 2-fold higher risk of dying of DCM compared with age-matched whites with DCM.22 Regarding sex-related differences, the overall effect of female sex on the prognosis of HF, especially DCM, is not clear at this time and could be confounded by differing pathogeneses and an underrepresentation of women in clinical trials. In the Italian Multicenter Cardiomyopathy Registry, women with idiopathic DCM presented with more advanced HF and had a trend toward worse survival.23 Analyses from MERIT-HR (Metoprolol Extended Release Randomized Intervention Trial in Heart Failure)24 and CIBIS-II (Cardiac Insufficiency Bisoprolol Study)25 suggested that female sex might be a significant independent predictor of survival in patients with HF, regardless of ischemic or nonischemic pathogenesis. Further studies will need to be conducted to provide more insight into the role of sex in the prognosis of DCM.The natural history of DCM is not well established for 2 reasons. First, DCM represents a heterogeneous spectrum of myocardial disorders that can progress at different rates.26 Second, the onset of the disease can be insidious, particularly in the case of familial or idiopathic DCMs, and could be missed for a significant period of time before the diagnosis. Approximately 25% of DCM patients with recent onset of symptoms of HF will have spontaneous improvement,27 but patients with symptoms lasting >3 months who present with severe clinical decompensation generally have less chance of recovery.27 Patients with idiopathic DCM have a better prognosis than those with other types of DCM.28It should be recognized that many of the natural history studies of DCM were performed before ACE inhibitors and β-blockers were used routinely. Also, device therapies and cardiac transplantation were not commonly available.17 More recent studies suggest that the prognosis for patients with DCM and mild left ventricular (LV) dilation might be more favorable, perhaps reflecting earlier diagnosis and better treatment. A number of variables imply a poor prognosis in patients with DCM, including LV and right ventricular (RV) enlargement, reduced LV and RV ejection fraction (EF), persistent S3 gallop, right-sided HF, elevated LV filling pressures, moderate to severe mitral regurgitation, pulmonary hypertension, electrocardiographic findings of left bundle-branch block (LBBB), recurrent ventricular tachycardia, renal and hepatic dysfunction, elevated levels of brain natriuretic peptide (BNP), persistently elevated cardiac troponin levels, peak oxygen consumption <10 to 12 mL·kg−1·min−1, serum sodium <137 mmol/L, advanced NYHA functional class, age >64 years, and myocytolysis on endomyocardial biopsy (EMB).In the United States, the cause of death appears to be pump failure in approximately two thirds and sudden cardiac death in approximately one third of all deaths of patients with DCM.28–30 In existing clinical studies, patients with idiopathic DCM had a lower total mortality than patients with ischemic heart disease.28Diagnostic Strategies in DCMEvaluation of patients with DCM involves common diagnostic strategies recommended1 for patients with HF or cardiomyopathy and requires a thorough understanding of the complex, diverse pathophysiology that must be individualized to the patient. The general approach of the writing committee is outlined in Figure 1.1Download figureDownload PowerPointFigure 1. Diagnostic strategies in DCM. BUN indicates blood urea nitrogen; CAD, coronary artery disease; CMP, cardiomyopathy; CRP, C-reactive protein; CT, computed tomography; DCM, dilated cardiomyopathy; ESR, erythrocyte sedimentation rate; HbA1c, hemoglobin A1c; HF, heart failure; LVEF, left ventricular ejection fraction; MCS, mechanical circulatory support; MR, magnetic resonance; PAN, polyarthritis nodosa; PCR, polymerase chain reaction; RA, rheumatoid arthritis; SPEP, serum protein electrophoresis; and UPEP, urine protein electrophoresis.*Current definition per 2013 guidelines1. Heart failure with reduced ejection fraction (HFrEF; ejection fraction <40%) or heart failure with borderline preserved ejection fraction (HFpEF; borderline ejection fraction 41%-49%). †These diagnostic tests are part of a routine workup of initial evaluation of a patient with heart failure.1Overall Management Strategies for DCMThe differential treatment benefit seen in DCM patients compared with patients with ischemic cardiomyopathy has been observed in several randomized clinical trials. Differential patient responsiveness to digoxin31 or amiodarone32 suggests that there could be response differences between ischemic and nonischemic HF; however, similar older reports of survival difference with β-blockers33 and amlodipine34 in patients with DCM but not ischemic cardiomyopathy were not reproduced in subsequent large-scale randomized trials. This has raised the question of whether there is truly a difference in response to treatment according to pathogenesis of HF. Currently, it is accepted that guideline-directed medical and device therapies, including implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy (CRT) for HF, are beneficial in DCM.1Diagnostic and Treatment Strategies for Specific CardiomyopathiesIn the following sections, diagnostic and treatment strategies for specific cardiomyopathies such as cardiac amyloidosis, cardiotoxins, peripartum cardiomyopathy, cardiac sarcoidosis, myocarditis, autoimmune cardiomyopathy, endocrine and metabolic cardiomyopathies, and genetic cardiomyopathies will be reviewed.Diagnostic and Treatment Strategies for Cardiac AmyloidosisDefinition, Pathogenesis, Epidemiology, and PrognosisCardiac amyloidosis usually starts as restrictive cardiomyopathy with mildly depressed LV systolic dysfunction and significant diastolic HF and can progress to severe systolic dysfunction in advanced stages. Amyloidosis is a disease complex characterized by the deposition of protein fibrils in various organs, which leads to structural and functional derangement. There are various types of amyloidosis categorized on the basis of the type of protein fibrils deposited, as shown in Table 1. Amyloid deposition can occur in various organs, including the heart, kidney, liver, and nervous system. Cardiac involvement has been predominantly noted in amyloid light chain (AL) amyloidosis (also known as primary amyloidosis), hereditary, senile, and isolated atrial amyloidosis. The most common types of cardiac amyloidosis encountered in clinical practice are AL, senile, and certain hereditary/familial types.35Table 1. Pathology, Organ Involvement, and Survival in Various Types of AmyloidosisAmyloidosis TypeProteinCardiac InvolvementMedian Survival (mo)Extracardiac ManifestationsPrimary or light-chain (AL)Light chainUp to 50%13(4 mo if heart failure present)Kidney, liver, nervous system, skin, carpal tunnel syndromeHereditaryMutant transthyretinVariable70Kidney, nervous system, blindnessSenileTransthyretinCommon75Diffuse organ involvementIsolated atrialAtrial natriuretic factorLimited to heart…NoneReactive (AA)Amyloid A<10%25Kidney, liverDialysis relatedβ2-microglobulinUnknown…Joints, carpal tunnel syndrome, skeletalAA indicates amyloid A (reactive amyloidosis); and AL, amyloid light chain.Once amyloid infiltration involves the heart, prognosis significantly worsens. Although senile and familial cardiac amyloidoses have a relatively mild course, with a median survival of 70 to 75 months, cardiac involvement in AL amyloidosis leads to rapid progression in cardiac symptoms and a significant reduction in survival. Median survival in AL amyloidosis is ≈13 months but decreases drastically to 4 months with the onset of HF symptoms.36,37Pathophysiology and Clinical PresentationAmyloid deposits in the myocardial interstitium disrupt myocyte function and can lead to diastolic and systolic dysfunction. Amyloid deposits can also directly cause myocyte necrosis by oxidative stress, and this can contribute further to systolic dysfunction. Moreover, deposits in the conduction tissue can affect electrical conduction. Amyloid deposition in the valves can lead to thickening but rarely to significant dysfunction. Furthermore, amyloid protein can deposit in the media and adventitia of coronary arteries and veins, and this can potentially result in cardiac ischemia. Amyloid deposits in the pericardium can result in the formation of pericardial effusion. In the early stages of cardiac amyloid deposition, there is an increase in myocardial stiffness leading to impaired diastolic function, which eventually leads to elevated filling pressures and diastolic HF with the restrictive cardiomyopathy phenotype. During these earlier stages, the heart is typically normal in size with normal systolic function. With disease progression, systolic dysfunction develops.38Clinically, one of the main presentations encountered in patients with cardiac amyloidosis is with HF. Because of infiltration of the conduction system, abnormalities in the form of atrioventricular block are not uncommon. Atrial tachyarrhythmias can also occur because of amyloid deposition in the atrial wall and as a result of atrial dilation in the setting of elevated filling pressures. Some patients develop angina from amyloid deposition in the coronary arteries. Typically, intramyocardial coronary arteries are affected, and thus, examination of the epicardial arteries by coronary angiography might not show significant obstruction. Presyncope and syncope are not an uncommon presentation, likely multifactorial, and include infiltration of the autonomic nervous system and adrenal glands, hypovolemia caused by nephrotic syndrome, cardiac arrhythmias, and inability of a stiff heart to adequately respond to positional changes.35,39,40DiagnosisDiagnosis of amyloidosis not only involves the demonstration of amyloid protein in tissue specimens but also requires the identification of which organs are affected and the definition of the type of amyloidosis. Cardiac amyloidosis is usually suspected on echocardiography, typically performed because of HF symptoms or performed for screening purposes when the diagnosis of amyloidosis has been established in other organs.Typical echocardiographic features of amyloidosis include thickened ventricular walls (right and left) in the setting of normal ventricular size, biatrial dilatation, presence of a pericardial effusion, and valvular thickening without significant dysfunction. Increased echogenicity of the myocardium, termed granular, sparkling, is not very sensitive or specific when evaluated in isolation but should raise suspicion when present in conjunction with other echocardiographic findings listed previously. Of note, the “granular, sparkling” finding has become less discernible because of newer echocardiographic techniques. An infiltrative disease process should be suspected if the ventricular walls are thickened in the absence of an obvious cause such as hypertension or aortic stenosis. Doppler studies typically demonstrate impaired LV relaxation and restrictive filling pattern. Initially, LV systolic function is preserved, but this gradually declines as the disease progresses.41–43Reduced QRS voltage amplitude on ECG is noted in the limb leads in ≈50% of patients with cardiac amyloidosis despite the presence of ventricular wall thickening on cardiac imaging. Other electrocardiographic features include a pseudoinfarct pattern in the precordial leads, atrial fibrillation, and atrioventricular conduction abnormalities.44Nuclear imaging with technetium pyrophosphate has been shown to be insensitive; however, if uptake is present, amyloid infiltration should be considered, depending on the clinical setting.45 A small study showed that the radioactive tracer technetium Tc 99m dicarboxypropane diphosphonate can be useful in distinguishing between AL and transthyretin (TTR) amyloidosis.46Late gadolinium enhancement in the subendocardium globally by cardiac magnetic resonance imaging (MRI) has been noted in patients thought to have cardiac amyloid involvement. The accuracy and utility of this imaging modality are still uncertain for the diagnosis of cardiac amyloidosis, but it could help identify the extent of cardiac involvement in patients with an established diagnosis of amyloidosis.47,48BNP levels can be helpful in the diagnosis and follow-up of patients with cardiac amyloidosis. Elevations in BNP have been demonstrated even without evidence of clinical HF or increased wall stress, which suggests that it might be caused not only by elevated ventricular filling pressure but also by direct myocyte damage caused by extracellular deposits of amyloid. Increased natriuretic peptide levels suggest cardiac involvement with a sensitivity of 93% and specificity of 90%.49,50 Elevated BNP levels have also been demonstrated to predict development of clinical cardiac involvement in the future.51 Moreover, BNP levels have been shown to predict prognosis and mortality.39,50 BNP levels decrease with chemotherapeutic treatment of AL amyloidosis, possibly suggesting organ response.52The definitive diagnosis of amyloidosis is made histologically from biopsies of abdominal fat pad, gingiva, rectum, bone marrow, or other affected organs such as heart, liver, and kidney. Light microscopy shows amorphous pink deposits in the interstitium. With Congo red staining, amyloid fibrils produce apple-green birefringence under polarized microscopy. Other confirmative methods include electron microscopy and proteomic typing by mass spectrometry.53,54 EMB that identifies amyloid protein in cardiac tissue provides the definitive diagnosis of cardiac amyloidosis. In patients with noncardiac tissue-proven systemic amyloidosis, echocardiographic or cardiac magnetic resonance (MR) findings suggestive of infiltrative cardiomyopathy (eg, wall thickness >12 mm) can support the diagnosis of cardiac amyloidosis without EMB.55 The next step is to identify the type of amyloidosis, because this is instrumental in determining treatment strategy and prognosis. Immunohistochemistry can be performed on the tissue samples with antibodies against amyloid A, κ- and λ-light chains, and TTR amyloid.41 If TTR amyloid is detected, DNA mutational analysis can help differentiate between senile and hereditary amyloidosis.54 The presence of serum or urine monoclonal gammopathy suggests the presence of AL amyloidosis but does not establish the diagnosis. In reactive (AA) amyloidosis, the deposited protein is serum amyloid A protein, an acute-phase protein that is normally soluble and whose plasma concentration is highest during inflammation. AA amyloidosis is a complication of a number of inflammatory diseases and infections such as tuberculosis, chronic osteomyelitis, and autoimmune diseases. AA amyloid deposits are primarily in the liver, spleen, and kidney and rarely affect the heart.Key Diagnostic Strategies for Cardiac AmyloidosisDiagnostic Recommendations With Strong Level of Consensus for Cardiac AmyloidosisIn patients suspected of having cardiac and systemic amyloidosis, identification of amyloid protein in tissues such as abdominal fat pad, gingiva, or rectum or affected organs such as heart, liver, and kidney is recommended to diagnose amyloidosis (Level of Evidence C).If TTR amyloid is detected from a biopsy specimen, DNA mutational analysis should be used to differentiate between senile and hereditary amyloidosis (Level of Evidence C).54When the diagnosis of amyloidosis has been established, imaging and further laboratory studies or biopsies should be considered to identify the organs involved (Level of Evidence C). The extent of organ involvement is critical in determining treatment strategies and prognosis.Echocardiography should be performed in patients suspected of having cardiac amyloidosis or patients with systemic amyloidosis and HF (Level of Evidence B).41–43Recommendations With Moderate Level of Consensus for Cardiac AmyloidosisNoncardiac tissue–proven amyloidosis along with echocardiographic or cardiac MRI findings suggestive of infiltrative cardiomyopathy and symptoms and signs of HF can be useful to diagnose cardiac amyloidosis without EMB (Level of Evidence C).In patients suspected of having cardiac amyloidosis, EMB is reasonable to identify amyloid protein in cardiac tissue, especially if there is no noncardiac tissue evidence of amyloidosis (Level of Evidence C).Natriuretic peptide (BNP or N-terminal proBNP) levels can be useful to detect early/preclinical cardiac involvement in patients with the diagnosis of amyloidosis and to predict future cardiac involvement and prognosis (Level of Evidence B).49–52Recommendations With Uncertainty for Cardiac AmyloidosisThe presence of serum or urine monoclonal gammopathy, which suggests the presence of AL amyloidosis, along with echocardiographic or cardiac MRI findings suggestive of infiltrative cardiomyopathy and symptoms and signs of HF may be considered to support the diagnosis of cardiac amyloidosis without EMB but does not establish the definitive diagnosis (Level of Evidence C).53–55Certain electrocardiographic features, such as presence of low QRS voltage in the presence of ventricular wall thickening, might be reasonable to suggest the presence of cardiac amyloidosis but do not confirm the diagnosis of cardiac amyloidosis (Level of Evidence C).44Use of nuclear imaging with technetium Tc 99m dicarboxypropane diphosphonate may be reasonable to distinguish between AL and TTR amyloidosis (Level of Evidence B).45,46TreatmentGeneral HF TreatmentTreatment is for the most part supportive. It includes management of HF, arrhythmias, and conduction system problems. However, the use of the standard HF treatment regimen can be challenging