Dilated Cardiomyopathy

综合医院 医学院 医学 家庭医学 医学教育
作者
Neal K. Lakdawala,Jeffery Winterfield,Matthew S. Lebo
出处
期刊:Circulation-arrhythmia and Electrophysiology [Ovid Technologies (Wolters Kluwer)]
卷期号:6 (1): 228-237 被引量:115
标识
DOI:10.1161/circep.111.962050
摘要

HomeCirculation: Arrhythmia and ElectrophysiologyVol. 6, No. 1Dilated Cardiomyopathy Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBDilated Cardiomyopathy Neal K. Lakdawala, MD, Jeffery R. Winterfield, MD and Birgit H. Funke, PhD Neal K. LakdawalaNeal K. Lakdawala From the Brigham and Women’s Hospital & Boston VA Hospital, Harvard Medical School, Boston, MA (N.K.L.); Cardiovascular Institute, Loyola University Medical Center, Maywood, IL (J.R.W.); and Harvard Medical School–Partners Healthcare Center for Personalized Genetic Medicine, Department of Pathology, Massachusetts General Hospital, Boston, MA (B.H.F.). , Jeffery R. WinterfieldJeffery R. Winterfield From the Brigham and Women’s Hospital & Boston VA Hospital, Harvard Medical School, Boston, MA (N.K.L.); Cardiovascular Institute, Loyola University Medical Center, Maywood, IL (J.R.W.); and Harvard Medical School–Partners Healthcare Center for Personalized Genetic Medicine, Department of Pathology, Massachusetts General Hospital, Boston, MA (B.H.F.). and Birgit H. FunkeBirgit H. Funke From the Brigham and Women’s Hospital & Boston VA Hospital, Harvard Medical School, Boston, MA (N.K.L.); Cardiovascular Institute, Loyola University Medical Center, Maywood, IL (J.R.W.); and Harvard Medical School–Partners Healthcare Center for Personalized Genetic Medicine, Department of Pathology, Massachusetts General Hospital, Boston, MA (B.H.F.). Originally published28 Sep 2012https://doi.org/10.1161/CIRCEP.111.962050Circulation: Arrhythmia and Electrophysiology. 2013;6:228–237Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2012: Previous Version 1 IntroductionDilated cardiomyopathy (DCM) is an important cause of sudden cardiac death (SCD) and heart failure (HF) and is the leading indication for cardiac transplantation in children and adults worldwide.1 It is characterized by ventricular chamber enlargement and systolic dysfunction with normal left ventricular wall thickness. Different causes can lead to DCM, including inherited, infectious, and inflammatory diseases. However, the majority of cases remain unexplained after a thorough review for secondary cause.2 Discoveries made during the past 20 years have revealed a genetic basis in both inherited and hitherto idiopathic forms, with many different genes implicated.3–8 These developments have enlightened both clinical diagnosis and investigation and have fostered informed therapeutic decisions.Genetic BackgroundGenetic causes are often suspected based on the presence of familial clustering of disease. Although initial estimates of familial involvement in DCM were as low as 2%,9 such ascertainment was derived from early studies that were limited to retrospective analyses of medical records. Recent studies, which assessed for hereditary disease with prospective pedigree analysis and echocardiography, have suggested that up to 40% of DCM may be inherited.10,11 Accordingly, the importance of considering familial disease in DCM has been emphasized in recent consensus statements.12,13The study of affected kindreds has revealed familial DCM to be mostly inherited in an autosomal dominant fashion with characteristic age-dependent penetrance and variable clinical expression (Figure 1). Autosomal recessive, X-linked, and mitochondrial forms have been described in a limited number of cases, often with associated skeletal myopathy.10 Although DCM may develop at any age, it usually does not present until adolescence or young adulthood (ie, age-dependent penetrance). Clinical manifestations can vary tremendously, even within individual families, where a proportion develop end-stage HF as infants, whereas others may survive to the seventh decade with mild subclinical DCM (ie, variable clinical expression).14 In a subset of familial cardiomyopathy, there are associated clinical features that are inherited with DCM.15 However, the majority of cases present with isolated DCM.Download figureDownload PowerPointFigure 1. Inheritance and expression patterns in familial dilated cardiomyopathy (DCM). Disease transmission from father to son supports autosomal dominant inheritance (arrow). Incomplete penetrance is demonstrated by individual A, who has no evidence of DCM, but is an obligate carrier of a disease variant by virtue of having an affected father and son. Variable clinical expression is evident with clinical manifestations differing among affected individuals within the kindred, which may obscure recognition of shared genetic disease. In this family, the presence of arrhythmias, conduction disease, and DCM are consistent with disease caused by a mutation in LMNA, which was subsequently identified in individual B. Black symbols indicate clinically affected individuals; white symbols, clinically unaffected individuals; circle, women; square, men; slash, deceased. +, LMNA mutation positive; –, LMNA mutation negative; AF, atrial fibrillation; AVB, atrioventricular block; LVEF, left ventricular ejection fraction; and SCD, sudden cardiac death.Genetic causes of DCM were initially identified through the study of affected families. However, sporadic, nonfamilial DCM may have a genetic cause as frequently as hereditary presentation.16 Accordingly, genetic causes should be considered equally in familial and nonfamilial DCM. Mutations in more than 40 different genes have been implicated in the pathogenesis of DCM. This concept of locus heterogeneity is further compounded by allelic heterogeneity, whereby different mutations within the same gene have been shown to cause DCM, with most being private to individual families.DCM Disease GenesMutations in different genes, encoding a diverse array of proteins, may cause DCM,17 and largely have been identified through genomewide linkage analysis4 and candidate gene sequencing.14 More recently, new technologies have enabled whole-exome sequencing,18 which is being increasingly used for gene discovery. Genes implicated to cause DCM encode components of the sarcomere, cytoskeleton (eg, Z-disk proteins), nuclear envelope, and sarcolemma. In addition to these structural elements, mutations have also been identified in genes important for calcium cycling (PLN),5 RNA splicing (RBM20),19 and protein trafficking (BAG3).18 A comprehensive review of confirmed and putative disease genes has been described in several recent publications17,20; an abbreviated list of disease genes is provided on Table 1.Table 1. Dilated Cardiomyopathy—Selected Disease GenesGene, ProteinClassInheritancePrevalence*Conduction DiseaseSkeletal MyopathyTTN, TitinSarcomereAD15%–25%–RareMYH7, β-myosin heavy chainSarcomereAD4%–8%–RareTNNT2, cTroponin-TSarcomereAD3%–6%––TPM1, α-tropomyosinSarcomereAD2%–4%––LMNA, Lamin A/CNuclear laminaAD, AR4%–8%†+++/–EMD, EmerinNuclear laminaXL<1%†+++++SCN5A, Nav1.5Ion channelAD1%–2%†++–DES, DesminIntermediate filamentAD, AR<1%++++/–ZNF9, DM2Nucleic acid-bindingAD<1%+++++DMD, DystrophinDystrophinXL–++++DSP, DesmoplakinDesmosomeAD, AR1%–3%––RBM20, RNA binding motif 20SpliceosomeAD3%–6%+/––BAG3, BCL2-associated athanogene 3CochaperonesAD2%–4%–+/–PLN, PhospholambanCalcium homeostasisAD<1%VCL, VinculinZ-DiskAD–––AD indicates autosomal dominant; AR, autosomal recessive; and XL, X-linked.Noncomprehensive list of DCM associated disease genes. Selected for inclusion were genes with strong data supporting pathogenesis or important associated phenotypes.*Estimated based on limited studies.†Prevalence higher (≈30%) in setting of concomitant conduction disease or arrhythmias.The principle genetic causes of DCM have been reported in sequencing studies of moderate-sized cohorts (n≈300) comprised of both familial and sporadic cases. These studies suggest that mutations in sarcomeric genes, including TTN (titin), MYH7 (myosin heavy chain), TNNT2 (cardiac troponin T), and TPM1 (α-tropomyosin), are the most common causes, collectively accounting for ≈30% of cases.8,16,21–23Mutations in LMNA, which encodes Lamin A/C, a nuclear envelope protein, have been shown to cause different phenotypes associated with DCM, including DCM with limb-girdle or Emery-Dreifuss muscular dystrophy. Patients with LMNA mutations and DCM also have electrical instability (DCM+E), with supraventricular arrhythmias and atrioventricular block often present before systolic dysfunction.3,24 In large DCM cohorts, LMNA mutations are present in ≈5% of patients.25 However, they are more prevalent (≈33%) in patients with a DCM+E phenotype.26Desmosome gene mutations are a known cause of arrhythmogenic right ventricular cardiomyopathy, but may also have a role in DCM. Some patients with arrhythmogenic right ventricular cardiomyopathy may present with left ventricular predominant disease, often caused by mutations in the desmosomal gene DSP (desmoplakin).27 Affected patients may present with an increased burden of ventricular tachyarrhythmia and coarse hair with palmoplantar hyperkeratosis (cardiocutaneous syndrome).27 Autosomal recessive cardiocutaneous syndrome with primary left ventricle (LV) involvement is termed Carvajal syndrome,28 although autosomal dominant forms have been described.29 Alternatively, DCM caused by desmosomal mutations may present without any apparent right ventricle involvement or excess arrhythmia.30DCM is a relatively common feature in several forms of inherited skeletal myopathies, including those caused by mutations in DMD (dystrophin),31DES (desmin),32EMD (emerin),33 and ZNF9.34 Mutations in these genes may cause cardiomyopathy without apparent skeletal myopathy,35 especially in women carriers of mutations in the DMD gene that resides on the X-chromosome.36Clinical PresentationHF, sudden death, or thromboembolism may be the presenting manifestation of DCM. Alternatively, patients may be diagnosed with subclinical DCM identified in the process of family evaluations. As described in the preceding section, clinical manifestations vary substantially even within an individual family. In families where the pathogenic mutation has been identified, most, but not all carriers of the disease-mutation, ultimately develop overt cardiomyopathy (ie, incomplete penetrance). DCM caused by mutations in the sarcomere genes MYH7, TNNT2, and TPM1 may present at any age; however, adverse outcomes seem to be more common with pediatric presentations.4,14TTN associated DCM typically does not present until adulthood, although adverse outcomes occur earlier in men.8 Alternatively, LMNA associated heart disease typically does not manifest until the third decade, usually with conduction disease or arrhythmia that precedes DCM.37Associated PhenotypesMost patients with familial DCM have isolated heart muscle disease; however, extracardiomyopathic phenotypes are present in a minority of cases (Table 2).Table 2. Associated Clinical Features Which Are Present in a Minority of Patients With Familial Dilated CardiomyopathyAssociated PhenotypeClinical FeaturesCommentAssociated Gene*Conduction diseaseSinus arrestMay precede DCMDESAV blockDMDInterventricular blockEMDLMNASCN5ASupraventricular arrhythmia prior to DCMPremature atrial contractionOften with slow ventricular responseEMDAtrial fibrillationLMNASCN5ASkeletal myopathyLimb girdleProximal muscle weaknessLMNAEmery-DreifussContractures, skeletal myopathy and wastingEMD, LMNAMyotonic dystrophyMyotonia, weakness, baldness and cataractsZNF9, DMPK1Duchenne/BeckerProgressive X-linked proximal myopathyDMDMyofibrillar myopathySlowly progressive proximal and distal weaknessDESHearing lossSensorineural hearing lossHearing loss typically occurs in 1st and 2nd decade of lifeEYAPalmoplantar keratodermaIncreased thickness of the palms and soles with woolly or excessively curly hairMay precede cardiac involvementDSPAVB indicates atrioventricular block; and DCM, dilated cardiomyopathy.*Selected, incomplete list of associated disease genes.Associated or preceding conduction disease and supraventricular arrhythmia (DCM+E) are characteristic of DCM associated with LMNA,37EMD, or SCN5A38 mutations. Atrioventricular block typically manifests as PR prolongation that may progress to compete heart block. Electrophysiological studies have revealed heart block to be intranodal in LMNA associated cardiomyopathy.39 Alternatively, interventricular conduction disease or sinus node dysfunction may be the presenting manifestations of DCM+E. Supraventricular tachyarrhythmias may begin as isolated premature atrial contractions that progress to permanent atrial fibrillation.3 These patients also seem to have a greater burden of ventricular tachyarrhytmias than would be anticipated based on the severity of systolic dysfunction.40The presence of LV hypertrabeculation without overt systolic dysfunction or congenital anomaly defines isolated left ventricular noncompaction. However, kindreds with both DCM and left ventricular noncompaction have been described, and both can be caused by sarcomeric gene mutations.41Although rare, sensorineural hearing loss may be an associated DCM phenotype in the context of dominant mutations in the transcriptional coactivator, EYA4.42 Hearing loss is reported to precede cardiac involvement by decades in affected families.43DCM may present with several types of inherited skeletal myopathy, including limb-girdle, Emery-Dreifuss, myotonic, myofibrillar, and dystrophin associated muscular dystrophies.44 Patients with overt skeletal myopathy may have subclinical DCM, with masking of cardiac symptoms because of the activity imitations imposed by skeletal myopathy.45 Alternatively, patients with cardiomyopathy may have unnoticed skeletal myopathy that may ultimately complicate advanced therapies such as cardiac transplantation.46 Elevated serum creatine kinase concentrations may indicate subclinical skeletal myopathy, regardless of type. Atrial arrhythmias and conduction disease may be the only cardiac manifestations in patients with skeletal myopathy, or may precede DCM.Clinical Evaluations of Familial DCMThe identification of left ventricular chamber dilation and systolic dysfunction with echocardiography is diagnostic of DCM and can allow consideration of secondary causes (eg, regional wall motion abnormalities in coronary heart disease). Isolated borderline left ventricular dilation or systolic dysfunction may represent an early stage of disease,11,47 and when seen within the context of a family history, can be diagnostic. Echocardiography is recommended for screening asymptomatic patients for DCM in affected families and for providing clinical imaging follow-up of affected individuals.13,48Electrocardiographic findings are nonspecific in most familial DCM, however, associated conduction disease should be considered. Prolongation of the PR interval is often the earliest manifestation of genetic DCM+E, and less common manifestations, such as atrial standstill, may develop with progressive disease.49 Likewise, frequent premature atrial contractions may be present early and may progress to permanent atrial fibrillation before the development of overt DCM.Stress testing serves a dual role in the evaluation of a patient with presumed familial dilated cardiomyopathy, detection of coronary heart disease, and quantification of exercise capacity. Individuals with genetic cardiomyopathy remain susceptible to coronary disease, which may result in 2 different causes of systolic dysfunction in the same patient. Alternatively, ischemic cardiomyopathy may be the cause of heart disease in patient who did not inherit the genetic cause of primary cardiomyopathy in an affected family (phenocopy). Exercise stress testing also allows for the objective quantification of functional capacity, which is a powerful determinant of survival among patients with HF50 and can prioritize consideration for advanced therapies (eg, cardiac transplantation).Ambulatory electrocardiography can be useful for symptom evaluation and risk stratification, especially in patients with a family history of SCD or frequent ventricular ectopy. In cases of suspected arrhythmogenic right ventricular cardiomyopathy, premature ventricular contractions in excess of 500/24 hours represent a minor criterion for diagnosis based on the Modified 2010 Task Force Criteria, although no diagnostic standard for ambient ectopy burden has yet been established for nonarrhythmogenic right ventricular cardiomyopathy cases of suspected DCM+E. In some cases of frequent ventricular ectopy associated with LV dysfunction, catheter ablation or pharmacological therapy has been associated with reversal of cardiomyopathy, and the origin of the pathogenic premature ventricular contractions in these cases would be considered idiopathic rather than secondary to a myocardial process.51Cardiac magnetic resonance imaging (CMR) provides accurate assessment of ventricular chamber size, wall thickness, and systolic function. CMR can be especially valuable in patients with poor echocardiographic image quality, but can also provide noninvasive tissue characterization. Delayed hyperenhancement (DE) of the CMR perfusion agent gadolinium indicates expansion of the extracellular space, which may be secondary to intramyocardial scar formation. The pattern of DE can differentiate coronary versus noncoronary heart disease with good specificity.52 In particular, a subepicardial or midmyocardial pattern of DE in a noncoronary distribution suggests nonischemic cardiomyopathy (Figure 2). Specific patterns of DE have been purported to indicate a particular genetic association; however, these findings are nonspecific and are also present in viral myocarditis or cardiac sarcoidosis.24Download figureDownload PowerPointFigure 2. Noncoronary pattern of delayed gadolinium enhancement imaged with cardiac MRI in familial dilated cardiomyopathy (DCM). Short-axis cardiac MRI (CMR) images reveal circumferential subepicardial delayed enhancement (DE) of gadolinium (arrows) in a young patient with familial DCM and palmoplantar keratoderma caused by a DSP mutation. The pattern of delayed enhancement of gadolinium is not specific for genetic heart disease, but is distinct from ischemic cardiomyopathy. LV indicates left ventricle; and RV, right ventricle. Images courtesy of Ravi Shah, MD, and Raymond Kwong, MD, Brigham and Women’s Hospital, Boston, MA.ManagementLifestyle RecommendationsAs with other forms of HF, patients with familial DCM are advised to limit excess dietary sodium and to avoid alcohol ingestion or exposure to other cardiotoxins—in particular, cocaine, amphetamines, and certain antineoplastic agents.12 Observational studies have found that competitive athletes have an increased rate of adverse events in LMNA associated DCM.37 Accordingly, it would be reasonable to advise against sustained endurance training in affected patients, even with minimal disease manifestations. Competitive sport is generally proscribed in DCM, consistent with consensus recommendations.53Medical TherapyIn patients with DCM, significant clinical benefit, including increased survival, has been associated with the use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-adrenoreceptor blockers (BB), aldosterone antagonists, and vasodilators. As described in consensus guidelines, these medications should be titrated to the dose used in clinical trials unless limited by side effect.12Patients with DCM were included in the pivotal trials that established the survival benefit associated with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and BB use in a broad spectrum of patients with DCM; from severe54,55-to-moderate56,57 HF to asymptomatic LV systolic dysfunction.58,59 The benefit conferred by aldosterone antagonists in patients with mild60 and severe HF61 was similar in patients with both nonischemic and ischemic cardiomyopathy. Therapy with the vasodilator combination of hydralazine and isosorbide dinitrate improved survival in patients with DCM.62,63 However, not all vasodilators are beneficial, including doxazosin62 and dihydropyridine calcium channel blockers,64 which did not improve outcomes in DCM.The proportion of study subjects with familial or genetic DCM was not specified in the large HF clinical trials. In a small, randomized, placebo-controlled trial of nongenotyped patients with suspected early familial DCM, carvedilol did not improve cardiac function, although longer term follow-up suggested benefit.47 Nonrandomized trials have supported the use of BB and angiotensin-converting enzyme inhibitors in patients with Becker and Duchenne Muscular Dystrophy.31Sudden Death Risk Stratification and Implantable Cardiac Device TherapyThe prevention of SCD is a primary concern in patients with inherited cardiomyopathy. Medical therapies, especially BB and aldosterone antagonists,57,61 reduce the risk of cardiac arrest in patients with DCM and should be used in accordance with guideline recommendations, as described in the previous section. Implantable cardioverter-defibrillator (ICD) therapy can offer incremental prevention of SCD and is advised in selected patients (Table 3).65 The use of ICDs for secondary prevention is noncontroversial, as patients with prior cardiac arrest or sustained ventricular tachycardia benefit from ICD placement.65Table 3. Accepted Indications for ICD Therapy in Familial Dilated CardiomyopathyIndicationICD Recommendation*Resuscitated sudden cardiac death from VF or VTClass ISustained VT and significant LV dysfunction†Class ILVEF≤35% and class II–III heart failure on optimal medical therapyClass IUnexplained syncope and significant LV systolic dysfunction† with inducible VT/VF at EPSClass IUnexplained syncope and significant LV systolic dysfunction†Class IIaSustained VT and normal or near normal LVEFClass IIaLVEF≤30% to 35% and class I heart failure on optimal medical therapyClass IIbFamily history of sudden deathClass IIbLV hypertrabeculation/noncompactionClass IIbEPS indicates electrophysiological study; LVEF, left ventricular ejection fraction; VF, ventricular fibrillation; and VT, ventricular tachycardia.*2008 AHA/ACC/HRS consensus guideline recommendations. Class I: Should be performed; Class IIa: Reasonable to perform; Class IIb: May be considered. ICD therapy is not advised for patients without reasonable expectation of survival with good functional status for more than 1 yr.The indication for primary prevention of SCD with ICD therapy in DCM is largely based on the severity of systolic dysfunction. The risk of SCD increases with decline in systolic function in coronary heart disease,66 nongenotyped DCM,67 and genetic DCM.68There is strong evidence to support the use of ICD therapy for primary prevention in patients with severe left ventricular systolic dysfunction. Evidence is most robust in patients with ischemic heart disease. However, trials have also been conducted in exclusively nonischemic DCM. In the DEFINITE trial, ICD therapy was studied in 458 patients with DCM, left ventricular ejection fraction (LVEF) ≤35%, NYHA class I–III HF, and ambient ventricular arrhythmias (eg, nonsustained ventricular tachycardia [NSVT] on ambulatory electrocardiographic monitoring).69 The risk of SCD was significantly reduced (hazard ratio, 0.20; confidence interval, 0.06–0.71; P=0.006), and there was an associated trend toward reduced all-cause mortality with ICD therapy. The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) of primary prevention, ICD therapy in patients with LVEF ≤35% and NYHA class II–III HF included a prespecified subgroup analysis in the 1213 patients with DCM.70 There was a nonsignificant trend toward reduced mortality (hazard ratio, 0.73; confidence interval, 0.50–1.07; P=0.06) in patients with DCM. Importantly, both of these studies were performed in patients receiving recommended BB and angiotensin-converting enzyme inhibitors therapy. Consensus guidelines recommend primary prevention ICD placement in patients who have severe systolic dysfunction (LVEF≤30% to 35%), are receiving optimal medical therapy, and have reasonable 1-year survival. Recommendations are strongest for patients with HF symptoms (NYHA class II and III).71 The role of ICD therapy for primary prevention of SCD is less well established in patients with lesser degrees of systolic dysfunction (eg, LVEF≥40%), although recent studies indicate increased risk of arrhythmic events in LMNA mutation carriers with lesser degrees of systolic dysfunction (LVEF<45%).72Beyond systolic dysfunction, there are accepted (Table 3) and emerging (Table 4) risk factors that can identify patients at increased risk of SCD who may benefit from ICD therapy. Consensus guidelines recommend ICD placement for patients with DCM and unexplained syncope, or a family history of SCD.71 However, ascertainment of a family history of SCD may be challenging. Anecdotally, patients often refer to these family events as heart attacks, which may falsely imply ischemic heart disease. Accordingly, consideration of other factors (age at death, concomitant atherosclerotic risk factors) and review of autopsy data may be needed to clarify the family history.Table 4. Potential/Emerging Indications for ICD Therapy in Familial Dilated CardiomyopathyIndicationNeed for pacemakerNonsustained VT on ambulatory electrocardiographic monitoringDelayed enhancement of gadolinium present on CMRGene-based diagnosis*CMR indicates cardiac magnetic resonance imaging; and VT, ventricular tachycardia.*LMNA, DES, SCN5A, Desmosomal.In a nongenotyped cohort of individuals with NSVT and DCM, the number and length of NSVT runs is predictive of major ventricular arrhythmias only in cases where LVEF exceeds 35%.73Compelling data do not support, and guidelines do not advise, the use of genetic testing for SCD risk stratification in patients with DCM.71 However, genetic testing for DCM is still in its infancy and thus, robust genotype–phenotype relationships are still rare. Because of the private nature of mutations in DCM, it is difficult to assess risk on a mutation basis. However, the type of mutation (eg, missense versus frame shift) may be predictive of events. For example, compared with missense mutations, splice-site mutations have been associated with increased risk of life-threatening ventricular arrhythmias and SCD in patients with LMNA associated heart disease.37,72 In addition to mutation type, male sex, mildly reduced LVEF (<45%), and the presence of nonsustained ventricular tachycardia signified increased risk of SCD in a cohort 269 carriers of LMNA mutations, independent of the degree of systolic dysfunction.72 Malignant ventricular arrhythmias did not occur in this cohort, unless a patient had at least 2 of these risk factors. Invasive electrophysiological studies has not effectively risk-stratified patients with nonischemic or genetic DCM40 and is not routinely advised.Preliminary reports suggest that DE identified with CMR can identify patients at increased risk of SCD.74 However, electroanatomic mapping has emerged as potentially superior to CMR DE for identification of myocardial scar substrates in patients with ventricular arrhythmias of right ventricle origin75,76 A comparison of CMR DE with electroanatomic mapping in LV cardiomyopathies has not yet been performed. The results of small studies notwithstanding, the role of genetic testing, ambulatory electrocardiographic monitoring, invasive electrophysiological studies, and advanced imaging for SCD risk stratification in DCM requires further study.As described above, certain genetic causes of DCM also cause AV block and sinus arrest (DCM+E), often before cardiomyopathy develops. Symptomatic bradyarrhythmias in these patients are appropriately treated with pacing. In patients with concomitant neuromuscular disease, such as myotonic dystrophy, placement of a permanent pacemaker is indicated for third degree or advanced second degree AV block (Class I recommendation), although implant can also be considered for any degree of AV block because of the unpredictable progression of heart block (Class IIb recommendation).71 These patients with established DCM+E, regardless of concomitant neuromuscular disease, remain at risk of SCD,68 and consideration should be given to placement of an ICD in lieu of pacing therapy alone.40 In a multicenter registry of 406 patients with genetically confirmed myotonic dystrophy type 1, 46 patients (11.3%) underwent permanent pacemaker implant and 21 (5.2%) received an ICD. Seven patients treated with pacemakers (15.2%) died of SCD. In comparison, 3/21 (14.3%) of ICD patients received appropriate therapies for ventricular arrhythmias, including patients without severe systolic dysfunction.77 In a small prospective study, Meune et al40 evaluated the efficacy of ICD therapy in patients (n=19) with LMNA associated heart disease who had symptomatic bradyarrhythmias but preserved systolic function (LVEF 58±12%). After 33.9±21.0 months follow-up, appropriate ICD therapies for ventricular tachycardia and ventricular fibrillation occurred in 42% of patients. However, larger studies have not confirmed these findings,37,72 and the role of ICD therapy in patients with genetic DCM who otherwise require pacing remains undefined. A reasonable approach would be to incorporate a patient’s individual risk (LVEF, ambient ventricular arrhythmia, family history), when selecting device therapy for heart block or bradyarrhythmia. Assessment of myocardial scar using either CMR or electroanatomic mapping to guide device selection in these patients has not yet been explored but merits further study.Cardiac resynchronization therapy improves survival and reduces HF symptoms in patients with systolic dysfunction, QRS prolongation, and mild78
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