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Imaging Phenotype vs Genotype in Nonhypertrophic Heritable Cardiomyopathies

2010; Lippincott Williams & Wilkins; Volume: 3; Issue: 6 Linguagem: Inglês

10.1161/circimaging.110.957563

1942-0080

Subha V. Raman, Cristina Basso, Harikrishna Tandri, Matthew R.G. Taylor,

Viral Infections and Immunology Research

HomeCirculation: Cardiovascular ImagingVol. 3, No. 6Imaging Phenotype vs Genotype in Nonhypertrophic Heritable Cardiomyopathies Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessResearch ArticlePDF/EPUBImaging Phenotype vs Genotype in Nonhypertrophic Heritable CardiomyopathiesDilated Cardiomyopathy and Arrhythmogenic Right Ventricular Cardiomyopathy Subha V. Raman, Cristina Basso, Harikrishna Tandri and Matthew R.G. Taylor Subha V. RamanSubha V. Raman From the Ohio State University College of Medicine (S.V.R.), Columbus, Ohio; University of Padua Medical School (C.B.), Padua, Italy; Johns Hopkins University School of Medicine (H.T.), Baltimore, Md; and University of Colorado Denver (M.R.G.T.), Aurora, Colo. , Cristina BassoCristina Basso From the Ohio State University College of Medicine (S.V.R.), Columbus, Ohio; University of Padua Medical School (C.B.), Padua, Italy; Johns Hopkins University School of Medicine (H.T.), Baltimore, Md; and University of Colorado Denver (M.R.G.T.), Aurora, Colo. , Harikrishna TandriHarikrishna Tandri From the Ohio State University College of Medicine (S.V.R.), Columbus, Ohio; University of Padua Medical School (C.B.), Padua, Italy; Johns Hopkins University School of Medicine (H.T.), Baltimore, Md; and University of Colorado Denver (M.R.G.T.), Aurora, Colo. and Matthew R.G. TaylorMatthew R.G. Taylor From the Ohio State University College of Medicine (S.V.R.), Columbus, Ohio; University of Padua Medical School (C.B.), Padua, Italy; Johns Hopkins University School of Medicine (H.T.), Baltimore, Md; and University of Colorado Denver (M.R.G.T.), Aurora, Colo. Originally published1 Nov 2010https://doi.org/10.1161/CIRCIMAGING.110.957563Circulation: Cardiovascular Imaging. 2010;3:753–765IntroductionAdvances in cardiovascular imaging increasingly afford unique insights into heritable myocardial disease. Because the clinical presentation of genetic cardiomyopathies may range from nonspecific symptoms to sudden cardiac death, an accurate diagnosis has implications for individual patients as well as related family members. The initial consideration of genetic cardiomyopathy may occur in the imaging laboratory, where one must recognize the patient with arrhythmogenic right ventricular cardiomyopathy (ARVC) among the many with ventricular arrhythmias referred to define the myocardial substrate. Accurate diagnosis of the patient presenting with dyspnea and palpitations whose first-degree relatives have lamin A/C (LMNA) cardiomyopathy may warrant genetic testing1,2 plus imaging of diastolic function and myocardial fibrosis.3 Because advances in cardiac imaging afford the detection of subclinical structural and functional changes, the imaging specialist must be attuned to the signatures of specific genetic disorders. With the increased availability of both advanced imaging and genotyping techniques, this review seeks to provide cardiovascular imaging specialists and clinicians with the contemporary information needed for more precise diagnosis of heritable myocardial disease. A companion article in this series covers imaging phenotype and genotype considerations in hypertrophic cardiomyopathy. This review details the clinical features, imaging phenotypes, and current genetic understanding for 2 of the most common nonhypertrophic cardiomyopathy conditions that prompt myocardial imaging: dilated cardiomyopathy (DCM) and ARVC. Although all imaging modalities are considered herein, considerable focus is given to cardiac magnetic resonance (CMR), with its unique capabilities for myocardial tissue characterization.Dilated CardiomyopathyDCM has a prevalence of at least 1 in 25004 and an incidence of 7 per 100 000/y.5 The condition was classically defined as "idiopathic" when a single member in a family was affected without a known cause and as "familial" when the DCM phenotype was present in 2 or more related family members.6,7 However, substantial work in the past few decades has confirmed that genetic factors are the underlying cause of both idiopathic and familial forms and that careful examination of the relatives of an index case often reveals other affected family members and a familial pattern of disease. These systematic studies of idiopathic and familial cases have shown that DCMs may be confined to ventricular enlargement and systolic dysfunction, or they may occur in the setting of extracardiac features, such as skeletal myopathy and elevated serum creatine kinase levels (muscular dystrophy–associated cardiomyopathies are not included in this review). Consideration of a primary genetic disorder presumes that other secondary causes, such as metabolic disorders, acute inflammatory conditions, valvular heart disease, toxins, and ischemic heart disease, have been excluded. Notably, presumed secondary DCM may occur in the setting of a genetic predisposition.8The incidence of DCM is increasing in part due to advances in diagnostics and increased awareness among physicians. In the early stages of the disease, minimal symptoms may be present and diagnosis delayed, a situation that often becomes apparent when other ostensibly "healthy" family members of a patient are evaluated and additional cases ascertained. Many cases of DCM have an apparent genetic origin, with 30% to 50% of cases suspicious for a primary genetic etiology.9–11 These estimates are complicated by the fact that DCM is classified as a "mixed" cardiomyopathy in deference to the broad list of genetic and exogenous causes in major classification guidelines.12 Although it is tempting to apply these guidelines as a mere road map to finding the "singular" cause of a patient's DCM, it is likely that both genetic and nongenetic factors interact to cause many instances of the disease. Despite the probable heterogeneity of etiology in DCM, the high risk of disease to biological relatives provides a compelling reason to assess each case of cardiomyopathy for the possibility of a primary genetic cause.DCM: Imaging PhenotypeThe phenotype of DCM is defined principally by cardiac enlargement and impaired systolic function.6,7,12 Echocardiography readily detects both. Similar features can be recognized by contrast x-ray ventriculography or nuclear imaging. For instance, DCM may be diagnosed in the patient whose symptoms are initially ascribed to ischemic heart disease and who undergoes stress nuclear scintigraphy that shows a dilated, hypocontractile left ventricle with no ischemia. Variability in cutoff values for abnormal chamber size across modalities, age, sex, and indices of body size should be taken into account when assessing for cardiac enlargement. Recognizing abnormal myocardial relaxation from mitral inflow and tissue Doppler velocities is particularly important, because some genetic conditions classified as DCM, such as LMNA cardiomyopathy, predominantly affect diastolic function in the initial stages of the disease. Although many other conditions such as hypertensive heart disease may also manifest as diastolic dysfunction, these echo Doppler findings warrant consideration of potential genetic etiologies when recognized in the context of a family history of cardiomyopathy or clinical markers of high risk (eg, malignant ventricular arrhythmia). Whereas a more precise etiologic determination may be limited, echo Doppler provides valuable information on the degree of pulmonary hypertension and left ventricular (LV) filling pressures, with prognostic implications.13 LV noncompaction may present as a distinct genetic cardiomyopathy,14 but it also may represent a phenotypic feature along a spectrum of other heritable cardiomyopathies.15Clues to a specific genetic cause may come from techniques like CMR. An appropriate protocol to evaluate the patient with DCM of unknown etiology should include 3 important techniques for myocardial characterization: T2* quantification,16 T2-weighted imaging or T2 mapping,17 and late gadolinium enhancement (LGE).18 In brief, T2* is an MR relaxation time whose value is shortened in tissues with iron aggregates. The introduction of T2*-based screening of patients with thalassemia, a genetic disease associated with myocardial siderosis due to transfusion-related iron overload, has dramatically reduced mortality in this population. Notably, patients with sickle cell disease may develop hepatic siderosis, but our laboratory and others19,20 have not found significant myocardial overload in these patients, despite lifelong exogenous iron overload, suggesting that additional, as-yet-undefined genetic factors may influence myocardial siderosis. A normal myocardial T2* exceeds 20 ms at 1.5 T; a diffusely shortened myocardial T2* in a patient presenting with cardiomyopathy without secondary causes such as chronic transfusions warrants consideration of hereditary hemochromatosis. T2* screening of large hereditary hemochromatosis cohorts has not been reported to provide a contemporary estimate of cardiac involvement, although histopathologic detection at autopsy examination after sudden cardiac death suggests that it may be underrecognized.21 T2 increases with tissue water's increased content or lower protein binding and may identify regions of myocardial inflammation or edema.22 The MR parameter T2 was recently reported to be increased in patients with dystrophin-associated cardiomyopathy.23LGE is the essential CMR technique for myocardial characterization in DCM, providing both diagnostic and prognostic value.24 LGE imaging leverages contrast-induced T1 shortening to distinguish between necrotic/fibrotic and normal myocardium. Although findings such as midmyocardial fibrosis may be nonspecific, they reliably distinguish DCM from infiltrative and ischemic cardiomyopathies. Notably, relying on angiography alone to exclude coronary artery disease as the cause of DCM could potentially misclassify up to 13% of cases.18 Similarly, LGE findings of nonischemic cardiomyopathy may coexist with infarct scar, which should prompt the interpreting team to consider nonischemic cardiomyopathy superimposed on ischemic heart disease. Genotypic evidence supporting DCM as an end-stage phenotype of hypertrophic cardiomyopathy25 underscores the importance of considering a genetic cardiomyopathy when appropriate phenotypic findings are detected by cardiac imaging (Figure 1). LGE positivity in a patient with ventricular arrhythmia as well as a concerning family history for heritable disease may warrant genetic testing; however, recognition that patients with genetic cardiomyopathies may be LGE-negative at presentation underscores the variability in phenotype and opportunities for imaging advances to better define signatures of genetic myocardial disease.Download figureDownload PowerPointFigure 1. CMR imaging in a 52-year-old man with ventricular arrhythmia on ambulatory ECG monitoring whose family history included a grandparent with sudden cardiac death at a young age. Echocardiography showed normal LV systolic function and mitral valve prolapse. CMR was performed and confirmed normal systolic function (left, end diastole; middle; end systole) but revealed midmyocardial fibrosis by LGE imaging (right, arrowheads). The patient underwent genetic testing via a 23-gene panel for DCM (GeneDx, Gaithersburg, Md) that revealed a mutation in myosin binding protein C.DCM: Current Status of Genetic TestingDCM is characterized by high genetic heterogeneity: >25 different genes have been linked to the DCM phenotype (Table 1).1,26–46. Early work identified the genes predominantly responsible for coding cytoskeletal proteins, and a "cytoskeletal hypothesis" implicating dysfunction of structural networks was proposed (Figure 2).47,48 More recent data have revealed that perturbations in proteins beyond the cytoskeleton can lead to DCM, and the idea of a "final common pathway" now extends to sarcomeric, ion channel, nuclear lamina, and desmosomal proteins. Accurate prevalence estimates for the pathogenesis of each gene have been difficult to obtain, in part because most studies have been conducted in cohorts of modest size (<200 families), with each individual gene often accounting for 20 genes offered in a single panel. Testing is available in the United States and Europe and is probably less available in other regions of the world, although even in the United States, testing may not always be covered by commercial insurance carriers.DCM: Benefits and Limitations of TestingFor many patients, the greatest benefit of genetic testing comes in evaluating family members at risk of developing the DCM phenotype. For the index patient with evident DCM, genetic testing is not needed to confirm the diagnosis, although it may help determine whether the disease is primarily due to a genetic defect versus another etiology. At-risk family members who have borderline changes on echocardiography may be considered for early treatment to prevent or delay progressive cardiac dysfunction, although studies supporting this approach in true genetic cases are lacking. It should be noted that mutations in LMNA may be more malignant than are mutations in other DCM genes, as LMNA mutation carriers appear to be at elevated risk for sudden death and a more rapid or severe course of heart failure.Testing should generally be undertaken after formal genetic counseling and a discussion of the benefits and limitations of testing in the context of the individual patient as well as the overall family structure. Because current genetic testing panels fail to identify a pathogenic mutation in up to 50% of cases, patients should be counseled on this important limitation of current testing. "Private" mutations, which are restricted to 1 or only a few families, are common, making predictions of genotype to phenotype unreliable, with the possible exception of LMNA mutations, which are expected to be more severe. Variants of unknown significance can be encountered and may be difficult to interpret, even after additional individuals in the family undergo testing. It has been recommended that strong consideration be given for referral to centers with experience in cardiomyopathy genetics if genetic testing is to be undertaken.52DCM: Family ScreeningIn deference to the large role of genetic factors in DCM, recommendations for collecting a detailed family history and offering genetic counseling have been proposed.52 The most common inheritance pattern is autosomal dominant, showing multigenerational involvement, equal numbers of affected males and females, and male-to-male transmission. Other inheritance patterns, though less common, have been described; indeed, the specific pattern of inheritance within a family can be used to guide genetic counseling and testing. In addition to evaluating a complete and accurate family history, direct clinical testing of first-degree relatives by objective measures such as ECG and echocardiography are important to identify latent cases. A review of the medical records of deceased individuals in a family can also be critical in uncovering past cases who were not recognized as manifesting the phenotype.Arrhythmogenic Right Ventricular CardiomyopathyARVC is an inherited cardiomyopathy characterized by fibrofatty replacement of the RV myocardium, leading to RV failure and arrhythmias.53,54 Prevalence estimates in the general population range from 1:1000 to 1:5000.55,56 It often affects young men who have an athletic lifestyle. Presenting symptoms range from palpitations to exertional syncope and sudden cardiac death.54 Arrhythmias in ARVC most frequently originate from the right ventricle and have a left bundle branch block morphology. The disease often affects the RV outflow tract, the base of the right ventricle, and the RV apex, collectively termed the "triangle of dysplasia." Early-stage patterns of RV involvement are poorly understood, making it difficult to diagnose early disease by imaging. Major and minor diagnostic criteria have been proposed that encompass structural, electrophysiologic, and histopathologic variables.57,58 Identification of abnormalities in RV structure and function constitutes an important part of the diagnosis of ARVC and accounts for a major or minor criterion based on the severity of the abnormality. The task force criteria, initially proposed in 1994, were recently revised to include quantitative data for RV functional evaluation, underscoring the importance of a thorough assessment of the right ventricle in cases of suspected ARVC.58ARVC is a familial disease in at least 50% of cases, usually transmitted as an autosomal dominant trait with variable penetrance.59,60 Reduced penetrance and variable expressivity, together with the availability of small families for clinical evaluation, might explain the underestimation of ARVC as a heritable disease. Family history alone cannot replace the prospective evaluation of family members in establishing inheritance of ARVC. In the absence of definite knowledge of gene-carrier status, the major clinical challenge consists in differentiating mild or atypical manifestations in family members from the so-called "phenocopies"; that is, nonhereditary diseases that can mimic ARVC, such as idiopathic RV outflow tract tachycardia, myocarditis, and sarcoidosis.ARVC: Imaging PhenotypeEchocardiography is widely available and is often the first imaging modality used to assess cardiac structure and function in cases of known or suspected ARVC (Figure 3; online-only Data Supplement I). Three-dimensional echocardiography has been shown to accurately quantify RV size and systolic function compared with CMR.61 Inherent limitations imposed by the acoustic window with ultrasound-based cardiac imaging in some patients may preclude visualization of the segmental RV abnormalities that constitute the phenotypic hallmarks of ARVC. X-ray right ventriculography is invasive and has fallen out of favor owing to the availability of noninvasive imaging techniques. The modified ARVC Task Force Criteria58 provide detailed cutoffs regarding abnormal RV size and wall motion; in brief, an RV ejection fraction ≤40% by CMR, or regional akinesia, dyskinesia, or aneurysm by 2D echo, CMR, or RV angiography constitute major criteria for ARVC.Download figureDownload PowerPointFigure 3. Transthoracic echocardiogram at end diastole (A) and end systole (B) indicates RV dysfunction in a 32-year-old woman who underwent defibrillator placement shortly after surviving sudden cardiac death. She was then referred for cardiac computed tomography to assess for possible ARVC. Maximum-intensity projection image in an oblique sagittal plane demonstrates the scalloped RV myocardium (arrowheads) and dyskinetic segments when comparing images reconstructed at end diastole (C) versus end systole.Cardiovascular computed tomography may sometimes be used to diagnose ARVC, particularly in the setting of contraindications to CMR (Figure 3). Although computed tomography–based recognition of intramyocardial fat is appealing,62 cine reconstructions (online-only Data Supplement II) are essential to assess regional RV wall motion given the challenges (even with the high spatial resolution of computed tomography) of defining fibrofatty replacement in a thin, diseased right ventricle.CMR is uniquely suited to evaluate ARVC: it not only provides excellent functional information for the right ventricle, but it also can provide tissue characterization to depict fibrosis and fatty infiltration in the right ventricle.63,64 CMR provides accurate quantitative assessment of RV size and of global and regional RV systolic function, important parts of the revised task force criteria. Limitations inherent to CMR include the presence of CMR-incompatible devices or foreign bodies, severe claustrophobia, and advanced renal disease that precludes use of the powerful LGE technique for myocardial characterization.CMR findings in ARVC include fat infiltration of the myocardium (Figure 4), global and regional RV dysfunction, and myocardial fibrosis. Dark-blood imaging may demonstrate replacement of ventricular myocardium with a hyperintense fat signal, which infrequently appears as a signal void on a corresponding fat-suppressed image. In the literature, the incidence of fat infiltration in ARVC has been reported to range from 60% to 100%, likely related to differences in patient selection.65 Fat infiltration often affects the basal right ventricle, RV outflow tract, and the RV anterior wall close to the tricuspid inlet. Relying on intramyocardial fat visualization to make the diagnosis is problematic, owing to the often-abundant epicardial fat and underscoring the need to carefully distinguish between abnormal fat infiltrating the RV myocardium and fat in the atrioventricular groove. Fat suppression helps distinguish epicardial fat from the unaffected RV wall, although failure to distinguish normal epicardial fat from pathologic RV infiltration may result in a misdiagnosis and/or overdiagnosis of ARVC.66 ARVC should be kept distinct from both fatty infiltration of the right ventricle and adipositas cordis. It is well known that a certain amount of intramyocardial fat is present in the RV anterolateral and apical regions, even in the normal heart, and that intramyocardial and epicardial fat increases with increasing body weight and age,67,68 although the prevalence is unknown.69–71 However, both the fibrofatty and fatty variants of ARVC show, besides fatty replacement of the RV myocardium, degenerative changes in myocytes and interstitial fibrosis, with or without extensive replacement-type fibrosis. As such, the suggestion of RV intramyocardial fat by dark-blood imaging should prompt closer attention to segmental RV function and LGE in the corresponding location to reduce the number of false-positive imaging-based diagnoses.Download figureDownload PowerPointFigure 4. ECG of a patient who presented with fatigue demonstrates classic ε waves of ARVC (left, arrowheads). Dark-blood CMR image shows extensive fatty infiltration that also involves the LV myocardium (right, arrows).Among CMR criteria, global and regional function is most useful in the diagnosis and is very reproducible.72 RV regional dysfunction often precedes global dysfunction and affects the triangle of dysplasia. Regional functional changes include focal hypokinesis, dyskinesis, and aneurysms (online-only Data Supplement II). By the time of diagnosis, the majority of probands with ARVC have global RV dysfunction. Reproducible CMR-derived measures of RV volumes and function, with published nomograms,58 are invaluable in the longitudinal evaluation of patients with borderline abnormalities and can be used to assign major or minor criteria for ARVC.Evaluation of plakophillin-2 (PKP2) mutation-positive, asymptomatic, first-degree relatives revealed minor crinkling contractions in the RV base that resembled an accordion.73 This sign was seen with a high prevalence in mutation-positive relatives and none of the first-degree relatives who did not carry the pathologic mutation. Reproducibility of this finding has not been systematically assessed, and the diagnostic and prognostic significance remains unknown.LGE imaging can noninvasively demonstrate RV fibrosis (Figure 5) and is an essential component of the CMR examination of patients with suspected ARVC.63 The extent of RV myocardial fibrosis is correlated with the degree of RV dysfunction, and it predicts inducibility of ventricular arrhythmias.63 LGE also assists in distinguishing phenocopies of ARVC-like sarcoidosis, which occasionally results in isolated cardiac involvement.74 Multiple, patchy regions of LV and septal hyperenhancement favor a diagnosis of sarcoidosis75 and may also be seen in myocarditis. Notably, fat infiltration is distinctly absent in both conditions.Download figureDownload PowerPointFigure 5. LGE image in the horizontal long-axis plane shows diffuse hyperenhancement of the RV myocardium, suggestive of fibrosis (arrows). Also shown is an area of focal hyperenhancement in the lateral LV myocardium (arrowhead).Recent evidence suggests that ARVC is a biventricular cardiomyopathy; the extent and severity of LV involvement may be related to the underlying genotype and can appear early in the disease course.76 Histopathologic data suggest an inflammatory component in left-dominant arrhythmogenic cardiomyopathy; further studies are needed to define the potential utility of T2 imaging in delineating this feature of the disease. In PKP2-related ARVC, the most common mutation in the Unites States, LV fat infiltration is seen in up to 25% of these patients and most commonly affects the posterolateral LV epicardium.73 Recently, tagged cine CMR has revealed regional LV dysfunction in the posterolateral LV wall in patients with early ARVC, even in the presence of normal global function.77 Midmyocardial hyperenhancement by LGE, which may be seen in DCM, and subepicardial hyperenhancement have been reported in ARVC, particularly in desmoplakin mutation carriers.78 This underscores the limitations in defining the underlying genetic abnormality by imaging phenotype alone. Individual patient assessment continues to require aggregate data assessment–history, examination, serologies, ECG, and imaging–in making the correct diagnosis.ARVC: Current Status of GeneticsSince the discovery of the first ARVC locus in 1994,79 multiple disease loci have been mapped, but the disease-causing genes remained elusive (Table 2).46,80–88 The genetic cause of the recessive variant Naxos syndrome was elucidated first, as it is a highly penetrant disease with a clearcut cutaneous phenotype.88 Notably, epidermal cells in the palms and soles as well as cardiomyocytes are exposed to high shear stress and share components of the mechanical junctional apparatus (desmosome and fascia adherens) that is responsible for cell-to-cell adhesion. Proteins from 3 separate families assemble (Figure 6)56 to form desmosomal cadherins (desmoglein and desmocollin), armadillo proteins (plakoglobin and PKP), and plakins (desmoplakin).Table 2. Genetic Causes of ARVCAuthors, ReferenceGene SymbolGeneChromosomal LocationOMIM*Mode of InheritanceCommentMcKoy et al88JUPPlakoglobin17q21#173325Autosomal-dominantNaxos diseaseAsimaki et al80#601214Autosomal-recessiveRampazzo et al85DSPDesmoplakin6p24#125647Autosomal-dominantCarvajal syndromeNorgett et al83#605676Autosomal-recessiveGerull et al46PKP2Plakophilin-212p11#602861Autosomal-dominantPilichou et al84DSG2Desmoglein-218q12#125671Autosomal-dominantSyrris et al86DSC2Desmocollin-218q12#125645Autosomal-dominantExtradesmosomal genesTiso et al87RYR2Ryr21q42–q43#180902Autosomal-dominantCPVTBeffagna et al81TGF-β3TGF-β314q23–q24#190230Autosomal-dominantMerner e