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Introduction : Cardiac amyloidosis is the most common cause of infiltrative cardiomyopathy and is associated with a poor prognosis. Transthyretin cardiac amyloidosis, particularly the type caused by the mutation that replaces the amino acid valine with the amino acid isoleucine at position 122 (Val122Ile), is most common among African- Americans above 65 years of age. Evidence suggests that this mutation is an important, though under-diagnosed, cause of heart failure in this population. Case presentation : A 74-year-old African American male with a diagnosis of non-ischemic cardiomyopathy for several years, presented with gradually worsening dyspnea on exertion and lower extremity edema. There is no known cardiac disease in his family. An echocardiogram was done showing a decrease in ejection fraction to 30% from 45% in the span of a year. An endomyocardial biopsy analysis identified transthyretin amyloid with the Val122Ile mutation, confirming the diagnosis of familial transthyretin cardiomyopathy. Discussion : Systemic amyloidosis is a group of diseases caused by the deposition of an abnormally folded, insoluble protein that can accumulate in multiple organs causing progressive and irreversible dysfunction. The mutations that most commonly induce variant transthyretin cardiac amyloidosis are Val122Ile, Val30Met and Thr60Ala. The Val122Ile mutation has been found to be present in 3–4% of the African American/Caribbean population. Conclusions : Familial amyloid cardiomyopathy is an uncommonly recognized cause of heart failure in the population, and patients may wait several years before accurate diagnosis, risking additional significant irreversible deterioration. Patients that meet the high-risk profile criteria – male gender, age 65 years and older, heart failure symptoms, symmetric left ventricular (LV) hypertrophy, and moderately depressed LV function – should likely undergo additional testing for cardiac amyloidosis. Keywords: amyloid; cardiomyopathy; transthyretin; cardiac amyloidosis; familial amyloid cardiomyopathy; TTR amyloidosis (Published: 25 November 2014) Citation: Journal of Community Hospital Internal Medicine Perspectives 2014, 4 : 25500 - http://dx.doi.org/10.3402/jchimp.v4.25500

Arrhythmogenic cardiomyopathy (ACM) is characterized by frequent cardiac arrhythmias. To elucidate the underlying mechanisms and discover potential chemical modifiers, we created a zebrafish model of ACM with cardiac myocyte-specific expression of the human 2057del2 mutation in the gene encoding plakoglobin. A high-throughput screen identified SB216763 as a suppressor of the disease phenotype. Early SB216763 therapy prevented heart failure and reduced mortality in the fish model. Zebrafish ventricular myocytes that expressed 2057del2 plakoglobin exhibited 70 to 80% reductions in I(Na) and I(K1) current densities, which were normalized by SB216763. Neonatal rat ventricular myocytes that expressed 2057del2 plakoglobin recapitulated pathobiological features seen in patients with ACM, all of which were reversed or prevented by SB216763. The reverse remodeling observed with SB216763 involved marked subcellular redistribution of plakoglobin, connexin 43, and Nav1.5, but without changes in their total cellular content, implicating a defect in protein trafficking to intercalated discs. In further support of this mechanism, we observed SB216763-reversible, abnormal subcellular distribution of SAP97 (a protein known to mediate forward trafficking of Nav1.5 and Kir2.1) in rat cardiac myocytes expressing 2057del2 plakoglobin and in cardiac myocytes derived from induced pluripotent stem cells from two ACM probands with plakophilin-2 mutations. These observations pinpoint aberrant trafficking of intercalated disc proteins as a central mechanism in ACM myocyte injury and electrical abnormalities.

Cardiomyocyte cell division and replication in mammals proceed through embryonic development and abruptly decline soon after birth. The process governing cardiomyocyte cell cycle arrest is poorly understood. Here we carry out whole exome sequencing in an infant with evidence of persistent postnatal cardiomyocyte replication to determine the genetic risk factors. We identify compound heterozygous ALMS1 mutations in the proband, and confirm their presence in her affected sibling, one copy inherited from each heterozygous parent. Next, we recognise homozygous or compound heterozygous truncating mutations in ALMS1 in four other children with high levels of postnatal cardiomyocyte proliferation. Alms1 mRNA knockdown increases multiple markers of proliferation in cardiomyocytes, the percentage of cardiomyocytes in G2/M phases, and the number of cardiomyocytes by 10% in cultured cells. Homozygous Alms1-mutant mice have increased cardiomyocyte proliferation at two weeks postnatal compared to wild-type littermates. We conclude that deficiency of Alström protein impairs postnatal cardiomyocyte cell cycle arrest.

Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue with marked interfamilial and intrafamilial variation in phenotype. The primary defect in affected patients resides in the gene for fibrillin-1 (FBN1) on 15q21. Linkage analysis has shown no locus heterogeneity in the classic phenotype, although substantial allelic heterogeneity exists. Recently it has been shown that the size of the gene is approximately 200 kb. These and other factors have precluded routine mutation screening for presymptomatic and prenatal diagnosis. Previously we described four intragenic microsatellite polymorphisms that can be used for haplotype segregation analysis. The utility of this approach is limited because the markers do not fully span the gene and show incomplete informativeness, with 16% homozygosity for the most common haplotype. We have now identified and localized highly polymorphic microsatellite markers that fall within 1 Mb of FBN1. Complete haplotype heterozygosity was observed in a population of 50 unrelated control individuals when the flanking markers and existing intragenic polymorphisms were used in combination. We demonstrate the utility of haplotype segregation analysis in the presymptomatic diagnosis and counseling of families showing atypical or equivocal manifestations of MFS.

This editorial refers to ‘Cardiovascular manifestations in men and women carrying a FBN1 mutation’, by D. Detaint et al. doi:10.1093/eurheartj/ehq258 We are rapidly entering an era of personalized genomic medicine. The complete sequencing of the human genome was first announced >9 years ago, and soon afterwards the annotated human genome sequence was available online.1 Today, DNA analysis that was once considered onerous has become routine. Although not perfect, ‘next-generation’ techniques for rapid and low-cost sequencing have been applied to whole human genome determination. The use of massively parallel, high-throughput sequencing to analyse the human genome was first published in 2008 with a reduction in cost estimated from US$100 million to ∼US$1 million2. Soon afterwards, two additional whole human genome sequences were reported, with estimated costs reduced even further.3,4 Investigators recently reported whole human genome analysis by another next-generation technique, Sequencing by Oligonucleotide Ligation and Detection (SOLiD) to determine the cause of recessive Charcot–Marie–Tooth disease.5 The estimated cost for this herculean task was

BackgroundIncomplete penetrance and variable expressivity of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) complicate family screening.ObjectivesThe objective of the present study was to determine the optimal approach to longitudinal follow-up regarding: 1) screening interval; and 2) testing strategy in at-risk relatives of ARVD/C patients.MethodsWe included 117 relatives (45% male, age 33.3 ± 16.3 years) from 64 families who were at risk of developing ARVD/C by virtue of their familial predisposition (72% mutation carriers [92% plakophilin-2]; 28% first-degree relatives of a mutation-negative proband). Subjects were evaluated by electrocardiography (ECG), Holter monitoring, signal-averaged ECG, and cardiac magnetic resonance (CMR). Disease progression was defined as the development of a new criterion by the 2010 Task Force Criteria (not the “Hamid criteria”) at last follow-up that was absent at enrollment.ResultsAt first evaluation, 43 subjects (37%) fulfilled an ARVD/C diagnosis according to the 2010 Task Force Criteria. Among the remaining 74 subjects (63%), 11 of 37 (30%) with complete re-evaluation experienced disease progression during 4.1 ± 2.3 years of follow-up. Electrical progression (n = 10 [27%], including by ECG [14%], Holter monitoring [11%], or signal-averaged ECG [14%]) was more frequently observed than structural progression (n = 1 [3%] on CMR). All 5 patients (14%) with clinical ARVD/C diagnosis at last follow-up had an abnormal ECG or Holter monitor recording, and the only patient with an abnormal CMR already had an abnormal ECG at enrollment.ConclusionsOver a mean follow-up of 4 years, our study showed that: 1) almost one-third of at-risk relatives have electrical progression; 2) structural progression is rare; and 3) electrical abnormalities precede detectable structural changes. This information could be valuable in determining family screening protocols.

Transthyretin (TTR) amyloidosis causes heart failure from cardiac deposition of TTR amyloid fibrils, the by-product of TTR homotetramer disassembly. Wild-type (WT) TTR deposition leads to senile amyloidosis, predominantly manifesting with cardiomyopathy. Missense mutations in the TTR gene result in familial TTR amyloidosis. Certain mutations are more likely to affect the heart, while others cause more neurologic involvement. Extracellular fibril deposition triggers intracellular stress response, upregulation of the inflammatory cascades, apoptosis, and organ dysfunction. Recent studies suggest that TTR cardiac amyloid may be a significant contributor to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). Summarized in this review are the molecular pathways underlying the cellular toxicity of TTR amyloid fibrils and the emerging therapies aimed at TTR tetramer stabilization, abrogation of TTR synthesis in the liver, or inhibition of amyloidogenesis.

There is an increased incidence of cardiovascular disease in osteogenesis imperfecta (OI), though its exact prevalence is not known. Because type I collagens are widely present in cardiac valves, ventricles, and vasculature, clinicians should be wary of associated conditions. These include valve insufficiency, heart failure, aortic aneurysm, and arterial dissection. Murine models with Col1a1 and Col1a2 mutations help to identify the cardiovascular manifestations that are predicted to occur in pelople with OI. Human population studies are also informative, but longitudinal studies are inherently limited by relatively small numbers. The pathophysiology of cardiovascular diseases in OI is poorly understood, but similar phenotypic features in other heritable disorders of connective tissue suggest that extracellular collagens may regulate growth factor signaling. Surgery for severe cardiovascular complications in OI should be considered in the context of associated risks, such as difficulties with airway access, bone fracture, poor wound healing, fragile capillaries, and platelet dysfunction.

The Journal provides the clinician and scientist with the latest advances in discovery research, emerging technologies, preclinical research design and testing, and clinical trials. We highlight advances in areas of induced pluripotent stem cells, genomics, biomarkers, multimodality imaging, and antiplatelet biology and therapy. The top publications are critically discussed and presented along with anatomical reviews and FDA insight to provide context.

Loeys-Dietz syndrome (LDS) is a connective tissue disorder that is characterized by a high risk for aneurysm and dissection throughout the arterial tree and phenotypically resembles Marfan syndrome. LDS is caused by heterozygous missense mutations in either TGF-β receptor gene (TGFBR1 or TGFBR2), which are predicted to result in diminished TGF-β signaling; however, aortic surgical samples from patients show evidence of paradoxically increased TGF-β signaling. We generated 2 knockin mouse strains with LDS mutations in either Tgfbr1 or Tgfbr2 and a transgenic mouse overexpressing mutant Tgfbr2. Knockin and transgenic mice, but not haploinsufficient animals, recapitulated the LDS phenotype. While heterozygous mutant cells had diminished signaling in response to exogenous TGF-β in vitro, they maintained normal levels of Smad2 phosphorylation under steady-state culture conditions, suggesting a chronic compensation. Analysis of TGF-β signaling in the aortic wall in vivo revealed progressive upregulation of Smad2 phosphorylation and TGF-β target gene output, which paralleled worsening of aneurysm pathology and coincided with upregulation of TGF-β1 ligand expression. Importantly, suppression of Smad2 phosphorylation and TGF-β1 expression correlated with the therapeutic efficacy of the angiotensin II type 1 receptor antagonist losartan. Together, these data suggest that increased TGF-β signaling contributes to postnatal aneurysm progression in LDS.

AIMS: We sought to determine the influence of genotype on clinical course and arrhythmic outcome among arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)-associated mutation carriers.METHODS AND RESULTS: Pathogenic mutations in desmosomal and non-desmosomal genes were identified in 577 patients (241 families) from USA and Dutch ARVD/C cohorts. Patients with sudden cardiac death (SCD)/ventricular fibrillation (VF) at presentation (n = 36) were younger (median 23 vs. 36 years; P < 0.001) than those presenting with sustained monomorphic ventricular tachycardia (VT). Among 541 subjects presenting alive, over a mean follow-up of 6 ± 7 years, 12 (2%) patients died, 162 (30%) had sustained VT/VF, 78 (14%) manifested left ventricular dysfunction (EF < 55%), 28 (5%) experienced heart failure (HF), and 10 (2%) required cardiac transplantation. Patients (n = 22; 4%) with >1 mutation had significantly earlier occurrence of sustained VT/VF (mean age 28 ± 12 years), lower VT-/VF-free survival (P = 0.037), more frequent left ventricular dysfunction (29%), HF (19%) and cardiac transplantation (9%) when compared with those with only one mutation. Desmoplakin mutation carriers experienced more than four-fold occurrence of left ventricular dysfunction (40%) and HF (13%) than PKP2 carriers. Missense mutation carriers had similar death-/transplant-free survival and VT/VF penetrance (P = 0.137) when compared with those with truncating or splice site mutations. Men are more likely to be probands (P < 0.001), symptomatic (P < 0.001) and have earlier and more severe arrhythmic expression.CONCLUSIONS: Presentation with SCD/VF occurs at a significantly younger age when compared with sustained monomorphic VT. The genotype of ARVD/C mutation carriers impacts clinical course and disease expression. Male sex negatively modifies phenotypic expression.

The traditional description of the Triangle of Dysplasia in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) predates genetic testing and excludes biventricular phenotypes.We analyzed Cardiac Magnetic Resonance (CMR) studies of 74 mutation-positive ARVD/C patients for regional abnormalities on a 5-segment RV and 17-segment LV model. The location of electroanatomic endo- and epicardial scar and site of successful VT ablation was recorded in 11 ARVD/C subjects. Among 54/74 (73%) subjects with abnormal CMR, the RV was abnormal in almost all (96%), and 52% had biventricular involvement. Isolated LV abnormalities were uncommon (4%). Dyskinetic basal inferior wall (94%) was the most prevalent RV abnormality, followed by basal anterior wall (87%) dyskinesis. Subepicardial fat infiltration in the posterolateral LV (80%) was the most frequent LV abnormality. Similar to CMR data, voltage maps revealed scar (0.5 mV) in the RV basal inferior wall (100%), followed by the RV basal anterior wall (64%) and LV posterolateral wall (45%). All 16 RV VTs originated from the basal inferior wall (50%) or basal anterior wall (50%). Of 3 LV VTs, 2 localized to the posterolateral wall. In both modalities, RV apical involvement never occurred in isolation.Mutation-positive ARVD/C exhibits a previously unrecognized characteristic pattern of disease involving the basal inferior and anterior RV, and the posterolateral LV. The RV apex is only involved in advanced ARVD/C, typically as a part of global RV involvement. These results displace the RV apex from the Triangle of Dysplasia, and provide insights into the pathophysiology of ARVD/C.

Background In Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C), a normal electrocardiogram (ECG) is considered reassuring. However, some patients with ARVD/C experiencing ventricular arrhythmias have a normal ECG. Objectives To estimate how often patients with ARVD/C experiencing ventricular arrhythmias have a normal ECG during sinus rhythm, and to provide a clinical profile of these patients. Methods We included 145 patients with ARVD/C experiencing a documented sustained ventricular arrhythmia. Conventional 12-lead sinus rhythm ECGs within 6 months of the event were reviewed for diagnostic Task Force Criteria (TFC). ECGs were classified as abnormal (≥1 TFC), nonspecific (abnormal, no TFC), or normal. Cardiologic investigations within 6 months of the event were evaluated as per TFC in those with a nonspecific or normal ECG. Results The ECG was nonspecific or normal in 17 of 145 (12%) subjects. Mean age of these patients was 41.3 ± 12.4 years and 14 (82%) were men, comparable to those with an abnormal ECG. Most patients with a nonspecific or normal ECG showed ≥1 TFC on Holter monitoring (n = 9 of 10) and signal-averaged ECG (n = 4 of 5), and all had nonsustained ventricular tachycardia recorded. Among 15 patients who underwent structural evaluation, 11 (73%) showed structural TFC (9 major and 2 minor). Conclusions Although most patients with ARVD/C experiencing arrhythmias have an abnormal ECG, a nonspecific or normal ECG does not preclude ARVD/C diagnosis. All patients with a nonspecific or normal ECG had alternative evidence of disease expression. These results alert the physician not to rely exclusively on ECG in ARVD/C, but to assess arrhythmic risk by comprehensive clinical evaluation.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy, characterized by right ventricular dysfunction and ventricular arrhythmias. Limited information is available concerning atrial arrhythmias in ARVD/C.The purpose of this study was to characterize spontaneous atrial arrhythmias in a large registry population of ARVD/C patients.Patients (n = 248) from the Johns Hopkins ARVD/C registry who met the diagnostic criteria and had undertaken genotype analysis were included. Medical records of each were reviewed to ascertain incidence and characteristics of atrial arrhythmia episodes. Detailed demographic, phenotypic, and structural information was obtained from registry data.Thirty-five patients with ARVD/C (14%) experienced one or more types of atrial arrhythmia during median follow-up of 5.78 (interquartile range 8.52) years. Atrial fibrillation was the most common atrial arrhythmia, occurring in 80% of ARVD/C patients with atrial arrhythmias. Patients developed atrial arrhythmias at a mean age of 43.0 ± 14.0 years. Atrial arrhythmia patients obtained a total of 22 inappropriate implantable cardioverter-defibrillator shocks during follow-up. Older age at last follow-up (P.001) and male gender (P = .044) were associated with atrial arrhythmia development. Patients with atrial arrhythmias had a higher occurrence of death (P = .028), heart failure (P.001), and left atrial enlargement on echocardiography (P = .004).Atrial arrhythmias are common in ARVD/C and present at a younger age than in the general population. They are associated with male gender, increasing age, and left atrial enlargement. Atrial arrhythmias are clinically important as they are associated with inappropriate implantable cardioverter-defibrillator shocks and increased risk of both death and heart failure.

Sir William Osler reportedly once said, “Varicose veins are the result of an improper selection of grandparents.” Indeed, our family history strongly influences many aspects of our cardiovascular system, with the magnitude of effect ranging from very strong for autosomal dominant genetic disorders to more subtle in the setting of complex multigenic diseases like coronary atherosclerosis and hypertension. Accordingly, the standard evaluation of any new patient who presents to a physician includes assessment of their family history. Unfortunately, the family history may sometimes be discounted as noncontributory without detailed review. This can be exacerbated by busy office schedules with declining amounts of time available for comprehensive evaluations. A few minutes saved might seem to justify the lack of focus on an aspect of history that is sometimes deemed not to be particularly useful. However, a thorough assessment of family history also may provide the key diagnostic information to determine the cause of an illness, to determine who else is at risk of disease within the family, to add useful prognostic information, and to help for family planning and reproductive decisions. A family history of sudden death should prompt consideration of a wide range of heritable cardiovascular conditions, including many monogenic disorders (Table). However, the terms used by the lay public to describe sudden death may not adequately explain the cause of death on initial consideration. For instance, the phrase “heart attack” may be used to describe sudden death of any etiology. Further questioning may help one to discern whether there was a history of heart failure, cardiomyopathy, coronary artery disease (or its risk factors), aortic aneurysm, or features of syndromic disorders that are associated with sudden death. View this table: Table. Monogenic Disorders Associated With Sudden Death A 40-year-old man presents to a physician for evaluation of palpitations. These occur briefly about once per …

Determining the prognosis of patients with heart failure is essential for patient management and clinical trial conduct. The relative value of traditional prognostic criteria remains unclear and the assessment of long-term prognosis for individual patients is problematic.To determine the ability of clinical, hemodynamic and echocardiographic parameters to predict the long-term prognosis of patients with idiopathic dilated cardiomyopathy.We investigated the ability of clinical, hemodynamic and echocardiographic parameters to predict the long-term prognosis of individual patients in a large, representative, contemporary cohort of idiopathic dilated cardiomyopathy (IDCM) patients referred to Johns Hopkins from 1997 to 2004 for evaluation of cardiomyopathy. In all patients a baseline history was taken, and physical examination, laboratory studies, echocardiogram, right heart catheterization and endomyocardial biopsy were performed.In 171 IDCM patients followed for a median 3.5 years, there were 50 long-term event-free survivors (LTS) (median survival 6.4 years) and 34 patients died or underwent ventricular assist device placement or transplantation within 5 years (NLTS; non-long-term survivors) (median time to event 1.83 years. Established risk factors (gender, race, presence of diabetes, serum creatinine, sodium) and the use of accepted heart failure medications (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta blockers) were similar between the two groups. Although LTS had younger age, higher ejection fraction (EF) and lower New York Heart Association (NYHA) class at presentation, the positive predictive value of an EF25% was 64% (95% CI 41%-79%) and that of NYHA class2 was 53% (95% CI 36-69%). A logistic model incorporating these three variables incorrectly classified 29% of patients.IDCM exhibits a highly variable natural history and standard clinical predictors have limited ability to classify IDCM patients into broad prognostic categories. These findings suggest that there are important host-environmental factors still unappreciated in the biology of IDCM.

Aims To investigate whether phospholamban gene (PLN) mutations underlie patients diagnosed with either arrhythmogenic right ventricular cardiomyopathy (ARVC) or idiopathic dilated cardiomyopathy (DCM). Methods and results We screened a cohort of 97 ARVC and 257 DCM unrelated index patients for PLN mutations and evaluated their clinical characteristics. PLN mutation R14del was identified in 12 (12 %) ARVC patients and in 39 (15 %) DCM patients. Haplotype analysis revealed a common founder, estimated to be between 575 and 825 years old. A low voltage electrocardiogram was present in 46 % of R14del carriers. Compared with R14del– DCM patients, R14del+ DCM patients more often demonstrated appropriate implantable cardioverter defibrillator discharge (47 % vs. 10 %, P < 0.001), cardiac transplantation (18 % vs. 2 %, P < 0.001), and a family history for sudden cardiac death (SCD) at < 50 years (36 % vs. 16 %, P = 0.007). We observed a similar pattern in the ARVC patients although this was not statistically significant. The average age of 26 family members who died of SCD was 37.7 years. Immunohistochemistry in available myocardial samples revealed absent/depressed plakoglobin levels at intercalated disks in five of seven (71 %) R14del+ ARVC samples, but in only one of nine (11 %) R14del+ DCM samples (P = 0.03). Conclusions The PLN R14del founder mutation is present in a substantial number of patients clinically diagnosed with DCM or ARVC. R14del+ patients diagnosed with DCM showed an arrhythmogenic phenotype, and SCD at young age can be the presenting symptom. These findings support the concept of ‘arrhythmogenic cardiomyopathy’.

Dilated cardiomyopathy (DCM) is an important cause of heart failure and the leading indication for cardiac transplantation worldwide.1 With careful evaluation of relatives, familial disease can be identified in ~30% of patients with seemingly idiopathic DCM.2 This connection indicates that genetic etiologies play an important role in disease pathogenesis. It also has important implications for families, because relatives are at risk for developing disease. Indeed, consensus guidelines for idiopathic DCM recommend that first-degree relatives of patients begin longitudinal echocardiography-based screening early in life.3 Therefore, greater understanding of the genetic basis of DCM will not only advance knowledge of fundamental disease biology, but will also improve clinical management of families by definitively identifying at-risk relatives, thereby allowing longitudinal screening to be focused only on mutation carriers. Characterizing the genetics of DCM has been a challenging task owing to incomplete knowledge of the genes involved in disease as well as difficulties determining if DNA variants identified in patients are clinically significant. More than 40 different genes have been implicated in causing DCM. Unlike hypertrophic cardiomyopathy (HCM), which is largely a disease of the sarcomere, the pathways leading to DCM are considerably more diverse, involving genes encoding components of the sarcomere, Z-disk, nuclear lamina proteins, intermediate filaments, and the dystrophin-associated glycoprotein complex.4 Individually, each of these genes provides a very modest contribution to the overall incidence of disease, and efforts to identify other DCM-associated genes are ongoing. As a result, current genetic testing strategies are relatively insensitive in DCM. For example, the Familial Dilated Cardiomyopathy Project analyzed 14 genes in >300 index patients and identified disease-associated variants in only 20%–30% of cases.5∓9 Furthermore, even if genetic testing identifies a variant that differs from the expected/reference genetic sequence in a patient with DCM, it can be very difficult to determine whether the variant is a true pathogenic mutation capable of causing disease, is disease modifying, or merely represents benign genetic variation.10,11 This difficulty reflects the remarkable complexity in human genomic variation.12 Correctly classifying DNA variants is obviously important to avoid false positive and negative genetic testing results, but there are no universal standards for interpretation. Interpretations are often based on only a small number of criteria, such as evolutionary conservation and absence of the DNA variant in a relatively small cohort of healthy control subjects. In addition to a more complete compendium of genes that cause DCM, rigorous standardized metrics to classify DNA variants, and greater experience genotyping broader populations with disease are needed. Unlike earlier studies in which genetic testing was performed in carefully cultivated research cohorts, in the present study we assess genetic testing in real-life clinical practice. Using structured criteria to classify the significance of DNA variants, we describe the prevalence of gene mutations in a diverse population of DCM patients referred to a single laboratory for clinical genetic testing. We also examine factors that may influence the likelihood of identifying a mutation, to better characterize the sensitivity, or yield, of genetic testing in the clinical setting. This information helps to shape the role of genetic testing in practice and to guide patient selection to maximize yield.

Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the heart. HCM is characterized by a wide range of clinical expression, ranging from asymptomatic mutation carriers to sudden cardiac death as the first manifestation of the disease. Over 1000 mutations have been identified, classically in genes encoding sarcomeric proteins. Noninvasive imaging is central to the diagnosis of HCM and cardiovascular magnetic resonance (CMR) is increasingly used to characterize morphologic, functional and tissue abnormalities associated with HCM. The purpose of this review is to provide an overview of the clinical, pathological and imaging features relevant to understanding the diagnosis of HCM. The early and overt phenotypic expression of disease that may be identified by CMR is reviewed. Diastolic dysfunction may be an early marker of the disease, present in mutation carriers prior to the development of left ventricular hypertrophy (LVH). Late gadolinium enhancement by CMR is present in approximately 60% of HCM patients with LVH and may provide novel information regarding risk stratification in HCM. It is likely that integrating genetic advances with enhanced phenotypic characterization of HCM with novel CMR techniques will importantly improve our understanding of this complex disease.

Limb girdle muscular dystrophy 1D/1E (OMIM nomenclature LGMD1D, Human Gene Nomenclature Committee LGMD1E), a skeletal and cardiac myopathy, has previously been linked to chromosome 6q23. We used laser capture microdissection to isolate cytoplasmic inclusions from skeletal muscle from a patient with LGMD1D/1E, performed mass spectrometry-based proteomics on these minute inclusions, and identified through bioinformatics desmin as their major constituent. Sequencing in this patient and family members identified the genetic basis of the previously reported 6q23 linked LGMD1D/1E to be due to an intron splice donor site mutation (IVS3+3A>G) of the desmin gene located on chromosome 2q35.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy characterized by fibrofatty replacement of the ventricular myocardium, right ventricular (RV) dysfunction, and ventricular arrhythmias. The Johns Hopkins ARVD Program Registry, which was established in

Depending on whom you talk to, translational science may have different meanings. The scientific community agrees that moving laboratory science into preclinical settings (T1 translation) and from there into humans (T2 translation) is part of the translational continuum. But beyond that, and when it comes to larger groups of people or even populations, it becomes more nebulous, and many put T3 (from patients to clinical practices) and T4 translation (from clinical practices to real world settings), as well as implementation science, in the same basket [1]. Yet, these are critical components of translational science. For the last decade, more emphasis has been put into translating the knowledge that we have gained through decades of basic and clinical science research into populations. Scientists and clinicians struggle with issues like adherence to medications and promoting behavioral changes that could stop the epidemic of chronic noncommunicable diseases (NCDs). Those are complex issues as they depend not only on individuals but also on communities, health-care systems, and country policies. Developing interventions that work requires resources, and many developed countries have embarked in efforts that support research and programs, in particular, at the community level. Although the challenge is still there, we have seen some progress on childhood obesity, tobacco consumption, and early cancer detection. When it comes to lowand middle-income countries (LMICs), the conversation, although similar, is more complex, and it has to take into account the realities of those countries, the limited resources and research infrastructures, and the triple, and sometimes quadruple, burden of disease of many of those countries. For cardiovascular disease (CVD), and since the identification of the major risk factors through the Framingham heart study, we have been able to decrease mortality significantly. In the USA, for example, the mortality due to CVD has decreased by 50 % in a few decades due in part to better prevention, control, and treatment [2]. However, CVD continues being the number one killer in the USA. Part is due to still inadequate detection and management of individuals at high risk and the adoption of unhealthy behaviors (poor diet, physical inactivity, tobacco use, and alcohol consumption), but lack of access to care and chronic disease management play a critical role. Sixty-three percent of the global mortality is due to NCDs, with CVD being the leading cause of NCD death (48 %). About 80 % of NCD-related deaths are ocurring in LMICs, as indicated by WHO (http://www.who.int/chp/ncd_ global_status_report/en). In 2010, the National Heart Lung and Blood Institute commissioned the Institute of Medicine a report on cardiovascular health in the developing world (www.iom.edu/globalcvd). Five years later, we have made some progress (http://www.scientificamerican.com/products/ cardiovascular-health), but a lot needs to be done. The areas of diagnostics and technology present tremendous promise, but it is crucial that before interventions are scaled up, evidence-based and rigorous scientific approaches are utilized to demonstrate their effectiveness. In recent issues of the Journal of Cardiovascular Translational Research, we presented four articles intended to review the current state of the science and provide opportunities for research and infrastructure building. We started with a focus on mobile technology, which has revolutionized the world, Editor-in-Chief Jennifer L. Hall oversaw the review of this article

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disorder involving diseased cardiac muscle. Bridging integrator 1 (BIN1) is a membrane-associated protein important to cardiomyocyte homeostasis and is downregulated in cardiomyopathy. We hypothesized that BIN1 could be released into the circulation and that blood-available BIN1 can provide useful data on the cardiac status of patients whose hearts are failing secondary to ARVC.To determine whether plasma BIN1 levels can be used to measure disease severity in patients with ARVC.We performed a retrospective cohort study of 24 patients with ARVC. Plasma BIN1 levels were assessed for their ability to correlate with cardiac functional status and predict ventricular arrhythmias.Mean plasma BIN1 levels were decreased in patients with ARVC with heart failure (15 ± 7 vs 60 ± 17 in patients without heart failure, P.05; the plasma BIN1 level was 60 ± 10 in non-ARVC normal controls). BIN1 levels correlated inversely with number of previous ventricular arrhythmia (R = -.47; P.05), and low BIN1 levels correctly classified patients with advanced heart failure or ventricular arrhythmia (receiver operator curve area under the curve of 0.88 ± 0.07). Low BIN1 levels also predicted future ventricular arrhythmias (receiver operator curve area under the curve of 0.89 ± 0.09). In a stratified analysis, BIN1 levels could predict future arrhythmias in patients without severe heart failure (n = 20) with an accuracy of 82%. In the 7 patients with ARVC with serial blood samples, all of whom had evidence of disease progression during follow-up, plasma BIN1 levels decreased significantly (a decrease of 63%; P.05).Plasma BIN1 level seems to correlate with cardiac functional status and the presence or absence of sustained ventricular arrhythmias in a small cohort of patients with ARVC and can predict future ventricular arrhythmias.

TRACS sought to describe the clinical outcomes and disease progression of transthyretin (TTR) cardiac amyloidosis (ATTR) in an observational study. Clinical course is largely determined by disease type with ATTR categorized as wild-type (ATTRwt) or genetic-variant protein (ATTRm). Prospective data are lacking in the most common TTR mutation, V122I, present in approximately 3.5% of African Americans.Patients with ATTRwt (n = 18) and V122I ATTRm (n = 11) were longitudinally assessed every 6 months for up to 2 years by functional class assessments, biochemical markers, and echocardiography.At baseline, no differences in clinical characteristics, biomarkers, or echocardiographic parameters were noted between patients with ATTRwt and patients with ATTRm. After 15.5 ± 8 months, there were 11 deaths and 1 cardiac transplant, with higher mortality (73% vs 22%, P = .03) and cardiovascular hospitalization (64% vs 28%, P = .02) among patients with ATTRm. The median survival from diagnosis was 25.6 months for ATTRm vs 43.0 months for ATTRwt (P = .04). Univariate predictors of mortality included disease duration, heart rate ≥ 70 beats/min, baseline stroke volume, left ventricular ejection fraction50%, and ATTRm status. For each 6-month increment, the mean 6-minute walk distance declined by 25.8 m, N-terminal pro b-type natriuretic peptide increased by 1,816 pg/mL, and left ventricular ejection fraction fell by 3.2%, for the entire cohort.In this prospective study, disease progression, morbidity, and mortality were observed in ATTR cardiomyopathy, particularly due to V122I, over a short duration. Given the prevalence of this mutation, further study of V122I in at-risk African American patients is warranted.

Although the mitral valve (MV) plays a critical role in cardiac function, preventing reversal of systolic flow retrograde into the left atrium, it is rarely afforded the attention received by the coronary arteries, the His–Purkinje system, or the four distinct cardiac chambers. Yet the MV is indeed a dynamic and vital structure, influenced by its developmental origin, its various intrinsic cell types, and numerous growth factors that can alter its homeostasis in health or disease. Both acquired and inherited conditions may affect morphology, function, and stability of the MV apparatus. Today, treatment for MV disease is largely surgical, yet new insights will inevitably lead to the discovery and investigation of novel therapeutics. This issue of Journal of Cardiovascular Translational Research highlights MV development and disease from widely varied perspectives. The normal MV apparatus consists of two leaflets, anterior and posterior, as well as the surrounding annulus, the papillary muscles, and its chordae tendineae that connect the papillary muscles to the leaflets. Each leaflet is divided into three segments according to the standard Carpentier nomenclature [1]. The saddle shape of the annulus reduces leaflet stress and optimizes function of the leaflets and associated chordae and papillary muscles [2–4]. The epidemiology of MV disease extends from common to rare. MV prolapse, which was once considered to affect as many as 15% or more of people in the population analyses, was rigorously defined and measured for its prevalence in the Framingham study as present in 2% of this cohort [2, 5]. Although less common in developed countries, rheumatic MV disease continues to wreak a heavy toll of cardiovascular morbidity and expense in many developing nations around the world. Ischemic mitral valve insufficiency complicates 20–55% of acute myocardial infarctions, and its presence portends worsened prognosis [6]. The articles in this issue approach investigation of MV disease from a variety of perspectives. Salhiyyah, Yacoub, and Chester provide a general overview of the cells that are present in the MV, their relationship to various inherited and acquired diseases, and their associated vasculature and innervation. Also at the cellular level, Bischoff and Aikawa focus on a critical step in valvulogenesis and valve homeostasis: endothelial–mesenchymal transformation. They introduce an intriguing concept that valvular endothelial cells serve as a reservoir of progenitor cells that may replenish other valve cells in response to injury or disease. Moving to the whole organ from a developmental perspective, Peal, Lynch, and Milan review the many distinct advantages of using zebrafish in cardiac valve investigation. Although there are notable differences between the heart of zebrafish and humans, there are crucial similarities for which zebrafish are highly relevant and readily analyzed. Hakuna, Kimura, Yoshioka, and Fukuda review their groundbreaking work on angiogenic and angioinhibitory factors, such as periostin and chondromodulin, respectively. A highly regulated balance between these factors is required not only for normal cardiac valve development, but also for its homeostasis with aging and acquired diseases. Three specific disorders with prominent MV pathology are also highlighted in this issue. Since the recognition that FBN1 mutations cause Marfan syndrome over 20 years ago, there has been a sea change in our understanding of its pathogenic basis [7]. The traditional thinking that a deficiency of fibrillin-1 would lead to inevitable structural collapse of affected tissues fails to adequately explain certain aspects of this disease, such as elongation and thickening of the MV. With that in mind, research during much of the past decade has evaluated a regulatory role for fibrillin-1 in maintenance of appropriate latent binding of transforming growth factor beta (TGFβ) [8, 9]. Accordingly, Judge, Rouf, Habashi, and Dietz review the pathogenesis of MV disease in Marfan syndrome and associated inherited disorders of TGFβ dysregulation. X-linked MVP is another rare condition that sheds important light onto MV morphogenesis and function. Investigators in the west of France astutely recognized that some men with MV disease requiring surgical repair had mild elevation in their activated partial thromboplastin time with mild deficiency of Factor VIII, encoded by a gene at chromosome Xq28 [10]. This important observation led to assembly of a unique cohort for a standard positional cloning approach that led to their discovery of FLNA mutations in a nearby but different gene at the same chromosomal locus [11]. As reviewed by Lardeux, Kyndt, Lecointe, Le Marec, Merot, Schott, Le Tourneau, and Probst, filamin A is a large protein with many interacting proteins and pathways. Not surprisingly, there is a wide spectrum of different phenotypes caused by FLNA mutations, and current investigations seek to understand its regulatory or functional role in MV development and function—as with fibrillin-1—reinforcing the theme of regulatory and developmental defects induced by mutations of structural proteins [12]. MV disease in hypertrophic cardiomyopathy is also reviewed in this issue. We have known for more than 20 years that sarcomere gene mutations cause this disorder of inappropriate cardiac hypertrophy, which is often complicated by MV pathology that is central to the pathophysiology of obstruction but of unknown origin. Hagege, Bruneval, Levine, Neamatalla, Desnos, and Judge highlight the spectrum of MV abnormalities known to occur in this condition, their consequence, and current theories regarding their cause, in which alterations in developmental pathways translate to disease of the adult MV. By their very nature, review articles tend to look retrospectively at a body of relevant research, and as one reads these manuscripts, the gaps in our knowledge are quite notable. We are well on the way to recognizing the relevant factors that cause MV pathology, yet our treatments today remain largely surgical. The next phase of investigation will focus on translating these discoveries into targeted treatments. Funding by agencies such as the US National Institutes of Health, the European Union, and private foundations like Fondation Leducq is critical for the assembly of talented teams of investigators with complementary but varied strategies and perspectives, facilitating cross-fertilization of ideas. Looking to the future, we anticipate that these lines of investigation will lead to improved therapies, and will also facilitate the addition of MV diseases to the growing list of disorders for which personalized medicine finds inevitable application in the years ahead.

This international consensus statement provides the state of genetic testing for the channelopathies and cardiomyopathies. It summarizes the opinion of the international writing group members based on their own experience and on a general review of the literature with respect to the use and role of genetic testing for these potentially heritable cardiac conditions. This document focuses primarily on the state of genetic testing for the 13 distinct entities detailed and the relative diagnostic, prognostic, and therapeutic impact of the genetic test result for each entity. It does not focus on the therapeutic management of the various channelopathies and cardiomyopathies. Treatment/management issues are only discussed for those diseases (i.e., LQTS, HCM, DCM + CCD, RCM) in which the genetic test result could potentially influence treatment considerations. Writing recommendations for genetic diseases require adaptation of the methodology normally adopted to prepare guidelines for clinical practice. Documents produced by other scientific societies have acknowledged the need to define the criteria used to rank the strength of recommendation for genetic diseases.1 The most obvious difference is that randomized and/or blinded studies do not exist. Instead, most of the available data are derived from registries that have followed patients and recorded outcome information. The authors of this statement have therefore defined specific criteria for Class I, Class IIa or b, and Class III recommendations and have used the conventional language adopted by AHA/ACC/ESC Guidelines to express each class. All recommendations are level of evidence (LOE) C (i.e., based on experts' opinions). A Class I recommendation ( “is recommended” ) was applied for genetic testing in index cases with a sound clinical suspicion for the presence of a channelopathy or a cardiomyopathy when the positive predictive value of a genetic test is high (likelihood of positive result >40% and signal/noise ratio >10; Table 3), AND/OR when …

Elongation and pathological thickening of the mitral valve (MV) is commonly seen in hypertrophic cardiomyopathy (HCM), and its pathogenic basis is poorly understood. Associated features include mal-positioning of the papillary muscles and MV, as well as systolic anterior motion (SAM) of the MV leaflets, which can worsen the turbulence and dynamic left ventricular outflow tract (LVOT) gradient. Coaptation of the MV leaflets depends on both anterior and posterior leaflet length and position, and failure of either to optimally adapt in this setting can result in mitral regurgitation or worsened LVOT obstruction. The cause of MV enlargement in HCM is not currently understood, and several different hypotheses may be relevant. The lack of correlation between MV size and the severity of left ventricular hypertrophy, as well as the early findings in genetically predisposed individuals with sarcomere mutations, suggest that it may be an intrinsic aspect of HCM in certain individuals. Other evidence points to a reactive process in the setting of excess production of paracrine growth factors in diseased myocardium that may influence valve overgrowth. Improved understanding of the responsible adaptive mechanisms will pave the way for studies targeted on the prevention and treatment of MV disease in HCM.

Marfan syndrome (MFS) is a systemic disorder of the connective tissue with pleiotropic manifestations due to heterozygous FBN1 mutations and consequent upregulation of TGFβ signaling in affected tissues. Myxomatous thickening and elongation of the mitral valve (MV) leaflets commonly occur in this condition. Investigation of murine models of this disease has led to improved understanding of the mechanisms that underlie many of the phenotypic features of MFS, including MV disease. Loeys–Dietz syndrome (LDS) is a related disorder due to heterozygous mutations in the genes encoding subunits of the TGFβ receptor, and it may also involve the MV leaflets with similar elongation and thickening of the MV leaflets. Although the genetic basis and pathogenesis of nonsyndromic MV prolapse has been elusive to date, insights derived from monogenic disorders like MFS and LDS can be informative with regard to novel gene discovery and investigation into the pathogenesis of MV disease. This manuscript will review the prevalence of MV disease in MFS, its pathogenic basis as determined in mice with Fbn1 mutations, and ongoing studies that seek to better understand MV disease in the context of fibrillin-1 deficiency or excessive TGFβ signaling.

Objectives The aims of this study were to determine the spectrum and prevalence of "background genetic noise" in the arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC) genetic test and to determine genetic associations that can guide the interpretation of a positive test result.Background ARVC is a potentially lethal genetic cardiovascular disorder characterized by myocyte loss and fibrofatty tissue replacement of the right ventricle. Genetic variation among the ARVC susceptibility genes has not been systematically examined, and little is known about the background noise associated with the ARVC genetic test.Methods Using direct deoxyribonucleic acid sequencing, the coding exons/splice junctions of PKP2, DSP, DSG2, DSC2, and TMEM43 were genotyped for 93 probands diagnosed with ARVC from the Netherlands and 427 ostensibly healthy controls of various ethnicities. Eighty-two additional ARVC cases were obtained from published reports, and additional mutations were included from the ARVD/C Genetic Variants Database.Results The overall yield of mutations among ARVC cases was 58% versus 16% in controls. Radical mutations were hosted by 0.5% of control individuals versus 43% of ARVC cases, while 16% of controls hosted missense mutations versus a similar 21% of ARVC cases. Relative to controls, mutations in cases occurred more frequently in non-Caucasians, localized to the N-terminal regions of DSP and DSG2, and localized to highly conserved residues within PKP2 and DSG2.Conclusions This study is the first to comprehensively evaluate genetic variation in healthy controls for the ARVC susceptibility genes. Radical mutations are high-probability ARVC-associated mutations, whereas rare missense mutations should be interpreted in the context of race and ethnicity, mutation location, and sequence conservation. (J Am Coll Cardiol 2011;57:2317-27) (C) 2011 by the American College of Cardiology Foundation

Angiotensin II (AngII) mediates progression of aortic aneurysm, but the relative contribution of its type 1 (AT1) and type 2 (AT2) receptors remains unknown. We show that loss of AT2 expression accelerates the aberrant growth and rupture of the aorta in a mouse model of Marfan syndrome (MFS). The selective AT1 receptor blocker (ARB) losartan abrogated aneurysm progression in the mice; full protection required intact AT2 signaling. The angiotensin-converting enzyme inhibitor (ACEi) enalapril, which limits signaling through both receptors, was less effective. Both drugs attenuated canonical transforming growth factor–β (TGFβ) signaling in the aorta, but losartan uniquely inhibited TGFβ-mediated activation of extracellular signal–regulated kinase (ERK), by allowing continued signaling through AT2. These data highlight the protective nature of AT2 signaling and potentially inform the choice of therapies in MFS and related disorders.

ObjectivesThe purpose of this study was to define the incidence and predictors of implantable cardioverter-defibrillator (ICD) therapy in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) after placement of an ICD for primary prevention.BackgroundPatients with a diagnosis of ARVD/C often receive an ICD for prevention of sudden cardiac death.MethodsPatients (n = 84) from the Johns Hopkins registry with definite or probable ARVD/C who underwent ICD implantation for primary prevention were studied. Detailed phenotypic, genotype, and ICD event information was obtained and appropriate ICD therapies were adjudicated based on intracardiac electrograms.ResultsOver a mean follow-up of 4.7 ± 3.4 years, appropriate ICD therapy was seen in 40 patients (48%), of whom 16 (19%) received interventions for potentially fatal ventricular fibrillation/flutter episodes. Proband status (p < 0.001), inducibility at electrophysiologic study (p = 0.005), presence of nonsustained ventricular tachycardia (p < 0 .001), and Holter premature ventricular complex count >1,000/24 h (p = 0.024) were identified as significant predictors of appropriate ICD therapy. The 5-year survival free of appropriate ICD therapy for patients with 1, 2, 3, and 4 risk factors was 100%, 83%, 21%, and 15%, respectively. Inducibility at electrophysiologic study (hazard ratio: 4.5, 95% confidence interval: 1.4 to 15, p = 0.013) and nonsustained ventricular tachycardia (hazard ratio: 10.5, 95% confidence interval: 2.4 to 46.2, p = 0.002) remained as significant predictors on multivariable analysis.ConclusionsNearly one-half of the ARVD/C patients with primary prevention ICD implantation experience appropriate ICD interventions. Inducibility at electrophysiologic study and nonsustained ventricular tachycardia are independent strong predictors of appropriate ICD therapy. An increase in ventricular ectopy burden was associated with progressively lower event-free (appropriate ICD interventions) survival. Incremental risk of ventricular arrhythmias and ICD therapy was observed with the presence of multiple risk factors.

Inherited forms of cardiomyopathy are common causes of heart failure. Applications of genetics in the evaluation and management of heart failure include the determination of inheritance patterns within families with cardiomyopathy, the evaluation of affected patients for syndromic features, the determination of people within families who are at risk of heart failure, and the identification of responsible gene mutations. Family planning may also be assisted by determination of a clear mutation that predisposes to heart failure. Genetic counseling is critical, and it should accompany the use of genetic testing in cardiovascular diseases. With the rapid pace of growth in technology that is used to determine DNA sequence, costs have declined and clinical application of genetic testing has expanded. This is particularly relevant for heart failure, because each of the familial forms of cardiomyopathy may be caused by a mutation in many different genes. Most families share a unique gene mutation, and appropriate interpretation of novel DNA variants is essential for proper use. The evaluation of risk of arrhythmia in familial forms of heart failure may benefit from genetic testing, as mutations in the genes encoding lamin A/C, desmin, and cardiac troponin T are associated with increased risk of sudden cardiac death. Because of its complexity and the rapid rate of change in available genetic testing options, the genetic evaluation of heart failure is best suited to tertiary referral centers with specific expertise in this area.

We are grateful for the 2 thoughtful letters concerning our recent article1 on the ECG features of arrhythmogenic right ventricular dysfunction (ARVD). Because ECGs are widely available and inexpensive, it important for those interested in this field to fully explore the diagnostic and prognostic potential of 12-lead ECGs. There were 3 main issues raised in these letters. The first concerned whether our control population was appropriate. As noted in our article, our study included 2 control populations. The first was a series of 27 patients who were evaluated in the ARVD clinic because of a first- or second-degree relative with ARVD. Each of these patients underwent a comprehensive evaluation to screen for ARVD, including an ECG, signal-averaged ECG, Holter, magnetic resonance imaging, and stress testing. The second control population was a series of 30 patients with a right bundle-branch block ECG pattern who did not have relatives with ARVD and were not being evaluated in our ARVD clinic. …

Background— The purpose of this study was to reevaluate the ECG features of arrhythmogenic right ventricular dysplasia (ARVD). The second objective was to evaluate the sensitivity and specificity of the standard and newly proposed diagnostic ECG markers in the presence of a right bundle-branch block (RBBB). Methods and Results— One hundred patients with ARVD (57 men; aged 39±15 years) and 57 controls (21 men; aged 40±17 years) were included. Among the 100 patients with ARVD, a complete RBBB was present in 17 patients, and 15 patients had an incomplete RBBB. T-wave inversion through V 3 demonstrated optimal sensitivity and specificity in both ARVD patients without a complete RBBB or incomplete RBBB (71% [95% confidence interval, 58% to 81%] and 96% [95% confidence interval, 81% to 100%], respectively) and in ARVD patients with incomplete RBBB (73% [95% confidence interval, 45% to 92%] and 95% [95% confidence interval, 77% to 100%], respectively). Between ARVD patients and controls with a complete RBBB, the only 2 parameters that differed were the prevalence of T-wave inversion through V 4 (59% versus 12%, respectively; P 1 P Conclusions— We evaluated comprehensively the diagnostic value of ECG markers for ARVD. On the basis of the findings, we propose an algorithm, with examination of QRS morphology being the first step, for ECG evaluation of ARVD patients. Definite criteria are then applied on the basis of the presence of no RBBB, incomplete RBBB, and complete RBBB to obtain the best diagnostic utility of the ECG.

Background Parietal block, defined as intra right ventricular (RV) conduction slowing, is a major diagnostic criterion for arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Objective We evaluated the utility of total RV endocardial activation duration (EAD) measured by 3-dimensional electroanatomic mapping during sinus rhythm in the diagnosis of ARVD/C. Methods Twenty-five consecutive patients with frequent left bundle branch block morphology premature ventricular complexes who underwent electroanatomic mapping as a part of the evaluation for ARVD/C were included in the study. All patients were evaluated using standard protocol that included electrocardiogram (ECG), signal-averaged ECG, Holter monitoring, echocardiography, and magnetic resonance imaging. Invasive testing was performed as indicated. Total RV EAD was measured as the time interval between the onset of RV activation to the latest activated region in the RV. Results The mean age of the study subjects was 38 ± 11 years, and 32% were men. Fourteen subjects were diagnosed with ARVD/C using task force criteria, and the remainder had idiopathic ventricular tachycardia. Although the surface QRS durations were similar, the total RV EAD was significantly prolonged in ARVD/C compared with idiopathic VT (83.9 ± 10 ms vs. 50.8 ± 7 ms, P 65 ms. RV EAD also showed significant negative correlation with RV ejection fraction. Conclusion Total RV EAD obtained by 3-dimensional electroanatomic mapping is a sensitive marker of intra-RV conduction delay in ARVD/C, and a total RV EAD of >65 ms accurately differentiates ARVD/C from idiopathic VT.

This guideline describes the approach and expertise needed for the genetic evaluation of cardiomyopathy. First published in 2009 by the Heart Failure Society of America (HFSA), the guideline has now been updated in collaboration with the American College of Medical Genetics and Genomics (ACMG). The writing group, composed of cardiologists and genetics professionals with expertise in adult and pediatric cardiomyopathy, reflects the emergence and increased clinical activity devoted to cardiovascular genetic medicine. The genetic evaluation of cardiomyopathy is a rapidly emerging key clinical priority, because high-throughput sequencing is now feasible for clinical testing and conventional interventions can improve survival, reduce morbidity, and enhance quality of life. Moreover, specific interventions may be guided by genetic analysis. A systematic approach is recommended: always a comprehensive family history; an expert phenotypic evaluation of the proband and at-risk family members to confirm a diagnosis and guide genetic test selection and interpretation; referral to expert centers as needed; genetic testing, with pre- and post-test genetic counseling; and specific guidance as indicated for drug and device therapies. The evaluation of infants and children demands special expertise. The approach to managing secondary and incidental sequence findings as recommended by the ACMG is provided. (J Cardiac Fail 2018;24:281–302)

Progressive enlargement of the aortic root, leading to dissection, is the main cause of premature death in patients with Marfan's syndrome. Recent data from mouse models of Marfan's syndrome suggest that aortic-root enlargement is caused by excessive signaling by transforming growth factor beta (TGF-beta) that can be mitigated by treatment with TGF-beta antagonists, including angiotensin II-receptor blockers (ARBs). We evaluated the clinical response to ARBs in pediatric patients with Marfan's syndrome who had severe aortic-root enlargement.We identified 18 pediatric patients with Marfan's syndrome who had been followed during 12 to 47 months of therapy with ARBs after other medical therapy had failed to prevent progressive aortic-root enlargement. The ARB was losartan in 17 patients and irbesartan in 1 patient. We evaluated the efficacy of ARB therapy by comparing the rates of change in aortic-root diameter before and after the initiation of treatment with ARBs.The mean (+/-SD) rate of change in aortic-root diameter decreased significantly from 3.54+/-2.87 mm per year during previous medical therapy to 0.46+/-0.62 mm per year during ARB therapy (P0.001). The deviation of aortic-root enlargement from normal, as expressed by the rate of change in z scores, was reduced by a mean difference of 1.47 z scores per year (95% confidence interval, 0.70 to 2.24; P0.001) after the initiation of ARB therapy. The sinotubular junction, which is prone to dilation in Marfan's syndrome as well, also showed a reduced rate of change in diameter during ARB therapy (P0.05), whereas the distal ascending aorta, which does not normally become dilated in Marfan's syndrome, was not affected by ARB therapy.In a small cohort study, the use of ARB therapy in patients with Marfan's syndrome significantly slowed the rate of progressive aortic-root dilation. These findings require confirmation in a randomized trial.

The purpose of this study was to determine the extent of left ventricular (LV) involvement in individuals predisposed to developing arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), and to investigate novel morphologic variants of ARVD/C.The discovery of desmosomal mutations associated with ARVD/C has led researchers to hypothesize equal right ventricular (RV) and LV affliction in the disease process.Thirty-eight (age 30 +/- 17 years; 18 males) family members of 12 desmosomal mutation-carrying ARVD/C probands underwent genotyping and cardiac magnetic resonance imaging (CMR). The CMR investigators were blinded to clinical and genetic data.Twenty-five individuals had mutations in PKP2, DSP, and/or DSG2 genes. RV abnormalities were associated with the presence of mutation(s) and with disease severity determined by criteria (minor = 1; major = 2) points for ARVD/C diagnosis. The only LV abnormality detected, the presence of intramyocardial fat, was present in 4 individuals. Each of these individuals was a mutation carrier, whereas 1 had no previously described ARVD/C-related abnormality. On detailed CMR, a focal "crinkling" of the RV outflow tract and subtricuspid regions ("accordion sign") was observed in 60% of the mutation carriers and none of the noncarriers (p0.001). The sign was present in 0%, 37%, 71%, and 75% of individuals who met 1, 2, 3, and 4+ criteria points, respectively (p0.01).Despite a possible LV involvement in ARVD/C, the overall LV structure and function are well preserved. Independent LV involvement is of rare occurrence. The accordion sign is a promising tool for early diagnosis of ARVD/C. Its diagnostic utility should be confirmed in larger cohorts.

Here, Mark Awad, Hugh Calkins and Daniel Judge tackle the known genetic mutations associated with arrhythmogenic right ventricular dysplasia/cardiomyopathy, and examine the complex issues surrounding genetic analysis in the clinical assessment of individuals with this condition. Arrhythmogenic right ventricular dysplasia/cardiomyopathy is an inherited cardiomyopathy estimated to affect approximately 1 in 5,000 individuals. Cardinal manifestations include right ventricular enlargement and dysfunction, fibrofatty replacement of myocytes in the right ventricle, characteristic electrocardiographic abnormalities, and ventricular arrhythmia most commonly arising from the right ventricle. The disease is frequently familial and typically involves autosomal dominant transmission with low penetrance and variable expressivity. Approximately 50% of symptomatic individuals harbor a mutation in one of the five major components of the cardiac desmosome. Nevertheless, other genetic modifiers and environmental factors complicate the clinical management of mutation carriers as well as counseling of their relatives. This Review summarizes the known genetic mutations associated with arrhythmogenic right ventricular dysplasia/cardiomyopathy, describes possible origins of recurrent mutations, presents theories on the pathogenesis of disease following a mutation, and discusses the current issues surrounding clinical use of genetic analysis in the assessment of individuals with this condition.

Prior reports have identified associations between SCN10A and cardiac disorders, such as atrial fibrillation and Brugada syndrome. We evaluated SCN10A in 151 probands with ARVD/C. In this cohort, 10 putatively pathogenic SCN10A variants were identified, including a novel frameshift insertion. Despite a known role for the encoded protein in peripheral nerve function, the proband with the frameshift variant had no discernible neurological abnormalities. Arrhythmic phenotypes were not different between those with a rare variant in SCN10A and those without. The prevalence of rare variants in SCN10A was similar among ARVD/C probands with and without a desmosome mutation and similar among healthy Caucasian controls. These results indicate the absence of a primary role for SCN10A mutations in ARVD/C.

Background: Echocardiographic (EC) indices of mechanical dyssynchrony (MD) are based largely upon longitudinal strain, whereas magnetic resonance imaging myocardial tissue tagging (MRI-MT) assessment is based on circumferential strain, the latter being the primary direction of myocardial contraction. Methods: We sought to compare cardiac MRI studies with an EC protocol using 2D imaging, tissue Doppler imaging (TDI), and M-mode in 32 subjects. Absolute strain, time to peak strain in 6 segments, TDI septal-to-lateral delay (SLD; MD if ≥ 70 ms), and M-mode septal-to-posterior wall motion delay (SPWMD; MD if ≥ 130 ms) were measured and compared to the MRI-MT-based CURE (circumferential uniformity ratio estimate, CURE; 0 –1, 0 = asynchrony, 1 = perfect synchrony; MD if < 0.75), which recently has been shown to predict clinical CRT response. Results: The 8 control subjects (normal QRSd; CURE 0.975 ± 0.01; SLD 26 ± 27 ms) had less MD by MRI-MT (p = 0.0001) and TDI (p = 0.04) as compared to 24 subjects with ejection fraction ≤ 35% (QRSd 135 ≤ 35 ms; CURE 0.695 ± 0.17; SLD 59 ± 39 ms). There was a moderate correlation between TDI and MRI-MT (R = 0.62), with a discordance rate of 22% overall and 25% in cardiomyopathy subjects, in some cases due to abnormal CURE with normal SLD and, in others, normal CURE with abnormal SLD. The M-mode assay (SPWMD) could not be assessed in 10 patients with septal akinesis (AK), although there was MD by TDI and MRI-MT in most of these subjects. In the patients without AK, the discordance rate between TDI and M-mode was 33%. Conclusions: MRI-MT assessment of circumferential strain and MD is complementary to TDI with a good correlation, but also a significant discordance rate.

Background: In this report we present the prevalence and significance of a novel MRI abnormality that we identified in desmosomal mutation positive asymptomatic relatives of arrhythmogenic right ventricular dysplasia (ARVD) patients. Methods: MRI of 38 first-degree relatives was analyzed for abnormalities blinded to the mutation status. Focal crinkling of the right ventricle (accordion sign) was observed in 15/25 mutation positive vs. 0/13 mutation negative patients. The presence of this finding was sought in 207 patients evaluated for ARVD blinded to clinical history and was correlated with electrophysiologic findings. Results: Mean age of the population was 32±16, 61% had a family history of ARVD. Based on non-invasive testing the 207 patients were classified into 4 groups 1) 106 normal, 2) 57 Idiopathic ventricular tachycardia (VT), 3) 33 probable ARVD, 4) 11 definite ARVD. A family history of ARVD was present in 74%, 0%, 67% and 36% respectively. 43 patients had the “accordion sign” and the prevalence in the four groups was 10%, 5%, 70% and 100% respectively. The abnormality was seen in the sub-tricuspid region in 62%, outflow tract in 30% in both regions in 8%. After excluding group 4, 48% of patients with the accordion sign had T wave inversion’s beyond V1 compared with 7% of those without the sign (p Conclusion: Focal crinkling of the RV termed “Accordion sign” may represent an early manifestation of ARVD that correlates with mutation positive status and predicts inducibility of ventricular arrhythmias.

Thoracic aortic aneurysm (TAA) is the life-threatening complication of Marfan syndrome (MFS), a connective tissue disorder caused by mutations in the fibrillin-1 gene. TAA is characterized by degradation of elastic fiber, suggesting the involvement of matrix metalloproteinase (MMP)-2 and -9, the activation of which is regulated by TIMP (tissue inhibitor of MMP) types 1 and 2. We hypothesized that MMP-2 and -9 were upregulated during TAA formation in Marfan syndrome, causing loss of elastic fibers and structural integrity. We studied mice, from 3 to 12 months, heterozygous for a mutant Fbn 1 allele encoding a cysteine substitution in fibrillin-1 ( Fbn1 C1039G/+ , designated as “Marfan” mice) (n=120), the most common class of mutation in Marfan syndrome. The littermates, Fbn1 +/+ served as controls (n=120). In Marfan aneurysmal thoracic aorta, mRNA and protein expression of MMP-2 and -9 were detected at 3 months and peaked at 6 months of age, accompanied by severe elastic fiber fragmentation and degradation. From 3 to 9 months, the MMP-2/TIMP-2 ratio increased by 43% to 63% compared with the controls. Dilated thoracic aorta demonstrated increased elasticity but distention caused a pronounced loss of contraction, suggesting weakening of the aortic wall. Breaking stress of the aneurysmal aorta was 70% of the controls. Contraction in response to depolarization and receptor stimulation decreased in the aneurysmal thoracic aorta by 50% to 80%, but the expression of α-smooth muscle actin between the 2 strains was not significantly different. This report demonstrates the upregulation of MMP-2 and -9 during TAA formation in Marfan syndrome. The resulting elastic fiber degeneration with deterioration of the aortic contraction and mechanical properties may explain the pathogenesis of TAA.

Arrhythmogenic right ventricular dysplasia (ARVD) is a heritable cardiomyopathy characterized by the fibrofatty replacement of right ventricular (RV) myocardium leading to RV failure and arrhythmias. This study evaluated the potential utility of tissue Doppler echocardiography (TDE) and strain echocardiography (SE) to quantitatively assess RV function and their potential role in diagnosing ARVD. Images of 30 patients with ARVD (diagnosed by task force criteria) and 36 healthy controls were obtained. Peak systolic velocity, early diastolic velocity, displacement, strain rate, strain, outflow tract diameter, and fractional RV area change were measured in all subjects. Peak RV systolic velocity (6.4 +/- 2.2 vs 9 +/- 1.6 cm/s, p