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Supplemental Digital Content is available in the text., Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease characterized by ventricular arrhythmias and progressive ventricular dysfunction. Genetic testing is recommended, and a pathogenic variant in an ARVC-associated gene is a major criterion for diagnosis according to the 2010 Task Force Criteria. As incorrect attribution of a gene to ARVC can contribute to misdiagnosis, we assembled an international multidisciplinary ARVC Clinical Genome Resource Gene Curation Expert Panel to reappraise all reported ARVC genes. Methods: Following a comprehensive literature search, six 2-member teams conducted blinded independent curation of reported ARVC genes using the semiquantitative Clinical Genome Resource framework. Results: Of 26 reported ARVC genes, only 6 (PKP2, DSP, DSG2, DSC2, JUP, and TMEM43) had strong evidence and were classified as definitive for ARVC causation. There was moderate evidence for 2 genes, DES and PLN. The remaining 18 genes had limited or no evidence. RYR2 was refuted as an ARVC gene since clinical data and model systems exhibited a catecholaminergic polymorphic ventricular tachycardia phenotype. In ClinVar, only 5 pathogenic/likely pathogenic variants (1.1%) in limited evidence genes had been reported in ARVC cases in contrast to 450 desmosome gene variants (97.4%). Conclusions: Using the Clinical Genome Resource approach to gene-disease curation, only 8 genes (PKP2, DSP, DSG2, DSC2, JUP, TMEM43, PLN, and DES) had definitive or moderate evidence for ARVC, and these genes accounted for nearly all pathogenic/likely pathogenic ARVC variants in ClinVar. Therefore, only pathogenic/likely pathogenic variants in these 8 genes should yield a major criterion for ARVC diagnosis. Pathogenic/likely pathogenic variants identified in other genes in a patient should prompt further phenotyping as variants in many of these genes are associated with other cardiovascular conditions.

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Diagnostic laboratories gather phenotypic data through requisition forms, but there is no consensus as to which data are essential for variant interpretation. The ClinGen Cardiomyopathy Variant Curation Expert Panel defined a phenotypic data set for hypertrophic cardiomyopathy (HCM) variant interpretation, with the goal of standardizing requisition forms. Phenotypic data elements listed on requisition forms from nine leading cardiomyopathy testing laboratories were compiled to assess divergence in data collection. A pilot of 50 HCM cases was implemented to determine the feasibility of harmonizing data collection. Laboratory directors were surveyed to gauge potential for adoption of a minimal data set. Wide divergence was observed in the phenotypic data fields in requisition forms. The 50-case pilot showed that although demographics and assertion of a clinical diagnosis of HCM had 86% to 98% completion, specific phenotypic features, such as degree of left ventricular hypertrophy, ejection fraction, and suspected syndromic disease, were completed only 24% to 44% of the time. Nine data elements were deemed essential for variant classification by the expert panel. Participating laboratories unanimously expressed a willingness to adopt these data elements in their requisition forms. This study demonstrates the value of comparing and sharing best practices through an expert group, such as the ClinGen Program, to enhance variant interpretation, providing a foundation for leveraging cumulative case-level data in public databases and ultimately improving patient care.

Dilated cardiomyopathy (DCM) is a cardiovascular disease of genetic aetiology that causes substantial morbidity and mortality, and presents considerable opportunity for disease mitigation and prevention in those at risk. Foundational to the process of caring for patients diagnosed with DCM is a clinical genetic evaluation, which always begins with a comprehensive family history and clinical evaluation. Genetic testing of the proband, the first patient identified in a family with DCM, within the context of genetic counselling is always indicated, regardless of whether the DCM is familial or non-familial. Clinical screening of at-risk family members is also indicated, as is cascade genetic testing for actionable variants found at genetic testing in the proband. Clinicians now have expansive panels with many genes available for DCM genetic testing, and the approaches used to evaluate rare variants to decide which are disease-causing continues to rapidly evolve. Despite these recent advances, only a minority of cases yield actionable variants, even in familial DCM where a genetic aetiology is highly likely. This underscores that our knowledge of DCM clinical genetics remains incomplete, including variant interpretation and DCM genetic architecture. Emerging data suggest that the single-variant Mendelian disease model is insufficient to explain some DCM cases, and rather that multiple variants, both common and rare, and at times key environmental factors, interact to cause DCM. A simple model illustrating the intersection of DCM genetic architecture with environmental impact is provided.

Precision medicine genetics study design requires large, diverse cohorts and thoughtful use of electronic technologies. Involving patients in research design may increase enrollment and engagement, thereby enabling a means to relevant patient outcomes in clinical practice. Few data, however, illustrate attitudes of patients with dilated cardiomyopathy (DCM) and their family members toward genetic study design. This study assessed attitudes of 16 enrolled patients and their family members (P/FM), and 18 investigators or researchers (I/R) of the ongoing DCM Precision Medicine Study during a conjoint patient and investigator meeting using structured, self‐administered surveys examining direct‐to‐participant enrollment and web‐based consent, return of genetic results, and other aspects of genetic study design. Survey respondents were half women and largely identified as white. Web‐based consent was supported by 93% of P/FM and 88% of I/R. Most respondents believed that return of genetic results would motivate study enrollment, but also indicated a desire to opt out. Ideal study design preferences included a 1‐hour visit per year, along with the ability to complete study aspects by telephone or web and possibility of prophylactic medication. This study supports partnership of patients and clinical researchers to inform research priorities and study design to attain the promise of precision medicine for DCM.

Aims: Both left ventricular (LV) and left atrial (LA) dysfunction and remodelling contribute to adverse outcomes in heart failure with reduced ejection fraction (HFrEF). Danicamtiv is a novel, cardiac myosin activator that enhances cardiomyocyte contraction.Methods and results: We studied the effects of danicamtiv on LV and LA function in non-clinical studies (ex vivo: skinned muscle fibres and myofibrils; in vivo: dogs with heart failure) and in a randomized, double-blind, single- and multiple-dose phase 2a trial in patients with stable HFrEF (placebo, n = 10; danicamtiv, n = 30; 50–100 mg twice daily for 7 days). Danicamtiv increased ATPase activity and calcium sensitivity in LV and LA myofibrils/muscle fibres. In dogs with heart failure, danicamtiv improved LV stroke volume (+10.6 mL, P < 0.05) and LA emptying fraction (+10.7%, P < 0.05). In patients with HFrEF (mean age 60 years, 25% women, ischaemic heart disease 48%, mean LV ejection fraction 32%), treatment-emergent adverse events, mostly mild, were reported in 17 patients (57%) receiving danicamtiv and 4 patients (40%) receiving placebo. Danicamtiv (at plasma concentrations ≥2000 ng/mL) increased stroke volume (up to +7.8 mL, P < 0.01), improved global longitudinal (up to −1.0%, P < 0.05) and circumferential strain (up to −3.3%, P < 0.01), decreased LA minimal volume index (up to −2.4 mL/m2, P < 0.01) and increased LA function index (up to 6.1, P < 0.01), when compared with placebo.Conclusions: Danicamtiv was well tolerated and improved LV systolic function in patients with HFrEF. A marked improvement in LA volume and function was also observed in patients with HFrEF, consistent with pre-clinical findings of direct activation of LA contractility.

Background: Each of the cardiomyopathies, classically categorized as hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy, has a signature genetic theme. Hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning >10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted. Methods: An international panel with clinical and scientific expertise in DCM genetics evaluated evidence supporting monogenic relationships of genes with idiopathic DCM. The panel used the Clinical Genome Resource semiquantitative gene-disease clinical validity classification framework with modifications for DCM genetics to classify genes into categories on the basis of the strength of currently available evidence. Representation of DCM genes on clinically available genetic testing panels was evaluated. Results: Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from 8 gene ontologies were classified as having definitive ( BAG3 , DES , FLNC , LMNA , MYH7 , PLN , RBM20 , SCN5A , TNNC1 , TNNT2 , TTN ) or strong ( DSP ) evidence. Seven genes (14%; ACTC1 , ACTN2 , JPH2 , NEXN , TNNI3 , TPM1 , VCL ) including 2 additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of these 19 genes, 6 were similarly classified for hypertrophic cardiomyopathy and 3 for arrhythmogenic right ventricular cardiomyopathy. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of the 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence. Conclusions: In the curation of 51 genes, 19 had high evidence (12 definitive/strong, 7 moderate). It is notable that these 19 genes explain only a minority of cases, leaving the remainder of DCM genetic architecture incompletely addressed. Clinical genetic testing panels include most high-evidence genes; however, genes lacking robust evidence are also commonly included. We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes.

Background Variants in TTN are frequently identified in the genetic evaluation of skeletal myopathy or cardiomyopathy. However, due to the high frequency of TTN variants in the general population, incomplete penetrance, and limited understanding of the spectrum of disease, interpretation of TTN variants is often difficult for laboratories and clinicians. Currently, cardiomyopathy is associated with heterozygous A‐band TTN variants, whereas skeletal myopathy is largely associated with homozygous or compound heterozygous TTN variants. Recent reports show pathogenic variants in TTN may result in a broader phenotypic spectrum than previously recognized. Methods Here we report the results of a multisite study that characterized the phenotypes of probands with variants in TTN. We investigated TTN genotype‐phenotype correlations in probands with skeletal myopathy and/or cardiomyopathy. Probands with TTN truncating variants (TTNtv) or pathogenic missense variants were ascertained from two academic medical centers. Variants were identified via clinical genetic testing and reviewed according to the American College of Medical Genetics criteria. Clinical and family history data were documented via retrospective chart review. Family studies were performed for probands with atypical phenotypes. Results Forty‐nine probands were identified with TTNtv or pathogenic missense variants. Probands were classified by clinical presentation: cardiac (n = 30), skeletal muscle (n = 12), or both (cardioskeletal, n = 7). Within the cardioskeletal group, 5/7 probands had heterozygous TTNtv predicted to affect the distal (3’) end of the A‐band. All cardioskeletal probands had onset of proximal‐predominant muscle weakness before diagnosis of cardiovascular disease, five pedigrees support dominant transmission. Conclusion Although heterozygous TTNtv in the A‐band is known to cause dilated cardiomyopathy, we present evidence that these variants may in some cases cause a novel, dominant skeletal myopathy with a limb‐girdle pattern of weakness. These findings emphasize the importance of multidisciplinary care for patients with A‐band TTNtv who may be at risk for multisystem disease., Recent reports show pathogenic variants in TTN may result in a broader phenotypic spectrum than previously recognized. We investigated TTN genotype‐phenotype correlations in probands with skeletal myopathy and/or cardiomyopathy. Although heterozygous TTNtv in the A‐band are known to cause dilated cardiomyopathy, we present evidence that these variants may in some cases cause a novel, dominant skeletal myopathy with a limb‐girdle pattern of weakness.

Advances in human genetics are improving the understanding of a variety of inherited cardiovascular diseases, including cardiomyopathies, arrhythmic disorders, vascular disorders, and lipid disorders such as familial hypercholesterolemia. However, not all cardiovascular practitioners are fully aware of the utility and potential pitfalls of incorporating genetic test results into the care of patients and their families. This statement summarizes current best practices with respect to genetic testing and its implications for the management of inherited cardiovascular diseases.

Background: Dilated cardiomyopathy (DCM) is a genetically heterogeneous cardiac disease characterized by progressive ventricular enlargement and reduced systolic function. Here, we report genetic and functional analyses implicating the rat sarcoma signaling protein, SOS1 (Son of sevenless homolog 1), in DCM pathogenesis. Methods: Exome sequencing was performed on 412 probands and family members from our DCM cohort, identifying several SOS1 variants with potential disease involvement. As several lines of evidence have implicated dysregulated rat sarcoma signaling in the pathogenesis of DCM, we assessed functional impact of each variant on the activation of ERK (extracellular signal-regulated kinase), AKT (protein kinase B), and JNK (c-Jun N-terminal kinase) pathways. Relative expression levels were determined by Western blot in HEK293T cells transfected with variant or wild-type human SOS1 expression constructs. Results: A rare SOS1 variant [c.571G>A, p.(Glu191Lys)] was found to segregate alongside an A-band TTN truncating variant in a pedigree with aggressive, early-onset DCM. Reduced disease severity in the absence of the SOS1 variant suggested its potential involvement as a genetic risk factor for DCM in this family. Exome sequencing identified 5 additional SOS1 variants with potential disease involvement in 4 other families [c.1820T>C, p.(Ile607Thr); c.2156G>C, p.(Gly719Ala); c.2230A>G, p.(Arg744Gly); c.2728G>C, p.(Asp910His); c.3601C>T, p.(Arg1201Trp)]. Impacted amino acids occupied a number of functional domains relevant to SOS1 activity, including the N-terminal histone fold, as well as the C-terminal REM (rat sarcoma exchange motif), CDC25 (cell division cycle 25), and PR (proline-rich) tail domains. Increased phosphorylated ERK expression relative to wild-type levels was seen for all 6 SOS1 variants, paralleling known disease-relevant SOS1 signaling profiles. Conclusions: These data support gain-of-function variation in SOS1 as a contributing factor to isolated DCM.

Background: The hypothesis of the Dilated Cardiomyopathy Precision Medicine Study is that most dilated cardiomyopathy has a genetic basis. The study returns results to probands and, when indicated, to relatives. While both the American College of Medical Genetics and Genomics/Association for Molecular Pathology and ClinGen’s MYH7 -cardiomyopathy specifications provide relevant guidance for variant interpretation, further gene- and disease-specific considerations were required for dilated cardiomyopathy. To this end, we tailored the ClinGen MYH7 -cardiomyopathy variant interpretation framework; the specifications implemented for the study are presented here. Methods: Modifications were created and approved by an external Variant Adjudication Oversight Committee. After a pilot using 81 probands, further adjustments were made, resulting in 27 criteria (9 modifications of the ClinGen MYH7 framework and reintroduction of 2 American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria that were deemed not applicable by the ClinGen MYH7 working group). Results: These criteria were applied to 2059 variants in a test set of 97 probands. Variants were classified as benign (n=1702), likely benign (n=33), uncertain significance (n=71), likely pathogenic (likely pathogenic; n=12), and pathogenic (P; n=3). Only 2/15 likely pathogenic/P variants were identified in Non-Hispanic African ancestry probands. Conclusions: We tailored the ClinGen MYH7 criteria for our study. Our preliminary data show that 15/97 (15.5%) probands have likely pathogenic/P variants, most of which were identified in probands of Non-Hispanic European ancestry. We anticipate continued evolution of our approach, one that will be informed by new insights on variant interpretation and a greater understanding of the genetic architecture of dilated cardiomyopathy. Clinical Trial Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03037632

Purpose Integrating genomic sequencing in clinical care requires standardization of variant interpretation practices. The Clinical Genome Resource has established expert panels to adapt the American College of Medical Genetics and Genomics/Association for Molecular Pathology classification framework for specific genes and diseases. The Cardiomyopathy Expert Panel selected MYH7, a key contributor to inherited cardiomyopathies, as a pilot gene to develop a broadly applicable approach. Methods Expert revisions were tested with 60 variants using a structured double review by pairs of clinical and diagnostic laboratory experts. Final consensus rules were established via iterative discussions. Results Adjustments represented disease-/gene-informed specifications (12) or strength adjustments of existing rules (5). Nine rules were deemed not applicable. Key specifications included quantitative frameworks for minor allele frequency thresholds, the use of segregation data, and a semiquantitative approach to counting multiple independent variant occurrences where fully controlled case-control studies are lacking. Initial inter-expert classification concordance was 93%. Internal data from participating diagnostic laboratories changed the classification of 20% of the variants (n = 12), highlighting the critical importance of data sharing. Conclusion These adapted rules provide increased specificity for use in MYH7-associated disorders in combination with expert review and clinical judgment and serve as a stepping stone for genes and disorders with similar genetic and clinical characteristics.

Background Pathogenic variants in TTN (OMIM 188840), encoding the largest human protein, are known to cause dilated cardiomyopathy and several forms of skeletal myopathy. The clinical interpretation of TTN variants is challenging, however, due to the frequency of missense changes, variable testing and reporting practices in commercial laboratories, and incomplete understanding of the spectrum of TTN‐related disease. Methods We report a heterozygous TTN deletion segregating in a family with an unusual skeletal myopathy phenotype associated with facial weakness, gait abnormality, and dilated cardiomyopathy. Results A novel 16.430 kb heterozygous deletion spanning part of the A‐ and M‐bands of TTN was identified in the proband and his symptomatic son, as well as in an additional son whose symptoms were identified on clinical evaluation. The deletion was found to be de novo in the proband. Conclusion Pathogenic variants in TTN may be an unrecognized cause of skeletal myopathy phenotypes, particularly when accompanied by dilated cardiomyopathy.

Background Variants in the cardiomyocyte-specific RNA splicing factor RBM20 have been linked to familial cardiomyopathy, but the causative genetic architecture and clinical consequences of this disease are incompletely defined. Methods and Results To define the genetic architecture of RBM20 cardiomyopathy, we first established a database of RBM20 variants associated with cardiomyopathy and compared these to variants observed in the general population with respect to their location in the RBM20 coding transcript. We identified 2 regions significantly enriched for cardiomyopathy-associated variants in exons 9 and 11. We then assembled a registry of 74 patients with RBM20 variants from 8 institutions across the world (44 index cases and 30 from cascade testing). This RBM20 patient registry revealed highly prevalent family history of sudden cardiac death (51%) and cardiomyopathy (72%) among index cases and a high prevalence of composite arrhythmias (including atrial fibrillation, nonsustained ventricular tachycardia, implantable cardiac defibrillator discharge, and sudden cardiac arrest, 43%). Patients harboring variants in cardiomyopathy-enriched regions identified by our variant database analysis were enriched for these findings. Further, these characteristics were more prevalent in the RBM20 registry than in large cohorts of patients with dilated cardiomyopathy and TTNtv cardiomyopathy and not significantly different from a cohort of patients with LMNA -associated cardiomyopathy. Conclusions Our data establish RBM20 cardiomyopathy as a highly penetrant and arrhythmogenic cardiomyopathy. These findings underline the importance of arrhythmia surveillance and family screening in this disease and represent the first step in defining the genetic architecture of RBM20 disease causality on a population level.

See Article by Hellwig et al Multigene panels for cardiogenetic conditions are cost-effective and informative when pathogenic variants are identified, but can become a source of frustration and potential misunderstanding when the result is a variant of uncertain significance (VUS). One of the 5 variant classification categories recommended by the American College of Medical Genetics and Genomics (ACMG),1 a VUS classification means that there is insufficient or conflicting evidence about a molecular alteration’s role in disease. Variant classification, as established by ACMG consensus, requires evaluating differently weighted pathogenic and benign criteria, then combining these criteria using a scoring rubric. The process can result in 1 of 5 classifications: benign, likely benign, VUS, likely pathogenic, and pathogenic (Figure). Figure. The American College of Medical Genetics and Genomics categories for classifying variants are shown, including benign, likely benign, likely pathogenic, and pathogenic, with greater degrees of pathogenicity shown as increasingly more darkly shaded boxes . The middle gray box is the variant of uncertain significance (VUS) category. Even though there is 1 class of VUS (represented here as 1 shade of gray), VUS classification could be subdivided into low, medium, or high probability, as discussed in the text. B indicates benign; LB, likely benign; LP, likely pathogenic; and P, pathogenic. A VUS classification is not an uncommon result in cardiovascular genetics. A recurring scenario is that of a new variant identified in a gene where other pathogenic variants are known to cause a condition. The variant, found in one patient who has the condition, is absent in reportedly unaffected individuals according to reference databases. Evolutionary conservation data suggests that the location where the variant occurred is well-conserved throughout species, suggesting that the location does not tolerate variation. Although this evidence supports pathogenicity, the variant has only been seen in one patient, …

The purpose of this document is to provide updated guidance for the genetic evaluation of cardiomyopathy and for an approach to manage secondary findings from cardiomyopathy genes. The genetic bases of the primary cardiomyopathies (dilated, hypertrophic, arrhythmogenic right ventricular, and restrictive) have been established, and each is medically actionable; in most cases established treatments or interventions are available to improve survival, reduce morbidity, and enhance quality of life. A writing group of cardiologists and genetics professionals updated guidance, first published in 2009 for the Heart Failure Society of America (HFSA), in a collaboration with the American College of Medical Genetics and Genomics (ACMG). Each recommendation was assigned to teams of individuals by expertise, literature was reviewed, and recommendations were decided by consensus of the writing group. Recommendations for family history, phenotype screening of at-risk family members, referral to expert centers as needed, genetic counseling, and cardiovascular therapies, informed in part by phenotype, are presented in the HFSA document. A genetic evaluation of cardiomyopathy is indicated with a cardiomyopathy diagnosis, which includes genetic testing. Guidance is also provided for clinical approaches to secondary findings from cardiomyopathy genes. This is relevant as cardiomyopathy is the phenotype associated with 27% of the genes on the ACMG list for return of secondary findings. Recommendations herein are considered expert opinion per current ACMG policy as no systematic approach to literature review was conducted. Genetic testing is indicated for cardiomyopathy to assist in patient care and management of at-risk family members.

Background Heart failure education programs are not standardized. The best form of education is unclear. We evaluated whether addition of a novel tablet application to nurse practitioner (NP) education was superior to NP education alone in reducing 30-day readmission after heart failure hospitalization. Methods From February 2015-March 2016, patients admitted to a quaternary academic center with primary diagnosis of heart failure were randomized to 1) treatment – NP education plus tablet application (interactive conditional logic program that flags patient questions to medical staff), or 2) control – NP education. The primary outcome was reduction in 30-day readmission rate. Secondary outcomes included satisfaction and education assessed via survey. Results Randomization included 60 patients to treatment and 66 to control. A total of 13 patients withdrew prior to intervention (treatment n = 4, control n = 1) or were lost to follow-up (treatment n = 3, control n = 5). The 30-day readmission rate trended lower for treatment compared with control, but results were not statistically significant (13.2% [7/53], 26.7% [16/60], respectively, P = .08). Similarly, satisfaction trended higher with treatment than control ( P = .08). Treatment patients rated explanations from their physicians higher than control (Always: 83.7%, 55.8%, respectively, P = .01). Conclusions NP education plus tablet use was not associated with significantly lower 30-day readmission rates in comparison with NP alone, but a positive trend was seen. Patient satisfaction trended higher and heart failure explanations were better with NP education plus tablet. A larger study is needed to determine if NP education plus tablet reduces readmission rates following heart failure admission.

The genetic evaluation of dilated cardiomyopathy (DCM) has been challenging, owing in large part to marked genetic heterogeneity. However, lower costs from next generation sequencing have enabled gene discovery and the expansion of genetic testing panels. These advances have improved molecular diagnostics and predictive testing in DCM. Here we provide a rationale and recommendation for clinical genetic testing in all of DCM.

Background— The cause of idiopathic dilated cardiomyopathy (DCM) is unknown by definition, but its familial subtype is considered to have a genetic component. We hypothesize that most idiopathic DCM, whether familial or nonfamilial, has a genetic basis, in which case a genetics-driven approach to identifying at-risk family members for clinical screening and early intervention could reduce morbidity and mortality. Methods— On the basis of this hypothesis, we have launched the National Heart, Lung, and Blood Institute- and National Human Genome Research Institute-funded DCM Precision Medicine Study, which aims to enroll 1300 individuals (600 non-Hispanic African ancestry, 600 non-Hispanic European ancestry, and 100 Hispanic) who meet rigorous clinical criteria for idiopathic DCM along with 2600 of their relatives. Enrolled relatives will undergo clinical cardiovascular screening to identify asymptomatic disease, and all individuals with idiopathic DCM will undergo exome sequencing to identify relevant variants in genes previously implicated in DCM. Results will be returned by genetic counselors 12 to 14 months after enrollment. The data obtained will be used to describe the prevalence of familial DCM among idiopathic DCM cases and the genetic architecture of idiopathic DCM in multiple ethnicity–ancestry groups. We will also conduct a randomized controlled trial to test the effectiveness of Family Heart Talk , an intervention to aid family communication, for improving uptake of preventive screening and surveillance in at-risk first-degree relatives. Conclusions— We anticipate that this study will demonstrate that idiopathic DCM has a genetic basis and guide best practices for a genetics-driven approach to early intervention in at-risk relatives. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT03037632.

The question is is left ventricular noncompaction (LVNC) a trait, phenotype, or disease? By trait, we refer to a discrete and measurable characteristic like eye color. The term phenotype expands this definition to include multiple observable traits derived from diverse genetic factors (genotype) and to recognize additional roles for the environment in shaping visible expression of a genetically defined trait. Pathological phenotypes, with their myriad signs, symptoms, diagnoses, and prognoses, are recognized as diseases and are most often associated with adverse clinical manifestations or need for medical or surgical intervention. See Article by Miller et al So where in this conceptual framework do we place LVNC? This is a well-debated topic1,2 and one that has been recently systematically and expertly reviewed in much greater depth than afforded by this editorial.1–4 Although LVNC has increasingly been recognized as a cardiomyopathy5—itself a term with clear disease connotations—mounting evidence now points to reclassification of LVNC as a distinct but not necessarily pathological phenotype. More specifically, the degree of compacted to noncompacted (NC) myocardium, by itself alone, does not seem to cause disease. Why phenotype rather than trait? Traits are considered to be genetically driven and not malleable by the environment. As defined above, genetics interacting with environment are best labeled as phenotype. Left ventricular (LV) morphology is not fixed for certain characteristics, including LV wall thickness or LV size. The former is well known to increase with severe hypertension or aortic stenosis, and the latter increases with volume overload from aortic insufficiency. With medical or surgical therapy, both conditions will regress. A similar paradigm has been observed with dilated cardiomyopathy—a disease phenotype associated with heart failure and arrhythmia for which the dilated or remodeled left ventricle will reverse remodel with appropriate medical therapy. Characteristics such …

The purpose of this review is to present our current understanding of the genetic etiologies that may cause or predispose to heart failure. We highlight known phenotypes for which a genetic evaluation has clinical utility. The literature continues to demonstrate and confirm a genetic basis for conditions that cause heart failure. Evidence suggests a genetic model involving rare and common variants of strong or weak effect, in combination with environmental factors that may manifest as familial or simplex disease. Clinical genetic testing is available for several phenotypes, which can aid in the diagnosis and identification of at-risk family members. The evaluation of heart failure should include investigating etiologies with a genetic basis. Conducting a genetic evaluation in patients with heart failure requires the ability to identify possible genetic etiologies in an individual’s phenotype, obtain relevant family history, and clinically interpret genetic testing results.

We describe the development and implementation of a randomized controlled trial to investigate the impact of genomic counseling on a cohort of patients with heart failure (HF) or hypertension (HTN), managed at a large academic medical center, the Ohio State University Wexner Medical Center (OSUWMC). Our study is built upon the existing Coriell Personalized Medicine Collaborative (CPMC®). OSUWMC patient participants with chronic disease (CD) receive eight actionable complex disease and one pharmacogenomic test report through the CPMC® web portal. Participants are randomized to either the in-person post-test genomic counseling—active arm, versus web-based only return of results—control arm. Study-specific surveys measure: (1) change in risk perception; (2) knowledge retention; (3) perceived personal control; (4) health behavior change; and, for the active arm (5), overall satisfaction with genomic counseling. This ongoing partnership has spurred creation of both infrastructure and procedures necessary for the implementation of genomics and genomic counseling in clinical care and clinical research. This included creation of a comprehensive informed consent document and processes for prospective return of actionable results for multiple complex diseases and pharmacogenomics (PGx) through a web portal, and integration of genomic data files and clinical decision support into an EPIC-based electronic medical record. We present this partnership, the infrastructure, genomic counseling approach, and the challenges that arose in the design and conduct of this ongoing trial to inform subsequent collaborative efforts and best genomic counseling practices.

Background The value of family history (FH) is well established, but its sensitivity to detect familial dilated cardiomyopathy (FDC) has been infrequently examined. Methods A genetic ancillary study was created as a component of the HF-ACTION trial, a multicenter, prospective, randomized clinical trial of exercise in patients with heart failure and an ejection fraction

Aldosterone antagonists (or mineralocorticoid receptor antagonists [MRAs]) are guideline-recommended therapy for patients with moderate to severe heart failure (HF) symptoms and reduced left ventricular ejection fraction (LVEF), and in postmyocardial infarction patients with HF. The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) trial evaluated the MRA eplerenone in patients with mild HF symptoms. Eplerenone reduced the risk of the primary endpoint of cardiovascular death or HF hospitalization (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.54-0.74, P.001) and all-cause mortality (adjusted HR 0.76, 95% CI 0.62-0.93, P.008) after a median of 21 months. Based on EMPHASIS-HF, an MRA is recommended for patients with New York Heart Association (NYHA) Class II-IV symptoms and reduced LVEF (35%) on standard therapy (Strength of Evidence A). Patients with NYHA Class II symptoms should have another high-risk feature to be consistent with the EMPHASIS-HF population (age55 years, QRS duration130 msec [if LVEF between 31% and 35%], HF hospitalization within 6 months or elevated B-type natriuretic peptide level). Renal function and serum potassium should be closely monitored. Dose selection should consider renal function, baseline potassium, and concomitant drug interactions. The efficacy of eplerenone in patients with mild HF symptoms translates into a unique opportunity to reduce morbidity and mortality earlier in the course of the disease.

Hypertrophic cardiomyopathy (HCM) is a myocardial disorder characterized by left ventricular (LV) hypertrophy without dilatation and without apparent cause (ie, it occurs in the absence of severe hypertension, aortic stenosis, or other cardiac or systemic diseases that might cause LV hypertrophy). Numerous excellent reviews and consensus documents provide a wealth of additional background.1–8 HCM is the leading cause of sudden death in young people and leads to significant disability in survivors. It is caused by mutations in genes that encode components of the sarcomere. Cardiomyocyte and cardiac hypertrophy, myocyte disarray, interstitial and replacement fibrosis, and dysplastic intramyocardial arterioles characterize the pathology of HCM. Clinical manifestations include impaired diastolic function, heart failure, tachyarrhythmia (both atrial and ventricular), and sudden death. At present, there is a lack of understanding of how the mutations in genes encoding sarcomere proteins lead to the phenotypes described above. Current therapeutic approaches have focused on the prevention of sudden death, with implantable cardioverter defibrillator placement in high-risk patients. But medical therapies have largely focused on alleviating symptoms of the disease, not on altering its natural history. The present Working Group of the National Heart, Lung, and Blood Institute brought together clinical, translational, and basic scientists with the overarching goal of identifying novel strategies to prevent the phenotypic expression of disease. Herein, we identify research initiatives that we hope will lead to novel therapeutic approaches for patients with HCM. The epidemiology of HCM suggests that it is present in ≈1 in 500 adults.9 Because of the delay in phenotypic expression of the disease, HCM is not commonly recognized clinically in young children, but when it is, it is much more frequently recognized in males.10 This is likely due to greater penetrance in young males.11,12 HCM is underdiagnosed clinically in blacks and in women, yet …

Background— The term p eripartum cardiomyopathy (PPCM) describes dilated cardiomyopathy (DCM) without known cause that occurs during the last month of pregnancy to 5 months postpartum. A related term, pregnancy - associated cardiomyopathy (PACM), refers to DCM onset earlier in pregnancy. Multiple studies have focused on inflammatory, immunologic, and environmental causes. An alternative hypothesis is that PPCM and PACM result, in part, from a genetic cause. In this study, we sought to test the hypothesis that rare DCM-associated mutations underlie a proportion of PACM or PPCM cases. Methods and Results— A systematic search of our DCM database designed for family-based genetic studies was undertaken for cases associated with pregnancy and the postpartum period; in the identified cases, clinical and molecular genetic data, including exonic and near intron/exon boundaries of DCM genes, were analyzed. Of 4110 women from 520 pedigrees in the Familial Dilated Cardiomyopathy Research Project database, we identified 45 cases of PPCM/PACM. Evidence of familial clustering with DCM was present in 23 unrelated cases. Of the 45 cases, 19 had been resequenced for known DCM genes, and 6 carried mutations. Five had PPCM, of which 3 were familial with mutations found in MYH7 , SCN5A , and PSEN2 , and 2 were sporadic with mutations in MYH6 and TNNT2 . One case had PACM and carried a mutation in MYBPC3. Conclusions— These findings suggest that a proportion of PPCM/PACM cases results from a genetic cause.

This review focuses on the genetic cardiomyopathies: principally dilated cardiomyopathy (DCM), with salient features of hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), regarding genetic etiology, genetic testing, and genetic counseling. Enormous progress has recently been made in identifying genetic causes for each cardiomyopathy, and key phenotype and genotype information is reviewed. Clinical genetic testing is rapidly emerging with a principal rationale of identifying at-risk asymptomatic or disease-free relatives. Knowledge of a disease-causing mutation can guide clinical surveillance for disease onset, thereby enhancing preventive and treatment interventions. Genetic counseling is also indicated for patients and their family members regarding the symptoms of their cardiomyopathy, its inheritance pattern, family screening recommendations, and genetic testing options and possible results.

In this emerging era of cardiovascular genetic medicine, increasing responsibility will be placed on cardiovascular practitioners to be aware of the latest clinical genetic testing methods and the knowledge base needed to interpret genetic test results. Some cardiovascular specialists will develop the expertise within the field to order genetic testing and interpret results, while other practitioners will refer patients to centers of excellence in cardiovascular genetic medicine. A previous article in the Cardiovascular Genetic Medicine: Clinical Perspectives and Future Applications series(1) highlighted an increasing recognition of the cardiomyopathies (hypertrophic [HCM], dilated [DCM], arrhythmogenic right ventricular dysplasia [ARVD]) and channelopathies (long QT syndrome [LQTS] and others) as genetic diseases, and focused on the importance of a targeted family history as a critical part of patient evaluation. The goal of this article, second in the series, is to provide a general framework for understanding the principles of genetic testing and genetic counseling. We review the growing number of genetic tests currently available to cardiac specialists, the selection of an appropriate test, and the numerous genetic counseling issues raised by the testing process. We also provide our preliminary recommendations for genetic testing in cardiovascular genetic medicine.

End-stage heart failure is associated with mortality equivalent to cancer, yet there is little information about palliative therapy for this disease. Chronic outpatient support with inotropes provides symptomatic relief and life extension for those select patients demonstrating dependence on positive inotropic therapy. The purpose of this review is to provide information about process and implementation of chronic outpatient support with inotropes in patients with end-stage heart failure.

Idiopathic dilated cardiomyopathy (IDC), a treatable condition characterized by left ventricular dilatation and systolic dysfunction of unknown cause, has only recently been recognized to have genetic etiologies. Although familial dilated cardiomyopathy (FDC) was thought to be infrequent, it is now believed that 30-50% of cases of IDC may be familial. Echocardiographic and electrocardiographic (ECG) screening of first-degree relatives of individuals with IDC and FDC is indicated because detection and treatment are possible prior to the onset of advanced, symptomatic disease. However, such screening often creates uncertainty and anxiety surrounding the significance of the results. Furthermore, FDC demonstrates incomplete penetrance, variable expression, and significant locus and allelic heterogeneity, making genetic counseling complex. The provision of genetic counseling for IDC and FDC will require collaboration between cardiologists and genetics professionals, and may also improve the recognition of FDC, the availability of support services, and overall outcomes for patients and families.

Aims Depressed sarcoplasmic reticulum (SR) Ca2+ cycling, a universal characteristic of human and experimental heart failure, may be associated with genetic alterations in key Ca2+-handling proteins. In this study, we identified a novel PLN mutation (R25C) in dilated cardiomyopathy (DCM) and investigated its functional significance in cardiomyocyte Ca2+-handling and contractility. Methods and results Exome sequencing identified a C73T substitution in the coding region of PLN in a family with DCM. The four heterozygous family members had implantable cardiac defibrillators, and three developed prominent ventricular arrhythmias. Overexpression of R25C-PLN in adult rat cardiomyocytes significantly suppressed the Ca2+ affinity of SR Ca2+-ATPase (SERCA2a), resulting in decreased SR Ca2+ content, Ca2+ transients, and impaired contractile function, compared with WT-PLN. These inhibitory effects were associated with enhanced interaction of R25C-PLN with SERCA2, which was prevented by PKA phosphorylation. Accordingly, isoproterenol stimulation relieved the depressive effects of R25C-PLN in cardiomyocytes. However, R25C-PLN also elicited increases in the frequency of Ca2+ sparks and waves as well as stress-induced aftercontractions. This was accompanied by increased Ca2+/calmodulin-dependent protein kinase II activity and hyper-phosphorylation of RyR2 at serine 2814. Conclusion The findings demonstrate that human R25C-PLN is associated with super-inhibition of SERCA2a and Ca2+ transport as well as increased SR Ca2+ leak, promoting arrhythmogenesis under stress conditions. This is the first mechanistic evidence that increased PLN inhibition may impact both SR Ca2+ uptake and Ca2+ release activities and suggests that the human R25C-PLN may be a prognostic factor for increased ventricular arrhythmia risk in DCM carriers.

We propose that stage D advanced heart failure be defined as the presence of progressive and/or persistent severe signs and symptoms of heart failure despite optimized medical, surgical, and device therapy. Importantly, the progressive decline should be primarily driven by the heart failure syndrome. Formally defining advanced heart failure and specifying when medical and device therapies have failed is challenging, but signs and symptoms, hemodynamics, exercise testing, biomarkers, and risk prediction models are useful in this process. Identification of patients in stage D is a clinically important task because treatments are inherently limited, morbidity is typically progressive, and survival is often short. Age, frailty, and psychosocial issues affect both outcomes and selection of therapy for stage D patients. Heart transplant and mechanical circulatory support devices are potential treatment options in select patients. In addition to considering indications, contraindications, clinical status, and comorbidities, treatment selection for stage D patients involves incorporating the patient's wishes for survival versus quality of life, and palliative and hospice care should be integrated into care plans. More research is needed to determine optimal strategies for patient selection and medical decision making, with the ultimate goal of improving clinical and patient centered outcomes in patients with stage D heart failure.

Background Familial dilated cardiomyopathy (FDC) is dilated cardiomyopathy of unknown cause occurring in 2 or more closely related family members. Methods and Results Members of 304 families suspected to have FDC were evaluated by family history (FH) and medical record review and were categorized as affected with idiopathic dilated cardiomyopathy (IDC), unaffected, unknown, or no data. Pedigrees were categorized with confirmed FDC, probable FDC, possible FDC or IDC based on strength of evidence. Of the 304 pedigrees, 125 were categorized as confirmed FDC, 48 were probable FDC, 72 were possible FDC, and 59 had sporadic, nonfamilial IDC. Numbers of living first- and second-degree family members, and median number of relatives available for FH was greatest with confirmed FDC, and diminished for probable and possible FDC, and IDC categories. LV dimensions increased and LV function worsened in index patients along the spectrum from confirmed FDC, probable FDC, possible FDC and IDC, and a greater proportion of IDC patients underwent heart transplant. However, the age of onset, duration of disease, the time to death or heart transplant, and most other findings were similar among the 4 categories. Conclusion Clinical characteristics of IDC and FDC are similar, precluding an FDC diagnosis from clinical features only.

Cardiac allograft left ventricular ejection fraction (LVEF) is an important measure of left ventricular systolic function. Despite widespread use of LVEF after transplantation, its normal range and prognostic value in cardiac allografts has not been defined.We conducted a retrospective cohort study among 292 consecutive adult heart transplant patients. Left ventricular ejection fractions were performed at 1, 3, 12, 24, and 48 months after transplantation using radionuclide ventriculography. Endomyocardial biopsies assessed rejection, right heart catheterization assessed loading conditions, and angiography assessed allograft coronary artery disease. We used Cox proportional hazards model to examine the predictive value of LVEF on late mortality.Of the patients who survivedor =4 years, the mean allograft LVEF decreased 4.7 units at 3 months, from 63.8 to 59.7; an additional 4.1 units at 12 months, from 59.7 to 55.6 (p0.001); and remained stable afterward. These changes were not associated with concurrent changes in loading conditions, episodes of rejection, or development of allograft coronary artery disease. Left ventricular ejection fraction lower than the 95% normal limit (40%) at 12 months was inversely associated with risk for late cardiac mortality (relative risk = 3.5, 95% confidence interval = 1.0-12.2), while controlling for recipient age, sex, donor age, and rejection episodes.The cardiac-allograft LVEF frequently decreases in the first year after transplantation. The 95th percentile of allograft LVEF value (40%) at Year 1 predicts late cardiac mortality among transplant recipients.

Although considerable effort has been devoted to the follow-up of hospitalized patients, the effectiveness and process of heart failure outpatient management have not been well demonstrated.All new patients referred to the program from April 1997 to September 1998 were followed and managed by comprehensive strategies including preemptive hospitalization. Quality of life (QOL) and patients' self-care adherence behaviors were measured at baseline, 3 months, and 6 months. Clinical outcomes were compared for the 6 months before and 6 months after referral. A total of 108 patients were recruited. Patients' self-care knowledge score was improved over time (difference score = 0.9, P.01). The proportion of patients weighing themselves daily increased by 24% (P =.02). The proportion of patients with New York Heart Association (NYHA) class III to IV was 67.6% at baseline and 49.1% at 6 months (P =.01). Compared with 6 months before referral, the program intervention was accompanied by a 52% reduction in the risk of hospitalization for cardiovascular causes (56.1% v 27.2%, P.001) and a 72% reduction in emergency room visits (53.6% v 14.5%, P.01). The total hospital admissions for cardiovascular causes decreased by 59% from 94 to 39; the total emergency room visits decreased by 77% from 83 to 19. The patients' QOL was improved over time with a change score of 11.2 (P.001) at 3 months and 10.7 (P.001) at 6 months.Our study shows the effectiveness of this heart failure outpatient management program.

The Short-Form 12 (SF-12) and Living With Heart Failure Questionnaire (LHFQ) are commonly used to measure quality of life (QOL) in heart failure outcomes research. Their comparative responsiveness, however, has not been documented.A prospective cohort study was conducted among patients attending a university-based heart failure clinic between April 1997 and September 1998. All patients received comprehensive heart failure care management. QOL of patients was assessed by the SF-12 and LHFQ at baseline and 3 months. Of 87 patients completing follow-up, the mean change score was 10.1 for the LHFQ and 5.8 for the SF-12 (both Ps.001). The change scores of the instruments were correlated (r = 0.61; P.001). The SF-12 had a greater ability than the LHFQ to statistically detect change in physical health but was less sensitive to changes in mental health. The LHFQ performed better than the SF-12 in the ability to distinguish the differences in perceived global health transition.The LHFQ is more responsive than the SF-12 to changes in QOL. The SF-12 should not be used alone to measure the changes in QOL of patients with heart failure.

OBJECTIVES This study aimed to characterize the clinical profile of familial dilated cardiomyopathy (FDC) in the families of four index patients initially diagnosed with idiopathic dilated cardiomyopathy (IDC) and to provide clinical practice recommendations for physicians dealing with these diseases. BACKGROUND Recent evidence indicates that approximately one-half of patients diagnosed with IDC will have FDC, a genetically transmissible disease, but the clinical profile of families screened for FDC in the U.S. has not been well documented. Additionally, recent ethical guidelines suggest increased responsibilities in caring for patients with newly found genetic cardiovascular disease. METHODS After identification of four families with FDC, we undertook clinical screening including medical history, physical examination, electocardiogram and echocardiogram. Diagnostic criteria for FDC-affected status of asymptomatic family members was based on left ventricular enlargement (LVE). Subjects with confounding cardiovascular diagnoses or body mass indices >35 were excluded. RESULTS We identified 798 living members from the four FDC pedigrees, and screened 216 adults and 129 children (age CONCLUSIONS We propose that with a new diagnosis of IDC, a thorough family history for FDC should be obtained, followed by echocardiographic-based screening of first-degree relatives for LVE, assuming their voluntary participation. If a diagnosis of FDC is established, we suggest further screening of first-degree relatives, and all subjects with FDC undergo medical treatment following established guidelines. Counseling of family members should emphasize the heritable nature of the disease, the age-dependent penetrance and the unpredictable clinical course.

Background: Echocardiographic criteria for left ventricular enlargement (LVE) used to classify subjects as affected in families with familial dilated cardiomyopathy (FDC) have been inconsistent. A recent report from a large Framingham echocardiographic study provides an opportunity to improve the assignment of LVE and FDC in kindreds, principally with a dilated phenotype. The objective of this study is to evaluate an alternative diagnostic criteria for FDC based only on LVE with no measure of fractional shortening (FS). Methods and Results: We compared our proposed criteria for LVE and FDC with previous approaches by applying them to 166 adults derived from three large FDC pedigrees. Our proposed FDC diagnostic criteria are a sex- and height-specific method based only on LVE, without regard for FS, set as a 97.5% upper limit for left ventricular end-diastolic dimension (LVEDD) from the Framingham study. Other methods used to assign LVE were (1) a 95% upper limit for LVEDD by the Framingham study; (2) the method of Henry et al. (1980) based on age and body surface area (BSA); and (3) the National Heart, Lung, and Blood Institute (NHLBI) method with a cut point of LVEDD greater than 2.7 cm/BSA. Three other commonly used diagnostic criteria for FDC were based on various LVE standards combined with an FS of 27% to 30%. For LVE, the Framingham-97.5% was the most stringent (21 of 134 subjects identified; 15.7%), the NHLBI standard the least stringent (57 of 161 subjects identified; 35.4%), and the Henry-112% method intermediate (44 of 161 subjects identified; 27.3%). More women were identified with the Framingham method (57.1%) versus the Henry-112% (40.9%). The Henry-112% and NHLBI methods identified 11.4% and 7.0% of subjects with body mass indices (BMIs) of 35 or greater, respectively. For FDC, our proposed FDC diagnostic criteria identified similar numbers of subjects (21 subjects) as the three other criteria (range, 22 to 27 subjects), but inconsistency was noted (54.2% to 66.7%), with kappa values from 0.49 to 0.55 resulting from different sensitivities to sex, LVE, FS, and BMI. Conclusion: Our proposed FDC diagnostic criteria are stringent to assign FDC family members as affected compared with other commonly used criteria. The use of LVEDD alone may be preferable for FDC family screening, although further validation of this approach with phenotypic and genotypic data from other large FDC pedigrees is needed.

Background: Over the past 10 years, efforts have been made to control the cost of care for patients with congestive heart failure (CHF) through reducing hospitalizations and shortening lengths of stay. Few data are available regarding the effectiveness of these intervention strategies on a community basis. Methods and Results: We analyzed the Oregon hospital discharge database. Multivariable methods were used to assess trends while controlling for confounding factors, such as age, sex, and comorbidity. The hospital admission rates for CHF were stable over time in all age groups. The age- and sex-standardized admission rate among people aged 65 years or older decreased slightly from 13.9/1,000 in 1991 to 12.9/1,000 in 1995. The annual hospital readmission rate remained constant over time, with an average rate of 15.3%. The average length of hospital stay decreased from 5.01 days in 1991 to 3.95 days in 1995. The in-hospital mortality rate decreased from 6.9% in 1991 to 4.7% in 1995, independent of length of stay. Conclusion: We observed stable hospital admission and readmission rates for CHF, accompanied by a decreasing trend in the length of hospital stay and in-hospital mortality. Our findings raise the possibility of improved care management for heart failure over time.

Background The Oregon Cardiac Transplant Program provides a regional service. Since December 4, 1985, 284 patients, including 14 children, from Oregon, Washington, Idaho, Alaska, and Hawaii, underwent 295 orthotopic heart transplantation procedures at the Oregon Health Sciences University. Eleven patients underwent transplantations twice. Methods Detailed, up-to-date follow-up data were available on all patients. All patients have been followed up prospectively for transplant-related complications. Results The most common recipient diagnoses were coronary artery disease (50%) or idiopathic cardiomyopathy (33%). The mean age of the recipients was 48 ± 15 years (range, 3 months to 68 years). Donor hearts were retrieved from a procurement area of a 1,500-mile radius that involved Oregon, Washington, Idaho, Nevada, Utah, California, and Canada. The mean donor age was 28 ± 11 years and the donor heart ischemia time was 180 ± 56 minutes. The median recipient waiting time was 75 days. Operative mortality was 6%. One-year, 5-year, and 10-year actuarial patient survival rates are 86 ± 2%, 74 ± 3%, and 59 ± 5%, respectively. The majority of survivors are in very good functional status. Conclusions Now, more than 10 years into its existence, the Oregon Heart Transplant Program has fulfilled its goal of providing a most effective treatment option for patients with end-stage heart disease in the region.

Background We conducted a multicenter, placebo-controlled trial designed to establish the efficacy and safety of carvedilol, a “third-generation” β-blocking agent with vasodilator properties, in chronic heart failure. Methods and Results Three hundred forty-five subjects with mild to moderate, stable chronic heart failure were randomized to receive treatment with placebo, 6.25 mg BID carvedilol (low-dose group), 12.5 mg BID carvedilol (medium-dose group), or 25 mg BID carvedilol (high-dose group). After a 2- to 4-week up-titration period, subjects remained on study medication for a period of 6 months. The primary efficacy parameter was submaximal exercise measured by two different techniques, the 6-minute corridor walk test and the 9-minute self-powered treadmill test. Carvedilol had no detectable effect on submaximal exercise as measured by either technique. However, carvedilol was associated with dose-related improvements in LV function (by 5, 6, and 8 ejection fraction [EF] units in the low-, medium-, and high-dose carvedilol groups, respectively, compared with 2 EF units with placebo, P< .001 for linear dose response) and survival (respective crude mortality rates of 6.0%, 6.7%, and 1.1% with increasing doses of carvedilol compared with 15.5% in the placebo group, P< .001). When the three carvedilol groups were combined, the all-cause actuarial mortality risk was lowered by 73% in carvedilol-treated subjects ( P P= .01) and was generally well tolerated. Conclusions In subjects with mild to moderate heart failure from systolic dysfunction, carvedilol produced dose-related improvements in LV function and dose-related reductions in mortality and hospitalization rate.

Background We tested the hypothesis that carvedilol inhibits clinical progression in patients with mildly symptomatic heart failure due to left ventricular (LV) systolic dysfunction. Methods and Results Patients (n=366) who had mildly symptomatic heart failure with an LV ejection fraction (LVEF) ≤0.35, had minimal functional impairment (defined as the ability to walk 450 to 550 m on a 6-minute walk test), and were receiving optimal standard therapy, including ACE inhibitors, were randomized double-blind to carvedilol (n=232) or placebo (n=134) and followed up for 12 months. The primary end point was clinical progression, defined as death due to heart failure, hospitalization for heart failure, or a sustained increase in heart failure medications. Clinical progression of heart failure occurred in 21% of placebo patients and 11% of carvedilol patients, reflecting a 48% ( P =.008) reduction in the primary end point of heart failure progression (relative risk, 0.52; CI, 0.32 to 0.85). This effect of carvedilol was not influenced by sex, age, race, cause of heart failure, or baseline LVEF. Carvedilol also significantly improved several secondary end points, including LVEF, heart failure score, NYHA functional class, and the physician and patient global assessments. Carvedilol reduced all-cause mortality but had no effects on the Minnesota Living With Heart Failure scale, the distance walked in 9 minutes on a self-powered treadmill, or cardiothoracic index. The drug was well tolerated. Conclusions Carvedilol, when added to standard therapy, including an ACE inhibitor, reduces clinical progression in patients who are only mildly symptomatic with well-compensated heart failure.

Background LMNA cardiomyopathy presents with electrocardiogram (ECG) abnormalities, conduction system disease (CSD), and/or arrhythmias before the onset of dilated cardiomyopathy (DCM). Knowing the time interval between the onset of CSD and its progression to DCM would help to guide clinical care. Methods and Results We evaluated family members from 16 pedigrees previously identified to carry LMNA mutations for the ages of onset of ECG abnormalities, CSD, or arrhythmia and of left ventricular enlargement (LVE) and/or systolic dysfunction. Of 103 subjects, 64 carried their family LMNA mutation, and 51 (79%) had ECG abnormalities with a mean age of onset of 41.2 years (range 18–76). Ventricular dysfunction was observed in 26 with a mean age of onset of 47.6 years (range 28–82); at diagnosis 9 had systolic dysfunction but no LVE, 5 had LVE but no systolic dysfunction, and 11 had DCM. Of 16 subjects identified with ECG abnormalities who later developed ventricular dysfunction, the median ages of onset by log-rank analyses were 41 and 48 years, respectively. Conclusions ECG abnormalities preceded DCM with a median difference of 7 years. Clinical surveillance should occur at least annually in those at risk for LMNA cardiomyopathy with any ECG findings.