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Advances in human genome sequencing have re-invigorated genetics studies of dilated cardiomyopathy (DCM), facilitating genetic testing and clinical applications. With a range of genetic testing options now available, new challenges arise for data interpretation and identifying single pathogenic variants from the many thousands of rare variants present in every individual. There is accumulating evidence that genetic factors have an important role in the pathogenesis of DCM. However, although more than 100 genes have been implicated to date, the sensitivity of genetic testing, even in familial disease, is only ∼25-40%. As more patients are genotyped, nuanced information about disease phenotypes is emerging including variability in age of onset and penetrance of DCM, as well as additional cardiac and extra-cardiac features. Genotype-phenotype correlations have also identified a subset of genes that can be highly arrhythmogenic or show frequent progression to heart failure. Recognition of variants in these genes is important as this may impact on the timing of implantable cardioverter-defibrillators or heart transplantation. Finding a causative variant in a patient with DCM allows predictive testing of family members and provides an opportunity for preventative intervention. Diagnostic imaging modalities such as speckle-tracking echocardiography and cardiac magnetic resonance imaging are increasingly being used to detect and monitor pre-clinical ventricular dysfunction in asymptomatic variant carriers. Although there are several examples of successful genotype-based therapy, optimal strategies for implementation of precision medicine in familial DCM remain to be determined. Identification of modifiable co-morbidities and lifestyle factors that exacerbate or protect against DCM development in genetically-predisposed individuals remains a key component of family management.

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.

Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction that is not explained by abnormal loading conditions (for example, hypertension and valvular heart disease) or coronary artery disease. Mutations in several genes can cause DCM, including genes encoding structural components of the sarcomere and desmosome. Nongenetic forms of DCM can result from different aetiologies, including inflammation of the myocardium due to an infection (mostly viral); exposure to drugs, toxins or allergens; and systemic endocrine or autoimmune diseases. The heterogeneous aetiology and clinical presentation of DCM make a correct and timely diagnosis challenging. Echocardiography and other imaging techniques are required to assess ventricular dysfunction and adverse myocardial remodelling, and immunological and histological analyses of an endomyocardial biopsy sample are indicated when inflammation or infection is suspected. As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM. Cardiac resynchronization therapy and implantable cardioverter–defibrillators may be required to prevent life-threatening arrhythmias. In addition, identifying the probable cause of DCM helps tailor specific therapies to improve prognosis. An improved aetiology-driven personalized approach to clinical care will benefit patients with DCM, as will new diagnostic tools, such as serum biomarkers, that enable early diagnosis and treatment., Dilated cardiomyopathy (DCM) is characterized by ventricular enlargement and impaired contractility without an underlying ischaemic origin. DCM has heterogeneous aetiologies (including gene mutations, infections and inflammation) and clinical presentations and can eventually result in heart failure.

Genome-scale sequencing creates vast amounts of genomic data, increasing the challenge of clinical sequence variant interpretation. The demand for high-quality interpretation requires multiple specialties to join forces to accelerate the interpretation of sequence variant pathogenicity. With over 600 international members including clinicians, researchers, and laboratory diagnosticians, the Clinical Genome Resource (ClinGen), funded by the National Institutes of Health (NIH), is forming expert groups to systematically evaluate variants in clinically relevant genes. Here, we describe the first ClinGen Variant Curation Expert Panels (VCEPs), development of consistent and streamlined processes for establishing new VCEPs, and creation of standard operating procedures (SOPs) for VCEPs to define application of the ACMG/AMP guidelines for sequence variant interpretation in specific genes or diseases. Additionally, ClinGen has created user interfaces to enhance reliability of curation and a Sequence Variant Interpretation Working Group (SVI WG) to harmonize guideline specifications and ensure consistency between groups. The expansion of VCEPs represents the primary mechanism by which curation of a substantial fraction of genomic variants can be accelerated and ultimately undertaken systematically and comprehensively. We welcome groups to utilize our resources and become involved in our effort to create a publicly accessible, centralized resource for clinically relevant genes and variants.

We have previously described 19 pedigrees with apparent lamin (Affected family members underwent exome sequencing to identify additional genetic cause of DCM in the 6 families with nonsegregatingIn 5 of 6 pedigrees, we identified at least 1 additional rare variant in a known DCM gene that could plausibly contribute to disease in theOur data support DCM as a genetically heterogeneous disease with, at times, multigene causation. Although the frequency of DCM resulting from multigenic cause is uncertain, our data suggest it may be higher than previously anticipated.

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 completion of the Human Genome Project has unleashed a wealth of human genomics information, but it remains unclear how best to implement this information for the benefit of patients. The standard approach of biomedical research, with researchers pursuing advances in knowledge in the laboratory and, separately, clinicians translating research findings into the clinic as much as decades later, will need to give way to new interdisciplinary models for research in genomic medicine. These models should include scientists and clinicians actively working as teams to study patients and populations recruited in clinical settings and communities to make genomics discoveries—through the combined efforts of data scientists, clinical researchers, epidemiologists, and basic scientists—and to rapidly apply these discoveries in the clinic for the prediction, prevention, diagnosis, prognosis, and treatment of cardiovascular diseases and stroke. The highly publicized US Precision Medicine Initiative, also known as All of Us, is a large-scale program funded by the US National Institutes of Health that will energize these efforts, but several ongoing studies such as the UK Biobank Initiative; the Million Veteran Program; the Electronic Medical Records and Genomics Network; the Kaiser Permanente Research Program on Genes, Environment and Health; and the DiscovEHR collaboration are already providing exemplary models of this kind of interdisciplinary work. In this statement, we outline the opportunities and challenges in broadly implementing new interdisciplinary models in academic medical centers and community settings and bringing the promise of genomics to fruition.

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.

The presentation, natural history, clinical outcomes, and response to therapy in patients with heart failure differ in some ways across populations. Women, older adults, and non-Caucasian racial or ethnic groups compose a substantial proportion of the overall heart failure population, but they have typically been underrepresented in clinical trials. As a result, uncertainty exists about the efficacy of some guideline-directed medical therapies and devices in specific populations, which may result in the under- or overtreatment of these patients. Even when guideline-based treatments are prescribed, socioeconomic, physical, or psychologic factors may affect non-Caucasian and older adult patient groups to a different extent and affect the application, effectiveness, and tolerability of these therapies. Individualized therapy based on tailored biology (genetics, proteomics, metabolomics), socioeconomic and cultural considerations, and individual goals and preferences may be the optimal approach for managing diverse patients. This comprehensive approach to personalized medicine is evolving, but in the interim, the scientific community should continue efforts focused on intensifying research in special populations, prescribing guideline-directed medical therapy unless contraindicated, and implementing evidence-based strategies including patient and family education and multidisciplinary team care in the management of patients.

Dilated cardiomyopathy (DCM) is a disease of the myocardium characterized by left ventricular dilatation and diminished contractile function. Here we describe a novel DCM mutation in the myosin regulatory light chain (RLC), in which aspartic acid at position 94 is replaced by alanine (D94A). The mutation was identified by exome sequencing of three adult first-degree relatives who met formal criteria for idiopathic DCM. To obtain insight into the functional significance of this pathogenic MYL2 variant, we cloned and purified the human ventricular RLC wild-type (WT) and D94A mutant proteins, and performed in vitro experiments using RLC-mutant or WT-reconstituted porcine cardiac preparations. The mutation induced a reduction in the α-helical content of the RLC, and imposed intra-molecular rearrangements. The phosphorylation of RLC by Ca²⁺/calmodulin-activated myosin light chain kinase was not affected by D94A. The mutation was seen to impair binding of RLC to the myosin heavy chain, and its incorporation into RLC-depleted porcine myosin. The actin-activated ATPase activity of mutant-reconstituted porcine cardiac myosin was significantly higher compared with ATPase of wild-type. No changes in the myofibrillar ATPase-pCa relationship were observed in wild-type- or D94A-reconstituted preparations. Measurements of contractile force showed a slightly reduced maximal tension per cross-section of muscle, with no change in the calcium sensitivity of force in D94A-reconstituted skinned porcine papillary muscle strips compared with wild-type. Our data indicate that subtle structural rearrangements in the RLC molecule, followed by its impaired interaction with the myosin heavy chain, may trigger functional abnormalities contributing to the DCM phenotype.

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.

Cardiovascular diseases (CVDs) are a major source of morbidity and mortality worldwide. Despite a decline of ≈30% over the past decade, heart disease remains the leading killer of Americans.1 For rare and familial forms of CVD, we are increasingly recognizing single-gene mutations that impart relatively large effects on individual phenotype. Examples include inherited forms of cardiomyopathy, arrhythmias, and aortic diseases. However, the prevalence of monogenic disorders typically accounts for a small proportion of the total CVD observed in the population. CVDs in the general population are complex diseases, with several contributing genetic and environmental factors. Although recent progress in monogenic disorders has occurred, we have seen a period of intense investigation to identify the genetic architecture of more common forms of CVD and related traits. Genomics serves several roles in cardiovascular health and disease, including disease prediction, discovery of genetic loci influencing CVD, functional evaluation of these genetic loci to understand mechanisms, and identification of therapeutic targets. For single-gene CVDs, progress has led to several clinically useful diagnostic tests, extending our ability to inform the management of afflicted patients and their family members. However, there has been little progress in developing genetic testing for complex CVD because individual common variants have only a modest impact on risk. The study of the genomics of complex CVDs is further challenged by the influence of environmental variables, phenotypic heterogeneity, and pathogenic complexity. Characterization of the clinical phenotype requires consideration of the clinical details of the diseases and traits under study. This update expands the prior scientific statement on the relevance of genetics and genomics for the prevention and treatment of CVDs.2 In the earlier report, we focused on the current status of the field, which consisted of predominantly family-based linkage studies and single-gene or mendelian mutations of relatively large phenotypic effect …

The number of clinically available genetic tests for heritable cardiovascular diseases has recently increased because of novel gene discoveries and advancements in DNA sequencing technologies. The purpose of this review is to provide up-to-date genetic testing information and guidance on how to incorporate genetic testing into cardiovascular medicine. Heritable cardiovascular conditions display vast genetic heterogeneity, genetic overlap between phenotypes, incomplete penetrance and variable expressivity, and are associated with risk for sudden cardiac death, making the practice of cardiovascular genetic medicine a great responsibility. Multigene testing panels now exist for many cardiovascular conditions, and test utility has recently been augmented by population-based genomic sequence datasets. Large amounts of DNA sequence data necessitate rigorous interpretation of this probabilistic information. Timely practice guidelines and expert statements have been published. To fully realize the benefits of clinical genetic testing in cardiovascular medicine, clinicians must implement several components including judicious genetic testing, pretest and posttest genetic counseling, interpretation and application of genetic test results, and cascade family genetic testing and clinical screening. Components important to the proper integration of cardiovascular genetic medicine are offered.

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

Background— Familial dilated cardiomyopathy (DCM) is a genetically heterogeneous disease with >30 known genes. TTN truncating variants were recently implicated in a candidate gene study to cause 25% of familial and 18% of sporadic DCM cases. Methods and Results— We used an unbiased genome-wide approach using both linkage analysis and variant filtering across the exome sequences of 48 individuals affected with DCM from 17 families to identify genetic cause. Linkage analysis ranked the TTN region as falling under the second highest genome-wide multipoint linkage peak, multipoint logarithm of odds, 1.59. We identified 6 TTN truncating variants carried by individuals affected with DCM in 7 of 17 DCM families (logarithm of odds, 2.99); 2 of these 7 families also had novel missense variants that segregated with disease. Two additional novel truncating TTN variants did not segregate with DCM. Nucleotide diversity at the TTN locus, including missense variants, was comparable with 5 other known DCM genes. The average number of missense variants in the exome sequences from the DCM cases or the ≈5400 cases from the Exome Sequencing Project was ≈23 per individual. The average number of TTN truncating variants in the Exome Sequencing Project was 0.014 per individual. We also identified a region (chr9q21.11-q22.31) with no known DCM genes with a maximum heterogeneity logarithm of odds score of 1.74. Conclusions— These data suggest that TTN truncating variants contribute to DCM cause. However, the lack of segregation of all identified TTN truncating variants illustrates the challenge of determining variant pathogenicity even with full exome sequencing.

Although the power of family history to identify a genetic predisposition to disease has been appreciated for some time, it is only recently, through the development of efficient methods for molecular genotyping and specific genetic tests, that a detailed genetic evaluation could be used to influence clinical medicine. Indeed, the mapping of the human genome and the more recent development of high-throughput methodologies have the potential to entirely transform how we think about genetic predisposition to disease. This represents a great opportunity to improve human health. Yet these recent technological advances also create new moral, ethical, and legal challenges that must be addressed before the opportunities to improve human health can be fully realized. In the present report, we summarize the existing regulatory landscape with respect to the use of genetic information in clinical medicine and offer new policy recommendations designed to facilitate the safe incorporation of the latest technologies and research findings into the clinical domain. Specifically, we focus on areas in which genetic evaluation, including personal and family history, examination, counseling, and testing, has the potential to impact the practice of cardiovascular medicine and research. ### Gene Patents Patent law is enshrined in the US Constitution in Article I, Section 8, and the principles imply that to be patent eligible, an invention needs to demonstrate novelty, utility, and nonobviousness. As such, although the patenting of raw naturally occurring materials has been generally rejected, where significant innovation is involved in its isolation, the patent office has generally granted protection (for example, insulin and adrenaline). In 1980, the US Supreme Court deemed a living organism patentable ( Diamond v Chakrabarty ) if “man-made,” as potentially accomplished via genetic engineering. In the wake of this decision, the US Patent and Trademark Office (USPTO) began to approve applications with DNA sequences central to the patent claim, initially …

PURPOSE OF REVIEW This review examines the application of next-generation sequencing (NGS) technologies in the identification of the causation of nonsyndromic genetic cardiomyopathies. RECENT FINDINGS NGS sequencing of the entire genetic coding sequence (the exome) has successfully identified five novel genes and causative variants for cardiomyopathies without previously known cause within the last 12 months. Continual rapidly decreasing costs of NGS will shortly allow cost-effective sequencing of the entire genomes of affected individuals and their relatives to include noncoding and regulatory variant discovery and epigenetic profiling. Despite this rapid technological progress with sequencing, analysis of these large data sets remains challenging, particularly for assigning causality to novel rare variants identified in DNA samples from patients with cardiomyopathy. SUMMARY NGS technologies are rapidly moving to identify novel rare variants in patients with cardiomyopathy, but assigning pathogenicity to these novel variants remains challenging.

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.

A great deal of progress has recently been made in the discovery and understanding of the genetics of familial dilated cardiomyopathy (FDC). A consensus has emerged that with a new diagnosis of idiopathic dilated cardiomyopathy (IDC), the clinical screening of first-degree family members will reveal FDC in at least 20% to 35% of those family members. Point mutations in 31 autosomal and 2 X-linked genes representing diverse gene ontogeny have been implicated in causing FDC but account for only 30% to 35% of genetic causes. Next-generation sequencing methods have dramatically decreased sequencing costs, making clinical genetic testing feasible for extensive panels of dilated cardiomyopathy genes. Next-generation sequencing also provides opportunities to discover additional genetic causes of FDC and IDC. Guidelines for evaluation and testing of FDC and IDC are now available, and when combined with FDC genetic testing and counseling, will bring FDC/IDC genetics to the forefront of cardiovascular genetic medicine.

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.

Background— Rare variants in >30 genes have been shown to cause idiopathic or familial dilated cardiomyopathy (DCM), but the frequency of genetic causation remains poorly understood. We have previously resequenced 9 genes in a cohort of idiopathic or familial DCM probands for rare variants, and now we report resequencing results for 5 more genes with established relationships to DCM. Methods and Results— Blood samples were collected, and DNA specimens were prepared from 312 patients, 181 with familial DCM and 131 with idiopathic DCM. Genomic DNA underwent bidirectional sequencing, and DNA of additional family members underwent analysis when a rare variant was identified. We identified rare variants in 34 probands (10.9% overall), including 29 unique protein-altering rare variants and 2 splicing variants that were absent in 246 control subjects (492 chromosomes). These variants were 12 MYBPC3 (myosin-binding protein C) in 13 (4.2%) probands, 8 MYH6 (α-myosin heavy chain) in 10 (3.2%), 6 TPM1 (tropomyosin) in 6 (1.9%), 4 TNNC1 (cardiac troponin C) in 4 (1.3%), and 1 TNNI3 (cardiac troponin I) in 2 (0.6%). Variants were classified as likely or possibly disease causing in 13 and 20 probands, respectively (n=33; 10.6% overall). One MYH6 variant was classified as unlikely to be disease causing. Conclusion— Rare variants in these 5 genes likely or possibly caused 10.6% of DCM in this cohort. When combined with our prior resequencing reports, ≈27% of DCM probands had possible or likely disease-causing variants identified.

Background— A key issue for cardiovascular genetic medicine is ascertaining if a putative mutation indeed causes dilated cardiomyopathy (DCM). This is critically important as genetic DCM, usually presenting with advanced, life-threatening disease, may be preventable with early intervention in relatives known to carry the mutation. Methods and Results— We recently undertook bidirectional resequencing of TNNT2 , the cardiac troponin T gene, in 313 probands with DCM. We identified 6 TNNT2 protein-altering variants in 9 probands, all who had early onset, aggressive disease. Additional family members of mutation carriers were then studied when available. Four of the 9 probands had DCM without a family history, and 5 probands had familial DCM. Only 1 mutation (Lys210del) could be attributed as definitively causative from previous reports. Four of the 5 missense mutations were novel (Arg134Gly, Arg151Cys, Arg159Gln, and Arg205Trp), and one was previously reported with hypertrophic cardiomyopathy (Glu244Asp). Based on the clinical, pedigree, and molecular genetic data, these 5 mutations were considered possibly or likely disease causing. To further clarify their potential pathophysiologic impact, we undertook functional studies of these mutations in cardiac myocytes reconstituted with mutant troponin T proteins. We observed decreased Ca 2+ sensitivity of force development, a hallmark of DCM, in support of the conclusion that these mutations are disease causing. Conclusions— We conclude that the combination of clinical, pedigree, molecular genetic, and functional data strengthen the interpretation of TNNT2 mutations in DCM.

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.

Considerable progress has been made to identify genetic causation of dilated cardiomyopathy (DCM). DCM is characterized by left ventricular dilatation and systolic dysfunction, and after known causes have been excluded has been termed idiopathic dilated cardiomyopathy (IDC). Studies of IDC that occurs in families, termed familial dilated cardiomyopathy (FDC) provided the initial phenotypic data to suggest genetic causation. The study of large families with linkage analysis and gene mapping methods have recently implicated 16 autosomal genes and two X-linked genes. Mutations in these genes account for approximately 20–30% of genetic causation, suggesting that additional genetic causation remains unknown. FDC demonstrates incomplete penetrance, variable expression, and significant locus and allelic heterogeneity, making diagnosis complex. Echocardiographic and electrocardiographic screening of first-degree relatives of individuals with IDC and FDC is indicated, as detection and treatment are possible prior to the onset of advanced, symptomatic disease. Genetic counseling for IDC and FDC may also be appropriate. It is anticipated that a great deal of additional genetic information yet to be discovered will add greatly to our understanding of the genetics of dilated cardiomyopathy.

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.

Remarkable progress has been made in understanding the genetic basis of dilated cardiomyopathy (DCM). Rare variants in >30 genes, some also involved in other cardiomyopathies, muscular dystrophy, or syndromic disease, perturb a diverse set of important myocardial proteins to produce a final DCM phenotype. Large, publicly available datasets have provided the opportunity to evaluate previously identified DCM-causing mutations, and to examine the population frequency of sequence variants similar to those that have been observed to cause DCM. The frequency of these variants, whether associated with dilated or hypertrophic cardiomyopathy, is greater than estimates of disease prevalence. This mismatch might be explained by one or more of the following possibilities: that the penetrance of DCM-causing mutations is lower than previously thought, that some variants are noncausal, that DCM prevalence is higher than previously estimated, or that other more-complex genomics underlie DCM. Reassessment of our assumptions about the complexity of the genomic and phenomic architecture of DCM is warranted. Much about the genomic basis of DCM remains to be investigated, which will require comprehensive genomic studies in much larger cohorts of rigorously phenotyped probands and family members than previously examined.

The value of family history (FH) is well established, but its sensitivity to detect familial dilated cardiomyopathy (FDC) has been infrequently examined.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 fraction35%. A FH-based study using a structured questionnaire mailed to all consenting individuals was incorporated into the genetic ancillary. FH responses were analyzed for dilated cardiomyopathy (DCM) in family members.Of the 741 individuals with data available, 358 (48.3%) had nonischemic and 383 (51.6%) had ischemic etiology, and of these 164 (45.8%) and 201 (52.4%), respectively, returned evaluable questionnaires. Of those with nonischemic etiology, 14/164 (8.5%) reported at least one first-degree family member with DCM or an enlarged heart; another 21/164 (12.8%) reported a FH of "cardiomyopathy," a less specific term to indicate DCM.At least 8.5% of patients with nonischemic etiology in the HF-ACTION genetic ancillary study provided FH indicating familial DCM, information important to inform further genetic analyses of this cohort and to plan other studies.

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.