Cardiovascular Genetic Medicine: Evolving Concepts, Rationale, and Implementation

Cardiovascular genetic medicine is devoted to the identification and understanding of cardiac conditions resulting from genetic and genomic mechanisms and to the development and validation of diagnostic and treatment algorithms and guidelines. Cardiovascular genetic medicine clinics now provide expert cardiovascular subspecialty care, genetic counseling and clinical genetic testing, and will eventually provide disease-specific gene or genetic therapies. Currently, the most tractable diagnoses for cardiovascular genetic medicine are the single-gene disorders: the cardiomyopathies, the channelopathies, and others. The recent explosion of genetic knowledge within the single-gene disorders and consequent rapid proliferation of genetic testing enables far greater numbers of individuals to directly benefit from this progress. A compelling rationale exists for this approach: cardiovascular single-gene diseases commonly present with life-threatening events (e.g., sudden cardiac death, heart failure, stroke, etc.), but identification, evaluation, and treatment of individuals with presymptomatic genetic risk has the promise to prevent or ameliorate cardiovascular morbidity and mortality. Cardiovascular genetic medicine programs also anchor training and research, thereby enabling the next generation of academic specialists in cardiovascular genetic medicine to continue to improve cardiovascular health.     

Family history: an essential tool for cardiovascular genetic medicine

We are pleased to provide a new section devoted to topics in cardiovascular genetic medicine. An emerging field, cardiovascular genetic medicine is devoted to the identification and understanding of cardiac conditions resulting from genetic mechanisms and to the development and validation of treatment algorithms and guidelines. Cardiovascular genetic medicine is rapidly enlarging, and we anticipate a broad range of comprehensive reviews. We will first focus on the most tractable diagnoses to apply the principles of cardiovascular genetic medicine: the cardiomyopathies such as dilated, hypertrophic, arrhythmogenic right ventricular dysplasia/cardiomyopathy and the channelopathies such as long QT syndrome and related disorders. These conditions follow classical or Mendelian genetics, otherwise known as the single gene disorders. As greater numbers of disease genes and their specific mutations are identified, and as large clinical cohorts of affected probands and their at-risk family members become available for study, clinical recommendations, and then guidelines, will follow. Progress is also evident for those conditions considered to be complex or multigenic diseases, such as coronary disease and hypertension, which affect large segments of the population. Risk alleles are now being identified that may rapidly lead to genetic testing to assess risk for these conditions. Cardiovascular genetic medicine must also be responsive to public concerns regarding confidentiality, and it must also demonstrate clinical integrity and utility for genetic testing. Our first topic features the role of family history in cardiovascular genetic medicine. Assisted by my clinical and research group -- genetic counselors and nursing personnel devoted to the field -- we have provided a glossary with explanations of genetic terminology, as illustrated in this first article, and will continue to do so for the series. We will prepare additional topics and others will be solicited from experts in the field. I also invite any potential contributors to propose and submit topics that are both of interest to you and relevant to the field. Please also give us your feedback, especially to improve the clarity, diversity, and timeliness of the genetic concepts presented. So, away we go.     

Clinical implications of direct-to-consumer genetic testing for cardiovascular disease risk

Direct-to-consumer (DTC) genetic testing for cardiovascular disease (CVD) is becoming increasingly accessible due to technological advances, falling prices, and assertive marketing. However, information to guide physicians and patients on how to interpret or react clinically to DTC genetic test results is scarce. We report the case of a 52-year-old man with a family history of CVD who had DTC genetic testing performed. We discuss selected results and interpretation of this testing and the outcome of subsequent lifestyle interventions. Despite the information this new technology seemed to provide, traditional advice on lifestyle modification was central to his management.     

Update 2011: clinical and genetic issues in familial dilated cardiomyopathy

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.     

Genetic counseling for inherited thrombophilias

Genetic testing for inherited thrombophilia, including mutation analysis for factor V Leiden and prothrombin G20210A, is commonly performed. Yet, tests for inherited thrombophilia are frequently ordered inappropriately, and without proper counseling about the risks, benefits and limitations of testing. Genetic counselors are uniquely trained to help people understand and adapt to medical, psychological and familial implications of genetic contributions to disease. In the context of thrombophilia, genetic counselors may serve as a resource to other clinicians to: (a) identify individuals and families at increased risk for inherited thrombophilia, (b) offer and explain testing to patients and families, as appropriate, (c) facilitate patient-focused decision-making and informed consent prior to testing, (d) interpret test results, (e) explain inheritance patterns and discuss implications of thrombophilia for family members and (f) provide education and support resources. This article will provide insight into the training and roles of genetic counselors, review indications for thrombophilia testing, and highlight specific issues related to genetic testing, including genetic discrimination concerns.     

Assessment of emergency department health care professionals' behaviors regarding HIV testing and referral for patients with STDs

The objective of this study was to evaluate human immunodeficiency virus (HIV) counseling, testing, and referral practices of emergency department health care professionals (i.e., medical doctors [MD], physician assistants [PA], nurse practitioners [NP], and registered nurses [RN]) for patients presenting with other sexually transmitted diseases (STD). All health care professionals from 10 emergency departments in a northeastern county were asked to complete an anonymous survey. The surveys were returned by 154 (41%) health care professionals (RN = 99, NP = 5, PA = 7, MD = 39, other = 4). The average years in practice were 11. Only 7% of respondents were certified to provide state mandated HIV pretest counseling (certification not required for MD). Respondents reported caring for an average of 13 patients per week with suspected STD. Fifty-five percent of respondents reported that they always or usually warn STD patients of their HIV risk, yet only 10% always or usually encouraged these patients to consent to HIV testing in their emergency department (RN = 7%, NP = 25%, PA = 0%, MD = 16%). Reasons for not offering HIV testing in their emergency department were follow-up concerns (51%), not certified to provide pretest/posttest counseling (45%), and too time consuming (19%). Twenty-seven percent of respondents indicated HIV testing was not available in their emergency department despite all hospital laboratories reporting HIV testing capability. Ninety-three percent of respondents were aware that confidential testing sites were available, but only 35% always or usually referred patients not tested in the emergency department elsewhere for testing. Emergency department health care professionals frequently fail to provide HIV counseling, testing, and/or referral for patients with suspected STD.     

The essential role of genetic counseling in inherited thrombophilia

The discovery of common genetic polymorphisms that predispose to venous thrombosis has led to the widespread availability of molecular testing for genetic thrombophilia traits. In terms of consent, genetic tests differ significantly from other types of laboratory test. We demonstrate the need for genetic counseling before and after genetic thrombophilia testing, but emphasize that such counseling need not be delivered by a specialist. We describe the potential advantages, limitations, and disadvantages of genetic testing for the common thrombophilic mutations that should be borne in mind when explaining testing to symptomatic individuals and asymptomatic relatives. In the vast majority of cases, genetic testing for thrombophilia is of limited value to the symptomatic patient, and provides minimal benefit over and above the family history when it comes to counseling at-risk family members.     

Genetic counseling and interpretation of genetic tests in familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer

PURPOSE: Genetic counseling and interpreting genetic test results can be complex. Moreover, without knowing the limitations of the methods used and the lifetime probability of developing cancer in individuals who carry a gene that predisposes to cancer, misinterpretation may lead to false assurance. The purpose of this review is to discuss how genetic counseling will benefit patients and their family, the genetic tests available for hereditary colorectal cancer syndromes, and the interpretation of results. METHODS: Current literature was reviewed and our clinical and research experiences were incorporated. RESULTS: This review serves as a guide to enable various health care providers to better counsel patients in their quest for advice on prevention, early detection, and surveillance for colorectal cancer. Notable topics of discussion are who should undergo genetic counseling and consider testing and how the interpretation of test results can be misleading; for example, understanding the difference between a no mutation detectedvs. a negative test result. CONCLUSIONS: Genetic counseling is of paramount importance for patients to fully understand the limitations of genetic testing and will aid in the management of patients who are susceptible to colorectal cancer.     

Attitudes of physicians toward objective measures of airway function in asthma

BACKGROUND: The National Asthma Education and Prevention Program (NAEPP) recommends pulmonary function testing as part of asthma evaluation. The objectives of this study were to determine the use of spirometry in patients with asthma by primary care physicians and asthma specialists, and to identify barriers to use of spirometry. METHODS: We developed, validated, and administered a mailed survey to primary care physicians and asthma specialists in the general community. We asked about the use of spirometry, access to spirometry, and barriers to spirometry use. RESULTS: Of 975 eligible subjects, 672 (69%) completed the survey. Asthma specialists were more likely to have an office spirometer (78% [216/277] vs. 43% [169/395], P <0.001) than were primary care physicians, and more likely to report measuring pulmonary function in at least 75% of their patients with asthma (83% [223/270] vs. 34% [131/388], P <0.001). In logistic regression analysis, factors most strongly associated with reported spirometry use (in at least 75% of patients) among asthma specialists were owning a spirometer, disagreeing with the statement that the test requires excessive use of office resources, and agreeing that spirometry is a necessary part of the asthma evaluation. Among primary care physicians, owning a spirometer, agreeing that the data are necessary for accurate diagnosis, and believing that they were trained to perform and interpret the test were most strongly associated with reported spirometry use. CONCLUSION: Pulmonary function testing is underutilized by physicians, with rates of utilization lowest among primary care physicians. Providing primary care physicians with better access to spirometry, through provision of a machine and appropriate training in its use and interpretation, may improve compliance with the NAEPP recommendations.     

Genetic Counseling in the Adult with Congenital Heart Disease: What is the Role?

New discoveries using high-resolution methods for detecting genetic aberrations indicate that the genetic contribution to congenital heart disease has been significantly underestimated in the past. DNA diagnostics have become more accessible and genetic test results are increasingly being used to guide clinical management. Adult congenital heart disease specialists seeking to counsel adults with congenital heart disease about the genetic aspects of their condition face the challenge of keeping abreast of new genetic techniques and discoveries. The emphasis of this review is on the genetic basis of structural cardiovascular defects. A framework for identifying adult congenital heart disease patients most likely to benefit from genetic testing is suggested, along with a summary of current techniques for genetic testing. The clinical and ethical challenges associated with genetic counseling are highlighted. Finally, emerging technologies and future directions in genetics and adult congenital heart disease are discussed.     

Key concepts in genetic epidemiology

This article is the first in a series of seven that will provide an overview of central concepts and topical issues in modern genetic epidemiology. In this article, we provide an overall framework for investigating the role of familial factors, especially genetic determinants, in the causation of complex diseases such as diabetes. The discrete steps of the framework to be outlined integrate the biological science underlying modern genetics and the population science underpinning mainstream epidemiology. In keeping with the broad readership of The Lancet and the diverse background of today's genetic epidemiologists, we provide introductory sections to equip readers with basic concepts and vocabulary. We anticipate that, depending on their professional background and specialist knowledge, some readers will wish to skip some of this article.     

The cost of asthma treatment in Spain and rationalizing the expense.

According to Weiss et al. [12], the main providers of asthma care in the United States in 1992 were general and family medicine + internal medicine (46%), pediatrics (19%), allergy (25%), pulmonary medicine (5%), and others (5%). In an overall climate of a shift of referral from primary care to the specialties, specialists will have to provide evidence that their intervention in the control of patients provides truly better clinical and economical outcomes than that of general practitioners. In order to support this hypothesis, we estimated: (1) the development of the costs of medication for asthma in a population of 40 million people (Spain) and (2) the correlation between these costs and the intervention of a specialized attendance. In Spain the annual costs incurring from allergic diseases are estimated to be approximately 1,500 million Euros and, the cost due to asthma alone is about 900-1,200 million Euros. There are two main ways to explain the size of these figures. First, the prevalence of allergic diseases is rising year by year. Second, the relevance of allergology in the control of asthma is often greatly reduced. This has resulted in a reduction in the etiological diagnosis and treatment with specific immunotherapy (SIT). However, SIT is the only specific causal treatment of allergic asthma that is able to modify the natural history of disease or disease progression. So, it is possible to hypothesize that this reduction in a proper etiological diagnosis and treatment could be a cause (among others) of increasing costs.     

Specialty differences in cardiovascular disease prevention practices

Objectives. The aim of this study was to examine physician specialty differences in cardiovascular disease prevention practices.Background. Despite the importance of cardiovascular disease prevention, little is known about current national practices, particularly physician specialty differences.Methods. Using a national survey of office visits, we evaluated differences in the propensity of physicians of different specialties to provide prevention services. We analyzed 30,929 adult visits to 1,521 physicians selected by stratified random sampling in the 1995 National Ambulatory Medical Care Survey. Standard and ordinal multiple logistic regression models were employed to estimate the independent effects of physician and patient characteristics.Results. A variety of cardiovascular disease prevention services were provided during an estimated 547 million adult office visits to US physicians in 1995, including blood pressure measurement (50% of visits), cholesterol testing (5%) and counseling for exercise (12%), weight (6%), cholesterol (4%) and smoking (3%). In addition, medication management was reflected by the report of antihypertensives in 12% of visits and lipid-lowering medications in 2%. Across these eight services, propensity to provide services varied consistently with specialty. Controlling for patient and visit characteristics and compared to general internists, the likelihood of providing services was higher for cardiologists (adjusted odds ratio 1.65, 95% confidence interval 1.44 to 1.89) but lower for obstetrician/gynecologists (0.75, 0.68 to 0.82), family physicians (0.69, 0.64 to 0.74), general practitioners (0.58, 0.53 to 0.63), other medical specialists (0.65, 0.59 to 0.72) and surgeons (0.06, 0.05 to 0.06).Conclusions. Cardiologists have the greatest propensity to provide cardiovascular disease prevention services, while primary care physicians vary substantially in their practices. These findings suggest a need to address variations in cardiovascular disease prevention.     

Prenatal HIV counseling,testing, and antiretroviral prophylaxis by obstetric and family medicine providers in Alabama

BACKGROUND: The study reported here assessed the implementation of recommendations for routine universal prenatal counseling and voluntary HIV testing among Alabama physicians who provide prenatal care and determined factors associated with noncompliance. METHODS: Voluntary, confidential mailed survey of obstetrics and family medicine practitioners. RESULTS: Of the 138 physicians who responded to a mailed survey in Alabama, 17 (12.3%) indicated that they did not offer universal HIV counseling and testing to pregnant women. Factors associated with failure to offer universal HIV counseling and testing included having more than 50% of patients refuse HIV counseling and testing when offered and never knowingly having given prenatal/perinatal care to women with HIV. Low/medium familiarity with the US Public Health Service recommendations for perinatal zidovudine use to reduce HIV transmission and physician specialty are also suggested as predictors of not offering universal testing. CONCLUSIONS: Despite the well-established benefits of antiretroviral prophylaxis to prevent vertical transmission of HIV, some physicians in Alabama have been slow to adopt universal testing of their pregnant patients for HIV in the prenatal period. Practitioner education is as important as patient education in eliminating pediatric HIV in the Deep South.     

Clinical and genetic issues in familial dilated cardiomyopathy

Idiopathic dilated cardiomyopathy (IDC) is characterized by left ventricular dilatation and systolic dysfunction after known causes have been excluded. Idiopathic dilated cardiomyopathy occurring in families, or familial dilated cardiomyopathy (FDC), may occur in 20% to 50% of IDC cases. Sixteen genes have been shown to cause autosomal dominant FDC, but collectively may account for only a fraction of genetic causation; it is anticipated that additional genes causative of FDC will be discovered. Familial dilated cardiomyopathy demonstrates incomplete penetrance, variable expression, and significant locus and allelic heterogeneity, making clinical and genetic diagnosis complex. Echocardiographic and electrocardiographic screening of first-degree relatives of individuals with IDC and FDC is indicated, as detection and treatment are possible before the onset of advanced symptomatic disease. Genetic counseling for IDC and FDC is also indicated to assist with family evaluations for genetic disease and with the uncertainty and anxiety surrounding the significance of clinical and genetic evaluation. Genetic testing is not yet commonly available, but its emergence will provide new opportunities for presymptomatic diagnosis.     

Transitions: noninvasive coronary angiography using electron beam computed tomography: technique, clinical application, future prospective

Electron beam computed tomography has been available clinically for 20 years. It is the only computed tomography scanner specifically developed for cardiac imaging. Over the past decade, with improvements in methodology and computer software, electron beam computed tomography has been shown to provide an excellent method to perform noninvasive coronary angiography. This article looks at the historical aspects of electron beam computed tomography and comments on how to perform and interpret electron beam angiography studies. The expanding development of noninvasive coronary and peripheral angiography methods using computed tomography will have a significant influence on cardiovascular specialists and their practices.     

Medicina personalizada: diagnóstico genético de cardiopatías/canalopatías hereditarias

Major advances in the field of molecular genetics have expanded our ability to identify genetic substrates underlying the pathogenesis of various disorders that follow Mendelian inheritance patterns. Included among these disorders are the potentially lethal and heritable channelopathies and cardiomyopathies for which the underlying genetic basis has been identified and is now better understood. Clinical and genetic heterogeneity are hallmark features of these disorders, with thousands of gene mutations being implicated within these divergent cardiovascular diseases. Genetic testing for several of these heritable channelopathies and cardiomyopathies has matured from discovery to research-based genetic testing to clinically/commercially available diagnostic tests. The purpose of this review is to provide the reader with a basic understanding of human medical genetics and genetic testing in the context of cardiovascular diseases of the heart. We review the state of clinical genetic testing for the more common channelopathies and cardiomyopathies, discuss some of the pertinent issues that arise from genetic testing, and discuss the future of personalized medicine in cardiovascular disease.     

The genetic contribution to coronary disease. The genetic factors related to lipid metabolism]

The increasing development of molecular genetics, the progress of the Human Genome Project, and the widespread application of its new methods and molecular techniques provide a new perception of coronary heart disease and a better recognition of genetic markers (mutations and polymorphism) related to new or traditional cardiovascular risk factors. An example of this has been the major effort made over the last years to evaluate and establish the genetic molecular mechanisms that are the basis of the synthesis of apolipoproteins, lipoprotein processing enzymes and lipoprotein receptors. These are some of the subjects discussed in this review [apoB, apoE, atherogenic lipid profile and CETP, and Lp(a)], in which the role of polymorphic alleles and isoforms in cardiovascular risk and coronary heart disease is stressed.