Heritable Cardiovascular Disease Research Articles

Evolving cardiovascular genetic counseling needs in the era of precision medicine.

In the era of Precision Medicine the approach to disease diagnosis, treatment, and prevention is being transformed across medical specialties, including Cardiology, and increasingly involves genomics approaches. The American Heart Association endorses genetic counseling as an essential component in the successful delivery of cardiovascular genetics care. However, with the dramatic increase in the number of available cardiogenetic tests, the demand, and the test result complexity, there is a need not only for a greater number of genetic counselors but more importantly, for highly specialized cardiovascular genetic counselors. Consequently, there is a pressing need for advanced cardiovascular genetic counseling training, along with innovative online services, telemedicine, and patient-facing digital tools, as the most effective way forward. The speed of implementation of these reforms will be of essence in the translation of scientific advancements into measurable benefits for patients with heritable cardiovascular disease and their families.

Correction to: Interpreting Incidentally Identified Variants in Genes Associated With Heritable Cardiovascular Disease: A Scientific Statement From the American Heart Association

Correction to: Interpreting Incidentally Identified Variants in Genes Associated With Heritable Cardiovascular Disease: A Scientific Statement From the American Heart Association

Interpreting Incidentally Identified Variants in Genes Associated With Heritable Cardiovascular Disease: A Scientific Statement From the American Heart Association

Rapid advances in genetic technologies have led to expanding use of diagnostic, research, and direct-to-consumer exome and genome sequencing. Incidentally identified variants from this sequencing represent a significant and growing challenge to interpret and translate into clinical care and include variants in genes associated with heritable cardiovascular disease such as cardiac ion channelopathies, cardiomyopathies, thoracic aortic disease, dyslipidemias, and congenital/structural heart disease. These variants need to be properly reported, the risk of associated disease accurately assessed, and clinical management implemented to prevent or lessen the disease so that cardiovascular genomic medicine can become both predictive and preventive. The goal of this American Heart Association consensus statement is to provide guidance to clinicians who are called on to evaluate patients with incidentally identified genetic variants in monogenic cardiovascular disease genes and to assist them in the interpretation and clinical application of variants. This scientific statement outlines a framework through which clinicians can assess the pathogenicity of an incidental variant, which includes a clinical evaluation of the patient and the patient's family and re-evaluation of the genetic variant in question. Furthermore, this guidance underscores the importance of a multidisciplinary team to address these challenging clinical evaluations and highlights how clinicians can effectively interface with specialty centers.

Understanding the molecular basis of HCM-causing mutations in cardiac myosin and cardiac myosin binding protein-C

Hypertrophic cardiomyopathy (HCM), a heritable cardiovascular disease marked by hypercontractility and abnormal thickening of heart muscle, affects up to 1 in 200 individuals. Mutations in sarcomere proteins result in HCM, but the mechanism by which these mutant proteins lead to hypercontractility and heart failure remains poorly understood, limiting clinical interventions for the same. We are currently focusing on two sarcomere proteins that together comprise ∼70% of all known HCM mutations: β-cardiac myosin and cardiac myosin binding protein-C, cMyBPC (a regulatory protein in the thick filament).

Mechanisms of Arrhythmogenicity of Hypertrophic Cardiomyopathy-Associated Troponin T (TNNT2) Variant I79N.

Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiovascular disease and often results in cardiac remodeling and an increased incidence of sudden cardiac arrest (SCA) and death, especially in youth and young adults. Among thousands of different variants found in HCM patients, variants of TNNT2 (cardiac troponin T—TNNT2) are linked to increased risk of ventricular arrhythmogenesis and sudden death despite causing little to no cardiac hypertrophy. Therefore, studying the effect of TNNT2 variants on cardiac propensity for arrhythmogenesis can pave the way for characterizing HCM in susceptible patients before sudden cardiac arrest occurs. In this study, a TNNT2 variant, I79N, was generated in human cardiac recombinant/reconstituted thin filaments (hcRTF) to investigate the effect of the mutation on myofilament Ca2+ sensitivity and Ca2+ dissociation rate using steady-state and stopped-flow fluorescence techniques. The results revealed that the I79N variant significantly increases myofilament Ca2+ sensitivity and decreases the Ca2+ off-rate constant (k off). To investigate further, a heterozygous I79N+/− TNNT2 variant was introduced into human-induced pluripotent stem cells using CRISPR/Cas9 and subsequently differentiated into ventricular cardiomyocytes (hiPSC-CMs). To study the arrhythmogenic properties, monolayers of I79N+/− hiPSC-CMs were studied in comparison to their isogenic controls. Arrhythmogenesis was investigated by measuring voltage (V m) and cytosolic Ca2+ transients over a range of stimulation frequencies. An increasing stimulation frequency was applied to the cells, from 55 to 75 bpm. The results of this protocol showed that the TnT-I79N cells had reduced intracellular Ca2+ transients due to the enhanced cytosolic Ca2+ buffering. These changes in Ca2+ handling resulted in beat-to-beat instability and triangulation of the cardiac action potential, which are predictors of arrhythmia risk. While wild-type (WT) hiPSC-CMs were accurately entrained to frequencies of at least 150 bpm, the I79N hiPSC-CMs demonstrated clear patterns of alternans for both V m and Ca2+ transients at frequencies >75 bpm. Lastly, a transcriptomic analysis was conducted on WT vs. I79N+/− TNNT2 hiPSC-CMs using a custom NanoString codeset. The results showed a significant upregulation of NPPA (atrial natriuretic peptide), NPPB (brain natriuretic peptide), Notch signaling pathway components, and other extracellular matrix (ECM) remodeling components in I79N+/− vs. the isogenic control. This significant shift demonstrates that this missense in the TNNT2 transcript likely causes a biophysical trigger, which initiates this significant alteration in the transcriptome. This TnT-I79N hiPSC-CM model not only reproduces key cellular features of HCM-linked mutations but also suggests that this variant causes uncharted pro-arrhythmic changes to the human action potential and gene expression.

Targeted exome analysis of Russian patients with hypertrophic cardiomyopathy.

BackgroundHypertrophic cardiomyopathy (HCM), described as the presence of hypertrophy of left ventricular, is the most prevalent heritable cardiovascular disease with predominantly an autosomal dominant type of inheritance. However, pathogenic alleles are not identified in at least 25% of patients with HCM, and the spectrum of pathogenic variants that contribute to the development of HCM in Russia has not been fully described. Therefore, the goal of our study was to identify genetic variants associated with the etiopathogenesis of HCM in Russian patients.MethodsThe study cohort included 98 unrelated adult patients with HCM. We performed targeted exome sequencing, an analysis using various algorithms for prediction of the impact of variants on protein structure and the prediction of pathogenicity using ACMG Guidelines.ResultsThe frequency of pathogenic and likely pathogenic variants in all HCM‐related genes was 8% in our patients. We also identified 20 variants of uncertain significance in all HCM‐related genes.ConclusionsThe prevalence of individual pathogenic variants in HCM‐related genes in Russian population appears to be lower than in general European population, which could be explained by ethnic features of Russian population, age characteristics of our sample, or unidentified pathogenic variants in genes previously not linked with HCM.

Abstract 212: Hypertrophic Cardiomyopathy Mutations With Opposite Effects on ß-myosin Biomechanics Show Similar Structural and Biomechanical Phenotypes in Human Induced Pluripotent Stem Cell Derived Cardiomyocytes (hipsc-cms)

Introduction: Hypertrophic cardiomyopathy (HCM) is the most prevalent heritable cardiovascular disease, commonly caused by mutations in beta cardiac myosin heavy chain (βMYH). We have measured the kinetics of isolated myosin proteins with different HCM mutations in βMYH and found an intriguing heterogeneity in kinetics and force production: some mutations increase whereas others decrease force and velocity; others result in no change. How these divergent molecular alterations converge to the final HCM phenotype: hypercontractility and cellular hypertrophy is still unknown. hiPSC-CMs provide a powerful tool for studying human cardiomyocyte biology including contractility, hypertrophic growth, and intracellular organization, but are limited by immature phenotypes and population heterogeneity in traditional culture environments. Methods and Results: We developed a micropatterned hydrogel platform that enhances force generation and promotes both structural and molecular hiPSC-CM maturation. Using CRISPR/Cas-9 gene editing in an isogenic hiPSC line, we created hiPSCs with two different βMYH mutations (P710R and D239N) that result in opposite effects on force at the molecular level, using in vitro motility and laser trap methods. Cell morphology was quantified by both fluorescence and transmission electron microscopy (EM) and force generation measured by traction force microscopy. Despite having opposite effects at the single molecule level, both HCM lines showed increased contractile force and cellular hypertrophy compared to isogenic controls. Immunostaining for βMYH and EM revealed organizational and microstructural changes including sarcomere and myofibrillar disarray, and thickened z-discs in cells containing these mutations. Both mutations had alterations in AMPK, MAPK, and calcineurin signaling shown to regulate hypertrophy. Discussion: Divergent biomechanical alterations due to HCM mutations at the single molecule level lead to common cellular-level structural and biomechanical phenotypes through activation of common signaling pathways.

Ability of Patients to Distinguish Among Cardiac Genomic Variant Subclassifications.

Clinical genetic testing for heritable cardiovascular disease has become a widely used tool to aid in the management of patients and their families. A 5-category variant classification system is commonly used for genetic test results, but some laboratories further subclassify variants of uncertain significance. How and whether patients perceive differences among the variant categories or subclassifications of variants of uncertain significance is unknown. We tested whether participants perceived differences in genetic variant subclassifications on outcomes including risk comprehension, risk perception, worry, perceived uncertainty, and intentions. Order-randomized hypothetical cardiovascular genetic results were given to 289 participants enrolled in a genome sequencing study. Three categories of variants were presented to participants: variants of uncertain significance, possibly pathogenic, and likely pathogenic. Responses to the first variant presented were analyzed in a between-groups analysis, and responses to all 3 variants were analyzed in a within-groups analysis. When presented with all 3 results, participants distinguished among the subclassifications on all outcomes (P<0.001). When given only a possibly pathogenic result, their risk perceptions were similar to those of variants of uncertain significance, but they were more worried and intended to behave as if they had received a likely pathogenic result. Individuals depended more on their affective responses such as worry when they received only one result (P<0.05). Participants are better able to distinguish pathogenicity subclassifications when presented with multiple categories. Individuals who receive a single uncertain result in a cardiovascular disease gene may benefit from interventions to decrease worry, calibrate risk perceptions, and motivate variant-appropriate behaviors.

Mechanobiology of Myosin Mutations and Myofibril Remodeling in iPSC-Cardiomyocytes

Hypertrophic cardiomyopathies are the most prevalent form of heritable cardiovascular disease and are caused by a host of mutations that result in hypercontractility, though the largest number of known mutations are found in beta cardiac myosin heavy chain (βMYH). Myosin is a key protein responsible for muscle contraction and is arranged into a dynamic, hierarchical structure of sarcomeres and myofibrils within cardiomyocytes. We have previously measured differences in the kinetics of isolated myosin proteins with different hypertrophic cardiomyopathy mutations in βMYH, but it has been difficult to determine how these alterations manifest at the cellular level. Induced pluripotent stem cell-derived cardiomyocytes provide a powerful tool for studying specific features of human cardiomyocyte biology including contractility, hypertrophic growth, and intracellular organization. We have developed a micropatterned hydrogel platform that promotes myofibril alignment, cardiomyocyte force generation, and other metrics of maturation. Using CRISPR-Cas9 gene-editing, we have created cell lines with specific βMYH mutations, including D239N and P710R. We used traction force microscopy in a preliminary study and measured increased forces in the mutant cells compared to isogenic controls, and we have observed larger cell size in one of the mutant lines in both patterned and unpatterned contexts. Infection with LifeAct adenovirus also allows for the visualization of actin structures including myofibrils and sarcomeres during cell spreading and the recovery of beating in cells recently transferred to patterned substrates. Immunostaining for βMYH revealed higher expression and more regular organization of sarcomeres in patterned cells, and we plan to use these techniques to quantify differences in myofibril and sarcomere organization in cells with βMYH mutations. This work provides valuable insight into the etiology of hypertrophic cardiomyopathy and the utility of induced pluripotent stem cell-derived cardiomyocytes as a model for human cardiac biology and disease.

Abstract 401: Functional Analysis of Coronary Artery Disease-associated PLPP3 Gene Variants

Heritable variants of the PLPP3 gene are associated with human coronary artery disease risk. Expression of the PLPP3 gene product, lipid phosphate phosphatase 3 (LPP3) is strongly increased in blood and vascular cells by pro-atherogenic, pro-inflammatory stimuli including oxidized LDL. PLPP3 is essential for vascular development in mice but animals with inducible post-natal or tissue specific inactivation of the gene exhibit accelerated development of aortic atherosclerosis. These observations suggest the hypothesis that PLPP3 normally functions to suppress the development and progression of atherosclerosis. The coronary artery disease-associated PPAP2B haplotype block is in the final intron of the gene. Recently published analysis of chromatin remodeling in oxidized LDL stimulated human monocytes identifies dynamic changes in these coronary artery disease associated loci. We show that several of these loci correspond to potential or identified regulatory genomic elements. Functional analysis of these elements identifies multiple cFos/AP1 and cEBP regulated transcriptional enhancer sequences that exhibit allelic variation that could impact on their function as regulators of PLPP3 gene expression. Some of these enhancer sequences bind their transcription factor targets in an allele specific manner and are functional activators of transcription from the PLPP3 promoter. Because haplotypes containing the coronary artery disease associated enchancer sequence variants are also associated with attenuated increases in PPAP2B expression in oxidized LDL treated human monocytes our observations support the hypothesis that heritable cardiovascular disease risk is associated with attenuation of cis acting enhancer sequences that normally promote LPP3 expression. These observations also raise the possibility that these intronic enhancers have longer distance or trans-acting effects on other genes that also contribute to coronary artery disease risk

Genotype-phenotype Correlations of Hypertrophic Cardiomyopathy When Diagnosed in Children, Adolescents, and Young Adults.

Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiovascular disease and a leading cause of identifiable sudden cardiac death (SCD) in the young. Herein, we sought to determine the genotype-phenotype correlations in a cohort of unrelated, genotyped patients diagnosed with HCM at a young age, as well as to characterize the differences between HCM diagnosed in adulthood and HCM diagnosed at a young age. From 1999 to 2011, 1053 unrelated patients diagnosed with HCM were enrolled in research-based genetic testing. The electronic medical record was reviewed to identify those with HCM diagnosed at ≤21 years (N = 137, mean age at diagnosis 13.2 ± 6 years, 64% male). From this cohort of patients recruited from a tertiary care referral center, the genetic test was positive in 71 (52%), which was significantly higher than patients diagnosed >21 years (31%; P < .001). Genotype-positive patients had increased maximum left ventricular wall thickness (24.9 ± 8.0 vs. 21.6 ± 7.4 mm, P = .01) and higher incidence of reverse-curve ventricular septal morphology (71% vs. 40%, P < .001). Unrelated to genotype status, 26/137 patients (19%) experienced significant HCM-related morbidity/mortality including progressive heart failure symptoms in 12, transplantation in 4, and death in 10. Among patients diagnosed with HCM during the first two decades of life, the yield of genetic testing is significantly higher than when diagnosed at later age. While the phenotype of young HCM patients is worse than patients whose HCM is diagnosed at later age, the phenotypes of genotype-positive and genotype-negative young patients were similar. Independent of genotype, nearly 30% of the patients with follow-up in this study had symptom progression, transplant, or death.

Provision of Cardiovascular Genetic Counseling Services: Current Practice and Future Directions

Cardiovascular genetic counseling has emerged as a specialty critical to the care of patients with heritable cardiovascular disease. Current strategies to meet the growing demand are not clear. We sought to characterize practice patterns of cardiac genetic counseling by developing a novel survey distributed to the National Society of Genetic Counselors (NSGC) Listserv to assess clinical practice, cardiovascular training, and education. Descriptive statistics were used to summarize clinical practice; Fisher's exact test and the Cochran-Armitage trend test were used to compare the practice of cardiovascular genetic counselors (CVGCs) to those who did not identify cardiology as a specialty (non-CVGCs). A total of 153 individuals completed the survey. Of the 105 participants who reported seeing a cardiac genetics patient, 42 (40%) identified themselves as a CVGC. The most common conditions for which genetic counseling was provided were hypertrophic cardiomyopathy (HCM) (71% of participants), dilated cardiomyopathy (DCM) (61%), long QT syndrome (LQTS) (56%), and genetic syndromes with cardiovascular disease (55%). CVGCs were significantly more confident than non-CVGCs in providing genetic counseling for seven cardiovascular diseases (2.3 × 10(-6) ≤ p ≤ 0.021). Eighty-six percent of genetic counselors sought additional education related to cardiovascular genetics and listed online courses as the most desirable method of learning. These data suggest a growing interest in cardiovascular genetic counseling and need for additional training resources among the NSGC membership.

Sudden Cardiac Arrest in a Young Patient with Hypertrophic Cardiomyopathy and Zero Canonical Risk Factors: The Inherent Limitations of Risk Stratification in Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy is the most common heritable cardiovascular disease and a common cause of sudden cardiac death (SCD) in young adolescents and athletes. Clinical risk stratification for SCD is predicated on the presence of established risk factors; however, this assessment is far from perfect. Herein, we present a 16-year-old male who was resuscitated successfully from his sentinel event of out-of-hospital cardiac arrest. Prior to this event, he was asymptomatic and lacked all traditional SCD-predisposing risk factors for hypertrophic cardiomyopathy.

Abstract 50: Cardiomyogenesis in Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most prevalent heritable cardiovascular disease and the leading cause of sudden death in young adults. HCM is characterized by regional ventricular hypertrophy in the absence of cavitary dilation. Myofibrillar disarray associated with mutations of sarcomeric proteins and collagen accumulation are considered major determinants of the disease phenotype. Septal hypertrophy has been viewed as the result of an increase in size of preexisting myocytes, but whether myocyte formation contributes to septal thickening has never been determined. Thus, 29 patients with HCM undergoing septal myectomy were studied, and 10 sex-, age-matched septa, collected from patients who died from causes other than cardiovascular diseases, were used as controls. Mutations of genes coding for contractile proteins were present in all cases of HCM; 79% of patients were in NYHA class III, 17% in class II, and 4% in class IV. Arrhythmic events consisting of atrial fibrillation and ventricular tachycardia were found in 11 patients. In 8 cases, HCM was diagnosed in family members as well. Septal thickness is the product of myocyte diameter and the number of myocyte across the septum. The thickness of the septum increased 2.3-fold in HCM (Controls: 11±1 mm; HCM: 25±8 mm, p&lt;0.001). Septal thickening in HCM was mediated by a 69% increase in myocyte number (Controls: 722±120; HCM: 1,217±375, p&lt;0.001) and a 31% increase in cell diameter (Controls: 16±3 λm; HCM: 21±4 λm, p&lt;0.001). Myocyte regeneration was confirmed by the expression of the cell cycle protein, Ki67. The number of Ki67-positive myocyte nuclei increased 15-fold in HCM (Controls: 400 myocytes/10 6 cells; HCM: 6,000 myocytes/10 6 cells, p&lt;0.001). In humans, myocyte formation is regulated by commitment of resident c-kit-positive cardiac stem cells (CSCs). In comparison with control hearts, the number of CSCs increased 2.7-fold in patients with HCM (Controls: 11±5 cells/mm 3 ; HCM: 30±17 cells/mm 3 , p&lt;0.01). Additionally, the expression of contractile proteins was detected in differentiating CSCs. In conclusion, myocyte regeneration and hypertrophy contribute to septal thickening in HCM and newly formed myocytes originate from growth activation and lineage specification of resident CSCs.

TGFβ‐inducible early gene‐1 (TIEG1) mutations in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiovascular disease. A recent study showed that male KLF10-encoded TGFβ Inducible Early Gene-1 knock-out mice (TIEG-/-) develop HCM with 13-fold up-regulation of PTTG1-encoded pituitary tumor-transforming gene 1. We hypothesized TIEG1 could be a novel candidate gene in the pathogenesis of genotype negative HCM in humans, possibly through a loss of its repression on PTTG1 expression. A cohort of 923 unrelated patients from two independent HCM centers was analyzed for mutations in TIEG's four translated exons using DHPLC and direct DNA-sequencing. Site directed mutagenesis was performed to clone novel variants. The effect of TIEG1 mutations on SMAD7 and PTTG1 promoters was studied using transient transfection and luciferase-assays. Altered expression of PTTG1 in cardiac tissue was studied by immunohistochemistry (IHC) to determine levels of PTTG1 protein in hypertrophic diseases. Six novel TIEG1 missense mutations were discovered in six patients (two males/four females, mean age at diagnosis 56.2±23 years, MLVWT 20.8±4 mm). Compared to WT TIEG1, five TIEG1 mutants significantly increased PTTG1 promoter function similar to TIEG1-/--mice. By IHC, PTTG1-protein expression was significantly increased in multiple models of hypertrophic cardiac disease, including TIEG1-mutation positive HCM compared to normal hearts. This is the first article to associate mutations in TIEG1 to human disease with the discovery of six novel, HCM-associated variants. Functional assays suggest a role for PTTG1 in the pathogenesis of TIEG1-mediated HCM. Up-regulation of PTTG1 seems to be a common pathway in hypertrophic heart disease, including TIEG1-mediated HCM.

Left cardiac sympathetic denervation in a pediatric patient with hypertrophic cardiomyopathy and recurrent ventricular fibrillation

Initially performed for angina in the early 1900’s [1], left cardiac sympathetic denervation (LCSD) has become an important therapeutic option in patients with long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) [2-5]. For these heritable channelopathies, LCSD has filled the therapeutic gap between daily medications (i.e. beta blockers) and implantable cardioverter-defibrillator (ICD) therapy. LCSD’s anti-fibrillatory properties have been demonstrated clearly for patients with LQTS where there is an estimated 90% reduction in LQT-triggered cardiac events post-denervation [2, 4]. Hypertrophic cardiomyopathy (HCM) is one of the most prevalent heritable cardiovascular disease and the most common cause of sudden cardiac death in young athletes [6]. Clinically, HCM is characterized by unexplained and unequivocal cardiac hypertrophy in the absence of hypertrophy-inducing conditions such as hypertension and aortic stenosis. Besides the underlying genotypic heterogeneity, HCM is characterized by profound clinical heterogeneity as well [6, 7]. Patients can display extremely varying degrees of hypertrophy, fibrosis, and left ventricular outflow tract obstruction, and have an increased propensity for potentially life-threatening ventricular arrhythmias [6]. A recent article reported success using neuraxial modulation, either LCSD or thoracic epidural anesthesia (TEA), in adult patients with refractory arrhythmias, including 3 patients with HCM [8]. Herein, we report a pediatric patient with HCM who underwent LCSD for his malignant, ventricular fibrillation-prone HCM substrate, in hopes of delaying cardiac transplantation.

Mutation Type Is Not Clinically Useful in Predicting Prognosis in Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM), or clinically unexplained hypertrophy of the heart, is a common genetic cardiovascular disorder marked by genetic and phenotypic heterogeneity. As the genetic mutations underlying the pathogenesis of this disease have been identified, investigators have attempted to link mutations to clearly defined alterations in survival in hopes of identifying prognostically relevant biomarkers of disease. While initial studies labeling particular MYH7 -encoded beta myosin heavy chain and TNNT2 -encoded cardiac troponin T mutations as “malignant” or “benign” raised hopes for mutation-specific risk stratification in HCM, a series of subsequent investigations identified mutations in families with contradictory disease phenotypes. Furthermore, subsequent proband-based cohort studies indicated that the clinical prognostic relevance of individual mutations labeled as “malignant” or “benign” in large referral centers is negligible. Herein, we seek to summarize the controversy and dispute the notion that mutation-specific risk stratification in HCM is possible at the present time. We provide evidence for clinicians and basic scientists alike to move beyond simple mutation descriptors to a more nuanced understanding of HCM mutations which fully captures the multi-factorial nature of HCM disease expression. Response by Ho on p 2450 Over the last 2 decades, the genetic underpinnings of heritable cardiovascular disease have begun to be unveiled, starting with the discovery of rare pathogenic mutations that cause cardiomyopathies and cardiac channelopathies. The simple paradigm of Mendelian inheritance, while helpful in certain monogenic disease processes, is fundamentally incapable of explaining the entirety of how complex diseases express in the context of complex human physiology under the influence of a myriad of intrinsic and extrinsic variables. Our understanding of the intricate interplay between 1 such intrinsic variable, the genome, and the manifestation of disease was advanced significantly in the decoding of a handful of human's genomes in February of 2001.1,2 Despite the decade …

Heritable Cardiovascular Disease in Women

Heritable Cardiovascular Disease in Women

Heritable Cardiovascular Disease in Women

Although coronary heart disease (CHD) is traditionally viewed as a disease predominantly of males, it is the number one cause of death among American women. Half of all CHD deaths occur in women, and death within the first few years of initial myocardial infarction is significantly higher in women. Few women, however, perceive a significant health risk from heart disease. The dramatic decline in CHD mortality from lifestyle modification suggests that environmental factors play a significant role in genetic expression. Family-focused nursing care affects generations of family members and can significantly reduce morbidity and mortality from CHD.

Congenital heart disease, heritable cardiovascular disease, and pregnancy

P ROFOUND CHANGES in the population of women with heart disease and pregnancy occurred in the Western world during the 20th century as the incidence of rheumatic heart disease decreased and the recognition of congenital heart disease increased. A new population at risk resulted from the increased survival of women with congenital heart disease. Recognition of this new population resulted from more precise diagnoses and the use of surgical and medical therapy. Increased awareness of the wide range of heritable cardiovascular disease resulted primarily from phenotypic family studies; however, modern diagnostic and genetic techniques give promise for more objective methods of diagnosis and for genetic counseling. Advances in obstetrics and anesthesia have decreased the direct risks of pregnancy in these patient groups and widened the range of clinical experiences. Prospective fetal studies demonstrated higher incidence figures for congenital cardiac defects in the offspring of parents with congenital heart disease than previously appreciated. Limited understanding of the pathogenesis of most congenital and heritable cardiovascular defects has stimulated extensive research in cardiac morphogenesis and embryogenesis. The incorporation of developing genetic, biochemical, and molecular techniques into the diagnostic evaluation and long-term study of these overlapping patient groups and their offspring give promise of further understanding of normal and abnormal embryogenesis and of placing genetic counseling on a firm, scientific basis.