Adult-onset Heart Disease Research Articles

Sex chromosome mechanisms in cardiac development and disease.

Many human diseases, including cardiovascular disease, show differences between men and women in pathology and treatment outcomes. In the case of cardiac disease, sex differences are exemplified by differences in the frequency of specific types of congenital and adult-onset heart disease. Clinical studies have suggested that gonadal hormones are a factor in sex bias. However, recent research has shown that gene and protein networks under non-hormonal control also account for cardiac sex differences. In this review, we describe the sex chromosome pathways that lead to sex differences in the development and function of the heart and highlight how these findings affect future care and treatment of cardiac disease.

Maternal obesity persistently alters cardiac progenitor gene expression and programs adult-onset heart disease susceptibility

ObjectiveHeart disease risk can be programmed by intrauterine exposure to obesity. Dysregulating key transcription factors in cardiac progenitors can cause subsequent adult-onset heart disease. In this study, we investigated the transcriptional pathways that are altered in the embryonic heart and linked to heart disease risk in offspring exposed to obesity during pregnancy. MethodsFemale mice were fed an obesogenic diet and mated with males fed a control diet. Heart function and genome-wide gene expression were analyzed in adult offspring born to obese and lean mice at baseline and in response to stress. Cross-referencing with genes dysregulated genome-wide in cardiac progenitors from embryos of obese mice and human fetal hearts revealed the transcriptional events associated with adult-onset heart disease susceptibility. ResultsWe found that adult mice born to obese mothers develop mild heart dysfunction consistent with early stages of disease. Accordingly, hearts of these mice dysregulated genes controlling extracellular matrix remodeling, metabolism, and TGF-β signaling, known to control heart disease progression. These pathways were already dysregulated in cardiac progenitors in embryos of obese mice. Moreover, in response to cardiovascular stress, the heart of adults born to obese dams developed exacerbated myocardial remodeling and excessively activated regulators of cell-extracellular matrix interactions but failed to activate metabolic regulators. Expression of developmentally regulated genes was altered in cardiac progenitors of embryos of obese mice and human hearts of fetuses of obese donors. Accordingly, the levels of Nkx2-5, a key regulator of heart development, inversely correlated with maternal body weight in mice. Furthermore, Nkx2-5 target genes were dysregulated in cardiac progenitors and persistently in adult hearts born to obese mice and human hearts from pregnancies affected by obesity. ConclusionsObesity during pregnancy alters Nkx2-5-controlled transcription in differentiating cardiac progenitors and persistently in the adult heart, making the adult heart vulnerable to dysregulated stress responses.

Standardized echocardiographic assessment of cardiac function in normal adult zebrafish and heart disease models.

ABSTRACTThe zebrafish (Danio rerio) is an increasingly popular model organism in cardiovascular research. Major insights into cardiac developmental processes have been gained by studies of embryonic zebrafish. However, the utility of zebrafish for modeling adult-onset heart disease has been limited by a lack of robust methods for in vivo evaluation of cardiac function. We established a physiological protocol for underwater zebrafish echocardiography using high frequency ultrasound, and evaluated its reliability in detecting altered cardiac function in two disease models. Serial assessment of cardiac function was performed in wild-type zebrafish aged 3 to 12 months and the effects of anesthetic agents, age, sex and background strain were evaluated. There was a varying extent of bradycardia and ventricular contractile impairment with different anesthetic drugs and doses, with tricaine 0.75 mmol l−1 having a relatively more favorable profile. When compared with males, female fish were larger and had more measurement variability. Although age-related increments in ventricular chamber size were greater in females than males, there were no sex differences when data were normalized to body size. Systolic ventricular function was similar in both sexes at all time points, but differences in diastolic function were evident from 6 months onwards. Wild-type fish of both sexes showed a reliance on atrial contraction for ventricular diastolic filling. Echocardiographic evaluation of adult zebrafish with diphtheria toxin-induced myocarditis or anemia-induced volume overload accurately identified ventricular dilation and altered contraction, with suites of B-mode, ventricular strain, pulsed-wave Doppler and tissue Doppler indices showing concordant changes indicative of myocardial hypocontractility or hypercontractility, respectively. Repeatability, intra-observer and inter-observer correlations for echocardiographic measurements were high. We demonstrate that high frequency echocardiography allows reliable in vivo cardiac assessment in adult zebrafish and make recommendations for optimizing data acquisition and analysis. This enabling technology reveals new insights into zebrafish cardiac physiology and provides an imaging platform for zebrafish-based translational research.

Maturation-Based Model of Arrhythmogenic Right Ventricular Dysplasia Using Patient-Specific Induced Pluripotent Stem Cells.

Cellular reprogramming of somatic cells to patient-specific induced pluripotent stem cells (iPSCs) enables in-vitro modeling of human cardiac disorders for pathogenic and therapeutic investigations. However, using iPSC-derived cardiomyocytes (iPSC-CMs) to model an adult-onset heart disease remains challenging because of the uncertainty regarding the ability of relatively immature iPSC-CMs to fully recapitulate adult disease phenotypes. Arrhythmogenic right ventricular dysplasia (ARVD) is an inherited cardiomyopathy characterized by pathological fibrofatty infiltration and cardiomyocyte (CM) loss predominantly in the right ventricle (RV), leading to heart failure and lethal arrhythmias. Over 50% of affected individuals have desmosome gene mutations, most commonly inPKP2encoding plakophilin-2. Using Yamanaka's pluripotent factors, we generated iPSC lines from ARVD patients withPKP2mutations. We first developed a method to induce metabolic maturation of iPSC-CMs and showed that induction of adult-like metabolic energetics from an embryonic/glycolytic state is essential to model an adult-onset cardiac disease using patient-specific iPSCs. Furthermore, we showed that coactivation of normal peroxisome proliferator-activated receptor (PPAR)-α and abnormal PPARγ pathways in ARVD iPSC-CMs resulted in exaggerated CM lipogenesis, CM apoptosis, Na(+)channel downregulation and defective intracellular calcium handling, recapitulating the pathological signatures of ARVD. Using this model, we revealed novel pathogenic insights that metabolic derangement in an adult-like metabolic milieu underlies ARVD pathologies, enabling us to propose novel disease-modifying therapeutic strategies.

Functional Characterization of a Novel Mutation in NKX2-5 Associated With Congenital Heart Disease and Adult-Onset Cardiomyopathy

The transcription factor NKX2-5 is crucial for heart development, and mutations in this gene have been implicated in diverse congenital heart diseases and conduction defects in mouse models and humans. Whether NKX2-5 mutations have a role in adult-onset heart disease is unknown. Mutation screening was performed in 220 probands with adult-onset dilated cardiomyopathy. Six NKX2-5 coding sequence variants were identified, including 3 nonsynonymous variants. A novel heterozygous mutation, I184M, located within the NKX2-5 homeodomain, was identified in 1 family. A subset of family members had congenital heart disease, but there was an unexpectedly high prevalence of dilated cardiomyopathy. Functional analysis of I184M in vitro demonstrated a striking increase in protein expression when transfected into COS-7 cells or HL-1 cardiomyocytes because of reduced degradation by the Ubiquitin-proteasome system. In functional assays, DNA-binding activity of I184M was reduced, resulting in impaired activation of target genes despite increased expression levels of mutant protein. Certain NKX2-5 homeodomain mutations show abnormal protein degradation via the Ubiquitin-proteasome system and partially impaired transcriptional activity. We propose that this class of mutation can impair heart development and mature heart function and contribute to NKX2-5-related cardiomyopathies with graded severity.

Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs

Cellular reprogramming of somatic cells to patient-specific induced pluripotent stem cells (iPSCs) enables in-vitro modelling of human genetic disorders for pathogenic investigations and therapeutic screens1–7. However, using iPSC-derived cardiomyocytes (iPSC-CMs) to model an adult-onset heart disease remains challenging due to the uncertainty regarding the ability of relatively immature iPSC-CMs to fully recapitulate adult disease phenotypes. Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited heart disease characterized by pathological fatty infiltration and cardiomyocyte loss predominantly in the right ventricle (RV)8, which is associated with life-threatening ventricular arrhythmias. Over 50% of affected individuals have desmosome gene mutations, most commonly in PKP2 encoding plakophilin-29. The median age at presentation of ARVD/C is 26 years8. We used Yamanaka’s methods1,10 to generate iPSC lines from fibroblasts of two patients with ARVD/C and PKP2 mutations11,12. Mutant PKP2 iPSC-CMs demonstrate abnormal plakoglobin nuclear translocation and decreased β-catenin activity13 in cardiogenic conditions; yet these abnormal features are insufficient to reproduce the pathological phenotypes of ARVD/C in standard cardiogenic conditions. Here we show that induction of adult-like metabolic energetics from an embryonic/glycolytic state and abnormal peroxisome proliferator-activated receptor-gamma (PPARγ) activation underlie the pathogenesis of ARVD/C. By coactivating normal PPAR-alpha (PPARα)-dependent metabolism and abnormal PPARγ pathway in beating embryoid bodies (EBs) with defined media, we established an efficient ARVD/C in-vitro model within two months. This model manifests exaggerated lipogenesis and apoptosis in mutant PKP2 iPSC-CMs. iPSC-CMs with a homozygous PKP2 mutation also displayed calcium-handling deficits. Our study is the first to demonstrate that induction of adult-like metabolism plays a critical role in establishing an adult-onset disease model using patient-specific iPSCs. Using this model, we revealed crucial pathogenic insights that metabolic derangement in adult-like metabolic milieu underlies ARVD/C pathologies, enabling us to propose novel disease-modifying therapeutic strategies.

Association of childhood adversities and early-onset mental disorders with adult-onset chronic physical conditions.

The physical health consequences of childhood psychosocial adversities may be as substantial as the mental health consequences, but whether this is the case remains unclear because much prior research has involved unrepresentative samples and a selective focus on particular adversities or physical outcomes. The association between early-onset mental disorders and subsequent poor physical health in adulthood has not been investigated. To investigate whether childhood adversities and early-onset mental disorders are independently associated with increased risk of a range of adult-onset chronic physical conditions in culturally diverse samples spanning the full adult age range. Cross-sectional community surveys of adults in 10 countries. General population. Adults (ie, aged ≥18 years; N=18303), with diagnostic assessment and determination of age at onset of DSM-IV mental disorders, assessment of childhood familial adversities, and age of diagnosis or onset of chronic physical conditions. Risk (ie, hazard ratios) of adult-onset (ie, at age >20 years) heart disease, asthma, diabetes mellitus, arthritis, chronic spinal pain, and chronic headache as a function of specific childhood adversities and early-onset (ie, at age <21 years) DSM-IV depressive and anxiety disorders, with mutual adjustment. A history of 3 or more childhood adversities was independently associated with onset of all 6 physical conditions (hazard ratios, 1.44 to 2.19). Controlling for current mental disorder made little difference to these associations. Early-onset mental disorders were independently associated with onset of 5 physical conditions (hazard ratios, 1.43 to 1.66). These results are consistent with the hypothesis that childhood adversities and early-onset mental disorders have independent, broad-spectrum effects that increase the risk of diverse chronic physical conditions in later life. They require confirmation in a prospectively designed study. The long course of these associations has theoretical and research implications.

Mutations in Cardiac T-Box Factor Gene TBX20 Are Associated with Diverse Cardiac Pathologies, Including Defects of Septation and Valvulogenesis and Cardiomyopathy

The T-box family transcription factor gene TBX20 acts in a conserved regulatory network, guiding heart formation and patterning in diverse species. Mouse Tbx20 is expressed in cardiac progenitor cells, differentiating cardiomyocytes, and developing valvular tissue, and its deletion or RNA interference-mediated knockdown is catastrophic for heart development. TBX20 interacts physically, functionally, and genetically with other cardiac transcription factors, including NKX2-5, GATA4, and TBX5, mutations of which cause congenital heart disease (CHD). Here, we report nonsense (Q195X) and missense (I152M) germline mutations within the T-box DNA-binding domain of human TBX20 that were associated with a family history of CHD and a complex spectrum of developmental anomalies, including defects in septation, chamber growth, and valvulogenesis. Biophysical characterization of wild-type and mutant proteins indicated how the missense mutation disrupts the structure and function of the TBX20 T-box. Dilated cardiomyopathy was a feature of the TBX20 mutant phenotype in humans and mice, suggesting that mutations in developmental transcription factors can provide a sensitized template for adult-onset heart disease. Our findings are the first to link TBX20 mutations to human pathology. They provide insights into how mutation of different genes in an interactive regulatory circuit lead to diverse clinical phenotypes, with implications for diagnosis, genetic screening, and patient follow-up.

Website of the week: Managing chronic diseases: kids' stuff

When children are considered in the context of chronic diseases, it is often with a view to preventing the problems of adult onset cancer and heart disease. In Britain, the Department of Health has initiated a National School Fruit Scheme for children to “protect them against chronic diseases in later life.” At the website (www.doh.gov.uk/schoolfruitscheme/), statistics show that eating green stuff remains among the least favourite activities of most children: “About half eat no peas and three in five eat no leafy green vegetables.” Sadly, chronic illness is not always confined to a child's distant future. Many children are affected by chronic diseases. The internet can be an ideal means of providing these children with knowledge and support. The National Asthma Campaign website contains a “kids' zone” (www.asthma.org.uk/kidszone/) that offers advice on coping with asthma attacks and attempts to provide answers to questions such as “What is asthma?” and “Why do I have asthma?” The “youth site” of Coeliac UK (www.coeliac.co.uk) combines education with entertainment, interspersing its information with interactive space invaders games. Diabetes UK (www.diabetes.org.uk/manage/teenzone/sort_it.htm) provides information relevant to teenagers. It offers advice on alcohol consumption and interactions between recreational drugs and insulin and glucose levels, along with strategies for gaining independence from protective parents. “Band-aides and Blackboards” (www.faculty.fairfield.edu/fleitas/contents.html) aims to provide age appropriate information for all children with chronic illnesses and to educate others (parents, teachers, other children, etc) on what it's like to grow up with a chronic medical condition. It addresses issues of stigma, fear, and coping at school and in hospital through the use of stories and children's personal accounts. “I have a ‘hidden’ medical problem. Most of the time nobody can see it, but sometimes I get very big bruises because of it,” says 9 year old J J, who has haemophilia. “Band-aides and Blackboards” deserves commendation to all. Could a website that promotes understanding and acceptance of children with chronic illness be more valuable than a Department of Health initiative promoting the consumption of cabbage?