Human cardiac-specific cDNA array for idiopathic dilated cardiomyopathy: sex-related differences

Haddad, Georges E.; Saunders, Lori; Crosby, Seth D.; Carles, Maria; Monte, Federica del; King, Kindra; Bristow, Michael R.; Spinale, Francis G.; MacGillivray, Thomas E.; Semigran, Marc J.; Dec, G. William; Williams, Steven A.; Hajjar, Roger J.; Gwathmey, Judith K.

doi:10.1152/physiolgenomics.00265.2007

Cited by 48 publications

(41 citation statements)

References 70 publications

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“…Intriguingly, Haddad et al reported sex-related differences in the gene expression profile of the failing myocardium. 65 They found deregulation of genes involved in energy metabolism and regulation of those related to transcription and translation in the failing myocardium of female patients with DCM, whereas genes related to muscle contraction were deregulated in the failing myocardium of male patients.…”

Section: Sex-specific Gene Expressionmentioning

confidence: 98%

“…They have usually compared gene expression between opposing pairs of samples, such as non-failing vs failing hearts, [53][54][55][56][57][58][59] ischemic vs non-ischemic hearts, 53,60 hypertrophic vs failing hearts, 61 atria vs ventricles 62 or male vs female failing hearts. 65 Gene Expression Profile of DCM Yang et al 53 performed microarray analysis of 4 human myocardial samples harvested from 2 patients without HF, 1 patient with DCM and 1 patient with ischemic cardiomyopathy (ICM) using the Affymetrix Hu6800 GeneChip microarray. They reported 12 genes with altered expression in both failing hearts compared with the normal hearts and 5 genes that were only detectable in the failing hearts.…”

Section: Microarray Analysis Of the Failing Myocardiummentioning

confidence: 99%

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Global Gene Expression Profiling in the Failing Myocardium

Asakura

Kitakaze

2009

Circ J

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Heart failure (HF) is a syndrome that involves multiple cellular mechanisms leading to a common phenotype of reduced ventricular contraction and cardiac chamber dilation. To clarify the mechanisms, a number of microarray analyses of the failing myocardium have been conducted. Gene expression profiles are usually compared between opposing pairs of samples, such as non-failing vs failing hearts, ischemic vs non-ischemic hearts, male vs female failing hearts or atria vs ventricles of failing hearts. Apart from these conventional methods, a different novel approach identified cardiac myosin light chain kinase (MLCK) as a HF-related gene by the comprehensive search for the genes that had an expression level that strongly correlated with the severity of HF; further investigations proved the important role of cardiac MLCK in HF. Moreover, a robust gene expression signature composed of 27 genes was revealed on analysis of 4 independent microarray data sets from the failing myocardium of dilated cardiomyopathy. The authors newly demonstrate 107 HF-related genes that were listed in 2 or more of 7 microarray data sets previously reported. Among these genes, many were observed to be involved in mitochondrial dysfunction and oxidative phosphorylation and 3 extracellular molecules, including periostin, pleiotrophin, and SERPINA3, which might become novel diagnostic and therapeutic targets for HF. These novel strategies warrant the new identification of specific genes that are linked to the pathophysiology of HF. (Circ J 2009; 73: 1568 -1576

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Section: Sex-specific Gene Expressionmentioning

confidence: 98%

Section: Microarray Analysis Of the Failing Myocardiummentioning

confidence: 99%

Global Gene Expression Profiling in the Failing Myocardium

Asakura

Kitakaze

2009

Circ J

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“…30 Gene expression profiling in end-stage failing human hearts has revealed similar sex differences as found in animals with HF: less downregulation of energy metabolism in female hearts and more matrix induction in male hearts. 31 …”

Section: Human Hearts: Sex Differences In Pathological Mhmentioning

confidence: 99%

Sex and Gender Differences in Myocardial Hypertrophy and Heart Failure

Regitz‐Zagrosek

Oertelt‐Prigione

Seeland

et al. 2010

Circ J

163

103

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EpidemiologyHeart failure (HF) is one of the leading hospital discharge diagnoses in the modern world and has enormous implications with respect to cardiovascular mortality and morbidity, to individual quality of life experiences and societal resource utilization. The number of patients with HF is continuously increasing. Approximately 10% of 70-year-olds are affected, with an increasing prevalence after that age. HF patients have a life expectancy of approximately 5 years, similar to patients with malignant disease. Women with HF are older than their male counterparts and more likely to exhibit a non-ischemic cause of the disease. 1 The population-based Framingham study suggests that the prognosis in women is significantly better than in men after the onset of HF. 2 However, despite the higher mortality in men, given the overall longer lifespan of women, total numbers of HF deaths are higher in women. The incidence of HF increases dramatically in the female population over 55 years, further compensating the sex differences in mortality. This also appears to account for the stronger correlation between age and mortality observed in women. In fact, in men the NYHA class at baseline is the strongest predictor of mortality, whereas in women it is age. African-Americans might have a higher incidence of HF than Caucasians, with men affected more frequently than females.Major risk factors in both sexes are: age, presence of diabetes, anemia, elevated blood pressure, presence of AF, myocardial hypertrophy (MH) and prior myocardial infarction. Distribution of risk factors differs between the sexes. Women more frequently exhibit hypertension 1,3 and diabetes mellitus. 1,3 Hypertension contributes to the population attributable risk for HF in women to a greater extent than in men. 4 Obesity, diabetes, and impaired glucose carry a greater risk in women and inhibit or impair myocardial metabolism more severely in women than in men. 5-7 Men are more likely to suffer from preexisting coronary heart disease 1,8 and dilated cardiomyopathy (DCM). In the Euro HF survey, systolic HF was found predominantly in men whereas women presented with HF with preserved ejection fraction (EF) or diastolic HF. 9-11 Both systolic and diastolic HF carry a poor prognosis, with astonishingly small differences. 12 MH is a major risk factor for HF and is a negative prognostic sign in itself. Interestingly, women are better protected against the development of MH than men. However, even though MH appears later in women than it does in men at a given hemodynamic load, once established, it is more malign in women. 13 Left ventricular (LV) mass has been presented as the strongest independent mortality predictor in females. Sex and Gender Differences in Myocardial Hypertrophyand Heart Failure Vera Regitz-Zagrosek, MD; Sabine Oertelt-Prigione, MD; Ute Seeland, MD; Roland Hetzer, MDHeart failure (HF) is a leading cause of cardiovascular mortality and morbidity in the Western world. It affects men at younger age than women. Women have more frequently diast...

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“…Nieminen et al (27) evaluated sex differences in patients hospitalized for acute heart failure in the EuroHeart Failure Survey II and found that men had DCM more frequently than women. Likewise, Haddad et al (13) reported that men with idiopathic DCM undergoing transplantation showed a different gene expression profile than women. Thus the EP4 KO model, with its sexual dimorphism in DCM, may represent a good model to understand the molecular basis of sex differences in disease progression.…”

Section: Sex Differences and Dcmmentioning

confidence: 99%

Gene expression profiling of dilated cardiomyopathy in older male EP4 knockout mice

Harding

Yang

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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Harding P, Yang XP, Yang J, Shesely E, He Q, LaPointe MC. Gene expression profiling of dilated cardiomyopathy in older male EP4 knockout mice. Am J Physiol Heart Circ Physiol 298: H623-H632, 2010. First published December 11, 2009; doi:10.1152/ajpheart.00746.2009.-Using a line of mice with cardiac-specific knockout (KO) of the EP4 receptor gene, experiments were designed to determine whether a cardiac phenotype developed with age. Cardiac function was assessed by echocardiography in 23-to 33-wk-old male and female KO and littermate controls (WT) mice. After echocardiography, hearts were removed to assess weight, and then some were further processed for histology [myocyte cross-sectional area (MCSA), interstitial collagen fraction (ICF), and macrophage infiltration] and some for extraction of total RNA and protein. Older male KO mice had reduced ejection fraction (EF) coupled with left ventricular dilatation. MCSA and infiltrating macrophages were not different between groups, but ICF increased by 39% in KO mice. In contrast to male KO mice, 30-to 32-wk-old female KO mice had only a slight reduction in EF. To understand gene expression differences between male WT and KO mice, we performed whole genome gene expression profiling (Illumina BeadChips) on hearts of 30-to 32-wk-old mice. Data indicated that 156 genes were overexpressed in the KO hearts more than twofold, including genes involved in remodeling, inflammation, and oxidative stress. Overexpressed chemokines/cytokines were further examined in hearts of 10-to 12-wk-old male KO mice, and we found that growth differentiation factor-15 (GDF-15) expression was higher in KO than in WT hearts. In conclusion, EP4 knockdown in cardiac myocytes in aged male KO mice is in part associated with increased fibrosis, reduced EF, and dilated cardiomyopathy. Early overexpression of GDF-15 in hearts of male KO mice may contribute to or be a marker of the disease phenotype. The absence of serious cardiac dysfunction in aged female mice suggests a sexual dimorphism in the phenotype.heart; remodeling; growth differentiation factor-15 THE PREVALENCE OF DILATED CARDIOMYOPATHY (DCM) is increasing every year and currently accounts for ϳ25% of cases of congestive heart failure. Its occurrence is greater in males and African Americans than in females or Caucasians. DCM is characterized by left ventricular dilatation and systolic dysfunction (i.e., impaired ejection fraction, EF). Ventricular wall thickness can be less than or equal to that of a normal heart, and fibrosis is present to a variable degree. The three major causes of DCM are inflammation, toxic stress (e.g., alcoholism), and genetics (autosomal dominant inheritance). For genetic forms of the disease, the penetrance is variable and age dependent (5).Animal models of DCM have been created by either selectively knocking out (KO) or over expressing a gene (1,3,6,10,16,22,32,36, 43). In most cases, the genes were chosen in a targeted approach because of studies showing functional significance of the gene product in vitro in myo...

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Human cardiac-specific cDNA array for idiopathic dilated cardiomyopathy: sex-related differences

Cited by 48 publications

References 70 publications

Global Gene Expression Profiling in the Failing Myocardium

Global Gene Expression Profiling in the Failing Myocardium

Sex and Gender Differences in Myocardial Hypertrophy and Heart Failure

Gene expression profiling of dilated cardiomyopathy in older male EP4 knockout mice

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