EGFR/IGF1R Signaling Modulates Relaxation in Hypertrophic Cardiomyopathy
Sıla AlgülMaike SchuldtEmmy MandersValentijn JansenSaskia SchlossarekRichard de Goeij-de HaasAlex A. HennemanSander R. PiersmaConnie R. JiménezMichelle MichelsLucie CarrierMichiel HelmesJolanda van der VeldenDiederik W.D. Kuster
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Diastolic dysfunction is central to diseases such as heart failure with preserved ejection fraction and hypertrophic cardiomyopathy (HCM). However, therapies that improve cardiac relaxation are scarce, partly due to a limited understanding of modulators of cardiomyocyte relaxation. We hypothesized that cardiac relaxation is regulated by multiple unidentified proteins and that dysregulation of kinases contributes to impaired relaxation in patients with HCM.We optimized and increased the throughput of unloaded shortening measurements and screened a kinase inhibitor library in isolated adult cardiomyocytes from wild-type mice. One hundred fifty-seven kinase inhibitors were screened. To assess which kinases are dysregulated in patients with HCM and could contribute to impaired relaxation, we performed a tyrosine and global phosphoproteomics screen and integrative inferred kinase activity analysis using HCM patient myocardium. Identified hits from these 2 data sets were validated in cardiomyocytes from a homozygous MYBPC3c.2373insG HCM mouse model.Screening of 157 kinase inhibitors in wild-type (N=33) cardiomyocytes (n=24 563) resulted in the identification of 17 positive inotropes and 21 positive lusitropes, almost all of them novel. The positive lusitropes formed 3 clusters: cell cycle, EGFR (epidermal growth factor receptor)/IGF1R (insulin-like growth factor 1 receptor), and a small Akt (α-serine/threonine protein kinase) signaling cluster. By performing phosphoproteomic profiling of HCM patient myocardium (N=24 HCM and N=8 donors), we demonstrated increased activation of 6 of 8 proteins from the EGFR/IGFR1 cluster in HCM. We validated compounds from this cluster in mouse HCM (N=12) cardiomyocytes (n=2023). Three compounds from this cluster were able to improve relaxation in HCM cardiomyocytes.We showed the feasibility of screening for functional modulators of cardiomyocyte relaxation and contraction, parameters that we observed to be modulated by kinases involved in EGFR/IGF1R, Akt, cell cycle signaling, and FoxO (forkhead box class O) signaling, respectively. Integrating the screening data with phosphoproteomics analysis in HCM patient tissue indicated that inhibition of EGFR/IGF1R signaling is a promising target for treating impaired relaxation in HCM.The article deals with current guidelines for diagnostics and treatment of hypertrophic cardiomyopathy (HCM) according to the latest recommendations of the European Society of Cardiology. Determined the prevalence of HCM, its causes, are the main clinical and instrumental methods of diagnosis, formulation of diagnosis. Also in the article the clinical prognosis factors and risk stratification of sudden death in this disease, medication and surgical approaches to the treatment of various forms of hypertrophic cardiomyopathy
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Pompe’s disease is a type II glycogen storage disorder resulting from deficiency of α-1,4 glucosidase. It is usually associated with dilated or hypertrophic cardiomyopathy. Association of apical hypertrophic cardiomyopathy is rarely seen. We present a case of a ten-month-old baby with clinical features of both apical hypertrophic cardiomyopathy and Pompe’s disease.
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Objective To investigate the diagnosis value of echocardiography on hypertropic cardiomyopathy.Methods The echocardiography image data of 43 patients with hypertrophic cardiomyopathy were retrospectively analyzed.Results Among the 43 patients with hypertrophic cardiomyopathy,there were 12 cases of obstructive hypertrophic cardiomyopathy,31 cases of nonobstructive hypertrophic cardiomyopathy ; 7 cases of symmetrical hypertrophic cardiomyopathy,34 cases of asymmetric hypertrophic cardiomyopathy,2 cases of apical hypertrophic cardiomyopathy; 2 cases of infantile hypertrophic cardiomyopathy.All patients were diagnosed definitely.Conclusions Echocardiograph has important value in the diagnosis of hypertrophic cardiomyopathy.
Key words:
Echocardiography ; Hypertrophic cardiomyopathy
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Proto-Oncogene Proteins c-akt
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Type 1 insulin-like growth factor receptor (IGF1R) signalling plays a critical role in normal cell growth, and in cancer development and progression. IGF1R and the insulin-like growth factors 1 and 2 (IGF1 and IGF2) are involved in various aspects of the malignant phenotype, suggesting that IGF1R is a potential target for cancer therapy. IGF1R is particularly important in the establishment and maintenance of the transformed phenotype, in mediating proliferation, and for the survival of tumour cells with anchorage-independent growth. IGF1R also exerts antiapoptotic activity and has a substantial influence on the control of the cell and body size. This property enables transformed cells to form macroscopic tumours and to survive the process of detachment required for metastasis. Pharmaceutical companies are investigating molecules that target IGF1R, including specific low molecular weight tyrosine kinase inhibitors and monoclonal antibodies, both of which possess various advantages and display different activity profiles. This review article focuses on the preclinical and clinical development of low molecular weight IGF1R tyrosine kinase inhibitors. It is critical to pursue a thorough molecular analysis of the metabolic activity of IGF1R to avoid possible side-effects of its inhibition.
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Hypertrophic cardiomyopathy (HCM), an uncommon condition of hypertrophied left ventricular walls, is characterized by diverse cardiac, clinical, and genetic findings. In this combined analysis of patient registries in Italy and the U.S., researchers evaluated the impact of sex on the clinical presentation and outcomes of patients with HCM. Overall, 393 women and 576 men with HCM were enrolled at three institutions, underwent standard …
Presentation (obstetrics)
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Objective:To explore the feasibility of the diagnosis of hypertrophic cardiomyopathy through analyzing clinical symptoms and signs,electrocardiogram and echocardiography,and to discuss the causes of misdiagnosis. Method:The clinical data of 36 cases with hypertrophic cardiomyopathy was analyzed. Result:Hypertrophic cardiomyopathy has diverse clinical manifestations and lack of specificity.So it is easy to be misdiagnosed,which requires us to make comprehensive consideration.Echocardiography examination can be used as the preferred method of clinical diagnosis and review. Conclusion:In order to reduce the rate of misdiagnosis and to early treat,we should improve the understanding of hypertrophic cardiomyopathy.
Clinical Diagnosis
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