Identification of Circulating Plasma Proteins as a Mediator of Hypertension-Driven Cardiac Remodeling: A Mediation Mendelian Randomization Study
Yuanlong HuLin LinLei ZhangYuan LiXinhai CuiMengkai LuZhiyuan ZhangXiuya GuanMuxin ZhangJiaqi HaoXiaojie WangJia-Ming HuanWenqing YangChao LiYunlun Li
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This study focused on circulating plasma protein profiles to identify mediators of hypertension-driven myocardial remodeling and heart failure.Keywords:
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Lipoproteins are a major risk factor for atherosclerotic cardiovascular diseases (ASCVD). Among the lipoproteins, low-density lipoproteins (LDL) have been shown to be causally associated with ASCVD development. In contrast, triglycerides or triglyceride-rich lipoproteins receive less attention than LDL because there is little definite evidence from randomized controlled trials. A Mendelian randomization study has recently been published in which a causal association could be estimated with observational datasets. Using such Mendelian randomization studies, ranging from common to rare genetic variations, triglycerides seem to be causally associated with ASCVD outcomes independent of LDL. Although the "causal association" of serum triglycerides and ASCVD is difficult to assert, accumulated evidence from clinical and Mendelian randomization studies, using common and rare genetic variations, strongly supports such an association. In this article, we provide a summary of investigations focusing on important causal associations between serum triglycerides and ASCVD from the clinical point of view.
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Introduction: The aim of this study was to investigate association between pulse pressure index (PPI) and left ventricular diastolic function measured via tissue Doppler imaging in hypertensive patients. Material and Methods:Seventy five 18 to 55 years old otherwise normal patients with hypertension were included in the study. Blood pressure measurement, echocardiographic examination were carried out according to the published guidelines. Normal diastolic function was defined as E/A ratio >1, Em>8 cm/s, Em/Am >1 or E/Em <8. Results: There were 26 men and 49 women in the study population with average age of 47±6 years. Average systolic and diastolic blood pressures were 133±15 mmhg and 83±6 mmhg respectively. 52% of the subjects (n=39) had normal diastolic function, 32 patients had grade I diastolic dysfunction and 4 patients had psuedonormal pattern. Patients with diastolic dysfunction had significantly higher systolic and diastolic blood pressure, pulse pressure, and PPI values compared to patients with normal diastolic function. Conclusion:This study showed that elevated PPI significantly correlates with increased E/Em and left ventricular diastolic dysfunction in hypertensive patients
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A conventional Mendelian randomization analysis assesses the causal effect of a risk factor on an outcome by using genetic variants that are solely associated with the risk factor of interest as instrumental variables. However, in some cases, such as the case of triglyceride level as a risk factor for cardiovascular disease, it may be difficult to find a relevant genetic variant that is not also associated with related risk factors, such as other lipid fractions. Such a variant is known as pleiotropic. In this paper, we propose an extension of Mendelian randomization that uses multiple genetic variants associated with several measured risk factors to simultaneously estimate the causal effect of each of the risk factors on the outcome. This “multivariable Mendelian randomization” approach is similar to the simultaneous assessment of several treatments in a factorial randomized trial. In this paper, methods for estimating the causal effects are presented and compared using real and simulated data, and the assumptions necessary for a valid multivariable Mendelian randomization analysis are discussed. Subject to these assumptions, we demonstrate that triglyceride-related pathways have a causal effect on the risk of coronary heart disease independent of the effects of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol.
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Abstract Background and Aims Pathology of the cardiovascular system is the leading cause of death in patients with CKD, while determining the causes of the formation of cardiac events is often difficult. Method We conducted an analysis of echocardiography data performed by 50 children with CKD. On the echoCG, the final systolic and diastolic sizes of the left ventricle (FSS and FDS), the final systolic and diastolic volumes of the left ventricle (FSV and FDV) were determined; measured the thickness of the interventricular septum (IVS) and the posterior wall of the left ventricle (PWLV). Left ventricular myocardial mass (LVMM) was determined by the formula proposed by R. Devereux and N. Reichek: LVMM = 1.04x (/ IVS+PWLV+FDS/3-FDS3) - 13.6where, IVS - thickness of IVS in diastole,PWLV-thickness of PWLV in diastole, FDS-final diastolic size of the left ventricle. Results We conducted an analysis of echocardiography data performed by 50 children with CKD. On the echoCG, the final systolic and diastolic sizes of the left ventricle (FSS and FDS), the final systolic and diastolic volumes of the left ventricle (FSV and FDV) were determined; measured the thickness of the interventricular septum (IVS) and the posterior wall of the left ventricle (PWLV). Left ventricular myocardial mass (LVMM) was determined by the formula proposed by R. Devereux and N. Reichek: LVMM = 1.04x (/ IVS+PWLV+FDS/3-FDS3) - 13.6where, IVS - thickness of IVS in diastole,PWLV-thickness of PWLV in diastole, FDS-final diastolic size of the left ventricle. Conclusion The mechanisms of damage to the heart and blood vessels in patients with CKD begin to function already in the initial stage of renal failure and increase as it progresses. The need to know the data of clinical, laboratory and instrumental examination methods at the terminal stage of CKD is dictated, first of all, by the possibility of exposure to them. An important stimulus for conducting an echocardiographic examination is the early detection and correction of cardiovascular disorders, in connection with the prospect of increasing the survival of patients after kidney transplantation.
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A conventional Mendelian randomization analysis assesses the causal effect of a risk factor on an outcome by using genetic variants that are solely associated with the risk factor of interest as instrumental variables. However, in some cases, such as the case of triglyceride level as a risk factor for cardiovascular disease, it may be difficult to find a relevant genetic variant that is not also associated with related risk factors, such as other lipid fractions. Such a variant is known as pleiotropic. In this paper, we propose an extension of Mendelian randomization that uses multiple genetic variants associated with several measured risk factors to simultaneously estimate the causal effect of each of the risk factors on the outcome. This "multivariable Mendelian randomization" approach is similar to the simultaneous assessment of several treatments in a factorial randomized trial. In this paper, methods for estimating the causal effects are presented and compared using real and simulated data, and the assumptions necessary for a valid multivariable Mendelian randomization analysis are discussed. Subject to these assumptions, we demonstrate that triglyceride-related pathways have a causal effect on the risk of coronary heart disease independent of the effects of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol.
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Ventricular remodeling is the molecular and cytological basis for the occurrence and progression of heart failure,with an overall impact on the ventricular function and survival of the patient.Studies show that pacing different parts of ventricle produces different ventricular activation sequence,pressure overload and myocardial blood supply,results in promotion,delay or reverse of left ventricular remodeling(LVR),and thus gives rise to different changes in cardiac function.
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