Impact of adipokines and insulin resistance on progression of prehypertension

描述（由申请人提供）： 收缩压（SBP）升高是心血管发病率和死亡率的主要风险因素。1因此，预防从高血压前期进展为持续性动脉高血压至关重要。2微血管稀疏（小动脉和毛细血管数量减少）被认为是高血压中靶器官损伤（TOD）的最早形式之一，3 4事实上，我们实验室的数据表明，使用新的毛细血管镜检查技术来识别毛细血管结构和功能的微血管改变，可以在1期高血压和高血压前期检测到靶器官损伤。以前的高血压微循环研究受到样本量的限制，缺乏包括少数民族人群，如非洲裔美国人，心血管发病率和死亡率高风险的种族人群，以及缺乏纵向数据。这项拨款提案将扩展先前研究的发现，同时解决这些限制。最近的证据还表明，炎症与高血压（HTN）有因果关系。5，6此外，迄今为止的研究表明，促炎脂肪因子对微血管功能有负面影响，而脂联素对微循环有保护作用。7促炎脂肪因子也可能引发内皮功能障碍（艾德）和胰岛素抵抗（IR）的发展。8胰岛素抵抗与高血压9和高血压前期10 -12相关，但因果关系尚未建立。13我们已经专门为这项拨款申请生成了进一步的初步数据，这些数据确实证明了促炎措施的相关性。CRP、IL 6与微血管功能、胰岛素敏感性（IS）、收缩压（SBP）的关系。因此，本项目旨在测试以下解释这些多重观察结果的统一假设。炎症性脂肪因子和胰岛素抵抗可预测并可能促进高血压前期向高血压的进展（图1，第3页）。这项研究的积极结果将证明未来的研究在分子或细胞水平上，使用实验设计。 我们将进行一项队列研究的340名血压正常和高血压前期的个人招募从基层医疗实践在费城，宾夕法尼亚州。在基线和随访时（入组后1.5-2年x 2次访视），我们将评估肥胖（体重指数、BMI、腰围、WC、腹部皮褶厚度、AST）、脂肪因子水平（IL-6、TNF 1、派-1、脂联素）、CRP、微血管功能、诊室血压（SBP诊室）和胰岛素敏感性（IS）。将在基线和最终访视时进行24小时动态血压监测（ABPM）。 这项研究的结果将有助于确定高血压的近因，潜在地降低相关的心血管发病率和死亡率。识别导致血管损伤的途径中的初始组分可能最终作为临床上有用的预测因子，用于识别具有发展微血管和大血管疾病风险的患者，为早期干预和预防提供关键机会。早期患者干预将通过避免不可逆的血管/内皮损伤和临床HTN的发展来最大限度地降低心血管风险。

DESCRIPTION (provided by applicant): Elevation in systolic blood pressure (SBP) is the leading risk factor for cardiovascular morbidity and mortality.1 Accordingly, prevention of the progression from prehypertension to sustained arterial hypertension is of critical importance.2 Microvascular rarefaction (reduced number of arterioles and capillaries) is considered one of the earliest forms of target organ damage (TOD) in hypertension, and may contribute to the development of chronic, sustained blood pressure elevation.3 4 Indeed, data from our laboratory demonstrate that target organ damage can be detected in Stage 1 hypertension and prehypertension, using the novel capillaroscopy technique to identify microvascular alterations in capillary structure and function. Prior microcirculation research in hypertension has been limited by sample size, the lack of inclusion of minority populations such as African-Americans, an ethnic population at high risk for cardiovascular morbidity and mortality, and the lack of longitudinal data. This grant proposal will extend findings from prior studies, while addressing these limitations. Recent evidence also suggests that inflammation is causally associated with hypertension (HTN).5, 6 Additionally, research to date indicates that pro-inflammatory adipokines have a negative impact on microvascular function, while adiponectin has a protective effect on the microcirculation.7 Proinflammatory adipokines may also initiate the development of endothelial dysfunction (ED) and insulin resistance (IR), two other major contributors to atherosclerotic disease.8 Insulin resistance is associated with hypertension9 and prehypertension10-12, but a causal link has not been established.13 We have generated further preliminary data specifically for this grant application that indeed demonstrates the association of pro-inflammatory measures (CRP, IL6) with microvascular function, insulin sensitivity (IS), and systolic blood pressure (SBP). Accordingly, this project is designed to test the following unified hypothesis explaining these multiple observations. Inflammatory adipokines and insulin resistance predict and may contribute to the progression of prehypertension to hypertension (Figure 1, p. 3). Positive findings from this investigation would justify future study at the molecular or cellular level, using an experimental design. We will conduct a cohort study of 340 normotensive and prehypertensive individuals recruited from a primary care practice in Philadelphia, PA. At baseline and at follow-up (1.5-2 years after enrollment x 2 visits), we will assess obesity (body mass index, BMI, waist circumference, WC, abdominal skinfold thickness, AST), adipokine levels (IL-6, TNF1, PAI-1, adiponectin), CRP, microvascular function, office blood pressure (SBP office), and insulin sensitivity (IS). 24 hour ambulatory blood pressure monitoring (ABPM) will be conducted at the baseline and final visits. Findings from this investigation will help to identify proximate causes of hypertension, potentially reducing the significant associated cardiovascular morbidity and mortality. Identification of initial components in pathways leading to vascular injury may eventually serve as clinically useful predictors for identifying patients at risk for developing microvascular and macrovascular disease, providing critical opportunities for early intervention and prevention. Early patient intervention will minimize cardiovascular risk by averting the development of irreversible vascular/endothelial damage and clinical HTN.