Impact of adipokines and insulin resistance on progression of prehypertension

描述(由申请人提供)： 收缩压升高(SBP)是心血管疾病发病率和死亡率的主要危险因素。1因此，防止从高血压前期到持续性动脉高血压的进展至关重要。2微血管稀疏(小动脉和毛细血管数量减少)被认为是高血压靶器官损害(TOD)的最早形式之一，并可能导致慢性、持续性血压升高。3 4事实上，我们实验室的数据表明，通过使用新的毛细血管检查技术来识别毛细血管结构和功能的微血管变化，可以在高血压前期和高血压前期检测到靶器官损害。以前关于高血压的微循环研究受到样本量、缺乏纳入非裔美国人等少数族裔人群、心血管发病率和死亡率风险较高的少数民族人群以及缺乏纵向数据的限制。这项赠款提案将扩展先前研究的结果，同时解决这些限制。最近的证据也表明炎症与高血压(HTN)有因果关系。5，6此外，到目前为止的研究表明，促炎性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促炎性脂肪因子还可能引发内皮功能障碍(ED)和胰岛素抵抗(IR)，这是动脉粥样硬化性疾病的另外两个主要贡献者。8胰岛素抵抗与高血压9和高血压前期10-12有关，但尚未建立因果联系。13我们为这项拨款申请产生了进一步的初步数据，确实证明了促炎措施(CRP，IL6)与微血管功能的关联。胰岛素敏感性(IS)和收缩压(SBP)。因此，该项目旨在检验以下解释这些多重观察的统一假设。炎症性脂肪因子和胰岛素抵抗可预测高血压前期向高血压的进展，并可能起到作用(图1，第3页)。这项研究的积极发现将证明未来使用实验设计在分子或细胞水平上进行研究是合理的。我们将对宾夕法尼亚州费城初级保健诊所招募的340名血压正常和高血压前期患者进行队列研究。在基线和随访时(登记后1.5-2年×2次随访)，我们将评估肥胖(体重指数、BMI、腰围、腰围、腹部皮褶厚度、AST)、脂肪因子水平(IL-6、TNF1、PAI-1、脂联素)、C反应蛋白、微血管功能、办公室血压(SBP办公室)和胰岛素敏感性(IS)。在基线和末次就诊时进行24小时动态血压监测(ABPM)。这项调查的结果将有助于确定高血压的直接原因，潜在地降低显著的相关心血管发病率和死亡率。识别导致血管损伤的通路中的初始成分最终可能成为临床上有用的预测指标，用于识别有可能发生微血管和大血管疾病的患者，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转的血管/内皮损伤和临床HTN的发展而将心血管风险降至最低。

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.