Age Associated Changes In Structural And Functional Cardio-Vascular Properties

该项目的总体目标是表征血管结构和功能的决定因素，并评估其对心血管发病率和死亡率的影响。主动脉脉波速度（aPWV）增加与临床死亡率有关，但与一般人群无关。在2488名老年人中测量了基线时的主动脉PWV。在平均4.6年的随访中，265人死亡，其中111人因心血管原因死亡。较高的主动脉aPWV四分位数与总死亡率（P= 0.010）和CV死亡率（P= 0.006）相关，与年龄、性别、种族、收缩压、已知CV疾病、肌酐、胆固醇和吸烟无关。因此，在总体健康、功能良好的社区居住人群中，动脉硬化的标志aPWV与较高的总死亡率和心血管死亡率相关（《循环》2005；111(25):3384-3390）。2. 代谢综合征是心血管疾病的一个潜在危险因素，但其在老年人中的患病率尚未得到充分研究。此外，代谢综合征的定义有两套标准，一套由世界卫生组织（WHO）提出，另一套由国家胆固醇教育计划（ATPIII）提出。我们发现，在心血管健康研究（CHS）的2175名基线无心血管疾病的老年参与者亚组中，该综合征的患病率按ATPIII标准为28.1%，按WHO标准为21.0%。两套标准为80.6%的参与者提供了一致的分类。多变量Cox比例风险模型显示，ATPIII标准定义的代谢综合征是冠状动脉或脑血管事件的独立预测因子，与38%的风险增加相关（HR 1.38, 95%CI 1.06-1.79, p< 0.01）。因此，根据ATPIII标准的定义，代谢综合征产生独立的预后信息，即使在调整了传统的心血管危险因素和代谢综合征的个别领域之后（Diabetes Care 2005;28(4):882-887）。3. 大动脉厚度和硬度的增加可能有助于解释为什么衰老是心血管疾病的最重要风险。几项大型研究表明，适度饮酒可以降低患心脏病和中风的风险。我们研究了饮酒是否会改变与年龄相关的动脉硬度和内膜内侧厚度（IMT）的增加。来自巴尔的摩老龄化纵向研究的563名志愿者接受了颈动脉双工超声检查，测量了IMT和动脉硬度指数。通过标准问卷评估酒精摄入量。酒精摄入量与僵硬指数呈u型关系，适度饮酒者僵硬指数最低；在调整心血管风险参数后，这种关系仍然存在。在调整其他心血管危险因素之前和之后，适度饮酒者的动脉僵硬度与年龄相关的增加比重度饮酒者和不饮酒者少50%。在酒精摄入量和IMT之间发现了显著的正u型关系，在调整了危险因素后，这种关系不再持续。因此，轻度至中度酒精摄入有利于调节动脉树的衰老。这种效应可以部分解释酒精摄入与心血管疾病之间的J型或u型关系（美国心脏杂志，2005;95:1006-10）。4. 长期β受体阻滞剂治疗可改善充血性心力衰竭（CHF）患者的预后。门诊-受体阻滞剂滴定通常需要经常去诊所监测血流动力学和症状。我们开发了一种自动语音交互远程医疗系统，使用家庭监控设备评估症状、脉搏和血压，这些信息通过电话传递到计算机数据库，供医疗保健提供者访问。49例未接受β受体阻滞剂治疗的CHF患者被随机分配到TeleWatch评估指导（TG）或门诊临床评估指导（CG）的卡维地洛滴定计划中，目标是在3个月内服用25mg BID。滴定决定是由不知道提供给他们的信息是通过TG还是CG数据获得的医生做出的。TG组的滴定时间明显短于CG组，分别为32.4天和67.8天，p< 0.001。多元线性回归分析显示，组分配（p< 0.001）、卡维地洛最终剂量（p=0.02）和NYHA分级（p=0.04）与滴定时间独立相关，而年龄、射血分数、脉搏和收缩压与滴定时间无关。因此，自动化远程医疗系统可以安全且显著地减少CHF门诊患者的卡维地洛滴定时间（美国心脏杂志，2006;51:844 - 91）。5. 许多研究表明，特质性愤怒和敌意与冠心病的发病机制有关。我们调查了来自巴尔的摩衰老纵向研究的年轻和老年健康志愿者的颈动脉内膜内侧厚度和僵硬度与愤怒频率（特质性愤怒）、表达（愤怒发泄）和抑制（愤怒发泄）的关系。我们发现愤怒抑制是颈动脉硬度的独立决定因素，但我们没有观察到愤怒和颈动脉厚度之间的任何关联。关注愤怒表达的行为干预是否能有效预防或逆转动脉僵硬及其伴随的心血管风险，值得进一步评估。[J] .中华医学杂志2006；19:1129-34。6. 动脉厚度和硬度随着年龄的增长而增加，并且越来越被认为是心血管发病率和死亡率的危险因素。由于这些复杂的性状可能受到多种遗传和环境因素的影响，因此寻找可能构成这些表型的新基因将需要全基因组的连锁和关联研究。我们评估了创始人群中血压和中心动脉结构和功能的遗传性，即由于有限的外部混合而在个体之间具有高度相互关联性的人群。我们招募了6148名受试者（57%为女性，711个家庭），占撒丁岛4个城镇14-102岁总人口的60%以上。遗传力是用简单方差成分模型评估的，该模型假设遗传因素之间的所有相似性都是由于加性遗传效应。收缩压、舒张压、舒张颈动脉直径、内膜内侧厚度和脉搏波速度（中央动脉硬度指标）的窄遗传力估计，经性别、年龄和年龄调整后，分别为0.258、0.187、0.443、0.185和0.226，表明18%至44%的差异可归因于遗传因素。因此，在这项对大型创始人群体的研究中，动脉结构和功能的指标显示出强大的遗传力估计，表明全基因组连锁和关联研究可能会成功识别导致这些性状变异的基因（PLoS Genet. 2006;2(8):e32）。

The overall goals of this project are to characterize the determinants of vascular structure and function, and evaluate their effects on cardiovascular morbidity and mortality 1. Increased aortic pulse wave velocity (aPWV) has been associated with mortality in clinical but not general populations. Aortic PWV was measured at baseline in 2488 older adults. Over an average of 4.6 years of follow-up, 265 deaths occurred with 111 categorized as cardiovascular in cause. Higher aortic aPWV quartile was associated with both total mortality (P = 0.010) and CV mortality (P=.006), independent of age, gender, race, SBP, known CV disease, creatinine, cholesterol and smoking. Thus, among a generally healthy, well-functioning, community dwelling population, aPWV, a marker of arterial stiffness, is associated with higher total and CV mortality (Circulation 2005;111(25):3384-3390). 2. The prevalence of the metabolic syndrome, a potent risk factor for cardiovascular diseases, has not been adequately explored in older individuals. Moreover, 2 sets of criteria have been proposed for the definition of the metabolic syndrome, one by the World Health Organization (WHO) and one by the National Cholesterol Education Program (ATPIII). We found that the prevalence of this syndrome in a subgroup of 2175 older participants from the Cardiovascular Health Study (CHS) free of cardiovascular disease at baseline to be 28.1% by ATPIII criteria, and 21.0%, by WHO criteria. The two sets of criteria provided concordant classification for 80.6% of participants. Multivariate Cox propotional hazard models showed that the metabolic syndrome defined with the ATPIII criteria, but not with the WHO criteria, was an independent predictor of coronary or cerebrovascular events, and was associated with a 38% increased risk (HR 1.38, 95%CI 1.06-1.79, p< 0.01). Thus, as defined by the ATPIII criteria, the metabolic syndrome yields independent prognostic information, even after adjusting for traditional cardiovascular risk factors and the individual domains of the metabolic syndrome (Diabetes Care 2005;28(4):882-887). 3. Increased thickness and stiffness of large arteries may contributeto why aging is the most important risk for cardiovascular diseases. Several large studies have shown that moderate alcohol consumption reduces the risk for heart disease and stroke. We examined whether alcohol consumption alters age-associated increases in arterial stiffness and intimal medial thickness (IMT). A total of 563 volunteers from the Baltimore Longitudinal Study of Aging had carotid duplex ultrasonography with measurements of IMT and an arterial stiffness index. Alcohol intake was assessed by a standard questionnaire. A U-shaped relationship was found between alcohol intake and stiffness index, with the lowest index in moderate drinkers; this relationship persisted after adjustment for cardiovascular risk parameters. Moderate drinkers showed 50% less age-associated increase in arterial stiffness than heavy drinkers and nondrinkers, both before and after adjusting for other cardiovascular risk factors. A significant positive u-shaped relationship was found between alcohol intake and IMT, which did not persist after adjustment for risk factors. Thus, light to moderate alcohol intake favorably modulates aging of the arterial tree. This effect may explain in part the J- or U-shaped relationship between alcohol intake and cardiovascular disease (Am J Cardiol. 2005;95:1006-10). 4. Long-term beta blocker therapy improves outcomes in patients with congestive heart failure (CHF). Outpatient beta blocker titration usually requires frequent clinic visits to monitor hemodynamics and symptoms. We developed an automated voice-interactive telemedicine system to assess symptoms, pulse, and blood pressure using home monitoring devices with information relayed via the telephone to a computer database which could be accessed by health ccare providers. Forty-nine patients with CHF not receiving beta-blockers were randomized to a TeleWatch assessment guided (TG) or outpatient clinic assessment guided (CG) carvedilol titration schedule with a goal of 25 mg BID over a three month period. Titration decisions were made by physicians blinded as to whether the information provided to them was obtained using the TG or CG data. The titration time was significantly shorter in the TG, compared to the CG group, 32.4 days versus 67.8 days, p< 0.001. On multiple linear regression analysis, group assignment (p< 0.001), final carvedilol dose (p=0.02) and NYHA class (p=0.04), were independently correlated to the duration of titration, while age, ejection fraction, pulse and systolic blood pressure were not. Thus, an automated telemedicine system can safely and significantly decrease the time to achieve carvedilol titration in CHF outpatients (Am Heart J 2006;151:844.e1-10. 5. Numerous studies have implicated trait anger and hostility in the pathogenesis of coronary heart disease. We investigated the associations of anger frequency (trait anger), expression (anger-out) and suppression (anger-in) with carotid artery intimal medial thickness and stiffness in younger and older healthy volunteers from the Baltimore Longitudinal Study of Aging. We found that anger suppression is an independent determinant of carotid arterial stiffness, but we did not observe any association between anger and carotid arterial thickness. Whether behavioral interventions focusing on anger expression can be effective in preventing or reversing arterial stiffness and its attendant cardiovascular risks deserve further evaluation. (Am J Hypertens 2006;19:1129-34). 6. Arterial thickness and stiffness increase with advancing age, and are increasingly recognized as risk factors for cardiovascular morbidity and mortality. Because these complex traits are likely to be affected by a multiplicity of genetic and environmental factors, the search for novel genes that may underlie these phenotypes will require genome wide linkage and association studies. We evaluated the heritability of blood pressure and central arterial structure and function in a founder population, i.e. one with high degrees of interrelatedness among its individuals due to limited external admixture. We recruited 6,148 subjects (57% women, 711 families), representing over 60% of the total population aged 14-102, from a cluster of 4 towns on the island of Sardinia. Heritabilities were assessed with simple variance components models, which assume that all similarities between genetic factors are due to additive genetic effects. The narrow heritability estimates for systolic BP, diastolic BP, diastolic carotid diameter, intimal medial thickness, and pulse wave velocity (an index of central arterial stiffness), adjusted for sex, age and age2, are respectively 0.258, 0.187, 0.443, 0.185 and 0.226, and indicate that 18% to 44% of the variance can be attributed to genetic factors. Thus, in this study of a large founder population, indexes of arterial structure and function show robust heritability estimates, indicating that genome wide linkage and association studies will likely succeed in identifying genes that contribute to the variance in these traits (PLoS Genet. 2006;2(8):e32).