Age Associated Changes In Structural And Functional Cardio-Vascular Properties

与年龄相关的心血管结构和功能的变化

• 批准号: 7592068
• 负责人: Edward G Lakatta
• 金额: $ 121.59万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7592068
• 关键词: Admixture; Adrenergic beta-Antagonists; Affect; Age; Age-Years; Aging; Alcohol consumption; Alcoholic beverage heavy drinker; Ambulatory Care Facilities; Anger; Arteries; Attenuated; Baltimore; Behavior Therapy; Blinded; Blood Circulation; Blood Pressure; Blood Vessels; Caliber; Cardiovascular Diseases; Cardiovascular system; Caring; Carotid Arteries; Cessation of life; Cholesterol; Class; Classification; Clinic; Clinic Visits; Clinical; Communities; Complex; Computers; Congestive Heart Failure; Coronary; Coronary heart disease; Creatinine; Data; Databases; Diabetes Mellitus; Disease; Dose; EFRAC; Education; Elderly; Environmental Risk Factor; Evaluation; Event; Family; Founder Generation; Frequencies; Gender; General Population; Genes; Genetic; Genetic Determinism; Genets; Goals; Hazard Models; Health; Heart; Heritability; Home environment; Hostility; Individual; Intervention; Island; Light; Longitudinal Studies; Measurement; Measures; Medial; Metabolic syndrome; Mission; Modeling; Modification; Monitor; Morbidity - disease rate; Outcome; Outpatients; Participant; Pathogenesis; Patients; Phenotype; Physicians; Physiologic pulse; Population; Prevalence; Prevention strategy; Property; Provider; Pulse taking; Questionnaires; Race; Randomized; Recruitment Activity; Regression Analysis; Risk; Risk Factors; Sardinia; Schedule; Shapes; Smoke; Standards of Weights and Measures; Stroke; Structure; Subgroup; Symptoms; Syndrome; System; Telemedicine; Telephone; Thick; Time; Titrations; Trees; Ultrasonography; Voice; Woman; Work; World Health Organization; aged; arterial stiffness; body system; cardiovascular disorder risk; cardiovascular risk factor; carvedilol; cerebrovascular; day; follow-up; genome-wide linkage; healthy volunteer; heart disease risk; hemodynamics; improved; indexing; modifiable risk; monitoring device; mortality; neglect; novel; prevent; prognostic; programs; sex; trait; volunteer

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).

该项目的总体目标是确定血管结构和功能的决定因素，并评估它们对心血管发病率和死亡率的影响1。主动脉脉搏波速度（aPWV）增加与临床死亡率相关，但与普通人群的死亡率无关。 对 2488 名老年人的基线主动脉 PWV 进行了测量。 在平均 4.6 年的随访中，发生了 265 例死亡，其中 111 例因心血管原因死亡。较高的主动脉 aPWV 四分位与总死亡率 (P = 0.010) 和 CV 死亡率 (P=.006) 相关，与年龄、性别、种族、SBP、已知的 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，aPWV（动脉硬化的标志）与较高的总死亡率和心血管死亡率相关（Circulation 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，针对代谢综合征的定义提出了两套标准，一套由世界卫生组织（WHO）提出，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 名老年参与者亚组中，基线时没有心血管疾病，根据 ATPIII 标准，该综合征的患病率为 28.1%；根据 WHO 标准，该综合征的患病率为 21.0%。 两组标准为 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，根据 ATPIII 标准（而非 WHO 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，并且与风险增加 38% 相关（HR 1.38，95%CI 1.06） -1.79，p<0.01）。 因此，根据 ATPIII 标准的定义，即使在调整传统心血管危险因素和代谢综合征的各个领域之后，代谢综合征也会产生独立的预后信息（Diabetes Care 2005；28(4):882-887）。 3. 大动脉厚度和硬度的增加可能解释了为什么衰老是心血管疾病最重要的风险。 几项大型研究表明，适量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僵硬度和内膜中层厚度（IMT）的增加。 来自巴尔的摩纵向衰老研究的总共 563 名志愿者接受了颈动脉双重超声检查，并测量了 IMT 和动脉僵硬度指数。通过标准问卷评估酒精摄入量。酒精摄入量与僵硬指数之间存在 U 形关系，适度饮酒者的指数最低；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，中度饮酒者与重度饮酒者和不饮酒者相比，与年龄相关的动脉僵硬度增加减少了 50%。酒精摄入量与 IMT 之间存在显着的正 U 形关系，但在调整危险因素后，这种关系并没有持续存在。 因此，少量至适量的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 形或 U 形关系（Am J Cardiol. 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β受体阻滞剂滴定通常需要经常就诊以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，信息通过电话转发到计算机数据库，医疗保健提供者可以访问该数据库。 49 名未接受 β 受体阻滞剂的 CHF 患者被随机分配接受 TeleWatch 评估指导 (TG) 或门诊评估指导 (CG) 卡维地洛滴定方案，目标是在三个月内每日两次服用 25 mg。 滴定决定是由医生做出的，他们不知道向他们提供的信息是否是使用 TG 或 CG 数据获得的。 与 CG 组相比，TG 组的滴定时间显着缩短，分别为 32.4 天和 67.8 天，p < 0.001。 在多元线性回归分析中，组分配 (p< 0.001)、卡维地洛最终剂量 (p=0.02) 和 NYHA 分级 (p=0.04) 与滴定持续时间独立相关，而年龄、射血分数、脉搏和收缩压压力没有。 因此，自动化远程医疗系统可以安全、显着地缩短 CHF 门诊患者完成卡维地洛滴定的时间 (Am Heart J 2006;151:844.e1-10.5)。大量研究表明，愤怒和敌意与冠心病的发病机制有关。我们研究了愤怒频率（特质愤怒）、表达（发怒）和抑制（发怒）与颈动脉内膜中层厚度和疾病的关系。来自巴尔的摩纵向衰老研究的年轻和老年健康志愿者的研究发现，愤怒抑制是颈动脉僵硬的独立决定因素，但我们没有观察到愤怒与颈动脉厚度之间是否存在任何关联。可以有效预防或逆转动脉硬化，其伴随的心血管风险值得进一步评估（Am J Hypertens 2006；19：1129-34）。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和死亡的危险因素。 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进行全基因组连锁和关联研究。 我们评估了创始人人群的血压和中央动脉结构和功能的遗传性，即由于外部混合有限而在个体之间具有高度相关性的人群。 我们从撒丁岛 4 个城镇群中招募了 6,148 名受试者（57% 为女性，711 个家庭），占 14-102 岁总人口的 60% 以上。 使用简单的方差分量模型评估遗传力，该模型假设遗传因素之间的所有相似性均归因于加性遗传效应。 根据性别、年龄和年龄 2 进行调整后，收缩压、舒张压、舒张期颈动脉直径、内膜中层厚度和脉搏波速度（中心动脉僵硬度指数）的狭义遗传力估计值分别为 0.258、0.187、0.443、0.185 和0.226，并表明 18% 到 44% 的方差可以是归因于遗传因素。 因此，在这项针对大量创始人群体的研究中，动脉结构和功能指数显示出稳健的遗传力估计，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差异的基因（PLoS Genet. 2006； 2(8):e32)。