Modifiable Determinants of Ventricular Arrythmias

描述(由申请人提供)：由于美国每年发生的400,000例SCD中，室性心动过速(VT)和/或室颤(VF)约占80%，识别VT/VF的危险因素对公共卫生具有重要意义。我们提交此申请是为了响应PA-03-015，该PA-03-015使用R21机制。这项计划需要利用现有的人类数据，不需要初步结果，并将研究计划限制在10页以内。在这一应用中，我们建议利用在室性心律失常触发因素(TOVA)研究期间收集的现有数据来确定已知高危人群中室性心律失常的预测因素。TOVA是一项多中心前瞻性队列研究，在美国31个中心招募了1188名ICD患者，旨在确定易感患者中VT/VF的触发因素。在研究过程中收集的关于临床特征、生活方式习惯、心理社会因素和药物的广泛信息，以及从500例ICD发作病例中收集和验证的电信号，为研究生活方式因素和药物对随后危及生命的室性心律失常的电击的影响提供了一个独特的机会。将在该人群中检验的具体假设包括心理社会因素(如愤怒和焦虑)、生活方式因素(如吸烟、酒精和体育活动)以及非传统抗心律失常药物(如他汀类药物和血管紧张素转换酶抑制剂)对VT/VF风险的影响。多变量Cox比例风险模型将被用来评估VT/VF确诊发作的暴露与ICD首次放电时间之间的关系，Anderson-Gill比例风险模型将被用来纳入复发的ICD放电。通过识别VT/VF在这一高危人群中特有的危险因素，可能会对室性心律失常的病理生理学有新的理解，这可能有助于在普通人群和高危患者中开发新的室性心律失常和SCO的预防方法。作为第二个目标，确定可能影响ICD痛苦休克风险的潜在可改变的生活习惯和药物可能会显著影响ICD患者的临床管理和随后的生活质量。

DESCRIPTION (provided by applicant): Since ventricular tachycardia (VT) and/or ventricular fibrillation (VF) underlie approximately 80% of the 400,000 SCDs that occur in the United states annually, the identification of risk factors for VT/VF is of public health importance. We are submitting this application in response to PA-03-015, which uses the R21 mechanism. This program requires the utilization of existing human data, does not require preliminary results, and limits the Research Plan to only 10 pages. In this application, we propose to utilize existing data assembled during the Triggers of Ventricular Arrhythmias (TOVA) study to identify predictors of ventricular arrhythmias in a population known to be at high risk. TOVA is a multi-center prospective cohort study that enrolled 1188 ICD patients at 31 centers in the United States and was designed to identify triggers of VT/VF among susceptible patients. The extensive information collected on clinical characteristics, lifestyle habits, psychosocial factors, and medications along with the collection and validation of electrograms from 500 instances of ICD firings over the course of the study provides a unique opportunity to examine the impact of lifestyle factors and medications on subsequent shocks for life-threatening ventricular arrhythmias. Specific hypotheses that will be examined in this population include the impact of psychosocial factors such as anger and anxiety; lifestyle factors such as smoking, alcohol, and physical activity; and non-traditional antiarrhythmic medications such as statins and angiotensin converting enzyme inhibitors on the risk of VT/VF. Multivariable Cox proportional hazards models will be used to evaluate associations between exposures and time to first ICD discharge for a confirmed episode of VT/VF, and Anderson-Gill proportional hazards models will be used to incorporate recurrent ICD discharges. By identifying risk factors specific for VT/VF in this high risk population, new understanding regarding the pathophysiology of ventricular arrhythmias may be gained, which may aid in the development of new preventive modalities for ventricular arrhythmias and SCO in the general population as well as in high risk patients. As a secondary goal, the identification of potentially modifiable lifestyle habits and medications that may influence risk of painful ICD shocks may significantly impact the clinical management and the subsequent quality of life of ICD patients.