Cardiac Risk Factors for Stroke: A Comprehensive Mendelian Randomization Study.
Cardiac Risk Factors for Stroke: A Comprehensive Mendelian Randomization Study.
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观察性研究表明，中风与心脏特征的关联超出了心房颤动，心源性栓塞的主要来源。然而，关于这些特征在卒中发病机制中的因果作用仍存在争议。在这里，我们利用遗传数据，使用孟德尔随机化框架系统地评估心脏特征与中风风险之间的关联。我们研究了66种心脏特征，包括心血管疾病，磁共振成像衍生的心脏成像，超声心动图成像和心电图测量，以及2样本孟德尔随机化方法中的血液生物标志物。在MEGASTROKE联盟的数据中（40585例/406111例对照），研究了每种特征的遗传易感性与卒中风险和卒中亚型的相关性。使用多变量孟德尔随机化，我们调整了与房颤、冠状动脉疾病和收缩压相关的潜在多效性或介导效应。正如预期的那样，我们观察到房颤和心源性卒中的遗传易感性之间以及冠状动脉疾病作为动脉粥样硬化和大动脉卒中的代表的遗传易感性之间存在很强的独立相关性。我们的数据驱动分析进一步表明，遗传易感性与心力衰竭和较低的静息心率与中风有关。然而，在多变量分析中，房颤、冠状动脉疾病和收缩压解释了这些相关性。遗传学预测的V1（心房性心脏病的心电图标记）P波终末力与大动脉卒中呈负相关。除了已知的临床风险因素外，现有的遗传数据不支持心脏性状对卒中风险的实质性影响。我们的研究结果强调，在研究中风的候选心脏危险因素时，需要仔细控制混杂因素和其他潜在的偏倚。
Observational studies suggest an association of stroke with cardiac traits beyond atrial fibrillation, the leading source of cardioembolism. However, controversy remains regarding a causal role of these traits in stroke pathogenesis. Here, we leveraged genetic data to systematically assess associations between cardiac traits and stroke risk using a Mendelian Randomization framework. We studied 66 cardiac traits including cardiovascular diseases, magnetic resonance imaging–derived cardiac imaging, echocardiographic imaging, and electrocardiographic measures, as well as blood biomarkers in a 2-sample Mendelian Randomization approach. Genetic predisposition to each trait was explored for associations with risk of stroke and stroke subtypes in data from the MEGASTROKE consortium (40 585 cases/406 111 controls). Using multivariable Mendelian Randomization, we adjusted for potential pleiotropic or mediating effects relating to atrial fibrillation, coronary artery disease, and systolic blood pressure. As expected, we observed strong independent associations between genetic predisposition to atrial fibrillation and cardioembolic stroke and between genetic predisposition to coronary artery disease as a proxy for atherosclerosis and large-artery stroke. Our data-driven analyses further indicated associations of genetic predisposition to both heart failure and lower resting heart rate with stroke. However, these associations were explained by atrial fibrillation, coronary artery disease, and systolic blood pressure in multivariable analyses. Genetically predicted P-wave terminal force in V1, an electrocardiographic marker for atrial cardiopathy, was inversely associated with large-artery stroke. Available genetic data do not support substantial effects of cardiac traits on the risk of stroke beyond known clinical risk factors. Our findings highlight the need to carefully control for confounding and other potential biases in studies examining candidate cardiac risk factors for stroke.