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Cardiac Risk Factors for Stroke: A Comprehensive Mendelian Randomization Study
Simon Frerich1, Rainer Malik1, Marios K Georgakis1
1Institute for Stroke and Dementia Research (S.F., R.M., M.K.G., M.D.), University Hospital, LMU Munich, Germany.
Insights
Genetic analysis reveals that cardiac traits, beyond atrial fibrillation, do not significantly increase stroke risk. Careful control for confounding factors is crucial when studying cardiac risk factors for stroke.
Area of Science:
- Cardiovascular Research
- Genetics
- Neurology
Background:
- Observational studies link cardiac traits to stroke, but causality is debated.
- Atrial fibrillation is the primary source of cardioembolic stroke.
- Investigating non-atrial fibrillation cardiac traits' role in stroke is essential.
Purpose of the Study:
- To systematically assess associations between 66 cardiac traits and stroke risk using genetic data.
- To determine the causal role of various cardiac conditions in stroke pathogenesis.
- To clarify the relationship between cardiac traits and stroke subtypes.
Main Methods:
- Employed a 2-sample Mendelian Randomization approach.
- Analyzed genetic predisposition for 66 cardiac traits against stroke risk in the MEGASTROKE consortium.
- Utilized multivariable Mendelian Randomization to adjust for atrial fibrillation, coronary artery disease, and systolic blood pressure.
Main Results:
- Confirmed strong associations between atrial fibrillation and cardioembolic stroke, and coronary artery disease and large-artery stroke.
- Observed associations between heart failure/lower heart rate and stroke, but these were explained by confounders.
- Found an inverse association between genetically predicted P-wave terminal force (atrial cardiopathy marker) and large-artery stroke.
Conclusions:
- Genetic evidence does not support significant causal effects of cardiac traits on stroke risk beyond established factors.
- Highlights the importance of controlling for confounding and bias in stroke risk factor research.
- Further research is needed to fully understand the complex interplay between cardiac health and stroke.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
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