Genes Bolster Case for Link Between Insomnia and CV Risk

The link between insomnia and cardiovascular disease likely has an underlying physiologic mechanism, according to a novel study that combined analyses on the genetic predisposition to insomnia with large cardiovascular-outcome databases.

The findings, published online August 19, 2019, ahead of print as a research letter in Circulation, highlight the need to address sleep issues in order to minimize cardiovascular risk.

“Conventional observational studies had shown that self-reported insomnia is associated with an increased risk of cardiovascular disease,” lead author Susanna C. Larsson, PhD (Karolinska Institute, Stockholm, Sweden), told TCTMD in an email. “However, such studies cannot determine whether insomnia causes cardiovascular disease or are merely associated with it. Thus, there was a need for a study like this, based on genetics, to determine whether the association between insomnia and cardiovascular disease is likely to be causal.”

Larsson and her team used available information on the genetic associations with coronary artery disease, heart failure, atrial fibrillation, and stroke from four public outcome datasets: the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus The Coronary Artery Disease Genetics consortium, the UK Biobank, the Atrial Fibrillation Consortium, and the MEGASTROKE consortium. Together, these databases comprised more than 1.6 million participants, most of European descent.

It was not possible to determine whether patients in these data sets actually experienced insomnia, so the investigators relied on genetic susceptibility to insomnia as a proxy. They identified single-nucleotide polymorphisms (SNPs) associated with insomnia complaints at genome-wide significance (P < 5x10^-8) in a meta-analysis of genome-wide association studies that included more than 1.3 million individuals. In total, 243 SNPs were included in the analyses of coronary artery disease, 246 in the analyses of heart failure and atrial fibrillation, and 244 in the analyses of ischemic stroke.

A unique feature of the study was the use of mendelian randomization (MR), which employs genetic variants associated with a particular risk factor (in this case, insomnia) to determine whether that risk factor is actually a cause of the disease (eg, cardiovascular disease). The risk of confounding by environmental factors is reduced because alleles are randomly allocated when passed from one generation to another. Since the presence of disease does not affect genotype, there is no reverse causation bias.

In the standard MR analysis that corrected for multiple testing, genetic liability to insomnia was associated with significantly higher odds of coronary artery disease, heart failure, and ischemic stroke but not of atrial fibrillation. These same patterns remained after multivariate analysis controlled for smoking, depression, and education, all of which are known to be genetically correlated with insomnia. They also did not change following the use of additional statistical techniques, with no evidence of directional pleiotropy.

Association Between Genetic Liability to Insomnia and CV Outcomes

* Significance was defined as ≤ 0.007 to account for multiple comparisons.

With respect to stroke outcomes in particular, genetic liability to insomnia was primarily linked with large-artery stroke (OR 1.13; 95% CI 1.03-1.24; P = 0.01), with only trends toward associations with small-vessel stroke (OR 1.08; 95% CI 0.99-1.17; P = 0.08) and cardioembolic stroke (OR 1.06; 95% CI 0.99-1.14; P = 0.08)

Larsson emphasized that the study does not provide information on the physiologic mechanisms that may link insomnia and cardiovascular disease. She pointed out, however, that “previous studies have shown that insomnia may lead to increased body weight, diabetes, and high blood pressure, all of which are risk factors for coronary artery disease, heart failure, and stroke. “

Manage Sleep to Mitigate Cardiovascular Risk

To this, Nieca Goldberg, MD (NYU Center for Women's Health, New York, NY), added that lack of sleep leads to increases in level of stress hormones such as cortisol and epinephrine. Goldberg, a spokesperson for the American Heart Association, noted that “studies have shown anywhere from 15% to 30% cardiovascular risk based on lack of sleep.”

The study, she continued, “is interesting in that they are taking a look at the genetic predisposition. . . . There are physiologic mechanisms that lead to it. It’s not just about saying someone is stressed and that’s why they can’t sleep.”

Goldberg emphasized that a key clinical message is that “sleep and sleep history are very important for clinicians to know.” Asking about sleep problems is becoming part of routine care in clinical cardiology, she said, but there is a need to increase awareness that this information is important to gather when assessing and managing patients’ cardiovascular risk. In the cardiovascular setting, patients who complain of difficulty getting or staying asleep, signs of sleep apnea—such as waking up with difficulty catching their breath, or palpitations, as well as hypertension that does not respond fully to multiple medication—should be referred to a sleep specialist, she recommended.