July 19, 2017

Proteomic Signatures Help Illuminate Links Between Sleep Apnea, Paroxysmal Afib

Studies find altered protein levels associated with inflammation, fibrosis

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Research at Cleveland Clinic exploring the relationship between obstructive sleep apnea (OSA) and paroxysmal atrial fibrillation (AF) has uncovered specific proteomic signatures — namely, blood proteins — indicating inflammation, fibrosis and oxidative stress in patients with both conditions. In addition, three months of treatment of OSA with continuous positive airway pressure (CPAP) therapy in patients with OSA and paroxysmal AF was associated with improved protein biomarker signatures.

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The novel series of investigations — presented at the American Thoracic Society’s (ATS) international conference in May 2017 — sheds new light on these two conditions and points to further directions for research in diagnostics and therapy.

“We already knew that obstructive sleep apnea is associated with atrial fibrillation, but the underlying mechanisms linking the two conditions are poorly understood,” explains lead investigator Reena Mehra, MD, MS, Director of Sleep Disorders Research in Cleveland Clinic’s Neurological Institute. “We found intriguing results that may help elucidate these mechanisms and lead us down a path to identify specific therapies to treat these conditions.” The work was a collaborative effort with functional atrial fibrillation genomics expert David Van Wagoner, PhD, and senior biostatistician John Barnard, PhD, both of Cleveland Clinic’s Lerner Research Institute.

Why the OSA-AF link matters

Previous epidemiologic studies have shown that AF is two to four times more common in patients with OSA than in the general population. Because of its sporadic nature, paroxysmal AF (defined as recurrent episodes of AF that self-terminate within seven days) is particularly difficult to diagnose. But as a precursor to continuous AF, the paroxysmal form is important to recognize: OSA-related AF is believed to have multiple negative consequences on the autonomic nervous system and on the heart’s structure and electrical system, leading to increased risk of stroke and permanent heart damage.

Proteomics — an emerging research tool

New technology in the field of proteomics allows rapid, unbiased identification and quantification of more than 1,000 proteins in a blood sample, enabling researchers to examine diseases in novel ways. Previous research by other investigators has separately observed upregulation of circulating pathologic biomarkers in patients with OSA and in patients with AF. The studies by Dr. Mehra’s team are the first to examine biomarkers in patients who have both conditions — and the first to analyze the effects of sleep apnea treatment on AF.

The studies involved rigorous phenotyping of paroxysmal AF and OSA, as well as standardized methods of blood collection — including the timing of sampling — which strengthen their findings, notes Dr. Mehra, who also has appointments in Cleveland Clinic’s Departments of Cardiovascular Medicine, Molecular Cardiology and Pulmonary Medicine.

The image at the top of this post shows a sample of the pathway and network analysis of protein associations used in this research.

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Biosignatures of OSA and paroxysmal AF revealed

The investigations involved aptamer-based proteomic studies using the SOMAscan® assay of 24 patients with paroxysmal AF and 24 patients without AF. Participants were predominantly male (63 percent), with a mean age of 61. The majority were obese. Subjects were categorized as having no OSA or having mild, moderate or severe OSA, defined by apnea-hypopnea index categories.

During a platform presentation of her findings at the ATS meeting, Dr. Mehra reported the following:

  • Relative to patients without paroxysmal AF, those with paroxysmal AF had altered levels of specific chemokines, interleukins, phospholipases and markers of fibrosis. Levels of some biomarkers correlated with degree of hypoxia and severity of OSA.
  • Among patients with paroxysmal AF, those with OSA had the same biosignature findings above while also having abnormal endothelial markers and lymphocyte activation markers relative to their counterparts without OSA.

“We believe we are seeing indicators of inflammation and oxidative stress in patients experiencing obstructive sleep apnea and paroxysmal atrial fibrillation,” says Dr. Mehra. “These biosignatures could one day help diagnose these conditions and serve as targets for developing and monitoring therapy.”

CPAP therapy alters biosignatures

Additional proteomics analysis was conducted on 12 participants with paroxysmal AF and OSA after three months of CPAP treatment. These subjects had the highest CPAP adherence in the earlier study.

Results showed that inflammatory biomarkers were quantitatively reduced from baseline levels after three months of therapy. Moreover, these reductions were accompanied by quantitative changes in (1) atrial and vascular remodeling proteins, (2) factors important to fibrosis development and (3) proteins implicated in thrombosis and stroke risk.

Next steps: Validate and extend

“The biomarkers we found are biologically plausible,” says Dr. Mehra, explaining that they could indicate pathological processes directly related to OSA and AF and might one day serve as excellent tools for diagnostics and disease monitoring or even as therapeutic targets.

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She cautions, however, that sample sizes were small and her team will need to continue their research to replicate, validate and refine the results. They also intend to investigate the relationship between protein profiles and ECG findings as well as echocardiographic left atrial structure in patients with paroxysmal AF and OSA.

The team anticipates publishing extended results in a full-length article next year.

“At this point, proteomic signature studies are discovery-based avenues of research,” Dr. Mehra adds. “They are especially important for generating new hypotheses for understanding these important conditions, with the goal of developing personalized medicine strategies based on biomarker predictors.”

Dr. Mehra is conducting this research with support of a grant from the National Heart, Lung, and Blood Institute.

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