What Links Obstructive Sleep Apnea to Cardiovascular Risk?

The link between obstructive sleep apnea (OSA) and cardiovascular risk is highly evidenced, but an underlying question eludes clinicians: is one condition causative of the other, or is this a confounding association?

A review of the evidence, mechanisms, and strategies for assessing impact of treating OSA and cardiovascular disease was provided during The Metabolic Institute of America’s (TMIOA) 2021 Heart in Diabetes sessions in New York, NY this weekend, by Henry Klar Yaggi, MD, MPH, Professor of Medicine and Director of the Yale Centers for Sleep Medicine at Yale School of Medicine.

As Yaggi explained, sleep apnea is an upper airway condition which features abnormal hypoxia that occurs as continuous events throughout a patient’s night. Patients progress from sleep to apnea/hypopnea, to hypoxia then arousal.

Some of this phenomenon carries over into the day, Yaggi suggested, as patients with OSA are at a significantly increased risk of developing systemic hypertension.

The Sleep Heart Health Study, a 20-year old, cross-sectional assessment of 6424 community-based participants, found that patients with higher-quartile OSA disease severity were at significantly increased relative risk of stroke and cardiovascular disease development.

These findings, however, do not distinguish whether the association is causative or confounding—nor do the findings from Yaggi’s colleagues at Yale, who conducted an observational cohort analysis of patients with and without OSA and no history of relevant cardiovascular events (myocardial infarction or stroke) in a sleep study.

The team found that patients with OSA were at significantly increased risk of transient ischemic attack (TIA), stroke, or all-cause death than patients without OSA in both unadjusted (hazard ratio [HR], 2.24; 95% CI, 1.30 - 3.86) and adjusted (HR, 1.97; 1.12 - 3.28) factors.

“All these observed associations imply a mechanism, which is believed to be due to the pathophysiology of obstructive sleep apnea-association sleep events,” Yaggi said.

A litany of OSA mechanistic factors could be causative or implicative of cardiovascular risk, Yaggi said:

• Intermittent hypoxia, in which “repetitive episodes of hypoxia and re-oxygenation that recurs could drive endothelial dysfunction.”
• Nocturnal sympathetic activation, in which obstructive respiratory events from OSA surges a patient’s blood pressure levels continuously throughout the night.
• The mechanical load in sleep apnea, which comes from an increase in transmural pressure, and decreases in cardiac output and cerebral blood flow.

What’s more, research has shown association between OSA and cardiometabolic disease. Restricted sleep associated with sleep apnea is also linked to the characteristics of “prediabetic state,” Yaggi explained. Epidemiologic studies have linked short sleep duration and shortened sleep breathing to increased risk of type 2 diabetes development. And clinical trials for SGLT2 inhibitors including ertugliflozin and empagliflozin have shown the agents are associated with an approximately halved incidence of OSA in treated patients.

Despite these promising developments of understanding, recommended OSA therapy remains consistent: continuous positive airway pressure (CPAP) treatment is associated with significantly improved symptoms, bettered quality of life, and positive influence on patient ability to operate a vehicle, among other daily needs.

Yaggi noted that both fatal and nonfatal cardiovascular outcomes in patients with OSA are more likely in instances of severe, untreated sleep apnea. However, he challenged the conclusion that this means CPAP therapy benefits cardiovascular outcomes; CPAP adherence is a major challenge in OSA, and those who adhere to it may also be leading healthier lifestyles that benefit cardiovascular risk reduction, Yaggi said.

“But many of the randomized, controlled trials—and we are in our infancy in obstructive sleep apnea research—have shown consistent dose-dependent responses to cardiovascular outcomes with CPAP,” he said.

That said, long-term clinical trials examining cardiovascular endpoints in sleep apnea patients using CPAP are difficult to conduct.

For one, the field is already equipped with pharmacological agents that treat the causal biologic pathways linking OSA and cardiovascular disease. Additionally, treatment adherence with CPAP is generally inconsistent among patients, OSA is heterogeneous disease, and safety considerations over equipoise (inducing risk of drowsiness-related accidents, among other outcomes, in controlled OSA patients).

“Long-term randomized controlled trials are just getting underway in our field,” Yaggi concluded. “(Excessively sleepy patients) are who we really need to be targeting, in terms of showing benefit of treating sleep apnea with CPAP.”