Narcolepsy and Cardiovascular / Cardiometabolic Risk: Important Connections

Narcolepsy is a chronic neurological sleep disorder that is characterized by excessive daytime sleepiness, disturbed nighttime sleep, REM dysregulation, and short REM sleep latency. It is estimated that the number of people suffering from narcolepsy in the United States is 135,000 to 200,000, and it impacts one in every 2000 people.

Patients with narcolepsy may fall asleep suddenly and the period of sleep may last from a few seconds to as long as an hour or more. The symptoms of narcolepsy can include excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations, and automatic behaviors. Cataplexy is often triggered by laughter or surprise, and sometimes fright, anger, or being startled. The excessive daytime sleepiness is a consistent symptom in all patients with narcolepsy, with the other symptoms occurring in approximately 10% to 25% of patients. Patients may also experience lack of energy, fatigue, depression, visual problems, weakness, difficulty concentrating, eating binges, and less tolerance to alcohol.  These problems can affect daily activities as patients often fall asleep in the middle of an activity, such as driving, eating, or talking, and if not treated, can interfere with academic, social, and work activities by hindering cognitive, social, and psychological functioning.

Several cardiovascular and cardiometabolic comorbidities, including overweight/obesity, dyslipidemia, cardiovascular diseases, hypertension, and type 2 diabetes or insulin resistance, are common in patients with narcolepsy.  Often these disorders are overlooked, but they have important implications in the management of patients with narcolepsy.

Narcolepsy type 1 (NT1) is a disorder attributed to autoimmune destruction of orexin (hypocretin) neurons, leading to sleep-wake instability, REM dissociative symptoms, and cataplexy.  The pathways that connect orexin and orexin deficiency to cardiovascular and cardiometabolic risk are numerous and not fully elucidated, however, several mechanisms of association have been proposed.  Orexin deficiency is associated with increased food intake and reduced basal metabolic rate (BMR), thus increasing the risk of overweight and obesity.  In addition to the awake circuit, orexin also plays a role in control of autonomic tone and in the hypothalamic-pituitary-adrenal (HPA) axis, which plays an important role in the homeostasis, including the metabolic and cardiovascular systems.  In fact, the interrelationships between hypocretin deficiency, DNS (disrupted nighttime sleep), EDS (excessive daytime sleepiness), comorbidities, and cardiometabolic risk, are often complex, and as mentioned above, not fully elucidated.  At present, it is not clear whether narcolepsy type 2 (NT2) is also impacted by increased cardiometabolic risk. 

These hypotheses, often derived from preclinical research, are also supported by epidemiological data.  For example, obesity is common in both children and adults with narcolepsy, and weight increase may occur at time of onset of narcolepsy; in turn, obesity can predispose for several other cardiometabolic comorbidities as well as obstructive sleep apnea.  As such, narcolepsy patients are at increased risk for insulin resistance and diabetes, and cardiometabolic comorbidities, including type 2 diabetes, dyslipidemia, and hypertension are prevalent in these patients.  Given these risk factors, it is not surprising to find out that cardiovascular disease (including stroke, MI, coronary revascularization, heart failure, and cardiac arrest) is more common in patients with narcolepsy than those without, as shown in the BOND study, and that mortality rates in narcolepsy patients are estimated to be higher compared to those without narcolepsy.


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