More than 18 million adults have sleep apnea, particularly adults with established cardiovascular disease. The characteristic intermittent pauses in breathing not only result in a frustrating loss of sleep for patients, but the condition is potentially life-threatening. Apnea commonly occurs with hypertension, arrhythmia, stroke, and heart failure, and there is an increasing perception that sleep apneas increase CV morbidity and mortality. CardioSource WorldNews Editor-in-Chief Christopher P. Cannon, MD, spoke with Christopher O'Connor, MD, director of the Duke Heart Center and editor-in-chief of JACC: Heart Failure, about the interactions between sleep apnea and CVD, the prevalence of these comorbidities, and how sleep and heart specialists can work together to treat these conditions.

Christopher Cannon, MD: Chris, obstructive sleep apnea is something that we see in cardiology all the time and I think now we're recognizing that it's a real disease that deserves our attention. It's not just the frustration of waking up at night or bothering a spouse with snoring—it has real consequences.

I think there's been an explosion in research for this disease. Our first goal is to more fully understand its epidemiology; from there, we can, hopefully, move towards better treatment. From the experiences in my office, it seems like this is a pretty prevalent disease, but, Chris, can you explain what the real numbers look like?

Christopher O'Connor, MD: For a long time, I think most cardiologists have probably shoved apnea to the sidelines in terms of their approach to cardiovascular patients. Now we're finally getting studies going, and with that comes a better understanding of the epidemiology of this condition.

It turns out sleep apnea affects about 50% of patients with cardiovascular disease. The data show a pretty strong association—if you have it, you have an increased cardiovascular risk. And, like many things in cardiology, what we don't have enough data on yet is how reducing risk will translate into reduction in cardiovascular events.

Although those trials are ongoing now and fairly far advanced, I think we probably should take a step back and say, "What is sleep apnea?" Most of us ask patients about their symptoms, like snoring or excessive daytime sleepiness, but, like sleep doctors, we quantify this as a condition with repeated apnea or hypopnea spells. Apnea is defined as a complete absence of airflow for more than 10 seconds, and hypopnea is defined as a 50% reduction. So, when you do these polygraphic sleep studies, the sleep community uses the apnea-hypopnea index, or the AHI. It sounds complicated but...

Dr. Cannon: It could be like a TIMI risk score!

Dr. O'Connor: Right, sort of like a "TIMI breath score." If you cross a threshold of five of these events per hour—some people use 10—then you do have what would be defined as sleep apnea.

The amount of hypoxemia, measured by the oxygen desaturation index, as well as the time spent below 90% O2 saturation are important risk markers.

The clinical symptoms like daytime sleepiness are also very important, but much less frequent in patients with cardiovascular disease than in "normal" obstructive sleep apnea patients. Physicians should also ask about choking or gasping during sleep; whether the patient awakens recurrently during sleep or has frequent nocturia; or if they experience morning headaches, significant daytime fatigue, or impaired concentration. These are more subtle findings, but not any less serious. It's absolutely clear that if you have sleep apnea with excessive daytime sleepiness, you're at risk not only for cardiovascular events, but also for personal injury.

Dr. Cannon: Now, how much of the diagnosis needs to come from a spouse or partner observing sleep patterns versus from the patient? I mean, would we be asking the patient or do you need the spouse to say, "Oh, he stops breathing," or "He has been a little off lately in terms of his mental activity."

Dr. O'Connor: That's a very good point. When I have patients in the clinic who are widows or live by themselves, they obviously don't know that they snore. Interestingly, though, I have one physician who I told to go ahead and set his iPhone recorder on before he goes to sleep, and he did actually realize he was snoring all night long. So, modern technology can help with diagnosis.

What I look for, as well, is a collar size or a shirt size that's great than 16. Few people ask that question, but it is a good place to start. In your clinic, you'll start noticing a lot of larger neck sizes, and think to yourself, "You know, I bet the probability here is pretty good that there will be some abnormalities." We shouldn't forget, though, that about one-third of the patients suffering from sleep-disordered breathing are lean and micrognathia can be an important clinical sign.

Dr. Cannon: When you see that combination in patients, are those the patients that you typically refer to sleep study?

Dr. O'Connor: Generally, yes. If they have a spouse, I'll give the details of their sleep, or "sleep architecture" as the sleep doctors call it; if they're a singular person, I do recommend a sleep study. What's happening now, Chris, is that there's more interest in ambulatory sleep monitors, somewhat like a Holter monitor, which don't require patients to spend a whole night in a sleep lab doing diagnostics. I think that's going to change the whole field for cardiologists.

Dr. Cannon: What is that monitor?

Dr. O'Connor: It's a monitor that will measure respiratory flow and effort and O2 saturation. Based on these data it will then give an evaluation of any apnea or hypopnea events. The correlation with the results from a formal polysomnography study has been pretty good. The formal study is quite expensive and, frankly, hard to arrange for many busy cardiologists, so it tends not to get done at the busy clinic.

Dr. Cannon: So, when we get the diagnosis of obstructive sleep apnea, what is the pathophysiology, then? Is the thick neck obstructing airflow, or is it related to the brain becoming hypoxic and, hence, not functioning right?

Dr. O'Connor: You've hit on a really important component of the pathophysiology, and that is there are two types of sleep apnea: obstructive sleep apnea, which is the obstruction to airflow; and central sleep apnea, which we see commonly in heart failure patients. In central sleep apnea, there is an impaired neural output to respiratory muscle movement, which leads to impaired ventilation in that pathway.

Dr. Cannon: Speaking of hypoxia, are there biomarkers, such as inflammation, that seem to be part of oxidative stress? Is it possible to measure biomarkers before and after treatment?

Dr. O'Connor: You can, and I think, in both obstructive and central sleep apnea, there is what I would call a cascade of adverse inflammatory, neurohormonal, sympathetic nervous system, metabolic, and mechanical processes that occur. This is particularly relevant for heart failure patients: their bursts of sympathetic activity can induce hypertrophy, arrhythmias, and death. Sudden death, in particular, is significantly associated with sleep apnea.

Greater sympathetic activation could be one of the mechanisms of this association, but there are definitely others. In the coronary arteries, hypoxia can induce oxidative stress in inflammatory pathways, and also seems to play a role in the field of dysfunction, based on the frequent desaturation that occurs.

Small studies have shown that, in terms of biomarkers, the N-terminal prohormone of brain natriuretic peptide (NT-proBNP) can be reduced significantly with treatment, but generally there's not as much sophisticated biomarker research as we've seen in other fields, although it is certainly emerging.

In terms of treatment, this is a very big issue for the heart failure population, where both types of apnea are common. However, the most common treatment available now is CPAP, or continuous positive airway pressure, which treats obstructive sleep apnea. One emerging new strategy—adaptive servo-ventilation—is designed to address obstructive sleep apnea as well as central sleep apnea.

So, what we have is CPAP for obstructive sleep apnea that addresses the patency of the upper airway, and adaptive-servo ventilation that stabilizes ventilation to eliminate central sleep apnea. This method of attacking both parts of the breathing cycle allows us to achieve normalization of sleep more efficiently.

Dr. Cannon: Are devices and studies supporting the use of this new strategy available now?

Dr. O'Connor: These things are available now, but the big trial we're all waiting for is called SERVE-HF. It's an approximately 1,300-patient study of heart failure and predominantly central sleep apnea being run in Germany, the UK, France, and other mostly Western European countries. In this event-driven trial, patients are randomized to either adaptive servo-ventilation or usual care. The events being looked at are heart failure hospitalization plus death.

Most of the studies in this field have only had a population of 50–100 patients. These studies show improvement in ejection fraction, quality of life, sleep performance, 6-minute walk—all of which are surrogate endpoints. SERVE-HF, on the other hand, is going to be the real clinical trial. It's just about to finish enrollment and will provide outcome data in about 2 years of further follow-up.

Few of these small studies of patients with coronary disease and obstructive sleep apnea, which compare CPAP with no treatment, are well-powered, but they do show signals of an improvement in risk. We've seen signals of non-sustained VT reduction, improvements in 6-minute walk test performance, increase in cognitive function, and other intermediate endpoints.

What's needed next is the funding to perform larger trials. The biggest obstructive sleep apnea study so far randomized about 750 patients; it was unable to show a significant risk reduction in the intention-to-treat analysis, but only in the on-treatment analysis.

The largest trial to date in central sleep apnea was the CANPAP trial, or the Canadian Positive Airway Pressure Trial for Heart Failure. It was stopped after having included 258 patients with heart failure who showed substantial improvement in surrogate endpoints at about 5 years. The study was under-powered to demonstrate a reduction in mortality, but, interestingly, the investigators recognized that CPAP alone was unsuccessful in suppressing all the apnea and hypopnea events. Maybe only half of the respiratory events were being addressed, so it was sort of a partial treatment. The development of this new adaptive servo-ventilation technology should address this issue, since it is currently the most effective treatment in controlling central sleep apnea.

Dr. Cannon: This is an exciting finding: it has demonstrated some benefit, but also opened the door to further benefits. I have to admit I haven't really thought about recommending CPAP to reduce events; I've tended to focus on using it to relieve patient discomfort, but this could help people in this high-risk patient population live longer. I suppose we'll wait for the trials to really try and demonstrate that.

Dr. O'Connor: Absolutely, and the other thing that I've omitted from my practice for years until I got more deeply involved in this field, is the relationship to atrial fibrillation. When a patient has atrial fibrillation, we ask, "Why did he develop atrial fibrillation already?" Often, I see risk factors for sleep apnea. I can treat it and then say, "Now we have an opportunity to control this." I think there's a real future here to keep investigating and raising awareness in this field.

Dr. Cannon: It does seem that a lot of the factors that improve outcomes, then, could also improve development of atrial fibrillation. That's becoming sort of the new epidemic amongst the elderly.

Well, thank you very much for joining this conversation, and we've definitely learned a lot that we can apply to our practices. Certainly, I'll be keeping an eye out for these ambulatory monitors, which will make testing, and then developing and delivering treatments, more widely accessible.

Dr. O'Connor: Thank you, Chris.

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DISCLOSURES: This program was sponsored by and developed in conjunction with ResMed. Dr. O'Connor reports having received research grants from ResMed. Dr. Cannon reports no relevant disclosures.

Keywords: Comorbidity, Risk Factors, Sleep Apnea Syndromes, Awareness, Prevalence, Biomarkers, Quality of Life, Attention, Continuous Positive Airway Pressure, Peptide Fragments, Cardiovascular Diseases, Atrial Fibrillation, Respiration, Natriuretic Peptide, Brain

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