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Sleep Apnea: Why Should We Look for Cardiac Biomarkers?

Published Online:https://doi.org/10.5664/jcsm.27928Cited by:1

INTRODUCTION

The estimated prevalence of obstructive sleep apnea (OSA) syndrome, defined by an apnea-hypopnea index (AHI) > 5 events/h determined by full polysomnography plus symptoms of excessive daytime sleepiness, in the Wisconsin cohort was 2% to 4%.1 When the presence of excessive daytime sleepiness was not required for definition, the prevalence of OSA leaped to 9% and 24%, respectively.1 Therefore, only one in approximately 5 subjects with an elevated AHI in the general population complains of excessive daytime symptoms. Among consecutive patients with systolic heart failure,2 stroke,3 hypertension,4 implanted pacemakers,5 and metabolic syndrome,6 the association between OSA and excessive daytime sleepiness is weak or non-existent. Therefore, contrary to the clinical perception based on patients referred to sleep centers, the absence of excessive daytime sleepiness among patients with OSA seems to be the rule and not the exception. Another reality that must be faced by the field is that OSA is probably much more common than initially imagined. One recent study that evaluated by full polysomnography a representative adult population (1,042 subjects) of the city of São Paulo, Brazil, found that the prevalence of OSA syndrome was 32.8%.7 The high prevalence may be explained by the use of new sensitive technologies to detect respiratory events (nasal pressure cannula) and the adoption of the most recent American Academy of Sleep Medicine criteria for OSA syndrome diagnosis (i.e., AHI > 5 + symptoms plus AHI > 15 events/h, independent of symptoms).8 The question raised is: what are the reasons for treating a patient with OSA when symptoms are not present? In this context, biomarkers could help to determine the systemic repercussions of OSA, stratify risk, and provide treatment guidelines. Biomarkers could also be a useful tool for the diagnosis of OSA, particularly because sleep studies are expensive and laborious. According to a standard definition, a biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.9 The search for a biomarker directs us to the first question. What are the reasons for treating a non-sleepy patient with OSA?

OSA is independently associated with hypertension, heart remodeling, atrial fibrillation, atherosclerosis, coronary artery disease, stroke, and risk for development of congestive heart failure.10 At least 4 distinct cohorts drawn from patients referred to a sleep laboratory in Spain,11 from the general population in Winsconsin,12 Busselton (Australia),13 and the Sleep Heart Health Study14 showed very consistently that severe OSA is independently associated with risk of future cardiovascular death, mainly due to stroke and coronary artery disease. There is also evidence that treating severe OSA with continuous positive airway pressure (CPAP) reduces the cardiovascular risk.11 Therefore, it is possible to argue that all patients with severe OSA should be treated. It must be stressed however that most studies reported so far are observational in nature. The field needs proper randomized studies in order to make a strong point and convince the cardiovascular community that treatment of OSA is able to decrease mortality. To this regard, studies such as the Sleep Apnea Cardiovascular Endpoints Study (SAVE) are a good example on how the field is rapidly maturing. The SAVE is a global initiative that will address the question whether CPAP reduces mortality in patients with high cardiovascular risk and OSA.

The second question that deserves close attention is that some studies have suggested that the beneficial effects of CPAP on the cardiovascular system are not observed in non-sleepy patients. On the other hand, there are several studies that do not support this hypothesis. One recent large multicenter randomized trial in Spain showed a small but significant fall in blood pressure after CPAP treatment in non-sleepy patients with severe OSA.15 Kohler and colleagues found endothelial dysfunction in patients with OSA that were minimally symptomatic.16 In another study that evaluated consecutive patients with metabolic syndrome, OSA was associated with increased markers of atherosclerosis independent of the presence or absence of excessive daytime sleepiness.6 Finally, there was no association between symptoms of excessive daytime sleepiness and the risk of future cardiovascular death in the Wisconsin sleep cohort.12

Therefore, despite some controversies highlighted above, there is reasonable evidence that the cardiovascular system is the primary target of OSA.17 Answering the question raised above, a cardiac biomarker could be used in clinical practice, providing additional support to identify subgroups of patients with OSA and higher cardiovascular risk, even in the absence of symptoms. This practice is relatively common in the cardiology setting. For instance, patients with atherosclerosis are at high risk of future cardiovascular events and should receive treatment designed to achieve aggressive reduction of low-density lipoprotein cholesterol.18 Biomarkers in patients with OSA must reflect the pathways linking OSA to the cardiovascular system. The potential candidates are multiple and include markers of sympathetic nervous system activation, oxidative stress, systemic inflammation, metabolic alterations, platelet activation, vascular endothelial function impairment, and arterial remodeling.10 It is also possible that the cardiovascular risk attributed to OSA will be influenced by genetic factors. The ideal biomarker should be also readily available in clinical practice, reproducible in different centers and be an accurate marker of future cardiovascular complications.

The search for biomarkers related to OSA and the cardiovascular system is already beginning. For instance, C-reactive protein is a marker of system inflammation that has been widely used as biomarker for future cardiovascular events.19 C-reactive protein is also independently associated with OSA20 and declines after OSA treatment.21 Unfortunately, the utility of C-reactive protein has been challenged from both the sleep and the cardiovascular field. The association between OSA and elevated C-reactive protein in clinical practice may be largely confounded by the effects of obesity on systemic inflammation.22 One recent study showed that C-reactive protein was not a good marker of future cardiovascular risk.23

On the other side of the spectrum, surrogate markers of atherosclerosis such as pulse wave velocity and carotid intima media thickness could be useful. These are robust and independent markers of future cardiovascular events24,25 and are also tightly linked to OSA.6,21 However, most of these measurements are not readily available in clinical practice and are restricted to research centers. One recent study in children studied urinary proteome in a group of children with and without OSA and showed that proteins such as uromodulin and kallikrein presented good sensitivity and specificity for the diagnosis of OSA.26 These are promising biomarkers that may help to diagnosis children with OSA. It is also possible to speculate that similar approaches are also possible in adults.

In conclusion, there is a strong rationale to support the concept that the cardiovascular system is the primary target of OSA. A number of patients with OSA are not aware of their disease and are not sleepy. These patients will raise 2 questions from their healthcare practioner:

  1. How much are alterations in my sleep pattern affecting my cardiovascular system?

  2. How much my will cardiovascular system benefit from treatment?

A cardiac biomarker may help to answer these questions. Any new candidate will need to be carefully studied before widespread clinical practice. Meanwhile, it is a reasonable clinical practice to consider that patient with OSA, even if not sleepy, are at high risk of future cardiovascular events.

DISCLOSURE STATEMENT

This was not an industry supported study. The authors have indicated no conflicts of interest or off-label or investigational drug use.

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