Background and rationale {6a}
Obstructive Sleep Apnea (OSA) and Cardiovascular Disease
In meta-analysis, the prevalence of sleep apnea in the general adult population ranges from 6–17%, reaching 49% at advanced ages. In a Brazilian epidemiological study, OSA affected 80 to 95% of the elderly. The most damaging consequence of OSA is an increase in cardiovascular morbidity and mortality. Cardiovascular diseases are responsible for 20% of deaths of Brazilians over 30 years old and lead to increased morbidity and mortality in over 30% of the elderly. Prospective population studies have shown that individuals with severe untreated sleep apnea have a higher risk of general and cardiovascular mortality, independent of traditional cardiovascular risk factors. Apnea patients, compared to the general population, are twice as likely to have hypertension, ischemic heart disease and cerebrovascular disease. In 2004, the National Heart, Lung, and Blood Institute committee proposed lines of research to enlighten the consequences of sleep disorders in heart disease. In 2008, the American Heart Association and the American College of Cardiology published a consensus indicating the need for researches like ours that addresses the major cardiovascular consequences of sleep apnea. The main reasons why sleep apnea is associated with cardiovascular diseases are the periods of intermittent hypoxia and the repeated nocturnal awakenings precipitated by apneas. Apnea occurs when anatomical and / or functional changes in the airway, associated with loss of tone in the pharyngeal dilator muscles during sleep, lead to airway collapse and interruption of airflow. Nighttime awakenings cause chronic sympathetic hyperactivity and intermittent hypoxia causes oxidative stress, which causes inflammation, the onset of endothelial dysfunction and, later, atherosclerosis. The association between coronary artery disease and sleep apnea appears to be consistent. In a cross-sectional analysis of the Sleep Heart Health Study cohort, individuals in the highest quartile of apnea-hypopnea index present a 27% risk increase for coronary artery disease. Sleep apnea increases the chance of having ischemic heart disease by 65% and having a heart attack by 71%. Our group demonstrated that sleep apnea is a more robust risk factor for coronary artery disease than classic factors such as cholesterol, in a sample excluding morbidly obese, diabetic and smokers.
Endothelial Function
The endothelium, by isolated area, is one of the largest organs in the body, composed of trillions of cells, weighing more than 1 kg and covering almost 3m² in a 70 kg adult male. It interacts with multiple systems and has been implicated in the pathogenesis of neurological, renal, liver, vascular, dermatological, immunological and cardiovascular diseases. It is a highly specialized tissue, responsible for vascular homeostasis through the regulation of arteriolar tone, platelet aggregation, smooth muscle cell growth and leukocyte adhesion. The endothelium regulates the vascular tone through the secretion vasodilator, such as nitric oxide (NO) and vasoconstrictors such as endothelin. Damage to the endothelium and dysfunction of this tissue are associated with the development of arterial hypertension and atherosclerosis. There are many molecular and cellular mechanisms involved with endothelial damage and vascular aging. Since inflammation and oxidative stress are part of these mechanisms, tackling with these two processes can be considered as future therapeutic targets for the prevention of cardiovascular disease. A review article on the topic states that a greater understanding of endothelial function provides not only a grasp of the pathophysiology of cardiovascular disease, but also an opportunity for clinical treatment, early detection of diseases, stratification of cardiovascular risk and evaluation of therapeutic response.
Flow-Mediated Dilatation of the Brachial Artery
The assessment of flow-mediated dilation (FMD) was first introduced in the 1990s as a non-invasive approach to examining vasodilator function in vivo. The FMD result quantifies the endothelium-dependent arterial function mediated by nitric oxide, being used as an indirect marker of vascular health. A meta-analysis that included 32 studies and 15,000 individuals concluded that the FMD result is an independent predictor of cardiovascular event and death. Each 1% dilation increase in the FMD result was associated with a 10% lower risk of cardiovascular event or death. In that study, the predictive effect of brachial FMD was more substantial for cardiovascular mortality than for general mortality, suggesting that impaired endothelial function is predominantly a cardiovascular risk factor.
The method has limitations that must be considered. Small changes in the methodological approach can critically influence results and decrease the exam reproducibility. Therefore, the compliance of guidelines with updated and standardized methodology is indicated to reduce measurement errors and improve FMD reliability in clinical studies.
Peripheral Arterial Tonometry
Peripheral arterial tonometry (PAT) is a non-invasive method of assessing endothelial function in clinical practice. The method was incorporated into several population and multicenter studies, such as the Framingham Heart Study. The results are based on digital pulse amplitude variation during reactive hyperemia induced by a 5-minute forearm cuff occlusion. It is operator/interpreter independent and provide immediate results, which are advantages compared to FMD. The reactive hyperemia index (RHI) obtained by PAT is considered to correlate significantly with coronary endothelial function. PAT is a predictor of cardiovascular risk in high-risk patients, according to several authors.− The method also has good reproducibility, according to studies by Brant et al and Reisner et al. In two large population studies, totaling more than 10,000 participants, there is only a modest correlation between FMD and PAT., Therefore, both methods will be used in this study, in order to quantify aspects of both macro and microvascular circulation and compare the two methods.
Endothelial Function and Obstructive Sleep Apnea
Sleep apnea is related to systemic inflammation, oxidative stress and endothelial dysfunction., These factors are protagonists in the process that leads patients with sleep apnea to develop cardiovascular disease. The association between endothelial dysfunction and sleep apnea was initially considered ambiguous because there are numerous common features among patients with endothelial dysfunction and sleep apnea. Age, obesity, smoking and alcohol consumption were factors cited as potential causes of the two conditions, confusing a possible cause-effect relationship. A meta-analysis by Wang et al concluded that moderate / severe sleep apnea was significantly associated with endothelial dysfunction, increased arterial stiffness and increased serum levels of inflammatory markers. The meta-regression data suggest that the adverse effect of moderate-severe sleep apnea on endothelial function is not modified by potential confounders, such as body mass index. Cross-sectional analyses of population studies and case-control studies consistently demonstrated an association between obstructive sleep apnea and impaired endothelium-dependent vasodilation. In-vitro experiments demonstrate that the serum of patients with sleep apnea impairs the migration of coronary endothelial cells. Our group published studies demonstrating that intermittent hypoxia causes oxidative stress, inflammation and damage to lipids and proteins.
Hydroxychloroquine
The hydroxychloroquine was initially an antimalarial drug. Due to its anti-inflammatory properties, it is commonly used to treat rheumatic diseases, in particular rheumatoid arthritis and connective tissue diseases such as systemic lupus erythematous. HCQ reduces the activation of the innate immunity system by inhibiting the stimulation of Toll-like receptors, which can play an important role in the activation of inflammatory cells in atherosclerotic patients. Some studies suggest that hydroxychloroquine also reduces the production of cytokines important in the pathogenesis of atherosclerosis, such as interleukin-1 and 6 and tumor necrosis factor alpha (TNF-α). , TNF-α block therapy was associated to a risk reduction of coronary artery disease among patients with rheumatoid arthritis.
In addition to its anti-inflammatory effects, HCQ has other properties that may be beneficial in the treatment of coronary artery disease. In patients with lupus, chloroquine inhibits the synthesis of several members of the matrix metalloproteinase family, especially MMP-9, enzymes capable of degrading interstitial collagen in the fibrotic layer of the atherosclerotic plaque.
Cohort studies have shown that HCQ lowers cholesterol in patients with lupus and rheumatoid arthritis.− In addition, in rheumatoid arthritis, the use of HCQ has been associated with a lower incidence of type 2 diabetes−, lower levels of glycosylated hemoglobin (HbA1c) and better sensitivity to insulin and beta cell function. In two randomized studies of diabetics with inadequate glycemic control, HCQ significantly reduced glucose levels. ,
In addition, HCQ may have antithrombotic properties. , In mice, HCQ reduced the size and duration of the thrombus, and caused a decrease in the thickness of the vascular wall and progression of atherosclerosis., In a case-control study, among patients with lupus, the use of HCQ was associated with a reduced risk of thromboembolic complications.
Sharma et al. reported in a retrospective study involving 1266 patients with rheumatoid arthritis an association between HCQ use and a 72% reduction risk of an outcome composed of acute coronary syndrome, cardiac revascularization, stroke, transient ischemic accident, peripheral arterial disease and sudden death.
Evidences from studies in patients with rheumatic diseases converges to a role for HCQ in reducing cardiovascular risk. However, its cardiovascular effects in patients at higher cardiovascular risk but without rheumatic diseases is unknown.
Some common side effects of hydroxychloroquine, occurring in 1–10% of users, include anorexia, emotional labiality, headache, blurred vision, abdominal pain, nausea, rash and itching. Rarely, in 0.1-1% of high-dose users, Stevens-Johnson syndrome, cardiomyopathy and retinopathy may occur.
Overall
Considering that sleep apnea is a chronic disease with an inflammatory component, as well as rheumatic conditions, HCQ, due to its favorable effects in the reduction of several cardiovascular risk factors, may improve endothelial dysfunction associated with sleep apnea.
Considering the low cost of HCQ, the high prevalence of sleep apnea in the elderly and the high morbidity and mortality of cardiovascular diseases, the search for feasible approaches in primary care that can reduce these outcomes is justified. Thus, the use of HCQ in patients with sleep apnea and at high risk for coronary artery disease represents an entirely new approach to this disease.