LITHUANIAN UNIVERSITY OF HEALTH SCIENCES MEDICAL ACADEMY
Audrius Alonderis
SLEEP APNEA IN CORONARY ARTERY
DISEASE PATIENTS: PREVALENCE,
CROSS-SECTIONAL PREDICTORS,
ASSOCIATION WITH LEFT
VENTRICULAR MORPHOMETRY
AND FUNCTION
Doctoral Dissertation Biomedical Sciences, Medicine (06B) Kaunas, 2019Dissertation was prepared at the Behavioral Medicine Institute (from Janu-ary 1, 2018 Neuroscience Institute) of Medical Academy of Lithuanian Uni-versity of Health Sciences during the period of 2013–2019.
Dissertation is defended extramurally. Scientific consultant
Prof. Dr. Olivija Gustienė (Lithuanian University of Health Sciences, Medical Academy, Biomedical Sciences, Medicine – 06B).
Dissertation is defended at the Medical Research Council of the Lithua-nian University of Health Sciences:
Chairperson
Prof. Dr. Habil. Limas Kupčinskas (Lithuanian University of Health Sciences, Medical Academy, Biomedical Sciences, Medicine – 06B).
Members:
Prof. Dr. Skaidrius Miliauskas (Lithuanian University of Health Sciences, Medical Academy, Biomedical Sciences, Medicine – 06B);
Prof. Dr. Aras Puodžiukynas (Lithuanian University of Health Sciences, Medical Academy, Biomedical Sciences, Medicine – 06B);
Prof. Dr. Vytautas Kasiulevičius (Vilnius University, Biomedical Sciences, Medicine – 06B);
Dr. Gražina Urbonavičienė (Aarhus University, Biomedical Sciences, Medicine – 06B).
The dissertation will be defended at the open session of the Medical Research Council of the Lithuanian University of Health Sciences at 12:00 on the 16th of April 2019, in the auditorium of prof. J. Blužas of the Department of Cardiology, Lithuanian University of Health Sciences.
LIETUVOS SVEIKATOS MOKSLŲ UNIVERSITETAS MEDICINOS AKADEMIJA
Audrius Alonderis
MIEGO APNĖJA TARP SERGANČIŲJŲ
IŠEMINE ŠIRDIES LIGA:
DAŽNIS, SUSIJĘ VEIKSNIAI,
SĄSAJOS SU KAIRIOJO SKILVELIO
MORFOMETRIJOS IR FUNKCIJOS
RODIKLIAIS
Daktaro disertacija Biomedicinos mokslai, Medicina (06B) Kaunas, 2019Disertacija rengta 2013–2019 metais Lietuvos sveikatos mokslų universiteto Medicinos akademijos Elgesio medicinos institute (nuo 2018-01-01 Neuro-mokslų institutas)
Disertacija ginama eksternu. Mokslinė konsultantė
prof. dr. Olivija Gustienė (Lietuvos sveikatos mokslų universitetas, Medicinos akademija, biomedicinos moksla, medicinai – 06B).
Disertacija ginama Lietuvos sveikatos mokslų universiteto medicinos mokslo krypties taryboje:
Pirmininkas
prof. habil. dr. Limas Kupčinskas (Lietuvos sveikatos mokslų universite-tas, Medicinos akademija, biomedicinos mokslai, medicina – 06B).
Nariai:
prof. dr. Skaidrius Miliauskas (Lietuvos sveikatos mokslų universitetas, Medicinos akademija, biomedicinos mokslai, medicina – 06B);
prof. dr. Aras Puodžiukynas (Lietuvos sveikatos mokslų universitetas, Medicinos mokslai, biomedicinos mokslai, medicina – 06B);
prof. dr. Vytautas Kasiulevičius (Vilniaus universitetas, biomedicinos mokslai, medicina – 06B);
dr. Gražina Urbonavičienė (Aarhus universitetas, biomedicinos mokslai, medicina – 06B).
Disertacija ginama viešame medicinos mokslo krypties tarybos posėdyje 2019 m. balandžio 16 d. 12 val. Lietuvos sveikatos mokslų universiteto Kardiologijos klinikos prof. J. Blužo auditorijoje.
Disertacijos gynimo vietos adresas: Eivenių g. 2, LT-50161 Kaunas, Lietuva.
CONTENT
LIST OF ABBREVIATIONS ... 7
INTRODUCTION ... 9
1. THE PURPOSE OF THE STUDY ... 11
1.1. Objectives of the study ... 11
1.2. Statements of the hypotheses ... 11
1.3. Scientific novelty of the study ... 12
2. REVIEW OF LITERATURE... 13
2.1. Sleep apnea: disease definition and diagnosis, epidemiology ... 13
2.1.1. Definition ... 13
2.1.2. Diagnostic measures ... 15
2.1.3. Epidemiology, prevalences ... 17
2.1.4. The apnea hypopnea index ... 19
2.2. Clinical presentation, risk factors for sleep apnea... 20
2.2.1. Risk factors for sleep apnea ... 20
2.2.2. Roles of gender and age in sleep apnea ... 21
2.2.3. Sleep apnea and obesity ... 23
2.2.4. Sleep apnea and hypertension ... 24
2.2.5. Sleep apnea and race/ethnicity ... 25
2.2.6. Sleep apnea and alcohol use, smoking, heredity ... 26
2.3. Sleep-disordered breathing and cardiovascular disease ... 26
2.3.1. Mechanisms linking sleep apnea to chronic cardiovascular disease ... 27
2.3.2. Left ventricular morphometry and sleep apnea ... 31
2.3.3. Longitudinal association between sleep apnea and cardiovascular events ... 33
2.4. Cardiovascular manifestation of sleep disordered breathing ... 36
2.5. Lithuanian sleep research ... 36
2.6. Summary of the literature review ... 37
3. MATERIAL AND METHODS ... 40
Ethics... 40
3.1. Study population ... 40
3.1.1. Polysomnographic data by apnea–hypopnea index category... 45
3.2. Methods ... 46
3.3. Statistical analysis ... 51
3.4. Correlation analysis of clinical features in the database ... 53
4. RESULTS ... 55
4.1. Prevalence and predictors of sleep apnea in CAD patients ... 55
4.1.1. The distribution of clinical features from the data set ... 55
4.1.2. Demographic and clinical characteristics of the patients with and without sleep apnea according to cutoff AHI≥5 ... 57
4.1.3. Predictors of sleep apnea according to different cutoff of AHI ... 59
4.1.4. Assumed models for multivariate logistic regression ... 60
4.1.5. Gender differences ... 61
4.2. The association of sleep disordered breathing with left ventricular remodeling in CAD patients ... 64
4.2.1. Clinical, polysomnographic and echocardiographic characteristics according to sleep apnea severity ... 64
4.2.2. Distribution of left ventricular geometric patterns ... 69
4.3. Determinants of left ventricular hypertrophy in the CAD patients ... 71
4.3.1. Predictors of concentric left ventricular hypertrophy ... 71
4.4. Study II. Impact of sleep apnea on left ventricular mass ... 74
4.4.1. Factors associated with sleep apnea in patients with CAD with LV ejection fraction ≥50% ... 74
4.4.2. Association between age and left-ventricular diastolic function parameters in the patients with CAD according to presence sleep apnea ... 78
5. DISCUSSION ... 85
5.1. Study I. Prevalence and predictors of sleep apnea in patients with CAD ... 85
5.1.1. Summary of findings ... 85
5.1.2. Prevalence of sleep apnea ... 85
5.1.3. Clinical risk factors associated with sleep apnea ... 87
5.1.4. The burden of undiagnosed sleep apnea ... 89
5.2. Study I: The association of sleep disordered breathing with left ventricular morphometry in CAD patients ... 91
5.2.1. Summary of findings ... 91
5.2.2. The prevalence of sleep apnea in CAD patients ... 92
5.2.3. Cardiac remodeling in hypertension and obesity ... 93
5.2.4. Left ventricular geometry ... 94
5.3. Study II: Impact of sleep apnea on left ventricular mass and diastolic function parametersin patients with CAD with LV ejection fraction ≥50% ... 95
CONCLUSIONS ... 99
LIMITATIONS AND STRENGHTS OF THE STUDY ... 100
PRACTICAL RECOMMENDATIONS ... 102
REFERENCE LIST ... 103
PUBLICATIONS ON THE DISSERTATION THEME ... 124
SANTRAUKA ... 150
CURRICULUM VITAE ... 181
LIST OF ABBREVIATIONS
A – late (atrial) diastolic filling (A wave)AASM – American academy of sleep medicine ACS – acute coronary syndromes
AD – anno Domini
AHI – apnea hypopnea index AI – apnea index
ANOVA – analysis of variance
ASE – American Society of Echocardiography BC – before Christ
BMI – body mass index (weight in kg)/height in m2) BP – blood pressure
BSA – body surface area CAD – coronary artery disease CI – confidence interval
CPAP – continuous positive airway pressure CSA – central sleep apnea
CV – cardiovascular; CVD – CV disease
DD – diastolic dysfunction DT – mitral deceleration time; E – early diastolic filling (E wave)
E/A – peak flow velocity in early diastole / peak flow velocity in atrial contraction
EDS – excessive daytime sleepiness (ESS>10) EF – ejection fraction
ESS – Epworth Sleepiness Scale (0–24, where >10 is considered abnormal)
FS – fractional shortening HDL – high density lipoprotein HF – heart failure
HI – hypopnea index HR – hazard ratio HT – hypertension IQR – interquartile range
IVRT – isovolumic relaxation time IVST – interventricular septal thickness LA – left atrial
LV – left ventricular or left ventricle LVDF – lefr ventricular diastolic function LVEDD – left ventricular end-diastolic diameter LVEF – LV ejection fraction
LVESD – LV end-systolic diameter LVH – LV hypertrophy
LVM – LV mass LVMI – LV mass index
LVPWT – LV posterior wall thickness LVWT – LV wall thickness
MI – myocardial infarction
NYHA – New York Heart Association ODI – oxygen desaturation index OR – odds ratio
OSA – obstructive sleep apnea
OSAHS – obstructive sleep apnea hypopnea syndrome OSAS – obstructive sleep apnea syndrome
PSG – polysomnography
RDI – respiratory disturbance index REM – rapid eye movement
RWT – relative wall thickness SA – sleep apnea
SAHS – sleep apnea-hypopnea syndrome SaO2 – arterial oxygen saturation
SAS – sleep apnea syndrome SD – standart deviation
SDB – sleep-disordered breathing SHHS – Sleep Heart Health Study
SPSS – Statistical Package for the Social Sciences SRBD – sleep-related birthing disorder
TIB – time in bed TST – total sleep time UK – United Kingdom
USA – United States of America WHO – World Health Organization WHR – Waist to Hip ratio
INTRODUCTION
Worldwide, the incidence of cardiovascular disease (CVD) continues to increase, and despite ongoing therapeutic advances, it continues to be asso-ciated with high rates of morbidity, hospitalization, and mortality [221, 278]. The onward march of CVD throughout the world clearly illustrates the need for new and innovative management strategies to further improve pa-tient outcomes. One area under active investigation is the treatment of sleep-disordered breathing (SDB), which is now recognized as a common comor-bidity in a number of CVDs. Mounting clinical evidence suggests that the presence of SDB may have important implications on the long-term out-comes of patients with CVD [9].
Epidemiological studies have revealed a high prevalence of sleep-disordered breathing in the middle-aged population: up to 24% of men and 9% of women. Undiagnosed sleep apnea (SA) is likely to be highly preva-lent, even in countries where diagnostic facilities have been available for a long time [123, 223, 286]. A subset of these patients has concurrent symp-toms of excessive daytime sleepiness attributable to their nocturnal breath-ing disorder and is classified as havbreath-ing obstructive sleep apnea (OSA)/hypo-pnea syndrome (OSAHS) (4–5% of the middle-aged population).
Over the past 25 years, several studies have documented snoring and OSAHS as risk factors for cardiac disease (artherosclerotic, acute myocar-dial infarction, arrhythmias). Morbidity and mortality risk is increased in the context of sleep disordered breathing (SDB; snoring and associated ap-neas), even when taking other risk factors into consideration [114, 115, 175, 270].
Sleep apnea research is an intriguing field providing considerable contri-butions to the cardiovascular literature with exciting insights for clinicians, basic scientists, and epidemiologists [100, 276, 277]. Sleep medicine is growing rapidly as a clinical discipline on the basis of the increasing recog-nition of SDB. The discovery of SA as episodes of obstructive, central and mixed apneas was reported in 1965 in Germany [120] and in 1966 in France [81] independently. The gold standard for diagnosing and outlining a treat-ment program is based on the polysomnogram. SA represents the vast ma-jority of SDB diagnosed by polysomnography (PSG). It is quickly becoming recognized as an independent risk factor for cardiovascular impairment [86, 100, 125, 171, 194, 210, 213, 216, 230, 280].
Therefore, in addition to management of traditional CAD risk factors, there are continued efforts to evaluate other factors and comorbidities that might contribute to the development and progression of CAD. One such
fac-tor is SDB, which is characterized by repetitive apneas, arousals from sleep, and intermittent hypoxia.
SA is a frequent sleep disorder that is known to be an independent risk factor for arterial hypertension. Potential confounding factors associated with both SA and arterial hypertension such as age, diabetes mellitus and obesity, have been explored extensively, and are considered as independent but additive factors. However, these factors are also contributors to left ven-tricular (LV) hypertrophy (LVH) and LV diastolic dysfunction, both of which are important causes of cardiovascular morbidity, and have been re-ported to be associated with SA for decades [35].
CAD and OSA are both complex and significant clinical problems. In pa-tients with stable CAD and preserved cardiac function most apneas are of obstructive origin [8, 184, 211]. Accelerated atherosclerosis might be one of the most important mechanisms responsible for development of vascular disorders in patients with OSA [161]. Sleep apnea is increasingly recog-nized as being important in the prognosis of patients with CAD; however, symptoms of SA are not easily identified, and as many as 80% of sufferers remain undiagnosed, calling for multidisciplinary collaboration between cardiologists and sleep specialists [57].
In addition, it is unknown if the thresholds for diagnosing and treating SA should be the same in people with cardiovascular (CV) disease and those who are otherwise healthy [249], or if the presence of SA changes the effect of traditional risk factors for CV events and mortality. At present, the consequences of untreated mild or asymptomatic SA are unknown.
There is still insufficient knowledge on an impact of SA on LV geometry and on potential effect of mild to moderate sleep-disordered breathing, which is prevalent, often asymptomatic, and largely undiagnosed in stable CAD [43, 48]. To date, however, there is a lack of knowledge regarding the impact of SA on diastolic dysfunction in patients with CAD.
We hypothesized that SA is largely undiagnosed in patients with CAD and that left ventricular morphology and function are affected by the effects of mild to moderate SA in this patients independently of the traditional CAD risk factors.
1. THE PURPOSE OF THE STUDY
The purpose of this cross sectional study was to determine prevalence of sleep apnea, characteristics, association with traditional CAD risk factors and to investigate association between sleep apnea and alteration in left ven-tricular morphometry and function in CAD patients.
1.1. Objectives of the study
1. To cross-sectionally investigate prevalence of sleep apnea and differ-ences in clinical and polysomnographic characteristics in CAD pa-tients with and without sleep apnea.
2. To explore whether routine clinical features from the study of patients with CAD could predict the presence of sleep apnea by two thresholds for diagnosing (apnea-hyponea index ≥5 and ≥15).
3. To determine whether there are differences in risk factors for the pres-ence of sleep apnea between men and women with CAD.
4. To cross-sectionally investigate the association between sleep apnea and left ventricular morphometry in CAD patients.
5. To identify association between left ventricular diastolic function pa rameters and sleep apnea in CAD patients with left ventricular ejec-tion fracejec-tion ≥50%.
1.2. Statements of the hypotheses We hypothesised, that in CAD patients:
1. Sleep apnea is common in CAD patients with no previous sleep apnea diagnosis. The traditional CAD risk factors such as age, male gender, obesity and hypertension, is more prevalent among patients with sleep apnea compared with patients without sleep apnea. Significant small correlations between some polisomnographic parameters and the severity of sleep apnea could be found.
2. Using the same set of potential clinical confounders, the prognostic factors of the presence of sleep apnea differ when adapting the two cutoffs of apnea-hypopnea index for sleep apnea diagnosis.
3. The risk factors for the presence of SA in women differ from those in men.
4. Mild to moderate sleep apnea is cross-sectionally related to higher prevalence of left ventricular hypertrophy and mild sleep apnea is cross-sectionally associated with concentric left ventricular hypertro-phy controlling for traditional recognized CAD risk factors;
1.3. Scientific novelty of the study
The most important novel finding of the study was the association of SA at any level of severity especially in mild form with alterations in left ven-tricular morphometry and function in patients with CAD patients.
The study is the first in Lithuania to systematically explore the potential underdiagnosis of SA in a large sample of consecutive CAD patients. The present study was performed in patients from a clinic-based CAD popula-tion characterized by a relatively high degree of comorbidity.
According to our knowledge, little research has been done in the world. Previous studies that were not able to fully control for confounding varia-bles suggested that severe SA is associated with changes is heart structure, including LV hypertrophy. Our study extends these findings by showing structural alterations associated with SA in mild to moderate form in pa-tients with CAD. In addition, hypertension and other confounding variables were fully controlled.
We also found that SA and hypertension are independently associated with heart structure abnormality, that’s quite possible that the association of SA and hypertension has additive effects when both conditions coexist. SA was associated with prevalence of concentric LV geometry. This increased prevalence may in part explain the increased rate of cardiovascular events in these patients.
Finally, our study presented a better understanding of interactions related to the consequence of sleep apnea on left ventricular morphometry in pa-tients with CAD.
Contribution of author
The author has mastered the polysomnography data evaluation methodologies. 806 patients in the cohort underwent full inlaboratory PSG recording. All records were scored and reviewed by author.
2. REVIEW OF LITERATURE
2.1. Sleep apnea: disease definition and diagnosis, epidemiology 2.1.1. Definition
Sleep-disordered breathing (SDB) includes a wide range of conditions linked by narrow upper airways and the loss of normal respiration patterns during sleep. The discovery of sleep apnea (SA) as episodes of obstructive, central and mixed apneas was reported in 1965 in Germany [120] and in 1966 in France [81] independently. SDB is a term used to describe a spec-trum of respiratory disturbances that occur during sleep. At one end of the spectrum, there are subjects with intermittent partial obstruction of the upper airways giving rise to snoring without fragmentation of sleep and no day-time symptoms (“simple snorers”). Habitual snoring is defined as snoring almost every night or as snoring at least 5 nights per week [117, 138, 139, 168, 205, 207, 286]. It is almost always present in patients with obstructive SA syndrome (OSAS).
In most epidemiology studies, and accordingly in this study, SA is de-fined by the number of obstructive apnea and hypopnea episodes per hour of sleep (apnea-hypopnea index, AHI), reflecting the degree of departure from the normal physiology of breathing during sleep. The term “OSA syn-drome” will be used to indicate a clinical entity defined by an elevated AHI in conjunction with hypersomnolence or related problems in daytime func-tion and is synonymous with the term “obstructive sleep apnea–hypopnea syndrome” (OSAHS) [288].
In this text we still use the terms SA, OSAS, although hypopnea are now included in the syndrome.
OSAHS is public health disease. It is the most common organic sleep disorder causing excessive daytime sleepiness (EDS). Sleep-related breath-ing disorders (SRBD) and sleep-disordered breathbreath-ing (SDB) refer to the same clinical disorder. The American Academy of Sleep Medicine formu-lated the definition for Sleep Apnea Hypopnea Syndrome (SAHS), also re-ferred as Sleep-Disordered Breathing Disorders, which is limited during sleep and is characterized by the following diagnostic criteria: either EDS not explained by other factors or a variety of symptoms, such as choking, gasping during sleep, recurrent awakenings from sleep, unrefreshing sleep, daytime fatigue, impaired concentration, accompanied by overnight poly-somnography demonstrating ≥5 obstructive breathing events per hour during sleep [4].
Sleepiness is the cardinal symptom of SDB, and the Epworth Sleepiness Scale (ESS) score progressively increases with an increased number of breathing events per hour during sleep. These findings are independent of age or sex [87, 286]. Also snoring without SDB has been associated with sleepiness [88]. However, the majority of patients with SDB did not com-plain of sleepiness, only 22% of females and 17% of males reported it [286]. This implies that conventional polysomnografic events of SDB do not corre-late well with sleepiness, and that there are some other reasons for sleepi-ness than SDB.
This in contrast to reports from the Sleep Heart Health Study (SHHS) where significant associations between daytime sleepiness and both self-reported snoring [88] and RDI [87] have been found. In another article from the same database, the prevalence of sleepiness was found to increase with severity of SDB and sleepy subjects were found to have a higher AHI and hypoxemic burden. In the latter study sleep-stage distribution, sleep time, sleep efficiency, and arousal index were not associated with sleepiness [16].
Bixler and co-workers reported that in the general population depression is the major risk factor for sleepiness, other risk factors being obesity, diabe-tes and young age [32]. They emphasised the importance of evaluating the mental health issues and metabolic syndrome whenever a patient complains of sleepiness, regardless of SDB. There is also a lack of adequate prospec-tive studies that have validated severity criteria for sleepiness [4].
Among multiple co-morbidities, SDB is the most common and least rec-ognized by cardiologists. Yet, SDB consisting of apneas (cessation of breathing for 10 seconds or longer) and hypopneas (reduction in breathing for 10 seconds or longer) are associated with acute and chronic pathophysio-logical processes, which ultimately result in excess cost, morbidity, read-missions, and mortality [110, 111, 113, 108].
A number of epidemiologic and mechanistic studies have recently gener-ated interest in the role of SA in the pathophysiology of cardiovascular dis-ease, a link that continues to require extensive investigation. Substantial progress has been made in the past 25–30 years in our understanding of the relationship between SA and CV disease [225]. Accumulating evidence im-plicates SA as an independent risk factor for hypertension, CAD and stroke. A variety of mechanisms may be operative. SA is a frequent sleep disor-der that is known to be an independent risk factor for arterial hypertension. Potential confounding factors associated with both SA and arterial hyperten-sion such as age, diabetes mellitus and obesity, have been explored exten-sively, and are considered as independent but additive factors. However, these factors are also contributors to left ventricular (LV) hypertrophy and LV diastolic dysfunction, both of which are important causes of
cardiovas-cular morbidity, and have been reported to be associated with SA for dec-ades [35].
2.1.2. Diagnostic measures
The wide range of possible severe consequences of untreated SA man-dates prompt diagnosis. At least from a clinical perspective the diagnostic procedure of SA can be divided in two parts, the measurement of obstruc-tive respiratory events and the evaluation of symptoms. The two factors most focused on are AHI and excessive daytime sleepiness.
The major challenge for the clinician is the differential diagnosis between benign snoring and snoring related to apnea. Individuals suffering from SDB may be unaware of symptoms other than daytime sleepiness, which can be due to a range of factors. Young and collegues estimated that 2 per-cent of women and 4 perper-cent of men in the middle-aged work force meet the minimal diagnostic criteria for the sleep apnea syndrome (an apnea-hypopnea score of 5 or higher and daytime hypersomnolence) [286]. Due to the strong association between snoring and apnea, self-reported or partner-reported snoring is often used as a proxy measure of apnea in population-bases studies. Habitual snorers, both men and women, tended to have a higher prevalence of apnea-hypopnea scores of 15 or higher [286]. There several new lines of research are emerging. One is increasing recognition that it is not only sleep duration and presence of sleep disturbances but also change in these parameters over time that is of relevance to future health.
The gold standard for the diagnosis is overnight polysomnography (PSG). This includes electroencephalographic, electrooculographic, electro-myographic, oxygen saturation, oral and nasal airflow, respiratory effort, electrocardiographic and leg movement recordings. Although home studies have been used, equipped with portable monitors, in order to measure oxy-gen saturation, heart rate, respiratory effort and airflow, they have had a lower efficacy for the diagnosis compared with full night polysomnography.
Other tests like actigraphy and multiple sleep latency tests may be used as part of the diagnosis of SA. The culmination of the diagnostic process is classification of SA as mild, moderate or severe. A diagnosis of SA requires the presence of repetitive apneas and hypopnoeas during sleep. This pres-ence is most reliably shown by attended overnight polysomnography in a sleep laboratory, in which sleep stages, arterial oxyhaemoglobin saturation, and respiratory movements of the rib cage and abdomen or respiratory ef-fort, or both, are recorded [4, 38].
Apnea in adults is defined as the cessation of airflow (>90% reduction in tidal volume) for ≥10 s. Hypopnea is characterized by a decrease but not
complete cessation of airflow by 30–50% of normal (reduction in tidal vol-ume of 50%–90%) usually in association with a reduction in oxyhemo-globin saturation by at least 3%–4%. These breathing disorders are com-monly encountered during sleep and have been strongly associated with the pathogenesis and progression of cardiovascular diseas [53, 249].
Obstructive sleep apnea (OSA) and central sleep apnea (CSA)
The sleep apnea can be divided into obstructive sleep apnea, central sleep apnea (CSA), and the combination of the two (mixed SA).
The fundamental difference between the major categories is the patho-physiologic mechanism, which causes the respiratory disturbance. CSA in-volves dysfunction of ventilatory control in the central nervous system (loss of ventilatory effort); in OSA the upper airway obstruction is most often caused by abnormal anatomy and/or abnormal control of the muscles that maintain the patency of the upper airway [25]. Depending on the severity of the physiologic abnormality, obstructive sleep disordered breathing may in-clude some variant forms. The diagnosis of SA syndrome (SAS) requires assessment of subjective symptoms and apneic episodes during sleep docu-mented by polysomnography [25].
OSA syndrome (OSAS or OSAHS) is a common form of obstructive sleep disordered breathing. OSAS is a prevalent disorder in which there is snoring, repetitive apneic episodes, and daytime sleepiness. Anatomical conditions causing upper airway obstruction (obesity or craniofacial abnor-malities such as retrognathia or micrognathia) can cause OSA.
CSA, much less common than OSA, is a disorder characterized by cessa-tion of breathing, which is caused by reduced respiratory drive from the cen-tral nervous system to the muscles of respiration. CSA is common in pa-tients with heart failure and cerebral neurologic diseases [39].
Normally, during sleep, genioglossus muscle activity decreases and dur-ing inspiration due to the negative airway pressure, the tongue falls bac k-ward. In susceptible individuals, this results in upper airway closure (ob-structive apnea) or narrowing (ob(ob-structive hypopnea). Obesity is the major risk factor for OSA, in part due to excess fat deposition in the pharynx. HF patients with OSA are commonly obese and snore habitually [109, 112].
Some patients have both types of respiratory sleep disorder. They are for the most part, patients with long-standing OSA or heart failure who have developed chronic malfunctioning of the respiratory regulatory system [95, 105].
In regards to SA, both CSA and OSA, is associated with three immediate adverse biological consequences: A) arterial blood gas abnormalities con-sisting of repetitive episodes of hypoxemia/hypercapnia which occur due to
apnea, followed by reoxygenation/hypocapnia associated with recovery from apnea, and B) large negative swings in intrathoracic pressure and C) arousals. These consequences are qualitatively similar for both OSA and CSA, but more pronounced with OSA.
2.1.3. Epidemiology, prevalences
SA has been recognised throughout human history, dating as far back as the 4th century BC. Numerous reports throughout the 19th century and the early part of the 20th century AD gave way to systematically conducted studies on patients with OSA and related syndromes [115, 155]. SA occurs throughout the entire lifespan, from neonates to the elderly. In adults, the frequency of disordered breathing during sleep increases with age and is poorly associated with an increased incidence of daytime sleepiness or other symptoms of OSAHS [33, 34, 65]. OSA, a subset of SDB, affects 2–5% of the population in the western world [204, 223, 268, 269] whilst in other parts of the world the condition is probably largely underestimated [288].
Prevalence estimates from studies with probability samples range, for OSA of at least mild severity (defined by AHI⩾5), from 3 to 28%; for OSA of at least moderate severity (defined by AHI⩾15), estimates range from 1 to 14% [28, 33, 34, 65, 82, 142, 286, 288]. The wide range of these esti-mates precludes adequate assessment of the population burden of OSA be-cause feasible means to reduce the burden are different for the extremes (i.e., 1 and 28%) [288]. When only those studies with in-laboratory poly-somnography conducted on large samples are compared, however, the prev-alence estimates are in closer agreement. Results from studies of cohorts in Wisconsin [286], Pennsylvania [33, 34], and Spain [65] are given in Table 2.1.3.1 [288].
Table 2.1.3.1. Prevalence of obstructive sleep apnea from three studies with similar design and methodology
Study N Age range years Estimated prevalence of AHI≥5 events/hour % (95% CI) Estimated prevalence of AHI≥15 events/hour % (95% CI)
Men Women Men Women
Visconsina 626 30–60 24 (19–28) 9 (6–12) 9 (6–11) 4 (2–7) Pensylvaniab 1,741 20–99 17 (15–20) Not given 7 (6–9) 2 (2–3) Spainc 400 30–70 26 (20–32) 28 (20–35) 14 (10–18) 7 (3–11)
a Young 1993 [286]; b Southern Pennsylvania Cohort (1996): two-stage probability samples
for men and women 20–100 years of age, N=1,741 [from Bixler 1998, 2001];
c
The first large epidemiologic polysomnographic study was conducted in Madison, Visconsin [286]. Data from the Wisconsin Sleep Cohort Study, a longitudinal study of the natural history of cardiopulmonary disorders of sleep, were used to estimate the prevalence of undiagnosed sleep-disordered breathing among adults and address its importance to the public health (Table 2.1.3.1). The authors estimated that 2% of women and 4% of men in the middle-aged work force met the minimal diagnostic criteria for the SA syndrome, defined as an AHI of 5 and daytime sleepiness. Up to 9% of women and 24% of men had an AHI of 5 without daytime sleepiness [286].
Because all three studies used two-stage stratified probability sampling with appropriate weighting techniques and used similar measurement meth-ods and definitions of hypopnea and AHI cutpoints, their concurrence is particularly reassuring. On the basis of the average of prevalence estimates from these studies of predominantly white men and women with mean BMI of 25 to 28, we estimate that roughly 1 of every 5 adults has at least mild OSA and 1 of every 15 has at least moderate OSA [288].
Although sleep disorders are very common, rigorous epidemiological studies in this field are fairly recent, in part because the discipline of sleep medicine is recent [207]. Population studies show that sleep deprivation and disorders affect many more people worldwide than previously thought.
The prevalence of OSA defined at an apnea-hypopnea index (AHI) ≥5 was a mean of 22% (range, 9–37%) in men and 17% (range, 4–50%) in women in eleven published epidemiological studies published between 1993 and 2013. OSA with excessive daytime sleepiness (OSAS) occurred in 6% (range, 3–18%) of men and in 4% (range, 1–17%) of women. The preva-lence increased with time and OSA was reported in 37% of men and in 50% of women in studies from 2008 and 2013 respectively [73, 74] (Fig. 2.1.3.1).
OSA is more prevalent in men than in women and increases with age and obesity. Smoking and alcohol consumption are also suggested as risk fac-tors, but the results are conflicting. Excessive daytime sleepiness is suggest-ed as the most important symptom of OSA, but only a fraction of subjects with AHI >5 report daytime sleepiness and one study did not find any rela-tionship between daytime sleepiness and sleep apnea in women [73].
The American Association of Sleep Medicine defined daytime sleepiness as mild, moderate and severe in relation to impact on social life during the daytime [4]. The Epworth Sleepiness Scale (ESS) is, however, the most of-ten used measure to define daytime sleepiness [74, 118, 119]. Diagnostic equipment and definitions of oxygen desaturations, apnea, hypopnea, OSA and daytime sleepiness has, changed over time, which in turn affects esti-mates of the prevalence of SA.
Fig. 2.1.3.1. Prevalence of OSA defined at an apnea-hypopnea index (AHI) ≥5 and OSAS (OSA+daytime sleepiness) among men and women
[Franklin 2015] [73] * In the same publication
2.1.4. The apnea hypopnea index
The Apnea Hypopnea Index (AHI) and oxygen desaturation levels are used to indicate the severity of SA.
Oxygen desaturation reductions in blood oxygen levels (desaturation) are recorded during polysomnography or limited channel monitoring. At sea level, a normal blood oxygen level (saturation) is usually 96–97%. Although there are no generally accepted classifications for severity of oxygen desatu-ration, reductions to not less than 90% usually are considered mild. Dips into the 80–89% range can be considered moderate, and those below 80% are severe [4].
The severity of SA is determined by the apnea-hypopnea index (AHI), which is the number of apneic and hypopneic events per hour of sleep. Rec-ommended diagnostic criteria for SA syndrome include an AHI of 5 or more, determined by overnight monitoring, and evidence of disturbed or
un-refreshing sleep, daytime sleepiness, or other daytime symptoms. The task force suggested AHI cutpoints of 5, 15, 30 events/hour to indicate mild, moderate, and severe levels of OSA [4].
An AHI <5 is considered normal and patients with very severe SA may have an AHI exceeding 100. Most of the studies have shown that ≈1 in 5 adults has at least mild SA and 1 in 15 has moderate or severe SA [53].
The severity of SA must be properly quatified, not only by indices (e.g., apnea index (AI), apnea-hyponea index (AHI), or respiratory disturbance index (RDI) but also by the number of oxygen desaturations, presence of cardiovascular effects, and degree of daytime sleepiness. The diagnostic cri-teria should also be adjusted for age [34].
2.2. Clinical presentation, risk factors for sleep apnea
Why it is so important to distinguish patients with sleep disordered breathing? A large number of population studies connecting SDB with CVD and higher mortality. He and coworkers [96] reported that about 40% of pa-tients with severe OSA died during a follow-up period of 8 years. Partinen and coworkers [206] observed a higher risk of death due to vascular disease in patients with untreated OSA. SDB has been shown to be associated with increased risk for stroke, CAD. In a large trial by Partinen and Guille-minault [92, 205], OSA patients were twice as likely to have hypertension, three times as likely to have ischemic heart disease and had four times as much cerebrovascular disease compared with the general population.
2.2.1. Risk factors for sleep apnea
Risk factors for SA include obesity, craniofacial abnormalities, male gender, short neck, increasing age, alcohol use, smoking, menopausal status in women and black race [54, 170]. Multiple logistic regression of clinical features available in the Sleep Heart Health Study suggested several inde-pendent predictors of AHI≥15, including male sex, age, BMI, neck girth, snoring and frequency of reported nocturnal respiratory pauses [290]. Obesi-ty is one of the main risk factors of SA since 60% to 90% of SA patients are obese and there is a strong positive correlation between BMI and SA [76, 77, 93, 153, 290].
Table 2.2.1.1. Risk factors for sleep apnea Obesity, body mass index (BMI) >30 kg/m 2 Neck circumference >40 cm
Male gender or postmenopausal status in women Positive family history of SA
Race
Age >40 years
Alcohol ingestion before bedtime Underlying hypertension
Metabolic syndrome Down syndrome Marfan disease
Bradley, 2009; Dasopoulou 2011 [38, 53]
Obesity and body mass index >30 kg/m2, neck circumference >40 cm,
male gender or postmenopausal status in women and positive family history of SA make the diagnosis of SA more probable [27]. Other risk factors for SA are race, age >40, alcohol ingestion before bedtime, underlying hyper-tension, metabolic syndrome, Down syndrome and Marfan (a genetic disor-der of the connective tissue) disease (Table 2.2.1.1).
Large studies of SA detected in population-based screening have shown that although male sex and obesity are clearly risk factors for SA (associated with 2- and 4-fold-higher prevalences, respectively), clinically significant SA is not rare in women or in nonobese persons and is even more common in older age compared with middle age.
Furthermore, in contrast to the high prevalence of pathological sleepiness in SA patient populations, excessive daytime sleepiness and SA are not strongly correlated in general population studies [33, 34, 288].
2.2.2. Roles of gender and age in sleep apnea
As age advances, sleep breathing related difficulties become increasingly common. A multimodal distribution of prevalence by age is often indicative of distinct disease subtypes with different aetiologies and consequences [116].
SDB occurs commonly in populations aged 65 yrs, but there is contro-versy regarding its significance in older people and its relationship to OSAS that occurs in middle age [147, 148]. In adults, the frequency of disordered breathing during sleep increases with age and is poorly associated with an increased incidence of daytime sleepiness or other symptoms of OSAHS [33, 34, 115].
In the absence of strong evidence from longitudinal studies, it remains unclear whether SA in the elderly is a distinct condition compared with how it presents in younger adults [128, 131]. Several OSAS studies in older pop-ulations report little or no association of OSAS with sleepiness, hyperten-sion, or decrements in cognitive function [7, 292].
For both genders the prevalence of SA plateaued around 60 years of age, after a steady increase from younger ages [131, 188]. It is postulated that an increase in fat deposits in the parapharynx and comorbid conditions predis-pose the elderly to development of OSA. Failure to fall asleep, frequency and duration of night awakenings and snoring are among common com-plaints in adults 65 years and older. The risk of OSA (AHI>10) for adults over 65 years is 6.6 times the risks facing those between 20 and 44 years [34, 223].
SA is more common in males than in females, with a ratio of 2:1. Meno-pause is a risk factor for SA [234]. SA prevalence increases in mid-life, but the existence of SA in childhood, adolescence and older age means that there is no simple positive correlation of SA with age [117]. SA affects male individuals more commonly than female individuals and may present with a number of signs and symptoms suggestive of the or with no symptoms whatsoever [249].
Until recently, SA was viewed as a “male” disease, but recent studies in the general population demonstrate that this condition is not rare in women, with at least 2% of middle-aged women having SA [33, 282, 286, 295]. However, SA is undiagnosed in more than 90% of women [283, 287]. The reason why OSA is more prevalent in men as compared to women across all age groups is unclear, but as discussed in a review by Young and colleagues (2002a), differences in sex hormones, upper airway shape, craniofacial mor-phology, pattern of fat deposition, and differences in occupational and envi-ronmental exposures have been proposed [288].
The paucity of data regarding SA in women and the limited understand-ing of gender differences in SA may be the root of the gender bias observed in this syndrome [284, 289].
Understanding gender differences in SA is a critical area of exploration. Recent studies examining gender differences in upper airway anatomy and function [181], polysomnographic features [199], symptom presentation [240, 259] and morbidity and health care utilization [274] have added to the growing body of knowledge in this area [282].
Whether gender differences exist in neurobehavioral performance and in important symptoms of SA such as excessive daytime sleepiness still remain inconclusive [282].
2.2.3. Sleep apnea and obesity
Obesity, especially central adiposity, is consistently recognised as one of the strongest risk factors for OSA. Given the worsening modern pandemic of obesity in western society, the prevalence of OSA is likely to increase further [223]. Obesity is characterized by the disproportionate growth of the components of body size, including adipose tissue and lean body mass. The malefic consequences of obesity are due both to the associated structural and functional cardiac alterations as well as the high prevalence of coexist-ing conditions, such as CAD, hypertension, sleep-disordered breathcoexist-ing (SDB), and diabetes mellitus [18, 56, 130].
A cause-effect and effect-cause relationship exists between body weight and OSA. A study in the UK found that 60 to 90% of patients with OSA have excessive body weight [273]. Patients with impaired glucose metabo-lism and high BMI are particularly at risk of severe OSA [258]. A cause-effect and cause-effect-cause relationship exists between body weight and OSA. A study in the UK found that 60 to 90% of patients with SA have excessive body weight [273].
Obesity is believed to predispose to OSA because of mass loading in the upper airway [239]. Controversy remains whether specific measures of body habitus, such as neck or waist circumference, are better predictors of SDB as compared with BMI alone. Neck circumference was in a population-based sample more important as a risk factor for snoring with increasing BMI in obese than in lean women [255].
As obesity is at epidemic proportions, the number of people affected by SA is likely to increase accordingly. Evidence of a positive “dose- response” relationship between BMI and SA is discussed extensively in literature. Wall and colleagues [273] estimate the odds of developing SA to be 6.6 times higher in individuals with 30+ BMI than normal BMI, and the odds increase drastically to 27.5 times for 40+ BMI [26, 220].
Emerging data from Europe suggest that the societal prevalence of the disorder may be even greater when modern diagnostic techniques are used: a community-based Swiss study of over 2,000 subjects diagnosed moderate-severe OSA (AHI≥15) in 23.4% and 49% of female and male subjects, re-spectively [100], potentially alarming findings which need to be confirmed in other studies and other population groups. Despite the important relation-ship with obesity, it is important to remember that not all subjects with obe-sity or with fat necks suffer from sleep apnea [122] and that about one-third of OSAS patients are non-obese.
LVH often develops, due to the coexistence of hemodynamic (cardiac workload) and non-hemodynamic components (including body composition
and activity of visceral fat [56]. The work of Pujante and coworkers was de-signed to explore the possible relationship between OSA and alterations of the LV mass in patients with morbid obesity. The influence of gender, men-opausal status, body composition, and cardiovascular risk factors were also taken into consideration. The results show a high prevalence of SA and LVM alterations in this population, especially for men and postmenopausal women. Interestingly, the AHI related to LVM independently of age, gen-der, menopausal status, and other cardiovascular risk factors, including hy-pertension. These results support a direct effect of OSA on LVM, and sug-gest that LVM should be assessed in all patients with morbid obesity and OSA, particularly men and postmenopausal women [222].
2.2.4. Sleep apnea and hypertension
OSA is now recognized as a risk factor for the development of sion in European and US international guidelines [212]. OSA and hyperten-sion are linked in a dose–response fashion. This is true even when the usual confounding factors such as age, alcohol and/or tobacco consumption and body mass index are taken into account [215].
Several large population-based, cross-sectional studies reported an inde-pendent association between these two conditions [31, 65, 73, 74, 93, 195, 283, 287]. Self-reported snoring is also a predictor of developing hyperten-sion in both males and females [102, 128, 164]. Hypertenhyperten-sion is highly prevalent in individuals with SA with estimates ranging from 50% to 90%, [60] whereas 30% and more of middle-aged men with hypertension also have SA, which is underdiagnosed.
Growing experimental and clinical evidences corroborate the association of OSA with subclinical signs of cardiovascular morbidity such as endothe-lial dysfunction and vasculature remodeling, oxidative stress, activation of inflammatory pathways and increased leukocytes/endothelial cells adhesion. Altogether this suggests that OSA could be a major although underestimated player in the atherogenesis [212, 248].
Large cross-sectional and longitudinal studies have shown a strong corre-lation between chronic SA and arterial hypertension, independent of poten-tial confounders [151, 165, 195]. A large prospective study also demonstrat-ed a strong association between the presence of SA and the development of hypertension [215]. A distinct feature of sleep apnea-induced hypertension is loss of the normal nocturnal decrease in blood pressure. This indicates a link between these two disorders [166].
SA and hypertension are both prevalent in the community and many in-dividuals suffer from both. Most of the literature agrees that SA is strongly
associated with hypertension and that there is a causal relationship between them, independent of possible confounding variables such as obesity, male gender, age, coexisting CVD, tobacco and alcohol use [70, 151, 244, 283, 249].
Peppard et al. analyzed the odds ratios for the presence of hypertension at a 4-year follow-up among 709 middle-aged participants in the Wisconsin cohort, all of who had been investigated with polysomnography at baseline. Biologically, the mechanisms mediating hypertension in OSA may be treshold dependent and become saturated at a certain level of AHI. Com-pared with subjects with reference category (AHI<1.0), the adjusted odds ratio for prevalent hypertension at follow-up was 1.2 (95% CI, 1.1–1.8) for (AHI, 1–4.9), 2.0 (95% CI, 1.3–3.2) for mild OSA (AHI, 5–14.9) and 2.9 (95% CI, 1.5–5.6) for moderate to severe OSA (AHI ≥15) [215]. The same group also provided data from a sub-group who were followed-up after a mean of 7 years using 24-hour blood pressure studies. Regardless of con-founders including baseline blood pressure and progress of SA, there was a significant dose-response relationship between the severity of SA at baseline and the risk of developing systolic non-dipping blood pressure during sleep [101].
2.2.5. Sleep apnea and race/ethnicity
In the USA, the prevalence of SA (AHI≥5) in the adult, mainly white, population aged 30–60 years, has been estimated at 24% in men and 9% in women, and, at an AHI≥15, at 9% in men and 4% in women, with no major differences noted between African-Americans and white people [290]. The corresponding prevalence of SA syndrome has been estimated at 4% in men and 2% in women [286]. In European populations, the most comprehensive data come from Spain, where 26% of men and 28% of women aged 30–70 years had an AHI≥5, and 14% of men and 7% of women had an AHI≥15 [65]. In a predominantly oriental male population from Hong Kong, aged 30–60 years, the prevalence of SA and SA syndrome at an AHI≥5 were 9% and 4%, respectively, and at an AHI≥15, 5% and 3%, respectively [41, 104].
These data suggest that SA is common in several racial and ethnic groups, but that most individuals with SA are asymptomatic. This factor could have public-health implications because relations between SA and cardiovascular diseases seem not to be related to the presence of symptoms of SA [291]. Of those with SA syndrome who could benefit symptomatically from its treatment, 75–80% remained undiagnosed in the USA [283].
2.2.6. Sleep apnea and alcohol use, smoking, heredity
Alcohol consumption and benzodiazepines, as well as other sedatives or medications that induce weight gain (antipsychotics, antiepileptics, and hormones) may exacerbate [29, 236]. Alcohol increases upper airway re-sistance and tends to induce OSA in healthy people and especially among chronic snorers. In Great Britain, one drink per day increased the odds of mild or worse SDB by 25% (OR=1.25; 95% CI, 1.07–1.46) among men. Alcohol acts as a depressant and when used before sleep disturbs the noc-turnal respiratory cycle, and may narrow the airways leading to apnoea. De-spite this plausible causal mechanism, there is little evidence from large population based studies that can associate alcohol use with SA [235].
Smoking may cause difficulties in initiating or maintaining sleep, and airway obstruction by nasopharyngeal oedema and airway inflammation [253]. Divergent findings also make it difficult to establish smoking as an independent risk factor for SA. Nasal obstruction and smoking can also in-crease the risk for developing OSA, possibly by causing pharyngeal narrow-ing as a result of inflammation [291]. For example, smokers were found to be three times more at risk of SA than never-smokers, and never-smokers did not have increased risk of SA than former smokers [217, 260].
Hereditary factors can also increase risk for reasons not fully elucidated [41, 291].
2.3. Sleep-disordered breathing and cardiovascular disease Many studies have alluded to a link between SDB and cardiovascular disease, but both (particularly OSAHS) may purely co-exist with type 2 dia-betes, for example [275], therefore proving that SDB as an independent risk factor for cardiovascular disease is not straightforward. Previous cross-sectional and longitudinal population-based studies (Wisconsin Sleep Co-hort [286], Pennsylvania Sleep CoCo-hort [33, 34] and the Cleveland Family Study [228, 229] confirmed only an association with OSAHS and multiple cardiovascular risk factors such as hypertension and diabetes. However, a large, prospective (11-year follow-up), multicentre, cohort study called the Sleep Heart Health Study [238] showed excess cardiovascular mortality and morbidity in those with OSAHS after correction of results for known con-founders.
Obstructive sleep apnoea syndrome (OSAS) is a frequent sleep disorder that is known to be an independent risk factor for arterial hypertension. Po-tential confounding factors associated with both OSAS and arterial hyper-tension, such as age, diabetes mellitus and obesity, have been explored
ex-tensively, and are considered as independent but additive factors. However, these factors are also contributors to LVH and LV diastolic dysfunction, both of which are important causes of cardiovascular morbidity, and have been reported to be associated with OSAS for decades [35, 36].
SA patients frequently have several risk factors for cardiovascular dis-ease development, [62–64, 216, 232]. These risk factors are entangled in such a way that it is difficult to isolate the relative contribution of SA to cardiovascular risk. SA is independently associated with several cardiovas-cular diseases, including hypertension, ischemic heart disease, atrial fibrilla-tion, cerebrovascular disease, and heart failure [238, 287]. Even patients with mild changes in their AHI, with values ranging between 0.1 and 4.9, were found to have an increased risk of developing systemic hypertension when compared with those who had an AHI of 0 [195]. However, the magni-tude of SA effects, as compared to other risk factors for cardiovascular dis-ease, is not well established.
OSA is an independent risk factor for CAD among adults, resulting in in-creased morbidity and mortality [79]. Patients with untreated OSA experi-ence an increased incidexperi-ence of cardiovascular events over those with con-trolled OSA. Similarly, the group with concurrent CAD and OSA experi-enced more pre-mature deaths than those without OSA [112].
Risk factors for CSA are closely associated with those of heart failure, and include male gender, higher New York Heart Association (NYHA) class, lower left ventricular ejection fraction (LVEF), waking hypocapnia, presence of atrial fibrillation, higher brain natriuretic peptide levels, and fre-quent nocturnal ventricular arrhythmias [42, 245]. Patients may be obese, but this is not as typical as in OSA. Signs and symptoms associated with CSA include insomnia, excessive daytime sleepiness, and/or fatigue [249]. Sometimes a sleep partner may report witnessed apneas or the unusual breathing pattern of Cheyne-Stokes respiration. Patients may also report frequent awakenings, poor quality sleep, and/or shortness of breath [249]. Paroxysmal nocturnal dyspnea may also be seen with CSA [249]. However, since many of these findings are common to heart failure, the presence of CSA is often overlooked by patients and clinicians, and thus may lead to its under-diagnosis.
2.3.1. Mechanisms linking sleep apnea to chronic cardiovascular disease
The role of SA in the pathophysiology of cardiovascular disease has gen-erated considerable recent interest. The pathophysiological mechanisms that associate these diseases together are complicated. SA can influence the
broad spectrum of conditions caused by CAD, from subclinical atheroscle-rosis to myocardial infarction [57, 158].
SA is increasingly being connected to cardiovascular disease both in terms of shared risk factors and physiological mechanisms. For some time, the medical field has recognized that factors such as obesity, high blood pressure, male gender, and increasing age are risk factors for both obstruc-tive sleep apnea and atherosclerotic heart disease, and that sleep apnea is more common in those with CAD [224].
Obstructive sleep apneas are part of the complex of heavy snorer’s dis-ease as defined by Lugaresi and colleagues [168]. Heavy snoring (i.e., par-tial upper airway obstruction), even without apneas, is associated with high-er pulmonary arthigh-erial pressure, daytime sleepiness, arthigh-erial hyphigh-ertension, and insulin resistance [31, 33, 171, 215]. SDB, even snoring, was inde-pendently associated with hypertension in both men and women. This rela-tionship was strongest in young subjects, especially those of normal weight, a finding that is consistent with previous findings that SDB is more severe in young individuals [31]. Heavy snoring is also associated with case fatali-ty and short-term mortalifatali-ty after a first acute myocardial infarction [106].
Since the initial observations of the physiologic events that might be operative in the pathogenesis of cardiovascular sequelae of SA over 25 years ago, substantial progress has been made towards understanding how SA is a risk factor for cardiovascular disease. These findings include SA induced changes in cardiac structure and function, abnormalities in me-tabolic function, and increases in inflammation, coagulability and sympa-thetic nervous system activity. These latter issues then interact to enhance atherogenesis and cardiac dysfunction [136, 225, 293].
Javaheri and coworkers summarized [107] a plausible pathogenic pathway from SA to cardiovascular disease using observations from 25 years ago in combination with current data as follows in Fig. 2.3.1.1.
The mechanisms involved in the association between SA and vascular diseases are complex and diverse. Patients with SA experience repetitive episodes of hypoxia and reoxygenation during transient cessation of breath-ing that may provoke systemic effects. These patients also present increased levels of biomarkers linked to endocrine-metabolic and cardiovascular alterations. The association between SA and cardiovascular disease involves a number of mechanisms such as the following: sympathetic activation, hypercoagulability, inflammation and production of pro-inflammatory cyto-kines, endothelial dysfunction, oxidative stress and metabolic dysfunction. All these mechanisms are associated with the development and progression of cardiovascular disease (Fig. 2.3.1.1).
Fig. 2.3.1.1. A schematic summary of the proposed mechanisms leading from physiologic alterations occurring during sleep apnea and hypopnea
to the development of cardiovascular disease
Modified from Javaheri S. et al J Am Coll Cardiol 2017;69(7):841–58 [107].
Increased sympathetic activity and intermittent hypoxia associated with apneic episodes has been proposed as a possible mechanism behind the association between OSA, systemic inflammation and cardiovascular di-sease [136, 250]. Sympathetic nerve activity increases and reaches its peak level at the end of the apnoea [250] and was reported in clinics to inhibit the recovery of LV systolic function in patients with OSA. One of the mecha-nisms is the imbalance between oxygen demand and supply created by systemic and coronary vasoconstriction. As sympathetic tonus is one of the main pathophysiological actors both in HF and CAD, this appears as the obvious culprit pathway linking OSA and cardiovascular diseases [22].
Oxidative Stress, Inflammation, and Endothelial Dysfunction
OSA and intermittent hypoxia are associated with early vascular changes. Endothelial dysfunction in OSA is the result of complex processes, including oxidation of lipoproteins, increased expression of adhesion molecules, increased monocyte adherence to endothelial cells, vascular smooth muscle proliferation, and increased platelet activation and aggregation [136] Animal and clinical data support a specific role for intermittent hypoxia in pro-moting cellular changes at the vascular wall level thus triggering
athero-Respiratory control instability Obesity Upper airway dysfunction S leep ap n ea C ar d io v as cu lar d is eas e Increased sympathetic nerve activity Metabolic dysregulation Inflammation Oxidative stress Vascular endothelial dysfunction Intermittent hypoxia Heart disease Hyperten-sion Atrial fibriliation
sclerosis. Independently, OSA impairs endothelial function by altering re-gulation of endothelial vasomotor tone and repair capacity while promoting vascular inflammation and oxidative stress [293].
A number of studies have demonstrated that OSA is associated with metabolic abnormalities. For example, in the Sleep Heart Health Study, levels of cholesterol and triglycerides increased as a function of increasing OSA severity [193]. These findings may be related to OSA induced inter-mittent hypoxia [1]. Furthermore, the prevalence of metabolic syndrome is higher among persons with OSA in comparison to those without OSA [203]. This finding appears to be driven primarily by the higher frequency of hypertension in persons with OSA. Whether these findings are causally related to OSA remains to be determined. However, OSA might potentially increase the risk of CAD by promoting dyslipidemia [225]. Identification of OSA as a potential causative factor in metabolic syndrome would have significant clinical impact and could improve the management and under-standing of both disorders [293].
Table 2.3.1.1. Cohort studies regarding SA and incidence of cardiovascular disease Cardio-vascular disease Cohort Sample size Dura-tion
(years) Findings Reference
Hyper-tension
WSC 893 4 or 8 Adjusted OR of AHI≥15, compared with AHI=0: 2.89
Peppard 2000 [215] Coronary
artery disease
SHHS 4,422 8.7 Significant association only on adjusted subgroup analy-sis of men ≤70. Adjusted HR for AHI≥30 compared with AHI<5: 1.68
Gottlieb 2010 [86]
Stroke WSC 1,475 4 or 8 Age and sex adjusted OR for AHI≥20, compared with AHI<5: 4.48, nonsignificant only when adjusted to BMI.
Arzt 2005 [15] Atrial fibrillation Sleep-clinic patients 3,542 4.7 Unadjusted HR of AHI≥5, compared with AHI<5: 2.18
Gami 2007 [77]
SA – sleep apnea, AHI – apnea-hypopnea index, BMI – body mass index, HR – hazard ratio, OR – odds ratio, SHHS – Sleep Heart Health Study, WSC – Wisconsin Sleep Cohort [Badran, 2014] [20].
The association of OSA with endocrine-metabolic and cardiovascular al-terations indicates that, more than a local abnormality, OSA should be con-sidered a systemic disease. A vicious cycle may also appear involving hypo-xemia-reoxygenation cycles, oxidative stress, and elaboration of
proinflam-matory cytokines promoting a more generalized inflamproinflam-matory state. SA re-search is an intriguing field providing considerable contributions to the car-diovascular literature with exciting insights for clinicians, basic scientists, and epidemiologists [100, 276, 277, 293].
Many of the reports correlating SA to vascular disease come from small longitudinal studies of incidental cardiovascular disease and studies evaluat-ing the effect of CPAP (Continuous positive airway pressure) intervention. However, largely due to the cost of SA diagnosis in large population sam-ples, many studies can only indirectly implicate SA in the etiology of CV disease.
In addition, comorbidities such as obesity and hypertension that coexist with the majority of SA patients make the independent risk of SA on vascular disease more difficult to assess [20]. Table 2.3.1.1 summarizes some cohort studies relating SA and incidence of cardiovascular disease [14–16, 20, 78, 86, 215].
In brief, the pathophysiological phenomena that take place in SA lead to increased sympathetic activation, increased oxidative stress, inflammation, vascular endothelial dysfunction, increased platelet aggregability and meta-bolic dysrhythmia. These mechanisms may be implicated in the pathogene-sis and promotion of CVD, such as hypertension, CAD, congestive heart failure, systolic and diastolic dysfunction of the left ventricle, cardiac ar-rhythmias, stroke, pulmonary hypertension and all-cause mortality [53, 237].
2.3.2. Left ventricular morphometry and sleep apnea
Description of left ventricular hypertrophy and remodelling in SA An increased mass of the left ventricle has generally been thought to be the consequence of compensation by the ventricle for a hemodynamic stimulus, such as an increased demand for cardiac work. If the heart is chal-lenged with a higher afterload, such as an aortic valve stenosis or an in-creased peripheral arterial resistance with arterial hypertension, the left ven-tricle is believed to respond with thickening of the ventricular walls and, ultimately, concentric LVH. If the heart is challenged with a higher preload, as in the case of a larger circulating blood volume in obesity or a regurgitat-ing valve, the left ventricle is believed to respond with dilatation and, ulti-mately, eccentric LVH. Both wall thickening and dilatation may initially serve as relevant compensation for the increased hemodynamic stress and improve cardiac function, but also increase the weight of the heart [159, 160, 167].
In 2016, Bodez and coworkers present an overview of how OSAS may promote changes in LV geometry and diastolic dysfunction through its best-known cardiovascular complication, arterial hypertension. In summary, pathophysiological mechanisms are widely shared by these conditions: re-petitive hypoxaemia reoxygenation sequences, bursts of sympathetic activi-ty, hormonal and metabolic dysregulation, oxidative stress, systemic in-flammation and mechanical haemodynamic disturbances. These all partici-pate in the development of LVH and LV diastolic dysfunction, even if the role of each component considered separately is not yet well understood; in truth, there is probably a multifactorial effect [35].
In 1990, Hedner and coworkers [98] conducted a case-control study comparing 61 OSAS and 61 control patients. The interventricular septum and LV posterior wall were thicker, and so the LV mass (LVM) and LVM index (LVMI) were significantly higher in OSAS patients. In 1995, Noda and coworkers [198] provided the first prevalence of LVH in OSAS pa-tients, defined by LV wall thickness ≥12 mm. LVH was reported in 42% of the whole cohort (n=51), in 31% when the AHI was <20 and in 50% when the AHI was ≥20. Using the same criteria for LVH, Cloward and coworkers [49] reported a prevalence of LVH of 88% among 25 obese and severe OSAS patients. A dose-response relationship was also observed between the severity of OSAS and the prevalence of LVH, using LVMI (normalized by height) for LVH assessment [21, 254].
The largest cross-sectional study, including more than 2000 subjects (the Sleep Heart Health Study) [44], confirmed that LVMI (normalized by height) was significantly associated with both the AHI and the hypoxaemia index, even after adjustment for age, BMI, systolic BP and diabetes, with an adjusted OR for LVH of 1.78 (95% CI 1.1–2.8) between patients with an AHI<5 and those with an AHI≥30. In this study, the prevalence of LVH reached 33% in severe OSAS patients. The reported LVH is often eccentric; for example, Myslinski and coworkers [190] observed in 2007 that eccentric LVH was the predominant LV geometry in patients with newly diagnosed OSAS. In this study [190] and in the Sleep Heart Health Study [44], the LV end-diastolic diameter in OSAS patients was significantly higher than in controls (or treated OSAS patients), and correlated positively with the AHI and the desaturation index. Eccentric LVH was also twice as frequent as concentric LVH among treated OSAS patients [36, 35].
Conversely, Cioffi and coworkers reported that relative wall thickness was positively correlated with the AHI [48]; in this study, where BP was not different across the OSAS severity groups, LVM did not differ significantly, but LV concentric remodelling was independently associated with moder-ate-to-severe OSAS (OR=7.6) and BMI (OR=1.09). Likewise, Koga and
coworkers reported that concentric LVH was the most common LV geome-try in 37 OSAS patients [35, 134].
Morbid obesity is frequently associated with abnormal LVM, particularly in patients with OSA; this association is independent of HT, BMI, body composition, and other clinical factors, supporting a direct role of OSA on LVM in morbid obesity. This suggests that OSA and LVM might be taken as predictors of the cardiovascular risk in these patients [222].
Diastolic dysfunction in sleep apnea
Existing data indicate that the evaluation of diastolic dysfunction (DD) has both diagnostic and prognostic importance in the management of CAD [178]. To date, however, there is a lack of knowledge regarding the impact of OSA on DD in patients with CAD.
The reported [35] prevalence of DD among OSAS patients varies from 23% to 56% [12, 21, 36, 75], depending on the sample size and the method of diastolic dysfunction assessment. Studies have reported a dose-response relationship between severity of diastolic dysfunction and severity of OSAS [45, 140, 241]. However, they did not use the same variables to characterize diastolic function or the severity of OSAS. Two studies carried out on small populations [45, 140] reported that lower minimum arterial oxygen satura-tion, but not AHI, was associated with the E/A ratio and a pro-longed IVRT. Other studies reported a significant correlation between E/A ratio and mean nocturnal oxygen saturation [126] or between e′ and the AHI [2]. However, in numerous studies, LV diastolic dysfunction was observed in OSAS patients, together with older age [21], higher BP [3, 35, 66, 135], higher BMI [135] or higher LVH [40, 66, 124, 135]. In a recent review, Baguet and coworkers [22] focused on common OSAS co-morbidities, such as hypertension and diabetes, which lead to OSAS-related cardiac disorders, such as CAD, LVH and atrial fibrillation, thus establishing a strong basis for a perfect continuum from diastolic dysfunction and heart failure with pre-served ejection fraction to systolic heart failure [35].
2.3.3. Longitudinal association between sleep apnea and cardiovascular events
Intermittent hypoxia, repetitive arousal from sleep or the large intrathora-cic pressure swings and increased sleeping blood pressure which are charac-teristic of SA are generally thought to be the most likely causal pathway through which SA causes cardiovascular disease [62, 156, 163]. Sleep dis-ordered breathing has been associated with oxidative stress, inflammation, and altered hormonal levels, all of which could affect the risk of cancer [46,
