Vol.48 - Número 4, Octubre/Diciembre 2019 Imprimir sólo la columna central

Sleeping with the enemy: Sleep apnea, atrial fibrillation,
bradyarrhythmias and sudden cardiac death

GABRIEL SALICA, JAVIER BONACINA
Hospital “Ángel C. Padilla”.
(4000) San Miguel de Tucumán, Argentina
E-mail
Recibido 18-OCT-2019 – ACEPTADO después de revisión el 19-NOVIEMBRE-2019.
There are no conflicts of interest to disclose.

 


ABSTRACT

Sleep apnea is a clinical entity characterized by alterations in airflow with a drop in arterial oxygen saturation that happen during sleep. This pathology is significantly associated with increase in cardiovascular morbidity and mortality, being an important factor for development of bradyarrhythmias, tachyarrhythmias and sudden cardiac death. In this review, we talk about the epidemiological, pathophysiological aspects of sleep apnea and its impact on the development of arrhythmias and sudden cardiac death.
Key words: Sleep apnea. Atrial fibrillation. Ventricular arrhythmia. Sudden cardiac death.

 

INTRODUCTION
Sleep apnea (SA) is a syndrome consisting of the appearance of recurrent episodes of decrease or absence of inspiratory air flow during sleep, for at least 10 seconds, associated to a drop in arterial oxygen saturation [1]. Apneas are classified into obstructive (OSA) and central (CSA); in the first one there may be anatomical narrowing of airway accompanied by excessive loss in muscle tone, which lead to airway collapse; in the second one, there is transient reduction of pontomedullary pacemaker in the generation of respiratory rhythm, reflecting changes in partial pressure of CO2 (pCO2), that may drop below the apnea threshold and lead to respiratory arrest [2-3]. SA affects 5% of the population of the US [4], with a greater prevalence in men than in women, and a significant association with increase in overall mortality and cardiovascular mortality, being considered a risk factor for hypertension (HTN), stroke, atrial fibrillation (AF), bradyarrhythmias, CAD and sudden cardiac death (SCD) [5-6]; in spite of this, it is still underdiagnosed [4] (Figure 1).


Figure 1. Prevalence of sleep apnea and cardiovascular pathology. HTN: Hypertension.


In this review, we will approach three cardiovascular scenarios with their epidemiological, pathophysiological and therapeutic aspects in relation to SA. These scenarios are: 1) AF, 2) bradyarrhythmias, including sinus node dysfunction (SND), atrioventricular (AV) conduction disorders, 3) ventricular arrhythmia and SCD.

 

ATRIAL FIBRILLATION
There are many pathologies associated to a higher risk of developing AF; among them, HTN, heart failure (HF), valve diseases among others; but recently, a direct relation between AF and SA has been proven, with an estimated prevalence of up to 50% [7,8]. In a study with more than 3500 patients with history of AF who underwent polysomnography, nocturnal desaturation appeared as an independent predictor for the development of AF. In this same study, the authors observed that an apnea-hypopnea index >40 and a body mass index >35 were independent predictors for the development of AF [9]. Monitoring of patients with cardioverter defibrillators showed more frequent episodes of nocturnal AF in patients with SA [10]. Gami verified in his study, that approximately half of patients with AF had chances of presenting SA and association of SA with AF was greater than the association of SA with traditional risk factors for the development of AF, such as body mass index, neck circumference and HTN [7]. It seems the more severe the SA, the greater the risk of AF; as the Sleep Heart Health Study showed that patients with severe SA presented a risk of AF fourfold greater than the rest of the population [11].

In the pathophysiology of SA and relation to AF development, there are several mechanisms involved (Figure 2), such as alterations in the autonomic nervous system (ANS) during apnea episodes. Specifically, it has been proven that the activation of local parasympathetic nerves may include atrial refractoriness shortening and local sympathetic nerves pacing operate as direct triggers for AF through early diastolic depolarization [12]. In an experimental study in animals, where a group of them had apnea induced, it was observed that in animals that underwent apnea, acute atrial dilatation occurred, and this is worse the greater the apnea duration. Likewise, in this group of animals, AF induction was easier and its duration was longer than in animals that did not undergo apnea episodes, performing optical mapping that recorded changes in refractory periods and in atrial conduction velocity that may facilitate AF induction and duration. These mentioned phenomena were accentuated as more apnea episodes were induced. In the same study, autopsy was performed on some animals, where it was manifest that in those in whom apnea episodes had been induced, there was connexin expression and distribution decrease, and marked fibrosis increase, thus creating the electrical substrate for AF production [13].


Figure 2. Autonomous alteration mechanism during apnea episode and development of atrial fibrillation (AF).

 

In brief, we could say that during the apnea episode, mechanical alterations occur such as acute atrial dilatation, ANS activation, with all of these triggering modifications in refractoriness, conduction velocity, besides triggering the onset of structural remodeling phenomena, such as fibrosis increase. The repetition over time of these short phenomena would enable reaching the fibrillation threshold for AF development and maintenance (Figure 3).

Figure 3. Pathophysiology of sleep apnea and development of atrial fibrillation (AF).

 

SINUS NODE DYSFUNCTION AND ATRIOVENTRICULAR CONDUCTION DISORDERS
For a while now, SA has been associated to bradyarrhythmias (AV conduction disorders and SND). Renna reported an incidence of 11% of SND in patients with SA and up to 25% of AV conduction disorders [11]. Other authors reported similar results and also found that such disorders were independent from the apnea mechanism being central or obstructive [14]. Almora et al, reported that SND is 10 times more frequent in patients with SA than in the general population [15]; which would indicate an association between both entities. A multicenter European study on patients with pacemaker indication due to bradycardias and AV block, found a high prevalence of undiagnosed SA, 58% in patients with SND and 68% in those with pacing indication due to AV conduction disorders [16].

In their pathophysiology, bradycardia episodes and pauses happen during apnea and hypopnea episodes, and not during the hyperventilation that follows these, and having a clear relation to SA severity [17]. Episodes of AV block and pauses could be due to intense vagal discharges; several years ago Tilkian showed that these could be prevented by the administration of atropine [18]; although the degree of severity influences a greater possibility of appearance of pauses or blocks and desaturation level seemed not to be involved. Koehler et al, showed in their study, the presence of AV conduction disorder with different degrees of saturation [19], which could be related to individual variation in each patient. An important aspect is bradyarrhythmias being produced during the REM phase of sleep, where oxygen desaturation and vagal discharge would be more emphatic. Some authors have shown that up to 50% of these patients may have sinus node recovery time prolongation and His bundle conduction anomalies; but observed that these anomalies improved with atropine administration [20]. Other authors reported contradictory results, with no evidence of conduction alterations [18]. All of this entails the main mechanism of block episodes and sinus dysfunction being due to exacerbated vagal tone. It is possible that during the REM phase of sleep, there may be loss of synchrony between breathing and cardiac activity, which may lead to an excessive autonomic discharge with strong chemo and baroreceptors stimulation, induced by hypoxemia and the great increase in intrathoracic pressure [21]. An issue to take into account is that pharyngeal obstruction during apnea episodes also stimulate pharyngeal mechanoreceptors, producing vagal discharge that may contribute to the presence of bradycardia [19].

In brief, we could say that hypoxemia produces an intense vagal discharge that occurs by the stimulation of several receptors simultaneously, which in turn coincide with the REM phase of sleep, when vagal discharge intensifies, leading to the production of blocks and pauses (Figure 4).

Figure 4. AV block mechanism in sleep apnea.

 

VENTRICULAR ARRHYTHMIA AND SUDDEN CARDIAC DEATH
A high incidence of ventricular arrhythmia has been reported in patients with SA close to 25%, including isolated premature ventricular contractions, bigeminy and nonsustained ventricular tachycardia (NSVT) [11]. Subsequent studies reported an even higher incidence, reaching 66% [22]. Cintra Dumas, in a study with more than 700 patients, found a 39% incidence of ventricular arrhythmias, and from them, 5% were NSVT; they also observed that the latter were more frequent when the apnea/hypopnea index (AHI) was greater than 15 [23]. In a study with 132 patients with 25% left ventricular ejection fraction (LVEF) who had a cardioverter defibrillator (ICD) implanted as primary prevention, it was observed that patients with SA had a higher incidence of ventricular arrhythmia with 53% of device interventions in relation to 9% of patients without SA. Bitter et al, evaluated 472 patients, in whom ICD was implanted as primary prevention with LVEF of less than 40%, who were followed for 48 months. When the ICD was interrogated, it was observed that patients with SA had device interventions with proper therapies earlier than patients with no SA; likewise, in the follow-up period, there were more ICD interventions with anti-tachycardia shocks or pacing in patients with SA, mainly in those with moderate to severe apnea [25]. In a meta-analysis including 9 studies and more than 1200 patients with heart failure and implanted ICD, the conclusion was that SA is associated to an increase in the incidence of proper therapies by the device in these patients, and that this association is independent from the apnea mechanisms, whether obstructive or central [26]. SA could be considered an indicator of mortality. In a clinical trial including 380 patients with a prolonged follow-up of 14 years, SA was a strong indicator of mortality for patients with moderate-to-severe SA [27]. In another study with a bigger number of patients (1022) and a shorter follow-up (5 years), SA was also a mortality indicator, even with lower AHIs [28]. Gami, in a more recent study with 1071 patients followed for 5 years, found that SA is a risk indicator for sudden cardiac death with a high statistical significance [29]. SA has also been reported to increase mortality risk in patients with heart failure and myocardial ischemia, with a higher incidence of sudden cardiac death (SCD) and heart failure progression [30]. Gami, studying more than 100 patients followed for 10 years found that patients with SA presented SCD events between 10 pm and 6 am, unlike patients presenting SCD who had no SA, where mortality was greater after 6 am [31]. This could suggest SCD pattern.

It has been observed that SA is an indicator of ventricular arrhythmia and sudden cardiac death, occurring by a series of mechanical, inflammatory and electrical modifications that will be described next.

Mechanical modifications: These mechanical changes in the myocardial structure are related to systolic and diastolic dysfunction that occurs in SA [32]. We have to remember that several risk factors coexist between heart failure and SA, such as obesity, HTN, diabetes and ischemic heart disease. There are several ways by which SA may lead to ventricular dysfunction, intermittent oxygenation, sympathetic activity, preload and postload increase caused by apnea events, gradually producing ventricular function impairment (Figure 5). In recent years, several studies showed that the presence of SA induces structural changes in both ventricles [33-34]. Recent studies showed that patients with SA present signs of left ventricular hypertrophy and biventricular filling alteration, even in absence of concomitant HTN. These alterations are greater when associated to HTN [35]. The percentage of asymptomatic systolic dysfunction in patients with mild-to-moderate SA is 55% [36]; just as a prevalence of 25% is being reported for diastolic dysfunction in patients with SA and this is increased as the severity of the apnea increases [37]. A failure to make an early diagnosis may lead to a progression in ventricular dysfunction and cause structural alterations that entail these mechanical modifications necessary to create a substrate appropriate for arrhythmias and SCD.


Figure 5. Alterations during sleep apnea that lead to structural changes.



Figure 6. Mechanical, inflammatory and electrical modifications that lead to sudden cardiac death.

 

Inflammatory changes: SA is associated to inflammatory cascade alteration, oxidation processes alterations, and reduction in the positive regulation of the participating genes [38]. This positive regulation would produce an increase in systemic inflammatory expression manifest by increase in proinflammatory mediators, such as C-reactive protein, interleukin-1, tumor necrosis factor and thrombosis mediator molecules such as fibrinogen  [39]. A meta-analysis with more than 23 studies confirmed the great systemic inflammatory activity in these patients, not just finding elevated levels of proinflammatory markers, but also observed in uvula and subepithelial edema of bronchial tissue biopsies, excessive infiltration of inflammatory cells and overexpression of interleukins [40]. Another meta-analysis showed not just inflammatory markers elevation, but that their level is related to SA severity [41]. These inflammatory changes also occur in the different arterial territories, favoring the processes of atherosclerosis. The activation of NADPH oxidase increases the formation of hydrogen peroxide (H2O2) and reactive oxygen and nitrogen species, with influence on the biological processes of fatty tissue, favoring the formation of cytokines as interleukin-1, interleukin-6 and tumor necrosis factor that promote leptin and adiposin release; also circulating monocytes are activated, expressing the chemotactic protein inducing endothelial surface molecule adhesion, reduction in expression and nitric oxide synthetase activity, promoting the apoptosis of endothelial cells. The activated monocytes migrate through the endothelial cells rupture toward the vessel wall and will turn into activated macrophages that will accumulate lipids, becoming foam cells, which are the initial prototype of a future atheromatous lesion [42]. Intermittent hypoxemia maintained chronically and accompanied by a diet rich in lipids induce hypercholesterolemia, liver peroxidation and resistance to insulin, even in the absence of obesity [43]. All these inflammatory changes favor atherosclerosis and coronary lesions, ischemic lesions and acute coronary syndromes. For many years it has been known that SA has an elevated prevalence of CAD, reported in some studies as close to 54% [44]. A meta-analysis with more than 5000 patients showed a clear association of acute coronary syndromes and SA with these events, which up to 25% were fatal, with apnea/hypopnea index being a significant risk marker [45]. The cardioprotective effect of sleep in these patients is lost, due to intense sympathetic activity during the REM phase of sleep, precipitating ischemic events, which manifest by ECG alterations during sleep [46-47]. Lee has reported in more than 100 patients admitted with ST elevation acute coronary syndromes, the negative impact of SA in an 18-month follow-up with an increase in reinfarctions, requirement of new revascularization procedures and hospitalization due to heart failure [48]. Subsequent studies found similar results, emphasizing that the treatment of SA may decrease new events [49].

Electrical changes: The sympathetic nervous system (SNS) plays an important role in electrical changes. Hypoxia cycles originated by apnea generate an increase in sympathetic activity by stimulation of central and peripheral chemoreceptors due to CO2 accumulation, causing effects such as increase in heart rate, peripheral vasoconstriction, renin-angiotensin system activation, translated into blood pressure increase [50]. This increase in sympathetic activity may not only occur at night, during apnea, but it would also persist during the day, because of loss in the sensitivity of beta receptors to catecholamines, with the subsequent deleterious effect on the cardiovascular system. Evidence of this is the increase in heart rate and blood pressure during the day [51]. Animal models of SA have confirmed the hypersensitivity of the carotid body as a result of intermittent hypoxia with plasticity of glomus cells of the carotid body with sensory facilitation and sensitization in the long term. All of this is associated to accumulation of chemical reactive forms of oxygen, of NOX2-dependent HIF1 and the protein transcriptional coactivator, which allow activation sustained over time. There is ANS dysfunction associated to SA with excessive activation of the CNS, inducing a neuroplasticity process, increasing the excitatory impulse to the rostral ventrolateral medulla, and maintains a high sympathetic tone, regardless of the sensory peripheral signs, due to pathological increase of the neuronal excitatory input and prevention of decrease in protective inhibitory signals [52-53]. Ziegler has shown that treatment with CPAP has decreased diurnal sympathetic activity and improved the sensitivity of beta receptors to catecholamines [54]. Sympathetic activity could be measured by an increase of catecholamines in urine [55], and also by indirect methods such as heart rate variability and turbulence, all of which are increased in patients with SA [56]. This exacerbated sympathetic activity affects myocardial repolarization. QT interval (QTI) represents ventricular systole and diastole; i.e. ventricular myocardial contraction and repolarization. QTI prolongation reflects a repolarization delay and a greater refractoriness dispersion. These changes create conditions that favor the appearance of ventricular arrhythmias [57]. In sleep, there is normally QTI prolongation, related to changes proper of autonomic function occurring during sleep [58]. In patients with SA, for a while now, QTI prolongation has been observed mainly at the onset of apnea, with subsequent shortening during post-apnea, during hyperventilation, particularly recorded in the REM phase of sleep [59]. This phenomenon is even more intense as AHI increases [53], characterized by a flattened relation between heart rate and QTI duration. This would be a reflection of alteration in the autonomous nervous system [60]. Baumert has observed in his study, QTI duration variation, with great beat-to-beat variability, mainly during the obstructive episode. This variation was related to the drop in oxygen saturation and AHI, leading to a positive relation as there is more oxygen saturation drop and AHI increase, with more beat-to-beat QTI variability [61]. This ventricular repolarization alteration phenomenon makes it heterogeneous, with areas of slow and rapid repolarization, affecting conduction velocity that becomes non-uniform in the different parts of the ventricle, favoring reentry mechanisms, ventricular arrhythmias and SCD. These disorders could be corrected by using continuous positive airway pressure (CPAP), with decrease in cardiovascular events [62]. These electrical changes may settle on molecular changes originated by potassium channels expression. Jiang found an increase in mRNA, in at least 5 out of 8 genes that encode myocardial potassium channels. Such results correlate with hypoxemia and apnea severity, affecting transcriptional factor HIF 1-a in its stability and conformation, which produces a lower amount of potassium channels and loss of function [63].

In brief, the set of mechanical, inflammatory and electrical changes create the necessary conditions for events occurring, which may lead to SCD.

 

TREATMENT
Treatment with CPAP has proven to reduce global cardiovascular risk [1]. The lack of treatment of SA may decrease the efficacy of AF treatment.

Kangala has reported after electrical cardioversion, AF recurrence in 82% in patients with untreated SA, in spite of these patients presenting less incidence of HTN, less body mass index than patients with treated SA that presented a recurrence of less than 42% [64]. The ORBIT-AF Registry, which included 10,133 patients, observed that 1 in each 5 patients with AF had SA. A lack of specific treatment for SA was a factor for progression of AF with less recurrence and hospitalization; besides a greater amount of cardiovascular events [65]. A meta-analysis with more than 3700 patients with SA and AF treated by ablation, verified a greater post-procedure AF recurrence in patients with untreated SA [66].

CPAP use reduced the incidence of ventricular arrhythmias and episodes of bradyarrhythmia [67]. The implementation of CPAP on patients with HF and SA has shown a favorable clinical effect on different cardiovascular system structure and function parameters. The beneficial effects would be a decrease in the activity of the sympathetic nervous system, both during sleep and daytime, improvement in endothelial vasodilation capacity, reduction of nocturnal blood pressure and heart rate, and increase in baroreflex sensitivity [68-69].

Marin et al, when evaluating mortality in patients with moderate and severe SA, in a 10-year follow-up, observed that patients treated with CPAP openly reduced the risk of fatal and nonfatal events, taking the risk of treated patients to a level similar to snorting patients with no SA [70].

 

CONCLUSIONS
SA is an underdiagnosed pathology, with nefarious consequences for cardiovascular health. It is an important risk marker for AF, bradyarrhythmias and SCD, which should be identified early and be treated to decrease cardiovascular risk.

 

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Publication: December 2019



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