Relation of the Severity of Obstructive Sleep Apnea in Response to Anti-Arrhythmic Drugs in Patients With Atrial Fibrillation or Atrial Flutter

doi:10.1016/j.amjcard.2012.03.037

The American Journal of Cardiology

Volume 110, Issue 3, 1 August 2012, Pages 369-372

https://doi.org/10.1016/j.amjcard.2012.03.037 Get rights and content

Atrial fibrillation (AF) is more common in those with obstructive sleep apnea (OSA) than in unaffected subjects and recurs more frequently in the presence of severe OSA after electrical cardioversion and AF ablation. However, it is unknown whether the severity of OSA influences the efficacy of antiarrhythmic drug (AAD) therapy in patients with OSA and AF. The aim of this study was to examine the impact of OSA severity on the treatment of patients with symptomatic AF using AADs. Sixty-one patients (mean age 62 ± 15 years, 21 women) treated with AADs for symptomatic AF who underwent overnight polysomnography were studied. Rhythm control was prospectively defined as successful if a patient remained on the same AAD therapy for ≥6 months with ≥75% reduction in symptomatic AF burden. Twenty-four patients (40%) had severe OSA. Thirty patients (49%) were rhythm controlled with AADs. Nonresponders to AADs were more likely to have severe OSA than milder disease (52% vs 23%, p <0.05); those with severe OSA were less likely to respond to AADs than participants with nonsevere OSA (39% vs 70%, p = 0.02). Nonresponders had higher apnea-hypopnea indexes than responders (34 ± 25 vs 22 ± 18 events/hour, p = 0.05), but there were no differences between these groups in minimum oxygen saturation or percentage of time spent in rapid eye movement sleep. In conclusion, patients with severe OSA are less likely to respond to AAD therapy for AF than those with milder forms of OSA.

Section snippets

Methods

The cohort used for this study and the techniques for measuring AF symptom burden have been previously described.⁶ Briefly, adults with documented AF or atrial flutter treated with ≥1 conventional AAD were prospectively enrolled in the Vanderbilt AF Registry, a clinical and genetic database. At enrollment and at 3, 6, and 12 months of follow-up, patients completed the modified University of Toronto AF Severity Scale (range 3 to 30) to gauge symptomatic AF burden.⁷ The AADs reported here reflect

Results

The analysis consisted of 61 subjects who underwent polysomnography and had serial evaluations of AF symptoms. Table 1 lists their demographics, cardiac histories, echocardiographic characteristics, and key sleep parameters stratified by response to AADs. Two-thirds were taking β blockers and/or calcium channel blockers; 50% were taking amiodarone, 25% were taking sotalol, and 25% were taking either flecainide or propafenone. Approximately half of the cohort (49%) had symptomatic response to

Discussion

This study provides data suggesting that severe OSA adversely affects the response to AADs in patients with symptomatic AF. Our findings that nonresponders to AADs (1) are more common in severe OSA than in milder disease and (2) have higher AHIs than responders are consistent with previous work in this area. A study from the Mayo Clinic showed analogous results for the treatment of AF with elective cardioversion; specifically, those with OSA were more likely to have recurrences of AF than those

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Cited by (130)

Inhibition of the acetylcholine-regulated potassium current prevents transient apnea-related atrial arrhythmogenic changes in a porcine model
2024, Heart Rhythm
More than 50% of patients with atrial fibrillation (AF) suffer from sleep disordered breathing (SDB). Obstructive respiratory events contribute to a transient, vagally mediated atrial arrhythmogenic substrate, which is resistant to most available antiarrhythmic drugs.
The purpose of this study was to investigate the effect of pharmacologic inhibition of the G-protein–gated acetylcholine-regulated potassium current (I_K,ACh) with and without acute autonomic nervous system activation by nicotine in a pig model for obstructive respiratory events.
In 21 pigs, SDB was simulated by applying an intermittent negative upper airway pressure (INAP). AF inducibility and atrial effective refractory periods (aERPs) were determined before and during INAP by an S1S2 atrial pacing-protocol. Pigs were randomized into 3 groups—group 1: vehicle (n = 4); group 2: XAF-1407 (I_K,ACh inhibitor) (n = 7); and group 3: nicotine followed by XAF-1407 (n = 10).
In group 1, INAP shortened aERP (ΔaERP –42.6 ms; P = .004) and transiently increased AF inducibility from 0% to 31%. In group 2, XAF-1407 prolonged aERP by 25.2 ms (P = .005) during normal breathing and prevented INAP-induced aERP shortening (ΔaERP –3.6 ms; P = .3) and AF inducibility. In group 3, INAP transiently shortened aERP during nicotine perfusion (ΔaERP –33.6 ms; P = .004) and increased AF inducibility up to 61%, which both were prevented by XAF-1407.
Simulated obstructive respiratory events transiently shorten aERP and increase AF inducibility, which can be prevented by the I_K,ACh-inhibitor XAF-1407. XAF-1407 also prevents these arrhythmogenic changes induced by obstructive respiratory events during nicotine perfusion. Whether I_K,ACh channels represent a target for SDB-related AF in humans warrants further study.
Prevalence of sleep apnea in unselected patients with atrial fibrillation by a home-monitoring device: The DAN-APNO study
2023, IJC Heart and Vasculature
Sleep apnea (SA), a modifiable risk factor in - atrial fibrillation (AF), is associated with worse outcomes in AF. We aimed to assess the prevalence and severity of SA in patients with AF, and, subsequently, to assess the positive predictive value (PPV) of moderate to severe SA by a home-monitoring device in comparison to cardio-respiratory monitoring (CRM) in consecutive patients with AF.
This cross-sectional study recruited unselected patients with AF without known SA from an out-patient clinic at Department of Cardiology, Herlev-Gentofte University Hospital. Participants underwent four consecutive nights of sleep-recording with the home-monitoring device NightOwl™ (NO). Moderate SA was defined as an Apnea-Hypopnea Index (AHI) of 15–29 and severe SA as ≥ 30 AHI. Participants with moderate to severe SA was offered CRM for validation of the diagnosis.
We included 126 patients with AF with a median age of 68 (interquartile range: 60–75) years, 42 (33 %) women, 70 (56 %) hypertension, 61 (48 %) hyperlipidemia and 49 (39 %) heart failure. NO detected severe SA in 36 (29 %) of patients with AF, moderate SA in 35 (28 %), mild SA in 45 (36 %) and no SA in 10 (8 %). Of 71 patients with moderate to severe SA by NO, 38 patients underwent CRM and the PPV of NO was 0.82 (31/38) to diagnose moderate SA and 0.92 (22/24) to diagnose severe SA by CRM.
Moderate to severe SA by NO was highly prevalent in patients with AF without known SA. A home-monitoring device such as NO could be an easy and feasible SA screening tool in patients with AF.
Effect of Widespread Sleep Apnea Screening on Progression of Atrial Fibrillation
2022, American Journal of Cardiology
Sleep apnea (SA) is recognized as a predictor of incident atrial fibrillation (AF) and AF recurrence after treatment. However, data on the prevalence of SA phenotypes in patients with AF and the effect of widespread SA screening on AF outcomes are scarce. We conducted a retrospective study of patients with AF referred for SA testing between March 2018 and April 2020. The screening was performed using home sleep testing or polysomnography. AF outcomes were examined by assessment of AF progression as defined by a change from paroxysmal AF to persistent AF, change in antiarrhythmic drug, having an ablation or cardioversion. Of 321 patients evaluated for AF, 251 patients (78%) completed SA testing. A total of 185 patients with complete follow-up data and SA testing were included in our analysis: 172 patients (93%) had SA; 90 of those (49%) had primarily obstructive sleep apnea, 77 patients (42%) had mixed apnea, and 5 patients (3%) had pure central apnea. Time from AF diagnosis to SA testing was associated with AF progression; after 2 years, the risk of AF progression increased (p <0.008). Continuous positive airway pressure treatment did not affect AF progression (p = 0.99). In conclusion, SA is highly prevalent in an unselected population of patients with AF, with mixed apnea being present in over 40% of the population. Early SA testing was associated with decreased rates of AF progression, likely because of earlier and potentially more aggressive pursuit of rhythm control.
Impact of CPAP on the Atrial Fibrillation Substrate in Obstructive Sleep Apnea: The SLEEP-AF Study
2022, JACC: Clinical Electrophysiology
Observational studies report that obstructive sleep apnea (OSA) is associated with an increasingly remodeled atrial substrate in atrial fibrillation (AF). However, the impact of OSA management on the electrophysiologic substrate has not been evaluated.
In this study, the authors sought to determine the impact of OSA management on the atrial substrate in AF.
We recruited 24 consecutive patients referred for AF management with at least moderate OSA (apnea-hypopnea index [AHI] ≥15). Participants were randomized in a 1:1 ratio to commence continuous positive airway pressure (CPAP) or no therapy (n = 12 CPAP; n = 12 no CPAP). All participants underwent invasive electrophysiologic study (high-density right atrial mapping) at baseline and after a minimum of 6 months. Outcome variables were atrial voltage (mV), conduction velocity (m/s), atrial surface area <0.5 mV (%), proportion of complex points (%), and atrial effective refractory periods (ms). Change between groups over time was compared.
Clinical characteristics and electrophysiologic parameters were similar between groups at baseline. Compliance with CPAP therapy was high (device usage: 79% ± 19%; mean usage/day: 268 ± 91 min) and resulted in significant AHI reduction (mean reduction: 31 ± 23 events/h). There were no differences in blood pressure or body mass index between groups over time. At follow-up, the CPAP group had faster conduction velocity (0.86 ± 0.16 m/s vs 0.69 ± 0.12 m/s; P (time × group) = 0.034), significantly higher voltages (2.30 ± 0.57 mV vs 1.94 ± 0.72 mV; P < 0.05), and lower proportion of complex points (8.87% ± 3.61% vs 11.93% ± 4.94%; P = 0.011) compared with the control group. CPAP therapy also resulted in a trend toward lower proportion of atrial surface area <0.5 mV (1.04% ± 1.41% vs 4.80% ± 5.12%; P = 0.065).
CPAP therapy results in reversal of atrial remodeling in AF and provides mechanistic evidence advocating for management of OSA in AF.
Pharmacological inhibition of acetylcholine-regulated potassium current (I<inf>K,ACh</inf>) prevents atrial arrhythmogenic changes in a rat model of repetitive obstructive respiratory events
2022, Heart Rhythm O2
Citation Excerpt :
Obstructive sleep apnea (OSA) is the most common sleep-related breathing disorder and is broadly associated with cardiovascular diseases.1 In patients with atrial fibrillation (AF), OSA is present in up to 70%2,3 and impairs catheter-based and pharmacological antiarrhythmic treatment.4–6 Some mechanisms, such as intrathoracic pressure changes, hypoxia, and fragmented sleep and intermittent arousals, have been suspected to contribute to a complex and dynamic AF substrate in the setting of OSA.3
In obstructive sleep apnea (OSA), intermittent hypoxemia and intrathoracic pressure fluctuations may increase atrial fibrillation (AF) susceptibility by cholinergic activation.
To investigate short-term atrial electrophysiological consequences of obstructive respiratory events, simulated by intermittent negative upper airway pressure (INAP), and the role of atrial acetylcholine-regulated potassium current (I_K,ACh) activated by the M₂ receptor.
In sedated (2% isoflurane), spontaneously breathing rats, INAP was applied noninvasively by a negative pressure device for 1 minute, followed by a resting period of 4 minutes. INAP was applied repeatedly throughout 70 minutes, followed by a 2-hour recovery period. Atrial effective refractory period (AERP) and AF inducibility were determined throughout the protocol. To study INAP-induced I_K,ACh activation, protein levels of protein kinase C (PKC_Ɛ) were determined in membrane and cytosolic fractions of left atrial (LA) tissue by Western blotting. Moreover, an I_K,ACh inhibitor (XAF-1407: 1 mg/kg) and a muscarinic receptor inhibitor (atropine: 1 μg/kg) were investigated.
In vehicle-treated rats, repetitive INAP shortened AERP (37 ± 3 ms vs baseline 44 ± 3 ms; P = .001) and increased LA membrane PKC_Ɛ content relative to cytosolic levels. Upon INAP recovery, ratio of PKC_Ɛ membrane to cytosol content normalized and INAP-induced AERP shortening reversed. Both XAF-1407 and atropine increased baseline AERP (control vs XAF-1407: 61 ± 4 ms; P > .001 and control vs atropine: 58 ± 3 ms; P = .011) and abolished INAP-associated AERP shortening.
Short-term simulated OSA is associated with a progressive, but transient, AERP shortening and a PKC_Ɛ translocation to LA membrane. Pharmacological I_K,ACh and muscarinic receptor inhibition prevented transient INAP-induced AERP shortening, suggesting an involvement of I_K,ACh in the transient arrhythmogenic AF substrate in OSA.
The Emergence of Inpatient Sleep Medicine: Screening for Sleep Disordered Breathing to Reduce the Burden of Cardiovascular Disease
2024, Current Sleep Medicine Reports

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: This work was supported by NIH, Grants HL65962 and HL075266 and an Established Investigator Award from the American Heart Association, Dallas, Texas.

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Arrhythmias and conduction disturbancesRelation of the Severity of Obstructive Sleep Apnea in Response to Anti-Arrhythmic Drugs in Patients With Atrial Fibrillation or Atrial Flutter

Section snippets

Methods

Results

Discussion

Am J Cardiol

Heart Rhythm

Heart Rhythm

J Am Coll Cardiol

Cardiovasc Pathol

Obstructive sleep apnea and the recurrence of atrial fibrillation

Circulation

High prevalence of obstructive sleep apnea in patients with resistant paroxysmal atrial fibrillation after pulmonary vein isolation

J Interv Card Electrophysiol

Arrhythmias and conduction disturbances
Relation of the Severity of Obstructive Sleep Apnea in Response to Anti-Arrhythmic Drugs in Patients With Atrial Fibrillation or Atrial Flutter