The main finding of the present study is the nearly 18-fold increase in the relative risk of nocturnal arrhythmia within 90 seconds (a physiologically-defined interval) following a respiratory disturbance in individuals with a broad range of SDB severity. Prior clinical and epidemiologic studies have established an association between SDB and arrhythmia (5
), but the temporal relationship between the two, particularly involving PAF and NSVT, has not previously been characterized. A small study in patients with central sleep apnea and heart failure demonstrated suppression of PVCs in the subset that responded to CPAP therapy (28
), suggesting indirectly a link between central apneas and ventricular ectopy. A small study of patients with severely depressed LV systolic function, severe SDB, and previously demonstrated ventricular ectopy on Holter monitoring demonstrated that PVCs occurred more frequently in the apneic phase of obstructive apneas than during other phases of the respiratory cycle (29
). Another study showed a higher frequency of apnea-associated compared to nonapnea-associated arrhythmias in 8 patients with SDB, left-ventricular dysfunction, and prior ICD placement (13
). However, none of these studies quantified the extent to which sleep-related respiratory disturbances operated as triggers for arrhythmias and none investigated PAF as an arrhythmia of interest.
A prior study from the SHHS reported an increased odds of arrhythmias among subjects with severe SDB (AHI ≥ 30 events/hour) compared to those with an AHI < 5 events/hour (10
). However, that analysis did not address the propensity for arrhythmias in individuals with more moderate levels of SDB, as is found more frequently in the general population. The current report analyzed all records of participants with an AHI < 30 events/hour. The majority of identified arrhythmias occurred among those with only moderate levels of SDB (AHI 5–30 events/hour). As shown by the moderate median AHI of our cohort and the finding that most of the respiratory disturbances preceding arrhythmias were hypopneas (as opposed to apneas), neither the severity of SDB nor the severity of individual respiratory disturbances needs to be extreme in order to increase the risk of arrhythmia.
In this study, we attempted to identify the relative contributions of hypoxia and arousal to arrhythmogenesis. We identified all ‘respiratory disturbances’ based solely on changes in airflow and effort signal amplitude, without requiring a linked desaturation or arousal. We then secondarily assessed whether the extent of linked desaturation or arousal was related to propensity for PAF or NSVT. In these analyses, the ORs for arrhythmia did not vary according to whether nadir saturation levels fell below 92% nor did they vary according to whether respiratory disturbances were associated with a cortical arousal. However, since more than one-half of the respiratory disturbances in the hazard/referent periods were associated with a desaturation of ≥ 3% (a commonly used clinical criterion) and the mean desaturation for all respiratory disturbances that occurred in hazard/referent periods was ~ 4%, it is possible that some degree of hypoxic stress was contributory to the observed associations. The overall small number of respiratory disturbances may have limited the ability to discern effects associated with arousal or desaturation. Nonetheless, our data also raise the possibility that additional mechanisms, such as large changes in intrathoracic pressure and stimulation of baroreflexes, may contribute to the link between respiratory disturbances and arrhythmias (25
In interpreting our findings, it is important to distinguish between relative and absolute risk. The overall frequency of arrhythmias in this community-based cohort was very low while the frequency of respiratory disturbances was moderate. Crude estimates of absolute arrhythmia rate suggest that 1 excess arrhythmia may occur per 1000 hours of sleep in subjects with a median AHI of 23 events/hour. The high and growing prevalence of SDB, which influences the effective ‘hazard period’ in the population, suggests that respiratory disturbances may contribute to a considerable number of excess episodes of PAF or NSVT. In addition, it is possible that risk is not evenly distributed in the population and that the rate of SDB-associated arrhythmias may be even higher among individuals with impaired cardiac function or with other risk factors that enhance their vulnerability to physiological stressors.
The high relative risk may provide insights into prior studies demonstrating adverse cardiovascular outcomes in patients with SDB, including AF. Our results reveal a significant association between the risk of PAF and the presence of a respiratory disturbance within the pre-defined hazard period. Significant associations between AF and SDB have been previously reported (9
); specifically, SDB is a risk factor for incident AF (11
) and for recurrence of AF following electrical cardioversion (31
). Repeated exposures to intervals of relatively high risk for PAF, both within a given night and over many nights, may result in an increasing cumulative burden of discrete PAF episodes over time. Each of these paroxysms may increase the propensity for further and sustained episodes of AF due to electrical remodeling within the atria (32
). Therefore, untreated SDB may serve as an ongoing source of AF stimulation leading ultimately to initiation or recurrence of clinically significant arrhythmia. Correspondingly, it is plausible that treatment of underlying SDB may inhibit progression of sub-clinical PAF to a more detrimental form of the arrhythmia. A marked rise in the prevalence of AF is anticipated in coming years with ~ 60% of that increase estimated to be attributable to obesity (33
). Our data, which temporally link SDB events and the risk of PAF, suggest that unrecognized SDB may be a contributing factor to the projected increase in AF due to obesity.
Our finding of increased risk of NSVT during the hazard period following a respiratory disturbance may provide further insight into the observed nocturnal predominance of sudden cardiac death in SDB patients (14
). For those with structural heart disease, the risk of SCD is higher in those with NSVT relative to those without it (34
). Therefore, our findings raise the possibility that, in a sufficiently susceptible population, SDB increases the nocturnal risk of SCD by providing frequent nocturnal exposure to a stimulus that increases the likelihood of ventricular arrhythmia. This possibility is supported by a recent study of heart failure patients with ICDs that demonstrated that appropriate anti-tachycardia therapies for VT or VF were delivered more frequently in those with SDB than in those without SDB; this relationship was present only during sleeping hours (36
). Furthermore, even in the absence of structural heart disease, SDB has been found to be highly prevalent in those with frequent PVCs and/or VT (37
); our results are consistent with this observation as well.
A strength of the present study was the utilization of the case-crossover design. Since individuals served as their own controls, this approach essentially eliminated confounding by subject characteristics that remained constant during the observation period, a challenge in all prior work in this area. In addition, the study participants are part of a community-based cohort, rather than ‘patients’ with a homogenous cardiovascular profile, and represent the full spectrum of SDB severity; both of these features enhance the generalizability of our findings.
A limitation of the current study is the small number of detected arrhythmias (38
), which reduced the ability to detect potential effect modification by underlying risk factors, subject characteristics, and sleep state effects. However, the case-crossover design allows for analytic efficiency as well as a minimum of confounding for between-individual comparisons. Detailed information regarding daytime arrhythmia prevalence and temporal distribution are not readily available, rendering impractical a direct comparison between the arrhythmia profiles of our cohort during wakefulness and sleep. We limited our assessment of nocturnal arrhythmias to PAF and NSVT; inclusion of complex ventricular ectopy as part of the analysis would have increased our sample size, perhaps at the expense of direct clinical impact of the results.
In summary, this study demonstrates that, across the range of SDB, the risk of clinically important nocturnal arrhythmias is markedly increased shortly after the occurrence of apneas and hypopneas during sleep. This work provides further evidence that intermittent airflow obstruction may lead to clinically important adverse cardiac effects, and that such effects may occur even in individuals without severe levels of SDB. Further research is needed to evaluate the ability of pharmacotherapy and/or SDB treatment to modify these associations.