The present study has mainly demonstrated that 12-week CRIC can decrease the AF burden in pacemaker-implanted patients, which need to be confirmed in large RCT with long-term follow-up in the future.
AF is a major risk factor for ischemic stroke and provokes important economic burden along with significant morbidity and mortality, both incidence and prevalence of which have increased over the last 20 years and will continue to increase over the next 30 years20. AF burden had not got enough attention for a long time and incorporated into stroke risks scoring systems may partly because of the difficulty to assess these data before. However, with wider usage of different types of CIEDs including pacemakers, ICD, CRT-D/P, and loop recorders, it is easier to monitor long-term atrial arrhythmias and evaluate the AF burden precisely, even if these arrhythmias are asymptomatic and may last only seconds21.
Another reason why AF burden was not valued perhaps is the controversial results of stroke risk between PAF and consistent AF in previous studies. Hart et al22 compared 460 intermittent AF participants with 1,552 sustained AF participants during aspirin therapy in the Stroke Prevention in Atrial Fibrillation studies, and found the annualized rate of ischemic stroke in patients with intermittent (3.2%) was similar to the patients with sustained AF (3.3%) after a mean of two years follow-up. However, another study drew a distinct conclusion6. They analyzed 6563 aspirin-treated patients with AF from the ACTIVE-A/AVERROES databases, and found that yearly ischemic stroke rates were 2.1, 3.0, and 4.2% for paroxysmal, persistent, and permanent AF, respectively, with adjusted hazard ratio of 1.83 (P < 0.001) for permanent vs. paroxysmal and 1.44 (P = 0.02) for persistent vs. paroxysmal.
However, AF in those studies was mainly identified with infrequent electrocardiographic techniques22, which identified predominantly PAF who are in AF most of the time. As mentioned above, with the wide application of more sensitive and accessible CIED for AF detection, especially the wide usage of DDD pacemakers, we now recognize a much larger prevalence of paroxysmal and short-lasting AF, for which the association with stroke may be different3 23.
Several studies have used CIED to detect AF in different populations and analyzed the association between AF burden and stroke or systemic thromboembolism3. Boriani et al performed a pooled analysis of data from 3 prospective studies (PANORAMA, Italian Clinical Services Project, and TRENDS), with 10,016 patients received an CIED implanted, which had at least 3 months of follow-up24. After adjustment for CHADS2 score and usage of anticoagulants, Cox regression analysis showed that AF burden was an independent predictor of stroke. The risk for stroke increased by about 3% for every additional hour increase in the daily maximum of AF burden24. A recent study23 found that patients with thromboembolism had higher incidence of pacemaker-detected AF and higher AF burden in the propensity score-matched cohort with comparable CHA2DS2-VASc score, and patients with AF episodes lasting > 6 min had higher risk of future stroke or thromboembolism on Cox regression analysis (propensity-adjusted HR, 6.75; P = 0.023). Besides thromboembolic events, AF burden was associated with the risk of major adverse cardiovascular events (MACE) 25. During a median 37.0 months follow-up of 852 patients undergoing CIEDs implantation, the incidence rate (IR) of MACE after AHREs onset was higher in patients developing AHREs ≥ 24 h (IR 1.13%/year) than AHREs ≥ 5 min (IR 0.63%/year, p = 0.030). Multivariable Cox regression analysis showed that AHREs ≥ 5 min (HR 1.788, 95% CI 1.247–2.562, p = 0.002) was interrelated to MACE, and the association was even stronger for AHREs ≥ 24 h (HR 2.390, 95% CI 1.481–3.857, p < 0.001). In our study, AF burden was decreased nearly 50%, about 2 hours per day, by 12 week CRIC (p༜0.001). Thus we can speculate that CRIC may be a potential therapy to reduce the risk of ischemic stroke and MACE in these AF patients, while that need to be verified in future studies.
The results of clinical studies associated with CRIC were not always consistent. A potential reason was the different parameters of CRIC, including pressure, duration of deflation and inflation, number of cycles, frequency of CRIC, etc. The total duration of CRIC also differed greatly in many studies, which may play a role in the divergent results. We found that 12-week CRIC was more effective than 4-week CRIC in reducing AF load analyzed by repeated measurement ANOVA in our study, which means that CRIC may enhance its effects in a dose-dependent patern15. Wei et al demonstrated that preconditioning plus postconditioning every day for 28 days (D1PostC) further attenuated inflammatory and hypertrophic responses, improved cardiac geometry, function, and hemodynamics in rat ischemia/reperfusion injury model compared with perconditioning plus postconditioning every 3 days for 28 days (D-3PostC) 26. There was also a dose-dependent improvement in survival at 84 days by Kaplan–Meier analysis in separate experiments26. Many clinical studies also support that CRIC brings benefits in various conditions, including healing of diabetic foot ulcer27, stroke recurrence in patients with symptomatic atherosclerotic intracranial arterial stenosis28, and cognitive domains in patients with non-cardiac ischemic stroke29.
The mechanism of effects of CRIC on AF has not been fully elucidated. Kosiuk et al17 demonstrated that 3 sessions of RIC reduced the inducibility (23.3% vs 46.6%, p = 0.003) and sustainability (15.1% vs 32.9%, p = 0.01) of PAF significantly, which was possibly mediated by decrease in dispersion of atrial refractory periods (16.0 ± 14.0 ms vs 22.7 ± 19.0 ms, p = 0.21) and reduction in atrial conduction delay. Han et al30 observed that AF recurrence in the 3 months after the PAF ablation was significantly lower in the RIC group than in the control group. The RIPC group also showed a lower increase in atrial remodeling marker Matrix Metalloproteinase-9 and endothelial dysfunction marker von Willebrand-factor in blood samples compared with the control group30. Our study has shown that HRV was improved in heart failure patients by CRIC, which was a marker of autonomic nervous stress19. As we known, cardiac autonomic nervous stress was closely related to emerging and development of AF. Thus, neural factors may play an important role in CRIC, too. CRIC could regulate immune/ inflammation system14 and improve cardiac remodeling31, which also plays an important role in the progression of AF. However, the exact mechanism in reduction of AF burden by CRIC need to be further exploited in the future.
In conclusion, we found that CRIC can significantly reduce the AF load in patients with pacemaker in a dose-dependent manner. CRIC, a noninvasive and promising adjunctive therapy, thereby may further improve the outcomes over well-established therapies in AF patients.
Limitation: The sample size of this study was relatively small, and the course of follow-up was not long, therefore we have not set mortality and morbidity of stroke as end points. The results of our study and other potential meaningful benefits by CRIC need to be verified in large RCT.