Atrial fibrillation is the most common cardiac arrhythmia and is associated with detrimental consequences. In addition to worsening patient’s quality of life, AF is associated with stroke, heart failure, and increased mortality(8). Sepsis is characterized by a systemic release of pro-inflammatory cytokines, high levels of circulating stress hormones, autonomic dysfunction, intravascular volume shifts and cardiovascular compromise(9), all of which are plausible risk factors for the development of AF(10).
New-onset AF in sepsis was defined as presence of AF in patients without prior AF, and the occurrence of AF was associated with sepsis. Some studies have assessed the relationship between new-onset AF and outcomes in ICU patients. A meta-analysis has shown that patients with sepsis who developed new-onset AF have higher mortality(11). Studies done in the ICU have shown that critically ill patients with new-onset AF have higher mortality and longer hospital stay (12–16). AF is also associated with mechanical ventilator weaning failure (17). Therefore, we aimed to gain a better understanding of the incidence and investigate whether new-onset AF in sepsis can be explained by increased circulating inflammatory cytokine concentrations.
Yu-Feng Hu et al(18) showed that inflammation has an important role in the initiation and maintenance of AF, and the electrophysiology and structural properties of the atria are critically affected by inflammatory processes, and the efficacy of the proposed anti-inflammatory drugs remains far from satisfactory. And, Nicholas A. Bosch et al(19) demonstrated that they identified two inflammation-related factors associated with AF risk during sepsis, increased inflammation, elevated C-reactive protein(greater than 70 mg/L) or WBC count (greater than 15 × 109/L) associated with increased AF risk. Some other experimental studies suggested that cytokines cause new-onset AF via mechanisms such as atrial remodelling(20, 21) or calcium overload in atrial myocytes(22, 23). However, no clinical study examined the association of circulating cytokine concentrations with new-onset AF in sepsis in patients. Our present study shows that circulating inflammatory cytokines are probably not the dominant causes of new-onset AF in real-life sepsis. Rather, cytokines probably have a weaker clinical role in the pathophysiology of new-onset AF in sepsis than suggested by the in vitro experiments, or their mechanisms are more complex and indirect than can be detected by correlations between cytokine concentrations and new-onset AF. However, other explanations are also possible. The pathophysiology of new-onset AF in sepsis is far from being fully understood.
In this study, we have revealed that BMI, hypertension, fibrinogen, hs-Troponin-T strongly correlated with the new-onset AF in sepsis, and clarification of the risk factors for AF during sepsis may improve our understanding of the mechanisms of arrhythmia development and help guide clinical practice.
Body Weight and New-Onset AF
Overweight and obesity are known risk factors for new-onset AF(24). Yun Gi Kim et al(25) found that the degree and duration of hypertension, as well as the presence of hypertension, were important factors for new-onset AF. Body weight status was significantly associated with new-onset AF and acted synergistically with hypertension. In a study of 34 patients, high-dominant frequencies or complex atrial fractionated electrogram sites were located adjacent to epicardial fat areas, which suggest that epicardial fat might maintain AF by releasing paracrine inflammatory mediators(26, 27). And free fatty acid overload in patients with obesity induces lipid accumulation within cardiomyocytes and apoptosis, which might also trigger regional inflammation(28). The potential pathophysiological mechanism of body weight and new-onset AF is that obesity-induced immune cell infiltration into the adipose tissue, particularly by M1 macrophages, as well as inflammation of adipose tissue and secreted proinflammatory cytokines occurs in patients with obesity.
Hypertension and New-Onset AF
The association between hypertension and AF in patients with sepsis is not yet established. However, based on the framingham heart study, hypertension increases the risk of AF by ≈ 1.5-fold(29). And the hypertensive people who have required medication for > 5 years had the highest risk of new-onset AF. Hypertension, if uncontrolled and long-standing, can lead to LVH, decreased diastolic function, and elevated LA pressure that will eventually lead to LA dilation and fibrosis(30). Those adverse changes in the LV and LA contribute to the development of new-onset AF(31, 32). Atrial stretch, owing to elevated left ventricular diastolic pressure in patients with hypertension, might activate regional RAAS, cardiac apoptosis, and oxidative stress, which can subsequently induce regional inflammation in the heart and correlated with new-onset AF in sepsis(33).
In our date, We found significant differences between two groups in hypertension, non new-onset AF in sepsis 48(26.4%), new-onset AF in sepsis 40(44.9%), (P < 0.05). Therefore, uncontrolled and long-standing hypertension is especially dangerous in terms of the occurrence of new-onset AF. Furthermore, the risk of new-onset AF showed a linear relationship with SBP and DBP. However, in our study, the SBP and DBP in patients with new-onset AF were not significantly higher compared to patients who never developed AF (SBP:t = 1.037, p = 0.301; DBP:t = 1.794, p = 0.074), because the inclusion criteria were different, and the patients with sepsis would affect heart function, reduce cardiac ejection function and affect blood pressure.
Fibrinogen and New-Onset AF
As a member of the coagulation system, fibrinogen plays an important role in the occurrence and development of sepsis. The earliest evidences about the role of coagulation activation during sepsis included histological demonstration of microvascular thrombosis in target organs of septic patients and the progressive decrease in platelet counts and coagulation factor levels in the late stages of sepsis, attributed to a “consumption coagulopathy”(34). In addition,fibrinogen was associated with the occurrence of AF. Fu R(35)found that compared with the controls, patients with AF had higher levels of fibrinogen (AF vs control: 3.3 ± 0.9 vs 3.0 ± 0.6 g/L, P = 0.02). Besides, Wei CC’s study (36)and Hu X’s study(37)also found the relationship between fibrinogen and AF. Our study shows that fibrinogen strongly correlated with the new-onset AF in sepsis, and the independent risk factors for the new-onset AF in sepsis.
According to relevant clinical studies(34), we considered that in patients with sepsis, blood coagulation disorder and microvascular thrombosis lead to cardiac microcirculation disturbance, affect myocardial blood supply, induce electrophysiological disorders of cardiomyocytes, and produce arrhythmias and AF, and Allan J. Walkey (38)found that the intensity and regulation of coagulation activation in sepsis seems to play a major role in the determination of patients’ outcome. Therefore, coagulation dysfunction may be one of the important causes of new-onset AF in sepsis, and our results provide targets for future studies focused on new-onset AF in sepsis prevention and treatment.
HS-Troponin-T and New-Onset AF
Information on the hs-TnT level has improved the prognostic information not only in patients with chest pain and acute coronary syndromes but also in patients with conditions such as congestive heart failure and stable atherosclerotic disease and even in apparently healthy elderly subjects. And Ziad Hijazi et al (39)found that hs-TnT levels can be detected in almost all patients (93.5%) with AF, levels of hs-TnT are often elevated in patients with AF, and the hs-TnT level is independently associated with an increased risk of stroke and cardiac death. However, Horjen AW et al (40)found that hs-TnI correlated weakly with biomarkers representing myocardial wall tension, inflammation and haemostasis in persistent AF, and hs-TnI release is an independent process parallel to other pathophysiological mechanisms associated with AF.
Based on the findings of the present study, we found that hs-TnT correlated with the new-onset AF in sepsis, and represented the independent risk factors for the new-onset AF in sepsis. And our results are consistent with those of Ziad Hijazi(39). There are several potential mechanisms that might explain this association between new-onset AF and HS-Troponin-T. One of the most important mechanisms is that atrial myocardial infarction, or ischaemia which will increase level of myocardial markers (such as HS-Troponin-T et al), will aslo induce atrial inflammation during the healing process, and might consequently induce AF(41).