Risk in atrial fibrillation: left atrial function matters

Abstract

This article refers to ‘Left atrial structure and function and the risk of death or heart failure in atrial fibrillation’ by R.M. Inciardi et al., published in this issue on pages xxx. The left atrium is a cardiac chamber whose main role has been traditionally considered the optimization of left ventricular (LV) filling and cardiac output. In this regard, there is a close interdependence between LV and left atrial (LA) function. LA reservoir function is influenced by LV contraction through the descent of LV base during systole, LA relaxation and stiffness, whereas LA conduit function is dependent on LV relaxation and preload, and LA booster pump function is influenced by LV compliance, LV filling pressures, and intrinsic LA contractility.1 Moreover, the left atrium possesses additional important properties, including endocrine function and regulatory function, which are tightly coupled with its mechanical function.2, 3 Atrial remodelling is the atrial response to stressors (mechanical, electrical, metabolic) and comprises three components4, 5: (i) structural (atrial dilatation in the setting of atrial fibrosis), (ii) functional (atrial mechanical dysfunction), and (iii) electrical (re-entry-prone milieu, created by alterations in ion channels, pumps, and exchangers with abnormal distribution and expression of gap junction connexin hemi-channels). These changes are conducive to atrial fibrillation (AF), which in turn is associated with further progression of atrial remodelling, correlating with the duration of AF.6 The changes in the atria in response to AF enhance the ability of the arrhythmia to sustain itself and recur (i.e. ‘AF begets AF’). In this issue of the Journal, Inciardi and colleagues assessed the association between LA structure and function and the risk of cardiovascular (CV) death or heart failure (HF) hospitalization in a non-valvular AF population of 971 patients (71 ± 9.4 years, 34.4% females, 54.6% history of HF) who underwent transthoracic echocardiography in the prospective echocardiographic sub-study of the Effective Anticoagulation with Factor Xa Next Generation in AF–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) study.7 LA structure was assessed with the LA volume index (LAVi) and LA function with the LA emptying fraction (LAEF = 100 * [maximal volume – minimal volume]/maximal volume) and LA expansion index (LAEi = [maximal volume – minimal volume]/minimal volume). Paroxysmal, persistent, and permanent AF were reported by investigators in 33%, 21%, and 46% of the cases, respectively. At the time of echocardiography, 321 patients (33%) were in sinus rhythm (74% had a history of paroxysmal AF). Over a median follow-up of 2.5 years, 142 patients (14%) experienced CV death or HF hospitalization. Higher LAVi and lower LAEF and LAEi were each associated with a higher unadjusted risk of the composite outcome and its components. After adjustment for clinical and echocardiographic confounders, only measures of impaired LA function were predictive of the composite outcome [hazard ratio (HR) per 1-standard deviation (SD) decrease of LAEF 1.35; 95% confidence interval (CI) 1.09–1.67; P = 0.005, and HR per 1 SD decrease of LAEi 1.34; 95% CI 1.06–1.69; P = 0.012]. These findings are in accordance with those of a previous study investigating the ability of parameters of LA morphology and function to predict HF and all-cause mortality in 1735 subjects with dyspnoea. The prognostic power of LAEi exceeded that of other well-established echocardiographic parameters including LAVi.8 Inciardi and colleagues7 should be congratulated for undertaking such a large and comprehensive study and commended for their thoughtful analytic approach to improve contemporary understanding of the contribution of LA mechanical dysfunction to the CV and HF risk in AF. This approach is further supported by the fact that several small studies of medical therapy (i.e. angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) as well as other therapeutic measures (e.g. ablation for AF or cardiac resynchronization therapy) demonstrated LA reverse remodelling,9, 10 especially in the early stages of LA structural and functional remodelling, with significantly improved outcomes including decreased AF recurrence. However, important aspects of the study design and cohort composition need to be considered when attempting to generalize these findings of Inciardi and colleagues.7 Structural remodelling of the atria is reflected through a variety of indexes, besides LA volume, including the degree of atrial fibrosis imaged with cardiac magnetic resonance.11 Admittedly, however, these techniques are complex and currently not widely available. Left atrial systolic function was not assessed. LAEF is a measure of overall LA emptying function (passive and active), whereas LAEi a measure of LA filling (reservoir function). LA systolic function can be successfully assessed both with traditional and novel sophisticated techniques.12 As AF is a cause of LA systolic dysfunction per se, evaluation of LA systolic function would have been an important add on in patients in sinus rhythm at the time of examination. The study of Inciardi and colleagues7 was virtually conducted in hypertensive patients (94.4% of the study population had a history of hypertension). Even mild hypertension, however, is associated with LA mechanical dysfunction.13 Moreover, LA mechanical dysfunction increases with the severity of hypertension. A cross-sectional study involving 236 untreated patients who underwent 24 h ambulatory blood pressure monitoring and two-dimensional echocardiographic examination demonstrated that LA function gradually deteriorated from patients with normotension, across patients with daytime hypertension, to patients with night- and day–nighttime hypertension.14 Hypertension ultimately increases the risk of AF, and because of its high prevalence in the population, it accounts for more cases of AF than other risk factors. Among patients with established AF, hypertension is present in about 60–80% of individuals.15 Despite the well-known association between hypertension and AF, several pathogenetic mechanisms underlying the higher risk of AF in hypertensive patients are still incompletely known. Thus, the study findings have been most likely affected not only from AF but hypertension as well, which is undoubtfully the most common risk factor for the development of AF. Caution, however, is required when extrapolating these findings in normotensive patients with non-valvular AF. In summary, the study of Inciardi and colleagues7 provides further evidence supporting the validity of LA function evaluation as a powerful and dynamic physiological marker of CV disease status in AF (Figure 1). This paper will undoubtfully contribute to the promotion of the use of LA function assessment to better risk stratify patients with AF. Conflict of interest: none declared.