Left Atrial Myopathy in Heart Failure with Preserved Ejection Fraction

Abstract

This article refers to ‘Left atrial function in heart failure with preserved ejection fraction: a systematic review and meta-analysis’ by M.S. Khan et al., published in this issue on pages 472–485. Heart Failure (HF) with preserved ejection fraction (HFpEF) was initially referred to as ‘diastolic HF’ because of the traditionally perceived dominance of left ventricular (LV) diastolic dysfunction in the pathophysiology.1 While LV diastolic dysfunction clearly plays the central and often instigating role in HFpEF, we now know that the pathophysiology is much more complex. Left atrial (LA) myopathy has emerged as one of the most important ‘non-LV’ contributors to this syndrome. In the absence of histopathologic data, the term ‘LA myopathy’ may be used to broadly refer to LA structural remodelling, abnormalities in atrial systolic and diastolic function, and electrical remodelling, which often eventually lead to the development of atrial fibrillation (AF). Preservation of LA function appears to help mitigate the increase in pulmonary venous pressure that develops as LV diastolic reserve fails in HFpEF, effectively ‘protecting’ the lungs and right heart from the deleterious effects of LV diastolic dysfunction.2, 3 Conversely, a patient with LA dysfunction may be even more vulnerable to the damaging effects of high LV end-diastolic pressures. Atrial myopathy contributes to pulmonary venous hypertension during exercise in HFpEF due to losses in LA diastolic and systolic function,3-5 which then lead to worsening pulmonary congestion,6 symptoms of dyspnoea, alterations in lung function,7 and development of worsening pulmonary hypertension.3, 8 When sustained over long periods of time, cumulative exposure to these haemodynamic insults due to LA myopathy increases the risk of death and HF hospitalization in HFpEF.3, 8 Despite these emerging data, our current clinical assessment of the left atrium remains crude and one-dimensional with only a single structural parameter (maximal LA volume) incorporated in diagnostic guidelines.9 Notably, LA function is not typically assessed clinically, even as this is arguably the most important contributor to disease severity. In this issue of the Journal, Khan et al.10 report the results of a well-done and very timely meta-analysis, summarizing the published literature to date on measures of LA function in HFpEF. The inclusion criteria mandated the presence of HFpEF and some assessment of LA function, which could be using speckle-tracking echocardiography to assess LA filling (reservoir strain), LA passive emptying into the left ventricle (conduit strain), followed by LA active contraction (booster strain); or using volumetric indices of LA function from two-dimensional echocardiography (Figure 1). LA functional parameters were pooled using weighted mean differences across studies in a random effects model, and then linked to mortality and HF hospitalization when available.10 The authors identified 22 studies fitting the inclusion criteria, of which 16 included a control group.10 The final pooled data included 1974 HFpEF patients and 751 controls. Almost all studies used echocardiography for LA function assessment, with only three using magnetic resonance imaging. Sixteen studies included data on LA volumetric emptying fraction and 17 studies included LA strain. Essentially all measures of volumetric LA function were lower in HFpEF compared to controls (weighted mean difference −12%, −7% and −11% for reservoir, conduit and booster emptying fraction, respectively). Similarly, among 13 studies reporting LA reservoir strain, 5 studies of conduit strain and 9 studies of booster strain, these measures were consistently impaired in HFpEF, with the greatest magnitude of difference seen for LA reservoir strain (weighted mean difference −13%, −4%, −3%, respectively). However, heterogeneity was high (I2 53–88%) for all comparisons. Multiple sensitivity analyses were performed and reproduced the main results. Importantly, LA reservoir strain was associated with the composite of mortality and HF hospitalization, although this analysis included data from only two studies.10 In this meticulously performed meta-analysis, Khan et al.10 provide the most comprehensive, contemporary summary of LA dysfunction in HFpEF. While these data pooled from nearly 2000 patients add greatly to current understandings, there are a few important caveats to consider. Most patients included were in sinus rhythm: 7 studies completely excluded patients with history of AF, and only 3 of the 22 studies included patients in AF at the time of evaluation. This is important because patients with AF often display the most profound impairments in LA function.3, 5 Despite irregular heart rhythm and loss of atrioventricular synchrony, LA reservoir strain can still be measured with good reproducibility in AF,5 though conduit and booster strain are not measurable due to the absence of atrial contraction (Figure 1). The general exclusion of AF patients in many studies may have underestimated the true burden of adverse LA reservoir function in HFpEF. Even though underpowered, the Egger's test did suggest possible publication bias (P = 0.07) implying that some negative study results may not have been reported in the literature. Heterogeneity of summary estimates was also high, which may relate in part to differences in the specificity by which HFpEF was defined in the included studies, as well as differences in imaging techniques.10 Despite these limitations, the study by Khan et al.10 points to the potentially important role for greater use of LA function in the evaluation and management of HFpEF. Current echocardiographic guidelines emphasize annular relaxation velocity (an index of LV myocardial relaxation) and mitral inflow profiles in the assessment of diastolic dysfunction,11 but recent studies have suggested poor sensitivity of these indices in the diagnosis of HFpEF.12, 13 There are also technical limitations to Doppler-based assessments of filling pressure in HFpEF, particularly in the presence of AF, mitral annular calcification, wall motion abnormalities and ventricular pacing.11 In contrast, the assessment of LA reservoir strain is not subject to any of these limitations and may contribute greater accuracy beyond conventional measures in HFpEF.5 Despite the potential benefits of adopting greater use of LA strain, there are issues that remain unresolved. Different cut-points have been identified for use of LA reservoir strain in the diagnosis of HFpEF,4, 5 and no multicentre study has yet been conducted to demonstrate its accuracy in diagnosis. Although meta-analytic reference ranges for LA strain values are available, these are associated with high heterogeneity.14 Guidelines have been published for LA strain measurement,15 and once software packages and measurement techniques become standardized, this should decrease measurement heterogeneity. To summarize, it is now clear that LA myopathy is a major player in the pathophysiology of HFpEF. Two components of myopathy – structural remodelling and AF – are known to associate with greater disease severity and worse outcomes in HFpEF.11 Multiple single-centre studies have shown us that loss of LA function promotes lung congestion, pulmonary vascular disease, right heart dysfunction, and worsens exercise capacity in HFpEF.2, 3, 6, 8 Impairments in LA reservoir strain may also guide diagnostic evaluation by helping to distinguish HFpEF from non-cardiac dyspnoea.4, 5 Khan and colleagues have performed an important and rigorous systematic review that pools together data from all of these studies,10 providing compelling and robust evidence that calls for more widespread use of LA function assessment in the evaluation of patients with HFpEF. The next steps will be to define how best to standardize and use these important data. Dr. Reddy receives research support from a Pulmonary Hypertension Accelerated Bayer Award from Bayer Pharmaceuticals. Dr. Borlaug is supported by RO1 HL128526 and U10 HL110262. Conflict of interest: none declared.

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