Left Atrial Dysfunction: The Next Key Target in Heart Failure with Preserved Ejection Fraction

Left atrial (LA) remodeling and dysfunction are common in patients with heart failure (HF) with preserved ejection fraction (HFpEF).^1–4 The distending pressure of the LA is principally determined by left ventricular (LV) filling pressure during diastole, and therefore LA remodeling has been considered to be a secondary consequence of LV diastolic dysfunction. However, recent data have shown that LA dysfunction, rather than simply remodeling, may be more than a bystander, but rather an important player in the pathophysiology of HFpEF. Recent studies have shown that LA dysfunction is associated with worse symptoms, more severe pulmonary vascular disease, greater right ventricular (RV) dysfunction, depressed exercise capacity, and increase mortality in HFpEF.^1–6

Left atrial function may be assessed by conventional 2D and Doppler echocardiography, but recent studies have shown potentially greater utility of LA deformation analysis using speckle-tracking echocardiography. ^2–7 Abnormalities in LA mechanics are correlated with resting hemodynamics and clinical status, but it is unknown whether deranged LA mechanics can help identify patient with more profound hemodynamic responses to exercise in HFpEF.

In this issue of the Journal, Telles et al. present intriguing data that shed new light on the contribution of LA mechanics to abnormal exercise hemodynamics in patients with HFpEF.⁸ The investigators prospectively examined 71 subjects with EF ≥50% referred for exercise right heart catheterization because of exertional dyspnea. Participants were diagnosed with HFpEF (pulmonary capillary wedge pressure [PCWP] ≥15 mm Hg at rest and/or ≥25 mm Hg with exercise) or NCD (PCWP <15 mmHg at rest and <25 mmHg with exercise) according to contemporary standards.⁹ Two-dimensional echocardiography was performed to evaluate resting LA mechanical properties just prior to the invasive measurements. Phases of LA function were assessed by volumetric measurements and speckle tracking-derived longitudinal strain and strain rate. LA stiffness was then calculated as the ratio of PCWP or E/e’ to LA reservoir strain.⁸

Consistent with prior studies,^1–7 patients with HFpEF displayed reduced LA reservoir and pump function assessed by longitudinal strain, strain rate and LA ejection fraction, with increased LA stiffness as compared to NCD.⁸ LA conduit function was similar in the HFpEF and NCD groups. An extremely important observation was that neither LA volume nor LA volume index differed between the groups, meaning that LA function was the greater correlate of abnormal hemodynamics rather than structure. Among patients with HFpEF, increasing burden of atrial fibrillation (AF) was associated with greater LA mechanical impairment.⁸

As compared with NCD subjects, HFpEF patients displayed higher left and right-sided filling pressures with higher pulmonary artery (PA) pressure at rest and with exercise, and lower cardiac output during exercise, in agreement with earlier studies evaluating exercise hemodynamics.^9–11 The abnormalities in LA reservoir and pump strain assessed prior to exercise were strongly correlated with left heart filling pressure, PA pressure, PA elastance, and cardiac index at rest and, remarkably, during peak exercise. LA strain was also related to abnormal hemodynamic reserve responses with exercise, indicating that an abnormality in resting function could identify dynamic responses to stress. The authors importantly when on to show that the relationships between LA reservoir strain and exercise hemodynamics remained significant even after the exclusion of AF patients.⁸

Telles and colleagues then went on to evaluate the potential diagnostic ability of LA strain to discriminate HFpEF patients from NCD.⁸ In patients with BNP measurements (n=63), LA reservoir strain showed a good diagnostic accuracy (area under the curve 0.76)., and LA reservoir strain ≤33% demonstrated reasonable sensitivity (86%) and specificity (76%) to diagnose HFpEF, with significant net reclassification improvement in comparison to the 2016 ESC criteria.⁸

The investigators are to be commended on this important contribution, which confirms and extends upon earlier studies while providing important new insights regarding the role of LA dysfunction for understanding pathophysiology, and potentially, diagnosis in HFpEF.⁸ Why does the LA play such a key role in maintaining optimal cardiac performance in patients with HFpEF? The LA can be perceived as having two key duties: (1) it modulates LV filling through its reservoir, conduit, and pump functions to maintain LV preload and cardiac output, and (2) it helps to keep the lungs free of congestion through its compliance properties to absorb venous return from the lungs without untoward increases in pressure. As LA function deteriorates, the organs upstream of the left heart are compromised, leading to worsening pulmonary capillary hypertension, vascular remodeling, pulmonary arterial hypertension, and RV dysfunction, which then contribute to even greater morbidity and mortality in HFpEF (Figure 1).^1–6 This suggests that LA dysfunction may represent an important target for therapy, and that patients with HFpEF and greater burden of LA dysfunction might be viewed as part of a different sub-phenotype within the broader spectrum of patients, that is if a treatment could be applied targeting LA dysfunction.¹²

Figure 1. The role of left atrial dysfunction in the pathophysiology of heart failure with preserved ejection fraction.

As left atrial (LA) dysfunction develops from left ventricular (LV) diastolic dysfunction, the organs upstream of the left heart are compromised, leading to worsening pulmonary capillary hypertension, pulmonary vascular remodelling, pulmonary arterial hypertension, and right ventricular (RV) dysfunction. This suggests that LA dysfunction may represent an important upstream target for therapy, and that patients with HFpEF and greater burden of LA dysfunction might be viewed as part of a different sub‐phenotype of HFpEF. FAC, fractional area change; LVEDP, left ventricular end‐diastolic pressure; PA, pulmonary artery; PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; TAPSE, tricuspid annular plane systolic excursion; TV, tricuspid valve.

LA dysfunction could be targeted in three fundamental ways. Reduction of LV filling pressures (through a variety of means) will lower LA afterload and can improve LA structure and function in a manner analogous to systemic afterload reduction. Alternatively, agents that directly target myocardial structure and function in the left atrium may be also useful, such as neurohormonal antagonists.¹³ Finally, maintenance or restoration of AF may also be important. A substantial proportion of patients with HFpEF develop AF, and they suffer from more LA dysfunction, worse functional capacity, RV dysfunction, and increased risk of death.^{12, 14} Catheter ablation could be effective to reverse or at least prevent the serious consequences of AF in HFrEF,¹⁵ but this has yet to be tested in HFpEF.

Echocardiography plays a central role in the diagnosis of HFpEF.¹² However, it has become clear that currently used echocardiographic parameters such as E/e’, LA volume index, and LV hypertrophy are insensitive to identify HFpEF, especially when patients display no overt congestion at rest.^{9, 12} Even as LA volumes were similar between HFpEF and NCD in this study, LA function was markedly impaired as assessed by strain parameters, with incremental diagnostic value beyond current guidelines.⁸ LA reservoir strain ≤33% could identify HFpEF with reasonably high sensitivity (82%), but the cutoff used by the authors is based on previous reports of risk stratification and normal distribution, but not on diagnosis, and it seems to fall within normal range according to a recent European multi-center study (the lowest limits of normality: 26.1%).¹⁶

Like LV strain, there can be vendor variability of LA strain, which makes it more difficult to standardize absolute values. Other concerns include how LA strain is influenced by the presence of concomitant diseases such as mitral diseases, prior history of ablation, or atrial fibrillation. Further study is required to establish optimal cutoffs for LA strain to distinguish HFpEF from unexplained dyspnea. Ideally, such studies would involve LA strain assessment with the same vendor and definitive ascertainment of HFpEF by the invasive exercise hemodynamic test.

In summary, Telles et al. have provided exciting new data that again emphasizes the importance of LA dysfunction in HFpEF.⁸ By confirming the associations between LA dysfunction and hemodynamic derangements, the current data suggest a potential target for treatment in HFpEF, a syndrome for which there is no proven therapy. Further study is needed to determine how best to identify LA dysfunction, and how to optimally treat it to improve clinical outcomes.