Heart failure with preserved ejection fraction (HFpEF) is a common clinical syndrome with increasing prevalence. Patients with HFpEF experience similar patterns of morbidity and functional decline as do those with heart failure and reduced ejection fraction, but effective treatments for HFpEF are lacking. The pathophysiology of HFpEF is complex and the major gaps are still present today in our understanding of HFpEF pathophysiology and managing patients. Recent studies revealed that left atrial (LA) dysfunction may be an important player in the pathophysiology of HFpEF. LA function assessed with the novel technique of 2D speckle tracking echocardiography (2D-STE) is able to provide critical information about the status of cardiac function, therefore could be used as a marker for the severity of HFpEF. LA dysfunction may represent a potential therapeutic target for patients with HFpEF.
Heart Failure; HFpEF; Left VentricularEjection Fraction
Heart failure (HF) with preserved ejection fraction (HFpEF) is a complex syndrome characterized by heart failure symptoms and signs, but normal or near-normal left ventricular ejection fraction (LV-EF) . Epidemiological studies indicated that the prevalence of HFpEF within the population varies from 1.14% to 5.5%, and appears to be rising [1-4]. At least one-half of patients with HF indeed have preserved ejection fraction, and it is more likely seen in women, the elderly, people with a history of hypertension, obesity, and other cardiovascular risk factors [2,4 and 5]. Patients with HFpEF experience similar patterns of morbidity and functional decline as do those with heart failure and reduced ejection fraction (HFrEF) [4,5], but different from HFrEF which has classes of drugs to improve patients’ symptoms and outcome, the effective treatments for HFpEF are lacking [5,6]. One of the reasons is thought to be due to incomplete understanding of its pathophysiology therefore poor matching of therapeutic mechanisms and primary pathophysiological processes.
The diagnosis, classification of its severity, and management of HFpEF remain challenging due to the complicated pathophysiological processes, phenotypic manifestations, and frequent multiple concomitant illnesses [4,7]. In the clinical setting, echocardiography plays a key role in the evaluation and management of HFpEF. However, currently used techniques, 2D and Doppler echocardiography have shown several limitations [7,8]. 2D speckle tracking echocardiography (2D-STE) is a novel technique that has been shown a feasible and sensitive method for evaluating the LA deformation in patients with HFpEF. In this review, we will address the potential role of left atrial dysfunction assessed with 2D-STE in the diagnosis and clarification of the severity in patients with HFpEF according to our study and existing literature.
Diagnostic Criteria for HFpEF
The diagnosis of HFpEF is challenging. The guidelines for diagnosing HFpEF have been proposed by the American Society of Echocardiography and the European Association of Cardiovascular Imaging (ASE/EACVI) and the European Society of Cardiology (ESC) respectively [10,11]. In the guideline proposed by ASE/EACVI, the key functional alteration is the elevated left ventricular filling pressures (LVFP) in patients with signs and symptoms of heart failure and with the myocardial disease , while in the ESC guideline, the key functional alterations are the ratio of early diastolic transmitral inflow velocity to mitral annular tissue velocity (E/e’) ≥13 and an average septal-lateral e’ velocity < 9 cm/s. In addition, LV mass > 115g/m2 (men)/95g/ m2 (women) or LAVI > 34mL/m2 was considered as key structural alterations . The determination of elevated LVFP is mainly based on the mitral E/A ratio. If E/A ratio ≥ 2, the patients are considered as having elevated LV filling pressures. In patients with mitral E/A ratio between 0.8 and 1.9, further criteria (including left atrial volume index, peak velocity of tricuspid regurgitation, and E/e’) should be considered for finally determining elevated LVFP (Figure). Briefly, the diagnosis of HFpEF can be established if the following criteria were met : (1) symptoms and/or signs of heart failure; (2) LV-EF ≥50%; (3) elevated brain natriuretic peptide levels; (4) At least one of the following: 1) Associated structural heart disease (left ventricular hypertrophy and/ or left atrial hypertrophy); 2) Elevated LVFP or diastolic dysfunction. Moreover, both guidelines also highlighted the potential role of diastolic stress test for those patients with suspected HFpEF despite negative functional or structural criteria. Recently, several new algorithms were proposed for diagnosing HFpEF, such as diastolic stress test [10,11], HFA-PEFF score from Heart Failure Association , and H2FPEF score from the Mayo Clinic group .
Transthoracic 2D and Doppler echocardiography play a key role in the evaluation and management of HFpEF in the clinical setting. LV-EF (≥50%) measured using 2D-echocardiography is used as a cutoff for inclusion/exclusion criteria . However, some limitations were present regarding these quantitative methods [7,8 and 13-15]. And also, the accuracy of the E/e’ ratio in HFpEF has recently reported only a modest correlation between E/e’ and invasively obtained resting filling pressures (pooled r = 0.56) . Therefore, along with the further understanding of this disorder, the diagnostic criteria for HFpEF will likely continue to evolve.
The Pathophysiological Mechanisms
HFpEF was not caused simply by LV diastolic dysfunction, its pathophysiology is much more complex which is related to cardiac structural and functional alterations, and systemic and pulmonary vascular abnormalities. The essence of the pathophysiology of HFpEF is an increase of LVFP due to delayed active relaxation, intrinsic ventricular stiffness, or a combination of these factors [11,17]. Elevation in LVFP alters the Starling forces across the pulmonary capillaries through the left atrium, favoring filtration of water out of the vascular space and into the interstitium of lungs [18,19], induces alterations in gas exchange and pulmonary ventilation, and therefore reductions in aerobic capacity [20,21]. These factors prompt patients’ symptoms of dyspnea, especially during the stress of exercise. HFpEF is believed to be a heterogeneous entity. The majority of HFpEF patients do not have any known specific genetic, pericardial, myocardial, or valvular etiology. However, most patients have one or more comorbidities that may worsen HFpEF, such as hypertrophic cardiomyopathy, hypertension, diabetes, chronic kidney disease, obesity, and chronic obstructive pulmonary disease [22-25].
HFpEF and LA Function
The left atrium plays an important role in ensuring the proper performance of left ventricular function and systemic circulation . It is not just simply a conduit for LV filling. From a hemodynamic perspective left atrium is divided into three phases, LA reservoir, conduit, and pump function, all of which contribute to LV filling [13,26 and 27]. Conversely, LV function influences LA function. LA reservoir function is affected by LV contraction and LA compliance. LA pump function is influenced by LV end-diastolic pressure, LV compliance, and LA contractile properties, while LA conduit function is dependent on LV diastolic properties [27,28]. In patients with HFpEF, as LV diastolic filling pressures are elevated intermittently over time, there is secondary remodelling and dysfunction that develops in the left atrium, therefore, LA dysfunction is common in patients with HFpEF [9,29-31]. Studies have indicated that LA structure and functions provide incremental clinical and prognostic information in patients with HFpEF [8,13,14,27, and 32], it is associated with worse symptoms, more severe pulmonary vascular disease, greater right ventricular (RV) dysfunction, depressed exercise capacity, and increase mortality [29- 32,33 and 34].
Accurate evaluation of LA function has important significance. In clinical practice, LA function is usually assessed by 2D and Doppler echocardiography through analysis of pulmonary venous and transmitral flows, and LA myocardial velocities by tissue-Doppler echocardiography. However, these quantitative methods are affected by myocardial tethering, hemodynamic loading, and acquisition angle [7,8, and 13-15]. 2D-STE is a relatively new echocardiographic technique that tracks the spatial dislocation of speckles (natural acoustic reflections) for regional and global myocardial function analysis, it gives an excellent assessment of the atrial deformation profile during an entire cardiac cycle, closely following the LA physiology [35-37]. In contrast to Doppler-derived parameters, speckle tracking has the advantages of being angle-independent, less load-dependent, less affected by reverberations, side lobes, and drop-out artifacts. 2D-STE was found to be a feasible, reproducible, and sensitive method to assess LA function [37-39]. Several studies have shown that strain imaging can detect LA dysfunction before the manifestation of LA structural changes [40-42]. Reduction in LA strain was found to be an important predictor in separating patients with clinical HFpEF and asymptomatic diastolic dysfunction .
In our current study , we observed significant impairment of LA functions assessed with 2D-STE, including reservoir function, conduct function, and pump function in patients with HFpEF. With the cardiac functions further worsening (NYHA class II to class IV), the LA triphasic functions become even worse although the size of LA (LAD) has no significant changes. Correlation analysis indicated that LA triphasic function has a strong correlation with LV systolic function (LV-GLS %), and modest correlation with the LV diastolic function (E/e’), suggesting that LA function can be used as a sensitive marker for scaling the severity of HFpEF . Our study is consistent with an important study conducted by Telles and colleagues , they also observed that patients with HFpEF displayed reduced LA reservoir and pump function assessed by longitudinal strain, strain rate, and LA ejection fraction, with increased LA stiffness, while the LA volume/LA volume index has no difference compared to control group, meaning that LA function was the greater correlate of abnormal hemodynamic rather than structure.
In conclusion, patients with HFpEF displayed significant impairment of LA function assessed with 2D-STE, which may be an important player in the pathophysiology of HFpEF rather than simply a secondary consequence of LV diastolic dysfunction. LA triphasic functions are a sensitive marker for evaluating the severity of HFpEF, however, the cut-off value of LA function needs to be determined from large-scale studies. LA dysfunction may represent a potential therapeutic target for patients with HFpEF, warranted further investigation.
Conflict of Interest
The author has no conflict of interest to disclose.
Consent for Publication
All authors have read and agreed to the published version of the manuscript.
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