The present study, taking advantage of a unique large multicentric prospective cohort, demonstrates that:
- the PALS value is mostly influenced by age, LA size, and LV GLS
- the LV GLS is the strongest determinant of PALS; of note concomitant preserved PALS and reduced LV GLS is rare.
- PALS is related to age among patients with HF stage 0-A or B, whereas the LA size is more important in more advanced HF stages (B and C).
- Despite its multiple determinants, PALS is the superior echocardiographic parameter for characterization of the HF stages and for predicting the presence of symptoms.
PALS and GLS across HF stages. The present study is one of the largest cohorts, specifically addressing PALS correlates, and even more important the first study to analyze differences in atrial function across HF stages. There are a multitude of physiological features associated with PALS , but only a few are closely associated with PALS., The relationship between PALS and LV GLS has been previously reported in smaller studies conducted on healthy volunteers [6, 19], confirming the role of PALS as a marker of subclinical LV dysfunction . Thus, an accumulation of evidence suggests that PALS may help identify asymptomatic patients at higher risk of events in the lower HF stages. This pathophysiological role is less understood in the more advanced HF stage, where the interaction between atrial function and other hemodynamic features increases in complexity.
The present study's relatively large sample size and the wide range of explored atrial and ventricular strain values enlighten details of the PALS-GLS relationship. Indeed, the association between the two advanced echocardiographic measurements is not strictly linear, and it is rare to present with reduced GLS but preserved PALS. This aspect agrees with the potential anticipatory nature of reduced PALS towards a GLS reduction and reveals that low GLS almost invariably relates to low PALS. In other words, in patients with relatively preserved LV GLS, PALS value mostly reflects intrinsic atrial properties and holds its distinctive pathohistological role ; with a progressive reduction in GLS, the PALS value seems to depend more and more on LV function rather than on atrial properties.
Another novel result of the present study is that HF-stage influences the age-PALS relationship. Age seems a significant determinant of atrial stiffness in patients with no or limited cardiac involvement; however, in more advanced HF stages (B and C), different hemodynamic or biochemical drives increase LA stiffness, which becomes age-independent in HF-stage C. It is to be acknowledged that patients in HF stage B and C are older than those in stage 0-A, but the age-PALS correlation progressively decreases with the HF stage despite the similar age in stages B and C. This supports the change in determinants rather than the age ranges as a possible explanation for the significant interaction.
LA volume showed an independent association with PALS, which increased in strength moving from HF stage 0-A to C. The explanations for this behavior reside in the multiple pathophysiological meaning of LA size, which reflects the elevation of diastolic filling pressure over time [21, 22], the burden of mitral regurgitation , it is a sensitive morphophysiological expression of the severity of LV dysfunction, and to be a useful global index of the cardiovascular risk . Despite this strong physiological background, overall, PALS values were only partially explained by the LA volume (R = 0.46), making plausible the incremental value of the atrial function over LA size demonstrated in a variety of clinical contexts [25–27].
Limitations. The lack of follow-up is the main limitation of the study; however, the present study provides contemporary insights into PALS’ clinical meaning. Indeed, this atrial parameter was the most characterizing echocardiographic parameter of HF-stage, which is mostly a clinically defined stage, and it is not based on LA chamber characteristics or any of the PALS determinants. In invasive studies conducted in advanced HF, LA strain was the best determinant of pulmonary capillary wedge pressure among the echocardiographic features . This was confirmed across patient groups with varying LV ejection fraction , which ultimately explains the incremental clinical value (for symptoms as well as HF stage identification) observed in our study. There is a pathophysiological explanation of this PALS clinical value over its most important determinants: the atrial function may buffer the increased ventricular filling pressure as well as volume overload due to functional mitral regurgitation, therefore being the ultimate determinant of the patients’ symptomatic status . This has been demonstrated for PALS in the context of mitral regurgitation . Another limitation of the present study is the lack of a core lab for the assessment of echocardiographic measurements. However, no interaction between the primary regression model and centers was seen. This, together with the stable results using measurements performed by a consultant or those performed by a trainee enhance the applicability in the real world of our results.