The fibrotic process affecting LA secondary to MV diseases has been extensively reported in animal models. Increased levels of atrial collagen I in miniature pigs with chronic MR, mediated by the suppression of the histone deacetylase SIRT1 (silent information regulator 1), have been reported (121). Using a similar animal model, the upregulation of fibrosis-related gene transcription has also been demonstrated in LA walls, along with the increasing of angiotensin II tissue concentrations (122). In humans, analogous findings were described by Butts et al. who observed an important chymase activation in the LA walls of patients with MR, responsible for higher degrees of fibrosis, chamber enlargement, and decreased total emptying fraction (123).

Although a direct measure of LA fibrosis is very challenging in clinical practice, the early effects of such process may arise as a loss of compliance and a stiffness increase detectable through myocardial deformation analysis even before the chamber enlargement occurs. Cameli et al. demonstrated the usefulness of reservoir function, assessed through two-dimension speckle tracking echocardiography (2D-STE), to study the extent of LA fibrosis and the loss of function in 46 patients with severe MR. They showed a close negative correlation between the degree of fibrosis and the reservoir function providing histologic assessment in atrial samples obtained during cardiac surgery (124). The histologic analysis has also been used to demonstrate the correlation between the loss of reservoir function and the severity of fibrofatty myocardial replacement in 13 patients with organic MR studied with feature tracking CMR. Interestingly, the volumetric remodeling did not correlate with the degree of histological derangement that resulted with better reflected by reservoir function (125).

The remodeling process is progressive and characterized by two main phases: an early adaptation where the chamber is able to enlarge maintaining a normal SV, and a second phase where maladaptive remodeling prevails. Animal studies showed the association between MR progression and the bi-phasic atrial SV adaptation. At earlier stage, the LA enlargement favors the atrial shortening, which is essential to maintain adequate SV. Later, the SV starts to decline as the regurgitation progresses due to the shift of volume-force relationship toward a more unfavorable position (126). In humans, a significant negative correlation between ERO, reservoir, and contractile function has been reported in 102 patients with MR, including 14 patients with primary and 88 patients with secondary MR. Most of the examined cohort (84%) had a non-severe regurgitation with ERO lower to 0.2 cm², demonstrating that even a mild degree of MR may lead to significant LA remodeling (127). A similar result has been recently confirmed in 80 patients with mild (n = 15), moderate (n = 20), and severe (n = 45) degenerative MR studied with 3D transthoracic echocardiography and vector velocity imaging. LA contractility (responsible of the active SV component) increased in response to greater LA Volume before atrial contraction (LAVpreA) up to a point beyond which the active component decreased (128). This mechanism has been further confirmed in analyzing global and regional LA mechanics in 27 patients with chronic primary MR. Compared to controls, the LA ejection force (21.5 vs. 12.3 kilodynes), the reservoir strain (32.91 ± 14.26 vs 23.14 ± 7.96%,), reservoir strain rate (2.65 ± 0.87 vs 1.62 ± 0.53 s⁻¹), conduit strain rate (−2.02 ± 0.58 vs. −1.29 ± 0.59 s⁻¹), contractile strain rate (−2.55 ± 1.31 vs. −1.98 ± 0.65 s⁻¹), and the LA contractile tissue velocity (A′) (−5.39 ± 1.95 vs. −6.91 ± 1.80 cm/s) resulted to be all impaired, despite a similar global LA ejection fraction (31.34 vs. 29.23%), confirming the importance of active LA contraction in providing adequate LV filling (129).

In more advanced stages of MR, all the components of LA mechanic may be impaired (Figure 3). In 43 patients with chronic primary MR, due to myxomatous valve disease, LA reservoir and contractile function, and the LA EF were impaired, whereas the conduit function was preserved. Interestingly, regional differences in LA contractility emerged in the anterior wall, probably due to the eccentricity of the systolic, anteriorly directed regurgitation jet, hitting the anterior wall and altering local wall mechanics (130). LA subclinical dysfunction has been reported in 50 patients with MV prolapse determining mild (n = 14), moderate (n = 19), and severe (n = 17) MR. Reservoir function resulted to be progressively impaired through the MR degrees, showing negative correlations with EROA, vena contracta, LA area, and LA volume and positive correlations with LV LS and untwisting rate (131).

The LA mechanics analysis can be of additional value for symptoms prediction in subjects with MR. Using 3D speckle tracking (3DST), Saraiva et al. assessed the correlation between LA function and pulmonary pressures in 71 patients with organic chronic MR. They reported an association between pulmonary systolic pressures, LA reservoir, and contractile function and reservoir strain rate (132). Moreover, reservoir function was correlated with a worse functional capacity and HF symptoms (NYHA III) in patients with chronic severe primary MR. Interestingly, this parameter was also linked to age and diabetes mellitus, suggesting a more accelerated LA remodeling in diabetic patients (133).

The assessment of LA mechanics has a role in prognostic stratification, identifying subjects with more advanced disease stage. In 67 asymptomatic patients with chronic primary MR, a reduced LA reservoir (<31.7%) and LV untwisting rate (< −87.9°/s) were able to identify subjects who experienced hospitalization for HF, MV surgery, or death during follow-up (24.8 ± 17 months), confirming that impaired LA mechanics and not the regurgitation severity are linked to the outcome (31). Similarly, Yang et al. examined the prognostic significance of LA mechanics in 104 patients with asymptomatic chronic severe primary MR. At follow-up (13.2 ± 9.5 months), low reservoir function (odds ratio, 3.606; 95% CI, 1.294–10.052; p = 0.014) and low reservoir strain rate (odds ratio, 2.857; 95% CI, 1.078–7.572; p = 0.035) predicted the incidence of cardiovascular mortality or MV surgery due to new-onset HF (32). Another large study on 395 asymptomatic patients with primary degenerative MR of moderate severity is in agreement. Impaired reservoir strain, LA emptying fraction, larger LA indexed volume, and lower LV strain emerged as independent predictors of cardiovascular events (AF, stroke/ transient ischemic attack, acute HF, and cardiovascular death). A global reservoir function lower than 35% emerged as the best predictor of adverse outcome during a follow-up of 3.5 ± 1.6 years (AUC of global reservoir function:0.87) (43). Similar findings have been reported in 117 subjects with moderate to severe MR due to prolapse. LA emptying fraction (HR, 2.59), reservoir strain (HR, 3.06), and contractile strain (HR, 2.01) were independently associated with cardiac surgery or all-cause mortality (38).

The serial assessment of LA mechanics may provide early insights on the chamber remodeling progression. Fifty-five patients with severe chronic MR caused by mitral prolapse or flail underwent multiple echocardiographic evaluation during a follow up of ≤ 3 months. The variation of strain rate of reservoir function from baseline to follow-up emerged as the only predictor of accelerated LA remodeling (ΔLAVi ≥ median value). Additionally, a poor baseline reservoir strain rate was significantly associated with hastened deterioration of the same parameter during the follow-up period (134).

The surgical timing for MR is another clinical context where the assessment of LA mechanics may improve patient management. In a large cohort of patients with MV prolapse and different MR degrees, total LA emptying fraction [odds ratio (OR):0.78; p < 0.001], reservoir function (OR:0.91; p = 0.028), and contractile function (OR:0.86; p = 0.021) emerged as independent predictors for surgery indication. Total LA emptying fraction <50% demonstrated a 91% sensitivity and 92% specificity for predicting surgical indication (135). LA reservoir strain can be used to predict outcome after surgical correction in patients with chronic severe organic MR, with values lower than 24% identifying the worse survival during a median follow up of 6.4 years (29). Similar results have been confirmed in a cohort of 71 patients with primary severe MR undergoing surgical treatment, where LA reservoir function resulted as independent predictor of clinical and functional outcome and of LA fibrosis. Considering a composite event of HF and/or cardiovascular death, 5-year event-free survival was 90 ± 5% for LA reservoir strain ≥21% and 30 ± 9% for reservoir strain <21% (p < 0.0001). Moreover, it was associated with an improvement of NYHA class and Borg scale after surgery (50). Preoperative reservoir strain, LAVi, and age may also predict valve repair or replacement or atrial inverse remodeling, defined as a percentage of decrease in LA volume index (136).

Differently from organic or primary MR, that is a clinical condition leading to HF if untreated, functional, or secondary MR frequently comes as a direct consequence of LV dilatation and dysfunction, further impacting on prognosis and clinical status (137–140). Rest assessment of LA mechanics in HF with severe MR has a role in prognostic stratification (Figure 3). Palmiero et al. investigated LA function in 97 patients with HFrEF and severe functional MR identifying the LA emptying fraction as an independent predictor of cardiovascular death (141).

The evaluation of LA mechanics during exercise may provide additive information, with specific insights on valvular and functional reserve (142, 143). In asymptomatic patients with degenerative MR, the presence of exercise-induced pulmonary hypertension (PH) was associated with lower reservoir function with the 26.9% threshold being independent predictor of a worse symptom-free survival (36). The difference in atrial function between primary and secondary MR has been studied by Sugimoto et al. with exercise stress echocardiography and CPET in 196 patients with primary and secondary MR, including 66 HFrEF, 19 HFpEF, and 30 HF with mid-range ejection fraction (HFmrEF). Exercise reservoir strain and contractile function were impaired in any MR type but with secondary MR exhibiting a worse atrial reservoir function. This was associated with a worsen exercise performance, limited CO increase, impaired right ventricular–to–pulmonary circulation coupling, and the highest event rate. Furthermore, LA strain during exercise was predictive of all-cause mortality and hospitalization for HF (144).

Organic MR is characterized by progressive LA remodeling consisting of atrial wall fibrotic replacement leading to a loss of reservoir and contractile function, with prognostic significance for surgery prediction. Functional MR may present with an impairment of greater severity. The exercise-related LA functional reserve is associated with the exercise capacity and clinical outcome.

Only fewer studies have been conducted to assess the impact of mitral stenosis (MS) on LA mechanics. Myocardial structural remodeling in MS is a known morphologic substrate of LA dysfunction that may lead to AF and adverse outcome (145). Thus, assessment of LA function in combination with LA volumetry may help guiding clinical decisions in patients with MS. Caso et al. assessed the prognostic role of LA function in 53 asymptomatic patients with rheumatic MS, finding that the best predictor of adverse events (defined as symptoms, hospitalization for cardiac cause, AF, thrombo-embolic events, valvular surgery, or percutaneous commissurotomy) at 3-year follow-up was the average LA peak systolic strain rate (cut-off value of 1.69 s⁻¹), having a sensitivity of 88%, and a specificity of 80.6% (AUC:0.852) (146). Atrial mechanics analysis may be useful to predict the risk of AF in MS (Figure 3). In 81 patients with MS, an impairment of reservoir strain was observed in patient who developed arrhythmia at 5-year follow-up (13.4 ± 4.6 vs. 19 ± 5.2, p < 0.001) (147). Similarly, in a large cohort of asymptomatic patients with rheumatic MS that was followed up during 4 years, reservoir function was the best predictor of AF at multivariable analysis (AUC of.761 for a cut-off value of 17.4%) (30).

In order to assess possible correlation between LA function and exercise capacity in subjects with MS, Jung et al. evaluated the LA compliance (defined as 1,270 × mitral valve area by planimetry/E-wave downslope) during exercise in 33 asymptomatic patients with significant MS. Decreased LA compliance at an early stage of exercise (50 W during bicycle exercise) was an independent predictor of exercise intolerance. Moreover, a positive relationship was also noted between the chamber compliance and the pressure response of pulmonary circulation, with a more impaired LA compliance in patients who developed dyspnea at an early stage of exercise (148). Mahfouz et al. performed stress echocardiography to assess exercise intolerance in 75 patients with MV area of 1.81 ± 0.13 cm² and compared them with 40 healthy control subjects. Interestingly, 44% of asymptomatic patients with mild MS had exercise intolerance, and reservoir strain was significantly associated with exercise capacity in patients with mild MS (cut-off value: reservoir strain ≤ 26.5%) (46). Similarly, Chien et al. investigated the relationship between LA deformation as measured by 2DSTE derived LA strain and HF symptoms in 69 subjects with rheumatic MS, and found that NYHA class independently correlated with LA reservoir strain and reservoir strain rate (149).

LA reservoir function and compliance are related to exercise tolerance in MS. Reservoir function may predict the occurrence of AF.

In aortic stenosis (AS), the outflow obstruction caused by a valve narrowing determines LV concentric hypertrophy and a strong predisposition to HF. The increased afterload is responsible for LV pressure overload, hypertrophy, myocardial fibrosis, impaired relaxation, and finally LA abnormal mechanics. At early stages, LA function is preserved, thus helping in the maintenance of optimal CO, but at later stages, atrial dilatation and dysfunction occur with different mechanisms (150). It has been shown that only the reservoir function impairs progressively with AS severity (151). On the contrary, contractile function seems initially enhanced in subjects with severe valvular disease without pulmonary hypertension. The enhanced contractile function acts as a compensatory mechanism driven by Frank-Starling law (LA myocytes length is augmented since LA volume is increased). Once this mechanism is exhausted, the LA contractile function starts to decline, and the chamber starts to dilate.

The occurrence of HF symptoms, such as dyspnea in AS, may represent the decline of clinical conditions leading to unfavorable outcome. However, in clinical practice it may be challenging to correlate the symptom with the disease progression, since the dyspnea is a common condition in elderly people, but is not necessarily of pathologic significance. LA mechanics can provide useful insights in discriminating the origin of symptoms (Figure 4). A retrospective study on 40 patients with severe AS identified contractile function, assessed through 2DSTE, as the only independent predictor of HF symptoms (dyspnea, angina, dizziness, and syncope upon exertion) at multivariate logistic regression (OR = 0.242, p = 0.002) including AS severity, BNP, and LV diastolic function (cut-off: LA contractile strain rate <1.01 s⁻¹) (33). Recently, in a large cohort of 248 patients (202 symptomatic and 46 asymptomatic) with severe AS and preserved LV EF, the reservoir function emerged as the only parameter independently correlated with the presence of HF symptom, while LA dimensions and the echocardiographic parameters of both LV systolic and diastolic functions did not (44). Moreover, LA longitudinal strain parameters were inversely correlated with the worsening of NYHA class. These findings are consistent with the greater ability of LA mechanics in predicting prognosis when compared with LV mechanics analysis (34, 152, 153). Galli et al. (35) demonstrated that LA reservoir function (<21%) is predictive of major adverse cardiac events and HF in 128 symptomatic and asymptomatic patients with severe AS, while LV function parameters (ejection fraction and global longitudinal strain) are not. This result has been further confirmed in a recent study on 182 symptomatic and asymptomatic patients with moderate and severe AS (154). Moderate AS showed greater values of LA reservoir (23.1 vs. 13.8%, p < 0.001), conduit (11.5 vs. 6.5%, p < 0.001), and contractile function (11.5 vs. 7.1%, p < 0.001) when compared to severe valvular disease. On the other hand, no differences emerged when comparing LV EF, systolic, and diastolic diameters in the two populations (p > 0.1). The stronger prognostic and clinical significance of LA vs LV mechanics is attributable to the specific disease pathophysiology. The LV remodeling impacts on LA that dilates, enhancing reservoir and contractile function. This compensatory mechanism does not last for long time producing further pressure overload in pulmonary circulation and symptoms appearance. The inverse correlation between LA reservoir strain and PH in patients with severe AS and preserved LVEF, reflects this mechanism (155).

The importance of LA mechanics in predicting outcome in patients affected by severe AS has been corroborated by several studies reporting LA “reverse remodeling” in patients who underwent transcatheter aortic valve replacement (TAVR). LA enlargement has been reported as a marker of HF readmission after TAVR. In a large retrospective cohort of 546 patients, LA dilatation, identified by parasternal diameter (48.4 ± 7.9 vs. 43.1 ± 7.2 mm, p < 0.0001), was independently associated with readmission for congestive HF at 1-year follow-up (156). TAVR is generally associated with an improvement of LA mechanics, in particular, reservoir function, as assessed with 2DSTE 6 months after treatment (157). A similar improvement of LA reservoir and conduit function has been described after a longer follow up of 12 months, regardless of the AS severity, in 54 mixed severe AS (24 normal LVEF and normal flow, 16 with paradoxical low flow low gradient, and 14 with a reduced LVEF) (158).

According with the pathophysiology of AS disease, the exercise is the natural condition able to trigger LV afterload increase, LV, and LA pressure overload and therefore dynamic pulmonary congestion. While in healthy subjects, the LA reservoir and conduit functions are enhanced under stress conditions (16), the hypertrophic LV is expected to prevent relaxation and diastolic suction due to the lower compliance that chronically overloads the atrial chamber (15). Along with disease progression, LA exhausts its functional reserve leading to pulmonary congestion and symptoms appearance. Based on this pathophysiology, the rationale for dynamic assessment of LA mechanics is strong but still underused. Exercise testing with simultaneous invasive hemodynamic monitoring and Doppler echocardiography have been used to evaluate 39 patients with asymptomatic severe AS. LA size (LAVi ≥ 35 ml/m²) reflected the hemodynamic burden (augmented PCWP and PAP, decreased CI) and was associated at univariate Cox analysis with poor outcome (composite end-point of hospital admissions for AF, HF, and acute coronary syndrome, aortic valve replacement, and death), being a potential marker of increased hemodynamic burden during exercise. Moreover, this study suggested that when LA dilatation is overt and E/e′ is also increased, the pulmonary circulation overload is augmented, especially under stress conditions (159).

The study of LA mechanics has been shown to be more informative compared to the LV study, especially for the prediction of HF and functional capacity. LA reservoir function is a marker of inverse remodeling occurring after AVR. The assessment during exercise is a promising frontier for the identification of asymptomatic patients at higher risk.

The backward flow caused by aortic regurgitation (AR) may affect LV mechanics imposing chronic volume overload, increased LV stiffness, chamber dilatation, and dysfunction. The process can persist for a long period before symptoms onset due to the ability of the LV to compensate hemodynamic overload (67). LA involvement may result from several mechanisms, including impaired LV diastolic function, fibrosis, reduced compliance, and secondary MR (160), reflecting the AR stage.

A direct correlation between LA reservoir function and PH has been reported in patients with moderate or severe AR, with a 6% increase of PH risk for each unit of LA strain decrease (151). Recently, a large study on 554 patients with bicuspid aortic valve and moderate or severe AR showed that the LA enlargement (LAVI ≥ 35 ml/m²) was independently associated with adverse outcome (aortic valve surgery or mortality), when compared with patients with normal LAVi (43 and 60% vs. 23 and 36%, at 1 and 5 years of follow-up, respectively, p < 0.001) (161). In addition to LA enlargement, its contractile function is impaired in severe AR, as reported in 65 patients scheduled for AVR and assessed with 2DSTE. The evaluation 1 year after surgery showed a reduction in LAVi (38 vs. 32 ml/m², p < 0.001), and an improvement in both LA reservoir and contractile function (26 vs. 29% and 11 vs. 15%, respectively, p < 0.01) (162). These findings suggest that the volume overload imposed by AR affects LV morphology and function, along with LA mechanics, through diastolic impairment.

Although AR and AS are two distinct models of LV overload (AS determines a pressure overload while AR volume overload). They share some common effects on the LA mechanics (Figure 4). Cioffi et al. (163) compared 141 AS patients with 42 AR looking at LV geometry, LA size and function. In addition to LA size and ejection force significantly greater in AS group (Maximal LA Volume: 26 ± 7 vs 218 ± ml/m², p = 0.0009), LA enlargement has a positive correlation with LV mass depending on LV pattern. In particular, the concentric LV pattern is related to a greater LA volume and contractile function, irrespectively of valve disease, whereas the eccentric LV geometry does not determine a relation between LA size and LV mass.

Exercise testing can unmask patients reporting to be asymptomatic. Assessment of contractile reserve is a key element to reveal subclinical LV dysfunction. The absence of contractile reserve is more predictive of the development of systolic dysfunction both at follow-up (medical therapy) and postoperatively than parameters obtained at rest in subjects with severe AR (164). Patients with severe AR may show an exercise-induced fall in LVEF due to the hemodynamic consequences of volume overload and increased afterload (165). However, the reliability of this finding in predicting outcome is controversial and it is not specifically addressed in the most recent ACC/AHA and European society of cardiology (ESC) guidelines (93, 166). If the use of exercise is logical to trigger effort-related symptoms, then, in AR, the diastole shortening induced by chronotropic response can potentially reduce the regurgitation severity, hindering AR quantification (11). AR has been evaluated through a standard cardiac 1.5-T CMR scanner under steady-state submaximal exercise and at rest. The AR % decreased during exercise from 35 (9–26, 39, 56–92) % at rest to 16 (7–25, 56–72)% during exercise, p = 0.003. In addition, AR at rest correlates with an increase of cardiac index during submaximal exercise (R2 = 0.64; p = 0.001) (167). These findings support the use of submaximal exercise to evaluate LA adaptation during effort, favoring the use of exercise echocardiography to detect an abnormal response at early stages.

LA enlargement, loss of reservoir, and contractile function have been related to AR severity and adverse outcome in preliminary results. AVR has been shown to have a positive impact on reservoir and contractile function.

Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disorder with a prevalence of 1/200 people (168). Regardless the specific etiology, the advanced disease is characterized by LV hypertrophy, diastolic dysfunction, and increased LV filling pressures. LA adapts enlarging, increasing its contractile function until functional reserve exhausts resulting in overt dysfunction. 2DSTE has been used to describe global and phase-specific function in HCM patients (Figure 5). Total atrial deformation (defined as the sum of maximum positive and maximum negative strain during a cardiac cycle) has been shown to be significantly lower in HCM patients when compared to control subjects (169). All the three components of LA mechanics seems to be impaired in HCM patients compared to controls, in particular, strain rate at reservoir, conduit, and contractile phase has been showed to be 13, 17, and 10%, respectively lower (2.0 ± 0.6 vs. 2.3 ± 0.5 s⁻¹, 1.9 ± 0.8 vs. 2.3 ± 0.7 s⁻¹, 2.6 ± 0.8 vs. 3.0 ± 0.8 s⁻¹; p < 0.05) (170). The degree of LV hypertrophy and fibrosis, assessed through CMR, is directly proportional to the degree of LA impairment. Compared with healthy controls, LA conduit function in HCM is impaired, even without extensive LGE, thus with mild or absent LV fibrosis. Conversely, LA contractile function is reduced only in HCM patients with a higher degree of fibrosis, leading to a more advanced diastolic dysfunction, consequent to LA enlargement and functional impairment (171). A more advanced atrial myopathy and disfunction play a specific role in determining symptoms. Contractile function, explored with 2DSTE, emerged as the only independent predictor of HF symptoms with a cut-off of −0.92 s⁻¹ for contractile strain rate (sensitivity: 75%, specificity: 83%, area under the curve:0.83) in a series of 37 HCM patients, with enlarged atria compared to controls (28). In less advanced disease, LA dysfunction can be already present even if the chamber size is still in the normal range. In non-obstructive HCM patients with normal LA size and contractile function, reservoir and conduit components resulted impaired when compared with healthy controls. This finding is consistent with a lower degree of LV fibrosis, earlier disease stage and more preserved atrial physiology (172). On the other hand, LA function further lowers if LV outflow tract obstruction is present, as demonstrated comparing 50 obstructive, 50 non-obstructive and 50 healthy patients studied with feature-tracking CMR. The presence of obstruction has a great impact on LA EF (42.3 ± 8 vs. 47.2 ± 9%; p = 0.004), reservoir strain (14.5 ± 4 vs. 17.7 ± 5%; p = 0.002), strain rate (0.59 ± 0.2 vs.73 ± 0.2 s⁻¹; p = 0.001), contractile strain (6.1 ± 2 vs 7.5 ± 3%; p = 0.01), and strain rate (−0.44 ± 0.1 vs −0.58 ± 0.25 s⁻¹; p = 0.004) when compared to the non-obstructive HCM group (173) (Figure 5).

Different studies evaluated the prognostic role of LA function assessment in HCM patients. An early report identified total LA strain (the sum of reservoir and contractile function) as the strongest predictor of short term (12-month) outcome of death or hospitalization for cardiovascular causes, with the optimal cut-off of 21% (odds ratio 0.858, 95% CI 0.771–0.954, p = 0.005). The same parameter was also informative for the occurrence of AF requiring hospitalization (odds ratio 0.853, 95% CI 0.748–0.972, p = 0.017) (27). The long-term prognostic significance of LA function was further demonstrated in a large series of HCM subjects and controls, followed-up for 55 months. Total LA strain (−17.4%; p < 0.001), LV outflow tract obstruction (p < 0.001), and E/e' (10.3; p = 0.02) emerged as independent predictors of the composite endpoint of all-cause death, heart transplantation, LV assist device implantation, and clinical worsening (41). Recently, the prognostic value of LA function assessment has been addressed with the use of CMR. During a long follow up-up of 40.9 months, 59 patients with HCM (19.7%) out of 359 experienced the composite endpoint of cardiovascular death, resuscitated cardiac arrest, sudden cardiac death aborted by appropriate ICD discharge, and HF hospital admission. Reservoir and conduit components (HR, 0.94 and 0.89; p = 0.019 and 0.006, respectively) emerged as independent predictors of outcome, also after correcting for the extent of LV fibrosis, confirming the prognostic significance of LA mechanics and expanding the clinical applications of CMR-based myocardial deformation analysis (47).

Throughout the clinical history of HCM, the occurrence of AF marks a critical point potentially impacting on HF symptoms and prognosis. The study of LA mechanics can be informative on the occurrence of new-onset arrhythmia. In large series of HCM patients studied with 2DSTE, LA volume and reservoir strain were able to predict the occurrence of new-onset AF during a follow-up of 4.8 ± 3.7 years. The presence of LA reservoir strain >23.4% predicted a superior 5-year AF-free survival (98 vs. 74%, p = 0.002) (174). This finding has been recently confirmed by Vasquez et al. who reported a similar threshold for reservoir function (> 23.8%) and a threshold of 10.2% for conduit function to predict event-free survival during a follow-up of 5.83 ± 0.3 years (events defined as heart failure, stroke, and death) (42).

In HCM patients, LA mechanics may partially restore after surgical and non-surgical therapy, as observed in a subset of 20 patients with obstructive HCM who underwent septal myomectomy, after which LAEF (41.6 ± 13 vs 48.4 ± 10%; p =0.006), reservoir (14.1 ± 6 vs. 17.3 ± 7%; p = 0.01) and contractile function (6.8 ± 4 vs 9.8 ± 5%; 0.0001) increased at CMR (173). The reversibility of reservoir impairment after treatment provides an additional explanation of the clinical response to the septal reduction. These findings, obtained with non-invasive approach, are consistent with previous data reporting an improvement of LV relaxation with consequent increase of LV passive filling volume, decrease in LA volumes, ejection force (defined as: 0.5 x 1.06 x mitral annulus area x (peak A²), in kdyne), kinetic energy (0.5 x 1.06 x LA SV x (peak A²) in kerg), and a parallel reduction of NYHA class, with longer exercise duration (p < 0.05) (175).

Left Atrium (LA) mechanics progressively disrupt in HCM, reflecting the disease severity and fibrosis extension. Reservoir function is the first to decline, especially when HCM determines LVOT obstruction. All the components of atrial function are able to predict the outcome, representing valid prognostic markers.

Despite restrictive cardiomyopathies (RCMs) are known to be the least common among the heart muscle diseases, they include a wide group of conditions characterized by different pathogenesis, clinical presentation, diagnostic workflow, treatment, and prognosis (176). Some possible etiologies include infiltrative disorders, such as amyloidosis or sarcoidosis, storage disorders like Fabry disease, and idiopathic RCM. The ventricular myocardium generally presents with increased stiffness, responsible for the characteristic diastolic dysfunction, elevation of filling pressures, and atria dilation. Systolic function is usually preserved until the late stages of the disease. During exercise, the poor compliance of the ventricles hinders the rapid venous return, resulting in an important rise of the filling pressures and in a limited increase of SV (177). The progressive atrial enlargement may contribute to the onset of HF symptoms, atrial arrhythmias, or secondary atrioventricular valvular regurgitation.

In cardiac amyloidosis (CA), the LA dysfunction has been repeatedly studied. Loss of all components of atrial function characterizes cardiac amyloidosis regardless of the etiology (light chain, mutant or wild-type transthyretin). However, among the amyloidosis subtypes, transthyretin amyloidosis (ATTR) wild type generally present the worst reservoir and contractile function. Of note, even after adjusting for LA size, LV EF, and LV filling pressures, all LA function components are generally impaired in CA patients, when assessed with 2DSTE (Figure 5) (39, 178, 179). A significative alteration in the reservoir and contractile function has also been recorded with real-time 3D echocardiography, and there is evidence that, according to the progression of the disease, the LA mechanics gradually undergoes greater impairment (39, 179). Recently, myocardial deformation of both LA and LV have been shown to be linked to prognosis in CA. In particular, a reservoir function <13.2% demonstrated a 7.5-fold increased risk of all-cause mortality over a median follow-up of 5 years (95% CI 3.8–14.7, p < 0.001) in a cohort of 136 patients (48). Remarkably, in a large population of >900 subjects with ATTR, the LA stiffness, estimated as the ratio between E/e' and reservoir function, has been shown to be an independent marker of prognosis, after adjustment for the main echocardiographic and clinical parameters. In the same population, the presence of LA electro-mechanical dissociation (absence of valid mechanical contraction despite sinus rhythm at ECG) emerged as a distinct phenotype with impaired outcome, similar to subjects with AF (49). LA mechanics are therefore significantly impaired in infiltrative disease, with a growing evidence of a direct LA involvement contributing to the severe mechanics impairment.

Unlike cardiac amyloidosis, primary LA involvement is less clear in sarcoidosis. Small studies using 2DSTE reported impairment of LA reservoir function in sarcoidotic subjects when compared to controls, with a negative correlation with the disease stage. However, it is unclear if the loss of function is a consequence of a primary atrial involvement or simply a consequence of LV dysfunction (180, 181).

Left atrium (LA) reservoir function, evaluated by 2DSTE, has been reported to be significantly impaired in patients with Fabry disease even in presence of normal echocardiographic assessment (182, 183). It is still unclear if these findings can be primarily explained by the increase of LV filling pressures or by the direct depositions of sphingolipids in the LA. However, LA stiffness seems to be an early marker of atrial remodeling, already altered before the occurrence of LV hypertrophy (184). Conversely, a relevant impairment in atrial conduit function has been reported only in presence of LVH, and this may be justified by a more advanced LV diastolic dysfunction (184). Using CMR with T1 mapping to classify patients with Fabry disease, Bernardini et al. reported a progressive impairment of reservoir function, assessed with FT-CMR, according with the reduction of T1 mapping (index of subclinical disease) or the presence of LV hypertrophy (overt heart involvement) (185). Nevertheless, in another study, significant differences in the three LA function components were found only in Fabry disease with significant LV hypertrophy (186).

Despite the heterogeneity of restrictive diseases, the impairment of reservoir function has been reported as a common pathophysiological element. In aTTR-CA, the estimation of LA stiffness emerged as a strong and independent prognostic marker.

Dilated cardiomyopathy (DCM) is a complex pathological condition coursing with HF and representing the most common indication for heart transplantation worldwide (187), and it is characterized by the presence of LV dilatation and systolic dysfunction, worsened by abnormal LV filling pressures and functional mitral regurgitation in the most advanced stages (188, 189). At earlier stages, LA contractile function is augmented to maintain adequate LV filling, but later it decreases as a consequence of the increased afterload.

In a series of 160 DCM and 154 ischemic patients, studied with 2DSTE and CPET, LA reservoir and contractile functions were significantly reduced in the DCM group, with LA lateral wall reservoir and LA volume predictive of peak VO₂ (both p < 0.001) (190). Similar findings were reported by Cao et al. in 32 ischemic, 26 DCM, and 32 control patients where reservoir and contractile functions were more impaired in DMC subjects (191).

The prognostic role of contractile function loss and LA dilatation has been demonstrated in a large cohort of patients with DCM (192) and recently confirmed with the use of CMR (193). LA maximal volume (LA_max) resulted to be effective in predicting the occurrence of a composite endpoint including death or heart transplantation in a population of 337 patients with DCM who were followed-up for a mean period of 41 ± 29 months. Notably, patients with an increased LA volume (LAVi> 68.5 ml/m²) had a risk ratio of 3.8 compared with those with a preserved LA volume (194). In line with these results, indexed LA area assessed with standard echocardiography (with an optimal cut-off > 13 cm²/m²) emerged as the strongest index associated with the same composite outcome both in a univariate and a multivariate model in 275 DCM patients, whom events were recorded over a mean follow-up of 67 months (HR 6.58, 95% CI 2.43–17.86, p < 0.001 and HR 3.2, 95% CI 1.06-9.23, p = 0.038, respectively) (195).

The reliability of these results is confirmed by similar findings obtained assessing the LA geometry with CMR. In particular, LAVi resulted to be an independent predictor of a composite endpoint including all-cause mortality or cardiac transplantation evaluated in 483 consecutive patients affected by non-ischemic DCM who were prospectively followed-up over a median period of 5.3 years (HR per 10 ml/m² 1.08, 95% CI 1.01–1.15, p = 0.022). Furthermore, patients with an increased LAVi (> 72 ml/m²) showed a three-fold elevated risk of death or transplantation (HR 3.00, 95% CI 1.92–4.70, p < 0.001). LAVi was also independently associated with the secondary composite endpoints of cardiovascular mortality or cardiac transplantation (HR per 10 ml/m² 1.11; 95% CI 1.04–1.19, p = 0.003), and HF death, HF hospitalization, or cardiac transplantation (HR per 10 ml/m² 1.11; 95% CI 1.04–1.18; p = 0.001) (196).

Of note, some LA morphological and functional parameters demonstrated to have a prognostic role when evaluated under stress. In particular, in 84 DCM patients studied with dobutamine stress echocardiography and followed-up for a mean period of 17.0 ± 11.8 months, LAVi (HR 1.060, 95% CI, 1.035–1.087; p < 0.001) besides the variation of systolic LA strain (HR, 0.971, 95% CI, 0.946–0.996, p = 0.02) and the variation of passive LA strain (HR 0.942, 95% CI, 0.914–0.971, p < 0.001) emerged as independent predictors of cardiovascular events in two different multivariate Cox models. Interestingly, including LA strain parameters at rest and under dobutamine into multivariate Cox analysis provides an incremental benefit in predicting adverse cardiovascular events (197).

Left atrium (LA) enlargement and loss of reservoir function occurring in DCM reflects the disease severity and have a prognostic significance for composite endpoints. The use of dobutamine to test the LA functional reserve may have an incremental value in risk stratification.