Patient selection

The study initially involved 266 patients, prospectively registered between March 16, 2016, and March 16, 2023 [13]. The primary reason for selecting dipyridamole SE was to determine inducible ischemia in individuals with CCS. Exclusions were based on inadequate acoustic windows at rest, significant valvular or congenital cardiac anomalies, and severe non-cardiac conditions leading to a poor prognosis (like advanced cancer, terminal renal failure, or serious obstructive pulmonary issues). Each participant underwent TTE and SE, focusing on measurements of LAVI and LASr. From the initial pool, 4 (1.5%) were excluded from analysis for inadequate imaging of LAVI or missing LAVI data during stress, and 8 (3.0%) for inadequate imaging missing of LASr, leaving 252 participants (180 males, 71%; mean age 65 years ± 10 years) for the study. The protocol received approval from institutional ethics committees as part of the more comprehensive SE 2020 study (148-Comitato Etico Lazio-1, July 16, 2016; ClinicalTrials.gov identifier: NCT030.49995) and SE 2030 study (291/294/295 Comitato Etico Lazio-1, March 8, 2021; ClinicalTrials.gov identifier: NCT050.81115) [13, 14].

TTE

TTE was conducted with standard ultrasound equipment (Philips Epiq CVx), including comprehensive rest assessments and ejection fraction (EF) evaluations, executed by accredited cardiologists in line with the American Society of Echocardiography and the European Association of Cardiovascular Imaging guidelines [15].

SE

All subjects underwent dipyridamole SE (0.84 mg/kg in 6 min). SE followed existing protocols [16, 17], evaluating the wall motion score index (WMSI) at baseline and peak stress, in a four-point score ranging from 1 (normal) to 4 (dyskinetic) in a 17-segment model of the left ventricular (LV) [18]. LUS was utilized to identify B-lines, as vertical lines departing from the pleural line and synchronous with respiration; in a simplified 4-site scan, each space scored from 0 (normal horizontal A-lines) to 10 (white lung), with a cumulative score per patient from 0 (normal) to 40 (severely abnormal), was used [19]. All readers underwent quality control as already described [20].

Left atrial measurements

LAVI measurements were derived from apical 4- and 2-chamber views, with software-assisted planimetry (QLab Philips) and indexing to body surface area [15]. Care was exercised to exclude the LA appendage and pulmonary vein ostia during endocardial tracing. Low intra- and inter-observer variability for LAVI and LASr had been already confirmed among SE 2030 network readers [7, 9].

LASr was measured using speckle tracking echocardiography (STE) with frame rates between 40/s to 80/s, analyzing either from a 4-chamber view (average value from 6 LA segments) or a combined 4- and 2-chamber view (average value from 6 LA segments), as recommended by current guidelines [21, 22]. Offline analysis used the QRS point as a reference and a region of interest (ROI) of 3 mm, with measurements averaged over three cardiac cycles; LASr was estimated as the peak positive strain value corresponding to the period between the rand the T wave on the ECG and expressed in percentage values [21]. Abnormal values were set at ≥ 34 ml/m² for LAVI and ≤ 24% for LASr [23].

Statistical analysis

Data presentation varied as mean ± SD, number (N, percentage), or median [interquartile range (IQR)], as suited. Normal distribution of all continuous variables, was tested using the one sample Kolmogorov-Smirnov test. Logarithm (Log) transformation was performed on LAVI at rest (P < 0.001) and at peak stress (P < 0.001) values because of nonlinear distribution.

Group differences were evaluated using the Student’s t-test for normally distributed continuous variables, the Mann-Whitney U test for skewed continuous variables, and the chi-square (χ²) or Fisher exact tests for categorical variables. Pearson’s correlation coefficient was used to examine relationships between continuous variables.

Independent predictors of LAVI dilatation at peak stress and reduced LASr at peak stress were assessed by means of multiple linear regression analysis. Statistical significance was set at P < 0.05. All statistical calculations were performed using SPSS for Windows, release 20.0 (Chicago, Illinois).

Pathophysiological meaning of the observed results

The normal response of the LV to vasodilator stress is a reduction of LV filling pressures, an increase of LV contractility (around 10% from baseline) and unchanged pulmonary artery wedge pressure. In case of inducible ischemia or LV diastolic dysfunction with normal coronary arteries, the pulmonary wedge pressure and LV filling pressures increase [24, 25]. A similar pattern was found in the LA, with the most frequent pattern characterized by a 10% increase in LASr and a mild decrease or no change in LAVI, whereas the abnormal pattern is characterized by the development of LAVI dilation, reduction of LASr, and more B-lines. The functional unit LV-LA-lung alveolar-capillary barrier is tightly interconnected and ideally suited for a comprehensive assessment with SE, especially with dipyridamole stress which minimally degrades the image quality, only mildly although significantly increases the heart rate, and is an effective ischemic and, independently of ischemia, diastolic stress, probably for a direct, flow-independent effect of adenosine on cellular calcium fluxes [26], since dipyridamole acts through an accumulation of endogenous adenosine. Elevations of intracellular adenosine in specific types of cardiac disease, including those where myocardial energy reserve is limited, contribute to diastolic dysfunction by recruiting cross-bridges, and thereby increase myocardial stiffness [27].

Comparison with previous studies

The findings of the present paper are in agreement with previous studies showing the feasibility of LAVI and LASr assessment during SE performed with exercise or pharmacological stress [7–9]. The technical success rate can be even higher with dipyridamole stress, technically easier than exercise or dobutamine. This is especially important for LASr, since SR requires an adequate frame rate and the possibility of artifacts and inadequate signal-to-noise ratio increases with high heart rate. However, we limited our LA STE to LASr, by far the easiest to measure and the most reproducible of atrial strain parameters, which also include conduit strain and contraction strain [28].

Clinical implications

Step L of LA can be easily included in the comprehensive assessment of SE, with a simultaneous assessment of LA volume (with LAVI) and function (with LASr). There is a normal LA pattern, with unchanged-reduced LAVI and increased LASr, and a less frequent abnormal pattern, with marked LAVI dilation and decrease of LASr. These findings suggest that a simple SE can identify an incipient LA myopathy, more vulnerable to develop AF. These initial, observational studies are hypothesis-generating and should be now corroborated by future prospective studies evaluating whether the abnormal LA SE response is associated with greater chances to develop AF in the follow-up.

Study limitations

The study design was observational and the data analysis retrospective, although the data collection was prospective. Not all patients had all parameters, since the SE protocol rapidly evolved in recent years and the standard assessment of LAVI was only later enriched with the evaluation of LASr. The study design did not include a core lab assessment, but a preliminary quality control of one reader from each center, also to ensure the generalizability of the findings in the real world, as required by an effectiveness study [29].

In conclusion, vasodilator SE with combined assessment of LA volume and function, with pulmonary congestion with LUS, is feasible with a high success rate in patients with CCS. Pulmonary congestion is more frequent with a dilated LA with reduced atrial contractile reserve, but it may occur in a minority of patients with normal LAVI and normal LASr. Whether this pattern predicts the future occurrence of AF in patients in SR remains to be assessed in prospective, longitudinal, large-scale studies.