In this prospective study, consecutive CCSs patients referred to the echocardiography lab of the Lucca Hospital for a diagnostic evaluation from November 2020 to December 2022 were initially considered. The inclusion criteria were: 1) age > 18 years; 2) TTE of acceptable quality at rest; 3) no severe valvular or pericardial disease, pulmonary hypertension, acute and chronic inflammatory heart disease, severe bronchial asthma and/or chronic obstructive pulmonary disease or non-cardiac prognosis-limiting disease such as an advanced cancer; 4) willingness to give their written informed consent allowing scientific utilization of observational data, respectful of privacy rights.

Written informed consent was obtained in all patients. The study complies with the Declaration of Helsinki and was approved by the institutional ethics committee (Azienda USL Toscana Nordovest, decreto N. 1954, June 19, 2018).

The same commercially available machine [GE Vivid E95 (General Electric, Boston, MA, USA)] was used throughout the study period. All patients underwent comprehensive TTE at rest including assessment of the regional wall motion score index in a 16-segment model of the left ventricle, valvular function, and diastolic function. Modified biplane Simpson’s method was used to measure LV volumes and EF [7]. An average value of EF < 50%, as calculated from biplane method, was considered abnormal.

Per current recommendations, 2D-speckle tracking echocardiography was conducted for all patients offline. The frame rate was > 40 frames/s. Peak systolic LV-GLS was calculated using the average of 16 segment values (6 basal, 6 mid, and 4 apical segments) [8]. Due to the vendor-dependence of this parameter, an absolute GLS value ≤ 16.2% was considered abnormal being the best cut-off to predict events on a receiver-operating characteristics analysis [area under the curve 0.65, 95% (confidence Interval) CI 0.61–0.69; sensitivity 64%, specificity 61%] and broadly corresponding to the data proposed in the literature [9].

The same cardiac transducer was used for TTE and LUS. A 4-site simplified scan was adopted. At each site, B-lines (from 0 to 10) were counted, and a cumulative score (from 0 to 10) was obtained for each patient. An absolute B-lines value ≥ 2 units was considered abnormal [10].

TTE response was also summarized with an EF-B-lines-GLS score ranging from 0 to 3 as follows: score 0 (all markers within normal limits) or score 1–3, according to the number of abnormal steps (e.g., score 3 indicated all 3 steps were abnormal).

No patient was lost to follow-up. Deaths were identified from the national health service database while nonfatal events from review of the patient’s chart. Assessors were blinded to clinical and TTE results. The primary outcome measure was a composite endpoint of all-cause death, acute coronary syndrome (ACS; non-fatal myocardial infarction, hospitalization for unstable angina), and myocardial revascularization.

Categorical data are expressed in terms of the number of subjects and percentages while continuous data are expressed as mean ± standard deviation (SD). The cut-off values were determined a priori on the basis of existing literature for EF and B-lines and with a receiver-operating characteristics analysis for GLS. Kaplan Meier curves were used to evaluate and compare event-free survival while Cox regression was used to identify variables associated with the risk of future events. Univariable analyses by Cox proportional hazards models were performed to assess the association between each variable and the outcome. All variables with P < 0.10 in the univariable analysis were considered for inclusion in the Cox proportional hazards model and the variance inflation factor was used to assess collinearity. The incremental value of each parameter was evaluated comparing multivariable models with and without individual steps using global χ² value to evaluate the improvement of goodness-of-fit. Statistical significance was set at P < 0.05. SPSS 13.0, Chicago, IL, USA was used for analysis.

After a mean follow-up time of 14.2 months ± 8.3 months, 72 events occurred: 10 deaths, 11 ACSs (8 non-fatal myocardial infarctions, 3 hospitalizations for unstable angina), and 51 myocardial revascularizations (14 surgeries and 37 angioplasties). The event rate was lower in patients with EF ≥ 50% compared to patients with EF < 50% (Figure 3 upper panel), lower in patients with B-lines < 2 compared to patients with B-lines ≥ 2 (Figure 3 middle panel), and lower in patients with GLS > 16.2% compared to patients with GLS ≤ 16% (Figure 3 lowest panel). In multivariable analysis of the whole cohort, B-lines ≥ 2 [hazard ratio (HR) 1.76, 95% CI 1.05–2.97; P = 0.03] and GLS ≤ 16.2% (HR 2.00, 95% CI 1.17–3.45; P = 0.01) were independent predictors of events together with permanent atrial fibrillation (HR 2.90, 95% CI 1.38–6.07; P = 0.005) (Table 2). EF < 50% predicted outcome at univariable (HR 1.87, 95% CI 1.03–3.4; P = 0.04) but was not significant in multivariable analysis. In stepwise incremental analysis, B-lines ≥ 2 and GLS ≤ 16.2% added significant prognostic value to clinical variables, including permanent atrial fibrillation (Figure 4). The event rate rose progressively from TTE score 0 to score 1–2 to score 3, which showed a 5-fold higher event rate compared to score 0 (Figure 5).

The prognostic value of resting EF, GLS, and B-lines has been abundantly shown, confirmed, and reconfirmed in the literature. The evidence base dates back to the last 50 years for EF [3, 4, 11–15], the last 20 years for GLS [9, 16–23], and mostly the last decade for B-lines [24–30]. Previous large multicenter trials reported a close relationship between declining of EF and poorer prognosis both in patients with ACS [13, 14] and CCS [15]. GLS was found to be a powerful prognostic indicator in various cardiac conditions adding prognostic information over EF assessment [16, 17]. In the Copenhagen City Heart Study on a general population followed for a median of 11 months, GLS independently predicted morbidity and mortality and provided incremental prognostic information over current risk stratification models [19]. On note, each 1% deterioration of GLS was associated with 12% increased risk of acute myocardial infarction or cardiovascular death [18]. In addition, GLS allowed effective prognostication in patients with heart failure [16], ACS [18, 20], normal EF [21], and permanent atrial fibrillation [22]. Finally, it was independently associated with mortality in a large cohort of patients with suspected CAD referred for stress echocardiography [23]. Several studies showed that B‐lines predict adverse survival both in patients with chronic [24] and acute heart failure [25–30], including those with preserved EF [29]. The presence of B-lines at hospital discharge implied a worse prognosis also in the absence of rales in the auscultation [28]. To date, no study has evaluated the three parameters simultaneously in the same cohort showing the additive and incremental value of each of the three parameters, with the latest (GLS and B-lines) even outperforming EF in these consecutive populations with mostly preserved EF.

The present study underlines the importance of identifying and quantifying the 3 parameters—EF, GLS, and B-lines—when performing an echocardiographic examination. This implies the use of technology present in most if not all, echocardiographic machines such as GLS. LUS employs the same technology and transducer as TTE and is simple to learn, to use, and to quantify. GLS is operator-independent and requires a better-quality image than EF, but once the learning curve has been completed it can be performed off-line with minimal time and limited training requirements. The most time-consuming and less feasible parameter is EF, readily available now in some commercially available instruments with artificial intelligence-based automated analysis. In this way, the standard TTE exam is simpler, objective, and more informative as a first-line imaging technique in all CCS patients.

The single-center, prospective, observational study design was limited by the relatively small sample size for a prognostic study, with the need to include soft and subjective endpoints such as myocardial revascularization in the data analysis. However, the homogeneous methodology was also a potential advantage, since the same machine was used for vendor-dependent assessment of GLS, and the same operator (CL) performed all examinations eliminating the confounder of inter-operator variability affecting EF assessment. In addition, some parameters of recognized prognostic value such as severe mitral regurgitation or pulmonary hypertension were not assessed, by the selection, and may further contribute to the risk stratification potential of TTE supplemented by TTE and LUS.

In conclusion, TTE, STE, and LUS at rest offer additive and complementary information for the prediction of survival in CCS. The 3 items are EF, GLS, and B-lines. GLS and B-lines are even more feasible to obtain and simpler to measure than time-honored EF. They can be obtained in almost all patients, also in a semiautomatic or fully automated fashion, and are simple to image, analyze, and use. A simple TTE + STE + LUS score ranges from 0 (all parameters normal) to 3 (all parameters abnormal) and identifies a spectrum of annual event rates from < 4% to > 20% with no risk, no harm, no advanced imaging, and can be used in principle in all patients, by all doctors, with all machines.