Picano, Eugenio

Abstract Background Exercise stress echocardiography (ESE) is recommended in patients with mitral regurgitation (MR) when resting echocardiographic findings and symptoms do not align. However, the role of MR assessment in patients undergoing ESE for any indication remains uncertain. Purpose This study aimed to investigate whether the assessment of MR during ESE provides prognostic value beyond the evaluation of inducible regional wall motion abnormalities (RWMA) in patients undergoing ESE for any clinical indication, including suspected coronary artery disease (CAD). Methods Data were analyzed from a large multicenter and multinational prospective study. Current analysis included patients who underwent ESE for any indication and had MR (from 0= absent, to 3= severe) assessed at rest and peak exercise with an integrated qualitative, semi-quantitative, and (in selected cases) quantitative assessment. The primary endpoint was all-cause mortality. Results Of 1,351 included patients (age 56±16 years; 66% women; 30% with known CAD). MR score increased during exercise (rest=0.74±0.7 vs. peak=0.89±0.8, p<0.001), with severe MR present in 2% of patients at rest and 7% at peak ESE. Patients with severe MR during exercise (n=96, Group 1) compared to those with non-severe MR during exercise (n=1255, Group 2) showed more B-lines, lower left ventricular contractile and chronotropic reserve, and trend (p=0.09) to more frequent decrease in ejection fraction during ESE (Table 1). After a median follow-up of 2.1 years (IQR 1.0–6.9), 99 patients (7%) had died. Severe MR at rest was associated with increased mortality (log-rank p<0.001). Patients with severe MR at peak ESE had a higher risk of death compared to the other patients (log-rank p 0.035) (Figure 1). After adjusting for age, CAD, and inducible RWMA, severe MR with exercise remained strongly associated with an increased risk of death (adjusted-HR: 2.2, 95%CI 1.3-3.8, p=0.002). Similar results were seen with further adjustment for rest MR severity (adjusted-HR:1.9, 95%CI 1.02-3.5, p=0.004). Conclusion Patients, with and without CAD, with severe MR during ESE have greater functional impairment expressed by more pulmonary congestion, blunted heart rate reserve, and lower left ventricular contractile reserve. The assessment of MR during ESE provides significant prognostic information, independent of resting RWMA or inducible ischemia. Incorporating MR evaluation into routine ESE protocols may improve clinical decision-making and patient outcomes.Fig 1 Survival by MR at peak exercise Table 1

Abstract Background The presence of the significant left ventricular outflow tract gradient (LVOTG) changes clinical symptoms, prognosis and treatment in hypertrophic cardiomyopathy enabling the classification into its obstructive (HOCM) and non-obstructive form (non-HOCM). However, the more detailed functional characteristics and comparison of these forms remains poorly known. Purpose To compare the demographic, clinical and echocardiographic features between non-HOCM (defined as LVOTG < 30 mmHg) and HOCM patients enrolled into multi-centred study in years 1996-2024 as well as to analyse their long –term prognosis in relation to registered LVOTG. Methods We enrolled 1533 HCM patients (age 51 ± 15 years, 965 males, 63%) with ejection fraction (EF) ≥50%, referred for rest transthoracic echocardiography (TTE) in 27 centers, nevertheless quantitative assessment of LVOTG was available in 1252 patients. Survival analysis was performed in a subset of 1200 patients with follow-up information. Beyond standard TTE, the number of B-lines, the maximal diastolic velocity of coronary flow in left anterior descending artery (LAD) as well as left ventricular force defined as the ratio of systolic blood pressure plus LVOTG divided by left ventricular end-systolic volume was assessed with specification of hypercontractile phenotype (HP) as the highest force quartile. Additionally age and sex matched control group was included. Results Compared to non-HOCM patients, HOCM showed a bit higher body mass index (27 ± 4 vs 26 ± 4 kg/m2, p = 0.001), were often burdened with diabetes and hypertension, presented more advanced NYHA class and higher risk of SCD, see Table. In the echocardiographic assessment HOCM presented lower end-systolic left ventricular volume (LV ESV: 27 ± 14 vs 29 ± 13 ml, p = 0.014) although maintained equal stroke volume and even higher ejection fraction (EF: 69 ± 8% vs 67 ± 7%, p < 0.001), cardiac output (CO: 4.3 ± 1.7 vs 4.0 ± 1.4 l/min, p < 0.001) and force in comparison to counterparts without LVOTG. This high-contractility performance was however sustained at the cost of larger left atrium volume index (LAVI: 49 ± 19 vs 40 ± 15 ml/m2, p < 0.001), higher coronary flow velocity (43 ± 12 vs 27 ± 13 cm/s, p < 0.001) as well as more frequent B-lines in the lung assessment. During a median follow-up of 87 months (interquartile range 45 – 143 months), 131 all-cause deaths occurred and not only patients with HOCM but also those with HP showed the worse long-term survival, see Figure. Conclusion HOCM remains the form of HCM burdened with more overt clinical symptoms, signs and prognosis. On the other hand LVOTG seems to be important but not always necessary element of this presentation, which seems to be related even more tightly to general hypercontractility phenotype reflected by higher force and resting coronary flow.Table.Non-HOCM vs HOCM comparison Figure.Force and LVOTG prognostic value

Abstract Background Angina with non-obstructive coronary artery disease (ANOCA) is increasingly recognized in clinical practice but effective therapy is difficult to apply due to the heterogeneity of pathophysiological substrates: structural coronary microvascular dysfunction (CMD), functional (vasospastic) CMD, epicardial artery vasospasm, non-cardiac chest pain. Current guidelines recommend invasive coronary function testing with inherent limitations in cost, risk, and access. Objective To evaluate the feasibility of a step-wise, multi-marker, multi-stress assessment of ANOCA patients by stress echocardiography (SE). Methods In an observational, prospective, multicenter, international study, we enrolled 1146 ANOCA patients (age =65.6±11.6years, 636 men, 55, %). All patients underwent a vasodilator SE (adenosine or dipyridamole) with coronary flow velocity reserve (CFVR) measurement in the mid-distal left anterior descending artery (LAD). In a subset of patients with a normal CFVR and strong clinical suspicion for vasospasm, a hyperventilation (HYPER) test (30 deep breaths/min for 5 min) was performed, followed by semi-supine exercise (EX) if negative. Positivity criteria were stress-specific: CFVR < 2.0 for vasodilators; coronary flow velocity (CFV) reduction ≤ 10% from baseline with HYPER; inducible RWMA 2.for HYPER and HYPER-EX Results Of the 1146 patients, 244 (21%) showed abnormal CFVR i.e. structural CMD (Figure 1). In the subset of 68 patients with normal vasodilator CFVR , entering a strategy of sequential stepwise approach, 40 pts underwent HYPER showing a paradoxical vasoconstrictor response despite the increase in the double product (59 %), with RWMA in 11 (16%). Of the remaining patients with normal CFVR and normal response to HYPER, 28 underwent HYPER-EX showing inducible RWMA in 7 (10%) patients. The remaining 21 patients (31%) showed all 3 tests normal: see figure 2. Conclusion In patients with ANOCA, a stepwise multi-marker (CFVR and RWMA) and multi-stress (vasodilators, HYPER, and EX) SE identifies 4 distinct phenotypes and actionable therapeutic targets: structural CMD (reduced CFVR with vasodilator); functional vasospastic CMD (paradoxical decrease of CFV with HYPER), epicardial artery vasospasm (inducible RWMA with HYPER or HYPER-EX); non-cardiac chest pain with normal response all tests and all markers. Our research emphasizes the usefulness of versatile, patient-tailored noninvasive testing in patients with ANOCA to unmask the functional heterogeneity of the endotypes underlying the same phenotype. Figures: 1. Overall population of ANOCA (N=1146)-vasodilator CFVR 2. Pilot study in ANOCA with CFVR>2.0 (N=68)Overall population of ANOCA (N=1146) Pilot study in ANOCA with CFVR>2.0

Abstract Background Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous entity including patients with different phenotypes of near normal, normal, and supernormal left ventricular (LV) function. Objectives To assess the value of resting LV elastance (also known as force) with transthoracic echocardiography (TTE) to identify HFpEF phenotypes. Methods In a prospective, observational, multicenter study, 2380 HFpEF patients were recruited from July 2016 to May 2024. Systolic blood pressure (SBP) was measured. We assessed LV end-diastolic volume (EDV), end-systolic volume (ESV), EF, force (SBP/ESV), stroke volume (SV), arterial elastance (AE), ventricular-arterial coupling (VAC), and left atrial volume index (LAVI). Global longitudinal strain (GLS) was available in 1164 (48.9%) patients. 680 patients finished follow-up with a composite end-point of major adverse cardiac events (MACEs). Patients were divided into three groups: low force (< 25th percentile, Group 1, < 3.24 mmHg/ml), intermediate force (≥ 25th percentile and ≤ 75 thpercentile, Group 2, 3.24-5.48 mmHg/ml), and high force (> 75 th percentile, Group 3, >5.48 mmHg/ml). Results The 3 groups showed a gradient with descending values (Group 3>2>1) for SBP, EF, GLS, AE, and VAC, with the opposite gradient (Group 1> 2> 3) for EDV, ESV, SV, and LAVI values (all P<0.01). After a median follow-up of 16 months, 205 MACEs occurred in 138 patients. Cumulative MACEs rate was lowest in group 2 (14.7% person-year), higher in group 1 (16.1% person-year) and 3 (22.9% person-year, log rank p = 0.036). Conclusions HFpEF patients present with different LV contractile phenotypes, easily identified with resting LV force and volumetric TTE. The dominant hemodynamic feature of hypocontractile phenotype is a preload recruitment with larger LV EDV and normal SV, while the hypercontractile phenotype is characterized by a small LV with reduced SV. The hypercontractile and hypocontractile phenotypes are associated with a higher risk of subsequent events.

Abstract Backgrounds Transthoracic echocardiography (TTE) identifies a peculiar hypercontractile phenotype (HP) in patients with heart failure and preserved ejection fraction (HFpEF) with high resting left ventricular (LV) elastance (also called force). Objectives To assess the functional response and its prognosis associated with HP in HFpEF by stress echocardiography (SE). Methods In a prospective, observational, multicenter study, 1213 patients with HFpEF were divided into two groups based on the highest quartile of rest force: non-hypercontractile phenotype group (non-HP, < 5.64 mmHg/mL, Group 1, n= 910), and HP group (≥5.64 mmHg/mL, Group 2, n= 303). All patients underwent SE with at least 4 of the following stress parameters assessed: wall motion score index (WMSI), B-lines (4-site score), force-based LV contractile reserve, coronary flow velocity reserve (CFVR), and heart rate reserve (HRR). The employed stress was exercise (n=687), dobutamine (n=195), or vasodilators (n=331). SE score ranged from 0 (all steps normal) to 1-5, according to the number of abnormal steps. Follow-up was completed in a subset of 260 patients. Results The 2 groups showed similar values of peak stress WMSI but the global functional burden was higher in Group 2 patients: see table. In a subset of 260 patients who finished follow-up, there were 212 non-HP patients and 48 HP patients. During a median follow-up of 15 months (interquartile range: 10-20), 26 deaths, 20 heart failure (HF) rehospitalizations, and 64 major adverse cardiovascular events (MACEs) occurred. The cumulative HF rehospitalization rate and MACEs rate were higher in HP group (log-rank p<0.01): see figure. Rest force (HR, 1.17; 95% CI: 1.06-1.29; P: 0.040), rest SPAP (HR, 1.08; 95% CI: 1.02-1.14; P: 0.007) and ABCDE score (HR, 1.15; 95% CI: 1.01-1.66; P: 0.032) were independently associated with MACEs. Conclusions HFpEF patients with HP are functionally weaker with multiple vulnerabilities during stress and at higher risk of subsequent events compared to non-HP patients.Relation between resting values of force

Over the past decade, stress echocardiography has evolved from a test for assessing epicardial artery stenosis to a comprehensive functional test, targeting multiple cardiovascular parameters. The new approach includes several structured steps: (a) evaluating regional wall motion abnormalities to detect epicardial artery stenosis or vasospasm; (b) assessing pulmonary congestion and diastolic function via B-lines with lung ultrasound; (c) gauging preload and contractile reserve with volumetric echocardiography; (d) measuring coronary microvascular reserve using Doppler-based coronary flow velocity in the middistal left anterior descending artery; and (e) determining cardiac sympathetic reserve by tracking heart rate reserve on an ECG. This evolution was supported extensively by the Italian Society of Echocardiography and Cardiovascular Imaging (SIECVI), which played a key role in five areas: (1) developing the initial, curiosity-driven project; (2) disseminating protocols and results at national and international conferences, supporting logistic infrastructure and publication expenses; (3) establishing a digital platform (customized Redcap) for data entry and storage; (4) facilitating patient recruitment across 19 Italian centers; and (5) offering formal endorsement through six presidencies, adding credibility and reach beyond any single institution. The protocol quickly advanced from concept to high-impact publications, earning inclusion in 2024 specialty guidelines. Initially Italian-led, the study now includes 50 centers across 20 countries (e.g. USA and China). Beyond the 50 peer-reviewed papers published in 2016–2024, this study offers a novel, sustainable approach to cardiac stress testing, providing more information at lower costs, with zero radiation and minimal environmental impact. SIECVI’s endorsement was instrumental in amplifying the study’s rigor and outreach.

Stress echo (SE) 2030 study is an international, prospective, multicenter cohort study that will include >10,000 patients from ≥20 centers from ≥10 countries. It represents the logical and chronological continuation of the SE 2020 study, which developed, validated, and disseminated the “ABCDE protocol” of SE, more suitable than conventional SE to describe the complex vulnerabilities of the contemporary patient within and beyond coronary artery disease. SE2030 was started with a recruitment plan from 2021 to 2025 (and follow-up to 2030) with 12 subprojects (ranging from coronary artery disease to valvular and post-COVID-19 patients). With these features, the study poses particular challenges on quality control assurance, methodological harmonization, and data management. One of the significant upgrades of SE2030 compared to SE2020 was developing and implementing a Research Electronic Data Capture (REDCap)-based infrastructure for interactive and entirely web-based data management to integrate and optimize reproducible clinical research data. The purposes of our paper were: first, to describe the methodology used for quality control of imaging data, and second, to present the informatic infrastructure developed on RedCap platform for data entry, storage, and management in a large-scale multicenter study.