Zagatina, A

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 Obese patients often exhibit a clustering of cardiovascular risk factors and are frequently referred for noninvasive cardiac imaging. Coronary microvascular dysfunction (CMD) represents an early indicator of cardiovascular disease that can be noninvasively diagnosed using coronary flow velocity reserve (CFVR) measurements obtained during stress echocardiography (SE) in patients without evidence of obstructive coronary artery disease (CAD). Purpose This study aimed to evaluate the prognostic significance of CFVR in overweight and obese patients within a prospective multicenter cohort. Methods 2273 patients (mean age 65 ± 11 years; 51% women) classified as overweight or obese (for definition see Table) were included in 27 sites from 11 countries. All patients had normal left ventricular ejection fraction (EF ≥ 50%), no prior history of CAD, and underwent exercise or pharmacological SE, which was negative for inducible ischemia. CFVR of the left anterior descending coronary artery was assessed, with CMD defined as CFVR >2.0. Patients were divided into two groups based on the presence (Group 1) or absence (Group 2) of CMD. The primary endpoint was overall mortality. Results CMD was identified in 492 patients (22%), with a mean CFVR of 2.3 ± 0.5 across the study population. Group 1 patients (CMD) were older, with a greater prevalence of diabetes and metabolic syndrome compared to group 2 (no CMD) (Table). During a median follow-up period of 2.1 years (IQR: 1.2-3.7 years), 103 patients (5%) died. Patients with CMD had significantly worse late survival compared to those without CMD (3-year survival: 96 ± 1% vs. 96 ± 1%, p=ns; 6-year survival: 79 ± 4% vs. 93 ± 1%, p < 0.0001): see Figure. Multivariate analysis adjusting for age, sex, EF, body mass index, smoking habits, diabetes, dyslipidemia, arterial hypertension, and type of stress confirmed CMD as an independent predictor of mortality (hazard ratio: 1.8 [95% CI: 1.1–2.8], p = 0.01). Conclusions CMD, assessed via CFVR during SE, was a robust and independent prognostic marker of long-term mortality in obese patients with preserved EF and no evidence of inducible ischemia. These findings underscore the pivotal role of noninvasive assessment of CMD in refining risk stratification and guiding clinical decision-making in this high-risk population.

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

Abstract Background Heart failure and preserved ejection fraction (HFpEF) is a heterogeneous entity including patients with different phenotypes of reduced, normal, and supernormal left ventricular (LV) function. Objectives To assess the value of resting LV elastance 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 by 35 certified laboratories of 15 countries. HFpEF was diagnosed according to the European Society of Cardiology (ESC) guidelines. Systolic blood pressure (SBP) was measured. We assessed wall motion score index (WMSI), LV end-diastolic volume (EDV), end-systolic volume (ESV), EF, force (SBP/ESV), stroke volume (SV), arterial elastance (AE, SBP/SV), ventricular-arterial coupling (VAC, as SV/ESV), and left atrial volume index (LAVI). Global longitudinal strain (GLS) was available in 1164 (48.9%) patients. In 271 (11.4%) patients, N-terminal pro-brain natriuretic peptide (NT-proBNP) was assessed. Patients were divided into three groups based on rest force: low rest force group (< 25% percentile, Group 1), median rest force group (≥ 25% percentile & ≤ 75% percentile, Group 2), and high rest force group (> 75% percentile, Group 3). Results 330 (13.9%) patients presented with ischemic RWMA. 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, EDVi, ESV, ESVi, SV, SVi, and LAVI values (all P<0.01). Patients in Group 3 have higher NTproBNP level and higher percentage of B-line compared to groups 1 and 2 (P<0.05). The 3 groups were similar for values of coronary flow velocity, systolic pulmonary artery pressure, and E/e’ (see table). Univariable linear regression analysis showed that NTproBNP was correlated with force (r = 0.271, p < 0.001), VAC (r = 0.194, p = 0.001), LAVI (r = 0.327, p < 0.001), LVEDV (r = -0.245, p < 0.001), LVEDVi (r = -0.261, p < 0.001), LVESVi (r = -0.190, p = 0.002) and LVESV (r = -0.187, p = 0.002) (see figure). However, multivariable linear regression analysis showed that NTproBNP was independently associated with LAVI (β= 0.211, p < 0.001) and force (β= 1.804, p = 0.002). Conclusions HFpEF patients present with different LV contractile phenotypes, easily identified with resting LV force and volumetric TTE. LV force is linearly correlated with cardiac natriuretic peptide levels. The dominant hemodynamic feature of hypocontractile phenotype is a preload recruitment with dilation of LV EDV and normal SV, while the hypercontractile phenotype is characterized by a small LV with reduced SV. heat map

Abstract Background Hypercontractile phenotype of the left ventricle (LV) is an actionable therapeutic target in patients with chronic coronary syndromes (CCS), but its clinical recognition remains elusive. Purpose To assess the clinical variables associated with the hypercontractile phenotype of the LV, identified with supernormal values of an index of LV contractility such as LV force, also known as ventricular elastance. Methods In a prospective, observational, multicenter study, we recruited 5,122 patients (age 65± 11.1 years, 2974 males, 58%) with CCS referred for resting transthoracic echocardiography with technically successful volumetric echocardiography in 17 accredited laboratories. We measured systolic blood pressure (SBP) with a cuff sphygmomanometer. We assessed semi-quantitatively wall motion score index (WMSI), and quantitatively LV end-diastolic volume (EDV), end-systolic volume (ESV), ejection fraction (EF), force (SBP/ESV), stroke volume (SV), arterial elastance (SBP/SV), ventricular-arterial coupling (VAC, as SV/ESV), and cardiac output (CO = SV*heart rate).Univariable and multivariable logistic regression analysis assessed independent factors associated with the highest force sextile. Odds ratios (ORs) with the corresponding 95% confidence interval (CI) were estimated. Results For all the studied patients, EF was 59±11%. Force was 4.51±2.11 mmHg/ml, with reference sextile = 3.50-4.26 mmHg/ml, lowest sextile (Group 1) <2.60 mmHg/ml and highest sextile (Group 6) > 6.36 mmHg/ml. The correlation between the log of EF and the log of Force was significant with linear regression (r = 0.73, p < 0.001). Patients in the highest sextile of force showed lower values of WMSI, SV, EDV, and ESV, and higher values of arterial elastance and VAC (Table). By multivariable logistic regression model, the highest sextile of force was associated with age > 71 years (OR 4.35, 95% CI 3.06-6.18, p < 0.001), female sex (OR 4.48, 95% CI 3.62-5.54, p < 0.001), absence of beta-blocker therapy (OR 1.56, 95% CI 1.27-1.91), rest SBP> 159 mmHg (OR 6.86, 95% CI 5.03-9.35, p < 0.001), high heart rate (OR 1.03, 95% CI 1.02-1.04, p < 0.001), absence of prior MI (OR 1.31, 95% CI 1-1.72, p = 0.049), and higher LV EF at rest (OR 1.24, 95% CI 1.22-1.26, p < 0.001). Conclusions A hypercontractile phenotype of the LV with high force is associated with a small heart, reduced SV, and higher arterial elastance. It was clinically associated with advanced age, female sex, history of hypertension, absence of beta-blocker therapy, and high resting SBP.

Abstract Background/Introduction Cardiac stress tests are carried out in populations with a low probability of ischemic heart disease (IHD) much more frequently than in the past. Stress ECG remains a frequently used modality for the diagnosis of IHD in vast areas of the world with limited facilities. Purpose To assess the diagnostic value of stress ECG for diagnosing IHD using inducible regional wall motion abnormalities (RWMA) on stress echocardiography (SE) as the gold standard method of diagnosis. Methods The 12-lead ECG response was retrospectively analyzed in 4317 patients (age 64±13 years, 59.6% males) undergoing SE for chronic coronary syndromes who were prospectively recruited from 39 cardiac centers between March 2021 and February 2024. Exclusion criteria were left bundle branch block or pacemaker rhythm. ECG response was considered ischemic according to standard criteria (if ST-segment deviated >1.0 mm from baseline in ≥2 contiguous leads at 80 ms from J point) during an exercise (n=2980, 69.8%), dobutamine (n = 766, 18.0%), or vasodilator (n=519, 12.2%) SE. All patients underwent a comprehensive SE protocol with an assessment of wall motion score index (WMSI), B-lines (4-site simplified score), left ventricular contractile reserve (LVCR) based on force, coronary flow velocity reserve (CFVR) in the mid-distal left anterior descending artery (LAD), and heart rate reserve (HRR). Results ECG changes occurred in 641 patients (14.8%, Group 1) for the overall studied population. Compared to patients without ECG changes (Group 2, n=3676, 85.2%), patients with ECG changes showed higher values of peak WMSI and lower values of CFVR and LVCR (see table).Amongst patients without inducible RWMA (n=3553), there were 392 (11%) patients with an ischemic ECG at stress (89% specificity). Of 764 patients with inducible RWMA during SE, 249 had an ischemic ECG trace (sensitivity 33%). In patients without inducible RWMA, those with ischemic ECG changes showed similar abnormal stress B-lines (23% vs. 21%, p=0.719), LVCR (61% vs. 63%, p=0.602), CFVR (31% vs 33%, p=0.607) and HRR (37% vs 41%, p=0.097) compared to those without ECG changes. Amongst patients with inducible RWMA and ECG changes, CFVR was significantly lower in patients with ECG changes (39.2% and 60.8%, respectively, p<0.001). Conclusions Simple standard stress ECG diagnostic value in the current era in populations with a low probability of IHD seems to be low. However, during SE, stress-induced ischemic ECG changes are associated with more extensive RWMA and blunted global LVCR, with reduced CFVR in the LAD. Therefore, analysis of ST segment changes during stress imaging studies can offer additional, significant information.