Picano, Eugenio

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 The left ventricular (LV) hypercontractile phenotype (HP) plays a critical role in hypertrophic cardiomyopathy (HCM) and is usually identified with the left ventricular outflow tract gradient (LVOTG). Purpose To assess the systemic and coronary hemodynamic profile associated with HP identified with increased LV elastance (also known as force) at rest in patients with HCM. Methods We enrolled 1248 HCM patients (age 50 ± 15 years, 798 males, 64%) with ejection fraction (EF) ≥50%, referred for rest transthoracic echocardiography (TTE) in 14 quality-controlled sites from 7 countries TTE assessment included LVOTG, EF, and LV force (systolic blood pressure + LVOTG/LV end-systolic volume, mmHg/mL). Volumetric echocardiography with Simpson’s method was used to measure EF from end-diastolic volume (EDV) and end-systolic volume (ESV), stroke volume (SV), arterial elastance (AE) and ventricular-arterial coupling (VAC). We also assessed resting peak diastolic coronary flow velocity (D-CFV) in the mid-distal left anterior descending artery in a subset of 275 patients. Results EF equaled 68 ± 7%, force = 6.8 ± 5.3 mmHg/ml and LVOTG = 22 ± 28 mmHg. HP was identified as the highest quartile of force (> 7.85 mmHg/ml, mean value= 13.3 ± 7.0). HP showed the lowest SV (46 ± 18 ml) and EDV (61 ± 20 ml), with the highest AE (3.19 ± 1.35 mmHg/ml) and VAC (3.46 ± 1.59) compared to other quartiles (p<0.001) ( see Picture) . D-CFV was not higher in patients with HP (n = 65) compared to those (n = 210) without HP (41± 11 vs 38 ± 14 cm/s, p=ns, but higher in comparison to joint first and second Force quartile (n=122) vs 37 ±14 p =0.0472). Table displays the demografic, clinical and TTE parameters related to HP (Table). In multivariate logistic analysis 4 independent predictors of HP were identified: SBP >130 mmHg with OR 2.5, female sex with OR 5.4, LV EF >70% with OR 6.1 and LVOTG >30 mmHg with the highest OR = 6.3. Conclusion: HCM patients with HP exhibit a distinctive systemic hemodynamic and coronary physiology profile, characterized by low SV, high VAC, and supranormal baseline D-CFV compared to non-HP patients. These findings suggest reduced cardiovascular efficiency and increased myocardial oxygen demand, possibly detrimental over time.

Abstract Background The left ventricular (LV) force, also known as elastance, serves as a load-independent indicator of contractility and can be noninvasively assessed through echocardiography. In hypertrophic cardiomyopathy (HCM), the heightened presence of the active state of myosin heads results in an increased LV force. Purpose To assess the prognostic value of increased LV elastance at rest in patients with HCM. Methods We enrolled 1420 HCM patients (age 50±16 years, 907 males, 64%) with ejection fraction (EF) ≥50%, referred for rest transthoracic echocardiography (TTE) in 10 quality-controlled labs from 7 countries. TTE assessment included peak left ventricular outflow tract gradient (LVOTG), EF, and LV force (systolic blood pressure + LVOTG/LV end-systolic volume assessed with 2-D, mmHg/mL). All patients were followed up. All-cause death was the outcome measure. Results At a median follow-up of 83 months, 150 deaths occurred (Group 1). At study entry, Group 1 patients had the same ESC-Sudden cardiac death score compared to survivors (Group 2). In Group 1 compared to Group 2, TTE showed higher values of MR severity, E/e’ , left atrial volume index, estimated systolic pulmonary artery pressure, and force (see table). At multivariable Cox analysis, only age (HR =1.08, 95% CI=1.03-1.14, p=0.001) and force > median value of 5.3 mmHg/mL (HR = 2.14, 95% CI 1.53-2.99, p=0.020) were independent predictors of mortality. Ten-year survival was 95% in the pooled first (<3.8 mmHg/mL) and second (3.8-5.2 mmHg/mL) quartiles vs 80% in the pooled third (5.3-7.8 mmHg/mL) and fourth quartiles (>7.8 mmHg/mL), see figure. Conclusion HCM patients with higher values of resting LV elastance show a worse survival, highlighting the dark prognostic side of an excess of force in these patients. Table Legends E/e’, early mitral inflow to early mitral annulus motion ratio, EF, left ventricular ejection fraction, LAVI, left atrial volume index; LVOTG, left ventricular outflow tract peak gradient, MR, mitral regurgitation; MWT, maximal wall thickness, NYHA, New York Heart Association classification, RWT, relative wall thickness; SCD risk, risk score for sudden cardiac death in hypertrophic cardiomyopathy, SPAP, systolic pulmonary arterial pressure.Table.Clinical and TTE findingsFigure.Survival in the force quartiles

Abstract Background Atrial fibrillation (AF) is the most prevalent atrial tachyarrhythmia, affecting an estimated 2-4% of adults worldwide. AF is a well-recognized and treatable risk factor for stroke, but it often remains asymptomatic or subclinical, leading to underdiagnosis. This study aimed to identify distinguishing signs during exercise stress echocardiography (ESE) among patients in sinus rhythm (SR), with and without history of paroxysmal/persistent AF (PAF). Methods An international prospective cohort comprising 1035 consecutive patients was initially considered from 12 cardiology institutions. These patients were referred for clinically-driven ESE as part of the Stress Echo 2020-2030 study network. All patients underwent comprehensive ESE with the ABCDE protocol, which included assessment of B-lines, left ventricle contractile reserve (LVCR), ECG-based heart rate reserve (HRR), LV ejection fraction (EF), LV end-diastolic volume, E/e’, pulmonary artery systolic pressure estimation, tricuspid annular plane sytolic excursion (TAPSE), left atrium volume index (LAVi) and left atrium reservoir phase strain (LASr) at rest and with exercise. Results After excluding 89 patients who were in AF during the ESE, 946 patients in SR were included as the main study cohort (101 with and 845 without a history of PAF). A scoring system was then constructed using all independent variables that differentiate the two groups (those with and without history of PAF). Presence of systemic hypertension, rest LAVI>31ml/m2, rest |LASr|< 21%, stress LAVI >29 ml/m2, stress |LASr| <24%, stress E/e’ >7, ∆TAPSE <4.5 mm, HRR<1.87, and LVCR<1.6 were identified as the discriminators between patients with and without PAF. The composite score, summing all 9 items (with a total score range from 0 to 9), yielded a score of >4 as the best balance between sensitivity (87%) and specificity (60%) in predicting those with PAF. The receiver operating characteristic curve analysis of the scoring model showed an AUC of 0.79 (p-value <0.0001), Figure. Conclusion ESE evaluation can be a valuable adjunct for identifying patients in SR with history of PAF. This multifaceted approach enhances the potential for more accurate detection and clinical management of individuals in SR at risk for AF, who could be considered for aggressive monitoring programs to prevent the development of new onset AF and subsequent increase in cardiovascular risk.

Abstract Background Guidelines recognize the role of exercise stress testing in evaluating functional capacity in patients with asymptomatic severe aortic stenosis (AS). The study aimed to identify the prognostic role of exercise stress echocardiography (ESE) in asymptomatic severe AS. Methods We enrolled 153 asymptomatic patients (70±13 years; 88 male, 57%) with severe AS, aortic valve area (AVA) <1.0 cm2, mean aortic gradient ≥ 40 mmHg, ejection fraction (EF) ≥55%. All were referred for ESE in 7 quality-controlled centers from 5 countries. Rest and ESE assessment also included global longitudinal strain (GLS) and left atrial volume index (LAVI). B-lines were assessed by LUS with the 4-site simplified scan of the third intercostal space. A 4-point ESE score was based on 4 parameters (0 for normal, 1 for abnormal), with the following pre-determined cutoffs of abnormality: ∆-maximal aortic gradient (MAG) ≥20 mmHg; GLS at peak ≤ 19%, according to receiver operating characteristics curve analysis, stress B-lines ≥2; stress LAVI ≥ 34 mL/m2. Follow-up was completed in 142/153 patients (92%). Results At rest, AVA was 0.85±0.14 cm2, maximal aortic gradient: 79±14 mmHg, and peak aortic velocity: 4.42 ± 0.41 m/s. Mean EF at rest: 63.4±5.3% During a median follow-up of 1802 days (IQ range 651-2302), 41 events occurred in 39 patients: 15 all-cause deaths, 17 acute HF, 1 stroke, 1 myocardial infarction, and 7 coronary revascularization. Patients experiencing events displayed a greater increase in MAG during peak ESE, more B-lines with exercise, greater degree of LAVI dilation with exercise and slightly lower GLS compared to those without events (Table). Increase in ESE score was associated with a significant rise (p=0.001) in event incidence from score 0 (n=0/13, 0%) to score 1 (n=2/21, 9.5%), score 2 (n=10/42, 23.8%), and ≥3 (n=27/66, 40.9%), see figure. Conclusions In asymptomatic severe AS cases with preserved LV EF, comprehensive ESE provides early marker of potential cardiac decompensation at follow-up. The composite ESE index, including MAG, GLS, LAVI, and B-lines, holds promise as a prognostic predictor.TableFigure

Abstract Background Heart failure (HF) with abnormal left ventricular (LV) ejection fraction (EF) manifests in multiple phenotypes, each presenting distinct and potentially actionable therapeutic targets. This study aimed to assess the potential of the ABCDE+ stress echocardiography (SE) protocol in uncovering different phenotypes of non-ischemic HF. Methods With a retrospective analysis of prospectively acquired data, we identified 265 patients (mean age: 65.7±12.6 years; 154 males, 59.9%) with non-ischemic HF with EF<50% (mean =41.4±7.5) enrolled by 23 certified laboratories between 2021 and 2023. Ischemic origin was excluded based on data of angiography and medical history. ABCDE-SE was evaluated with exercise (n=98, 37.0%), dobutamine (n=50, 18.9%), or vasodilators (n=117, 44.1%). The protocol consisted of several steps: A assessed regional wall motion abnormality (RWMA); B evaluated number of B-lines; C measured left ventricular contractile reserve; Step D with coronary flow velocity reserve (CFVR) in the left anterior descending artery (LAD) was completed in 102 patients (38.5%); step E assessed heart rate reserve. Additionally, step F (evaluated in 188 patients at rest and 107 at peak stress) noted the presence of rest or stress-induced moderate-to-severe secondary mitral regurgitation. The SE response was graded on a scale from 0 (all steps normal) to 5 (all ABCDE+ steps abnormal). Results The mean ABCDE score was 1.5±1.2, ranging from 0 (n=59, 22.3%) to 5 (n=2, 0.8%) (see distribution of scores in Figure 1A). Abnormal results were observed in 21 subjects (7.9%) for A, 86 (32.5 %) for B, 147 (55.5%) for C, 42/102 (41.2%) for D, and 101 (38.1%) for E steps. Step F was abnormal in 22/188 (11.8%) at rest and in 16/107 (14.9%) at peak stress. The predominant "solitary phenotypes" (only one step abnormal) were impaired LV contractile function phenotype (step C in 47, 51.1%) followed by chronotropic insufficiency (step E in 17, 18.5%) and congestive phenotype (step B in 17, 18.5%) (see Figure 1B). The most frequent combined phenotype was BCE – congestive phenotype with impaired ventricular and heart rate reserves (28 [62.2%]). Notably, 38 patients (14.3%) demonstrated improved regional contractility, while 27 patients (10.2%) showed new regional wall motion abnormality (see Table). Conclusion Non-ischemic HF patients with abnormal EF exhibit a broad spectrum of phenotypes. Impaired left ventricular contractility, interstitial congestion, and chronotropic insufficiency are the most frequent abnormalities detected by ABCDE-SE. Up to one-quarter of such patients demonstrate normal SE results. This comprehensive approach paves the way for personalized, SE-guided therapy.

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 Abnormal (<50%) ejection fraction (EF) is a cornerstone of risk stratification and therapy, but also an imperfect proxy of left ventricular (LV) cardiac pump function, better assessed with stroke volume (SV). Aim To assess the value of SV in stratifying risk of patients with abnormal EF. Methods In a prospective, observational, multicenter study, we recruited 746 patients (age 66± 11 years, 536 males, 72%, 359 with previous myocardial infarction, 48%) with chronic coronary syndromes (CCS) and EF <50% referred for resting transthoracic echocardiography with technically successful 2-dimensional volumetric echocardiography in 17 accredited laboratories. We quantitatively assessed LV end-diastolic volume (EDV) and end-systolic volume (ESV) by Simpson’s biplane method. EF (EDV-ESV/EDV) and SV (EDV-ESV) were calculated from LV volumes. The outcome end-point was all-cause death. Results EF was 39±9%, SV 48±20 ml. There were 100 all-cause deaths during a median follow-up of 796 days (interquartile range 420-1286 days). Receiver-operating curve analysis identified SV≤31.4 ml/b as the best cut-off for predicting mortality. At multivariable analysis, after adjustment for age and prior myocardial infarction, EF <40% and SV ≤31.4 ml/b were significantly associated with decreased survival (HR 2.09, 95%, confidence intervals 1.09-4.01, p=0.024). The annual mortality was lowest (3.19%) in the group with mildly reduced (40-49%) EF and normal (>31.4 ml) SV, and highest (8.30%) in patients with both reduced EF and abnormal SV: see figure. Conclusion Patients with CCS and abnormal EF are a prognostically heterogeneous group, and the mortality rate is almost 3-times worse in patients with reduced EF and abnormal SV compared to patients with mildly reduced EF and normal SV. A simple resting volumetric two-dimensional echocardiography can offer an efficient risk stratification, beyond EF, with no extra imaging or analysis time.Figure

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.

Abstract Background Patients with lower extremity peripheral arterial disease (PAD) have a higher risk of cardiovascular events. Stress echocardiography (SE) based on regional wall motion abnormality (RWMA) is imperfect for risk stratification in PAD, but it can be complemented with an assessment of coronary flow velocity reserve (CFVR) in the mid-distal left anterior descending coronary artery. Purpose To assess the value of SE with RWMA and CFVR to predict survival in PAD. Methods In a retrospective analysis of prospectively acquired data in an observational, multicenter study, we recruited 359 patients (age 69±8 years, 240 [67%] males) with PAD referred for dipyridamole SE in 3 accredited laboratories. We assessed RWMA and CFVR (abnormal value <2.0). All patients were followed up for a median of 4.7 (interquartile range: 2.0 to 8.2 years). All-cause death was the outcome end-point. Results The positivity rate was 37/359 (10%) for RWMA and 159/359 (44%) for CFVR. During follow-up, 97 (27%) deaths were registered. At multivariable analysis, inducible RWMA and/or CFVR <2.0 (HR 2.58, 95% CI 1.65-4.04; p<0.0001), age ≥70 years, diabetes, dialysis treatment, and ejection fraction ≤50% were associated with decreased survival. The annual mortality was 7.4% in patients with RWMA and/or CFVR <2.0 and 2.7% in those with no RWMA and CFVR >2.0 (Figure, p<0.0001). Conclusion In patients with PAD, SE shows more than 4-fold higher prevalence of abnormal CFVR compared to RWMA. The prognostic value of CFVR outperforms RWMA, showing the importance of coronary microvascular dysfunction and diffuse, subcritical coronary atherosclerosis in determining the outcome.