Pellikka, Patricia A.

Abstract Background Stress echocardiography (SE) was recently upgraded to the ABCDE protocol: step A, regional wall motion abnormalities; step B, B-lines; step C, left ventricular contractile reserve; step D, Doppler-based coronary flow velocity reserve in left anterior descending coronary artery; and step E, EKG-based heart rate reserve. Aim to assess the prognostic value of ABCDE-SE in a prospective, large-scale, multicenter, international, effectiveness study. Methods From July 2016 to November 2024, we enrolled 7896 all-comers (age 65±11 years, 4742 [60.0%] males, ejection fraction 59±10%) with known or suspected chronic coronary syndromes (CCS) referred from 27 certified laboratories. All patients underwent clinically indicated ABCDE-SE, with ACE in all patients, step D in 6286, step B in 5951 and all 5 steps in 5918 pts. The employed stress modality was exercise (n=2407) or pharmacological stress (n=5489; with vasodilator, n=4503; or dobutamine, n=986). Each step was scored from 0 (normal) to 3 (severely abnormal) following EACVI recommendations 2024. SE response ranged from a score of 0 (all steps normal) to a score of 15 (all steps severely abnormal). All-cause death was the only end-point. Results During a median follow-up of 685 days (interquartile range: 387-1227), 370 deaths occurred. Step A negativity was associated with a 1.5% annual mortality. Annual mortality rate ranged from 0.4% persons/year for score 0 (n=958, 12.1%) up to 6.19% person/year for score ≥10 (n=346, 4.3%). (Figure). At multivariate logistic regression analysis, age (hazard ratio [HR] 1.008, 95% interquartile range [IQ]: 1.006-1.010, p<0.001), diabetes (HR 1.564, 95% CI: 1.263-1.936, p<0.001), resting ejection fraction (HR 0.983, 95% CI: 0.974-0.993, p=0.001), and ABCDE score 3-5 (HR 3.111, 95% CI 1.597-6.060, p=0.001), score 6-9 (HR 5.442, 95% CI 2.761-10.729, p<0.001), and score ≥10 (HR 8.826, CI 4.197-18.654, p<0.001) were independent predictors of mortality. Conclusion In patients with known or suspected CCS, SE negativity by simple wall motion criterion is unable to identify a low-risk group. ABCDE-SE allows an effective prediction of survival.Figure

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

Background: Older adults with severe aortic stenosis (AS) are at high risk of mortality unless treated by aortic valve replacement (AVR). The Society of Thoracic Surgery (STS) score is primarily used clinically to determine mortality risk from surgical AVR. Due to geriatric comorbidities unique to older adults, traditional methods of risk stratification with STS may have significant shortcomings. Administratively derived risk scores that have prognostic significance in the geriatric population may prove valuable. Methods: We reviewed patients at our hospital system with AS undergoing AVR (surgical and transcatheter) and administratively derived an Elder Risk Assessment (ERA) score from the health record. The ERA score is a composite of age, marital status, number of hospitalized days in previous 2 years, and comorbidities (diabetes, coronary artery disease (CAD), heart failure, stroke, pulmonary disease, cancer, and dementia). Kaplan-Meier method was used to estimate survival by ERA score tertile. Cox regression was used to determine association between ERA and survival after accounting for STS predicted risk. Results: There were a total of 228 patients that underwent AVR (TAVR: 59 (26.1 %); SAVR 167 (73.9%) and had ERA scores derived. The average age was 79.6 (SD 7.6) years) and there were 93 (40.8%) women. Patients were stratified by ERA score tertiles: low (≤6), mid (6-13), or high (≥14). Over a mean follow up of 5.8 (SD 3.1) years, lower ERA scores were associated with better long-term survival (p<0.001). After accounting for age, sex, and STS score, mid ERA (HR 1.61; 95% CI 1.00-2.59; p<0.001) and high (HR 2.90; 95% CI 1.79-4.69; p<0.001) were associated with mortality (reference: low ERA). For every 10-point increase in the ERA, there was a 2-fold increase in adjusted mortality risk (HR 2.14; 95% CI 1.58-2.90; p<0.001). Conclusions: Older adults undergoing AVR for severe AS have specific geriatric comorbidities that may be better characterized using the ERA score. This administratively derived score was independently associated with survival after accounting for the widely used STS risk score.

Background: Tricuspid regurgitation (TR) is associated with significant morbidity, but individualized treatment and timing of intervention are yet to be defined. We previously proposed and validated artificial intelligence electrocardiography (AI-ECG) scores for various diseases. Whether incorporating AI-ECG information adds to risk stratification above and beyond classical clinical parameters is unknown. Objectives: To identify AI-ECG scores independently associated with all-cause mortality in chronic TR and to create a composite AI-ECG risk score. Methods: Patients with a first echocardiographic diagnosis of ≥moderate TR between 2005-2016 and an ECG within ±15 days were included. The Tricuspid Regurgitation Impact on Outcome (TRIO) score was calculated as previously described based on 8 simple parameters (age, sex, severe TR, heart failure, lung disease, heart rate, creatinine and AST). AI-ECG probabilities of low ejection fraction, aortic stenosis, amyloid, cirrhosis, atrial fibrillation and hypertrophic cardiomyopathy were estimated by existing algorithms; the first 4 were associated with all-cause mortality and a composite AI-ECG risk score was calculated (0-4; 1 point for each AI-ECG above specific threshold). Results: A total of 12,377 pts were included (age 72±13 yrs, 55% women). Over a median follow-up of 1.3 yrs (IQR 0.1 to 4.4), 7,121 pts (58%) died. Mortality risk increased significantly with higher composite AI-ECG risk score (Fig. 1A). On multivariable analysis (proportional hazards method), the composite AI-ECG risk score remained independently associated with death, even after adjusting for age, sex, high NT-proBNP levels (>2,500 pg/mL), right ventricular systolic pressure (RVSP), diuretic use and TRIO risk score category (Fig. 1B). Conclusions: Patients with ≥moderate TR show progressively worse survival with increasing composite AI-ECG risk score. Incorporating AI-derived information from a simple and inexpensive ECG may identify patients with the highest risk of mortality beyond clinical risk scores as TRIO or classical clinical, laboratory and echocardiographic parameters. Prospective validation of this approach needs to be tested in future trials.

Intracardiac metastases from gastroenteropancreatic neuroendocrine tumors (NETs) are rare and challenging to diagnose. Lutetium (Lu)-177 DOTATATE therapy has demonstrated significant benefit in patients with metastatic NET; however, there are limited data regarding the direct impact on cardiac metastases. Patients with intracardiac metastasis from NET were evaluated. Patients were stratified by treatment with Lu-177 DOTATATE. Quantitative assessments of the progression of cardiac metastatic size (maximal diameter) and metabolic activity, as measured by maximal standardized uptake value (SUV max ), were performed on serial 68 Ga-DOTATATE PET imaging. In a cohort of 23 patients, 11 patients (47.8%) received Lu-177 DOTATATE therapy. Through a median of 2.2 years of follow-up, these patients showed some reduction in metastatic burden with a median reduction in maximal diameter of 1.0 mm (IQR: 0.0–3.0) and a median change in SUV max of −1.6 (IQR: −4.4 to 1.5). In contrast, patients who did not receive Lu-177 DOTATATE had some increase in maximal diameter of 0.5 mm (−2.0 to 2.0) and an increase in SUV max of 1.4 (−6.2 to 2.3). Overall, Lu-177 DOTATATE therapy may result in modest regression of intracardiac metastases as assessed by molecular imaging, whereas patients with cardiac metastases who did not receive therapy appeared to show progression.

Background A classification system describing clinical presentation before aortic valve replacement (AVR) has recently been proposed (stable valve syndrome [SVS]), mildly symptomatic (progressive valve syndrome), or with acute and severe signs and symptoms (acute valve syndrome [AVS]). We aimed to evaluate the clinical impact, health care costs, and resource use associated with the mode of clinical presentation at the time of AVR among patients presenting with aortic stenosis. Methods Using the Market Clarity database (2017–2023), patients >18 years old with aortic stenosis and undergoing AVR (transcatheter or surgical) were included. Patients were categorized as SVS, progressive valve syndrome, or AVS based on their clinical presentation during the 1 year before AVR. All‐cause death, heart failure hospitalization, total health care costs (index hospitalization plus 1‐year follow‐up), and resource use were compared across clinical presentation groups using adjusted regression models. Results Of the 24 075 patients undergoing AVR for aortic stenosis, 270 (1.1%) had SVS, 10 195 (42.3%) progressive valve syndrome, and 13 610 (56.5%) AVS. Compared with SVS, AVS presentation was associated with increased risk of 1‐year death (adjusted hazard ratio [aHR], 2.93 [95% CI, 1.1–7.8]; P =0.03) and heart failure hospitalization (aHR, 4.15 [95% CI, 1.6–11.1]; P <0.01) after AVR. The total costs of AVR and 1‐year follow‐up were significantly higher in both the progressive valve syndrome (difference $27 410 [$13 507–$41 314]) and AVS groups (difference $36 267 [$22 302–$50 232]) compared with patients with SVS. Conclusions AVS was frequent among patients undergoing AVR and was associated with increase in death, heart failure hospitalization, health care costs, and resource use 1 year after AVR, and SVS presentation was associated with the best clinical and economic outcomes.

Abstract Aims Chronotropic incompetence (CI) is a biomarker of cardiac autonomic dysfunction. The aim of the study is to assess the risk stratification value of CI during exercise or pharmacological stress echocardiography in patients with chronic coronary syndromes. Methods and results In a prospective, multicenter, international, observational study, we enrolled 13 445 patients with known or suspected chronic coronary syndromes who underwent stress echocardiography in 19 clinical sites from 10 countries using either exercise (n = 2594), dobutamine (n = 2440), or dipyridamole (n = 8411). Heart rate was automatically measured from the 1-lead ECG in the echocardiography monitor. We considered CI as failure to reach 85% of the maximal predicted (220-age) heart rate for exercise and dobutamine, and heart rate reserve (peak/rest heart rate) ≤ 1.22 (≤1.17 if in permanent atrial fibrillation) for dipyridamole stress. The primary outcome was all-cause death. CI was observed in 5045 patients (38%) and stress-induced regional wall motion abnormalities in 1648 (13%). Over a median follow-up time of 3.4 years (interquartile range, 1.6–9.1 years), there were 2426 (18%) deaths. The 10-year mortality was 39% in patients with and 21% in patients without CI (P &lt; 0.0001). CI was associated with a significant increase in 10-year mortality in all age groups ranging from ≤54 years to ≥75 years (P &lt; 0.0001). In addition, it was associated with increased mortality (P &lt; 0.0001) irrespective of β-blocker use. Cox multivariable analysis revealed that CI was an independent predictor of mortality (HR: 1.60, 95% confidence interval: 1.47–1.74; P &lt; 0.0001) together with age, male sex, diabetes mellitus, left ventricular ejection fraction, and resting heart rate. Conclusion In patients with chronic coronary syndromes, CI during exercise or pharmacological stress is a simple and objective predictor of survival.

Abstract Aims Our aim was to assess the clinical and prognostic significance of the left ventricular (LV) hypercontractile phenotype (HP) in hypertrophic cardiomyopathy (HCM), which until now remains unclear. Methods and results 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 laboratories from 13 countries. Two-dimensional volumetric TTE assessment included LV outflow tract gradient (LVOTG), LV EF, and LV force (systolic blood pressure + LVOTG/ESV, mmHg/mL). HP was defined as the highest quartile of the force (&gt; 7.32 mmHg/mL). Survival analysis was performed in a subset of 1200 patients with follow-up information. Compared with non-HP patients, HP showed higher heart rate (72 ± 14 vs. 67 ± 14 beats per minute, P &lt; 0.001), lower stroke volume (50 ± 22 vs. 67 ± 22 mL, P &lt; 0.001), larger left atrial volume index (44 ± 16 vs. 40 ± 16 mL/m2, P = 0.011) and higher coronary flow velocity in the mid-distal left anterior descending artery (n = 325, 41 ± 12 vs. 37 ± 14 cm/s, P = 0.021). Force was moderately related to LV EF (r = 0.48, P &lt; 0.001) and weakly to LVOTG (r = 0.36, P &lt; 0.001). During a median follow-up of 87 months (interquartile range 45–143 months), 131 all-cause deaths occurred. At multivariable Cox analysis, a force &gt; 7.32 mmHg (the fourth quartile for analyzed patients) was associated with a hazard ratio of 1.44 (95% Confidence intervals 1.00–2.07) for all-cause death, independently of LVOTG and LV EF. Conclusion HP in HCM is associated with a disadvantageous systemic, cardiac and coronary hemodynamic profile as well as lower survival in the long-term.

Background Atrial fibrillation (AF) impacts management decisions in valvular heart disease but its significance in patients with chronic aortic regurgitation (AR) is not well established. Objectives To evaluate the prevalence and prognostic role of AF in patients with chronic, haemodynamically significant AR. Methods Adults with chronic ≥moderate-to-severe AR, from March 2004 to April 2019, were retrospectively identified. Those with acute AR, moderate or worse other valve disease or prior valve surgery were excluded. Patients with AF were identified based on 12-lead ECGs, 1-lead ECGs (showing AF for ≥30 s), or episodes recorded by implanted cardiac devices. Primary outcome was all-cause mortality. Cox regression models were used to assess associations with mortality: model 1 adjusted for age, symptoms (New York Heart Association class II–IV), Charlson Comorbidity Index, left ventricle (LV) end-systolic volume index and AF; model 2 added left atrial volume index and model 3 further added systolic pulmonary artery pressure. Results Of the 1006 included patients (age 59±18 years; 822 (82%) men), 446 (46%) had hypertension and 364 (36%) had a bicuspid aortic valve. AF was present in 161 (16%) patients at the time of ≥moderate-to-severe AR diagnosis. During a median follow-up of 1.6 years (IQR 0.2–6.2), AF was associated with an increased mortality risk in univariate and in all three multivariable models (HR 1.61 (95% CI 1.07 to 2.43), HR 2.21 (95% CI 1.31 to 3.72) and HR 2.06 (95% CI 1.21 to 3.52), respectively), including after propensity matching (HR 1.58 (95% CI 1.01 to 2.48)). Conclusions AF is present in one in six patients with chronic≥moderate-to-severe AR and is associated with an increased risk of mortality even after adjusting for measures of LV systolic and diastolic function. There is a need for future prospective studies to validate these findings and evaluate AF as a potential trigger for early surgery.