Reduction In Left Ventricular Ejection Fraction Research Articles

Myocardial work indices and global longitudinal strain: equivalent prognostic value in chronic HFrEF

Abstract Background Non-invasive myocardial work (MW) indices can be estimated from pressure-strain loops obtained by integrating left ventricular global longitudinal strain (LVGLS) with brachial systolic blood pressure (SBP) and cardiac event timings (opening and closure of the aortic and mitral valve). Compared to LV GLS, MW indices offer the possibility to correct myocardial performance for LV afterload and dyssynchrony. Purpose To assess whether MW indices could provide additional prognostic value in a contemporary cohort of stable outpatients with chronic heart failure with reduced ejection fraction (HFrEF) on optimal medical and device therapy, with controlled afterload and no dyssynchrony. Methods We retrospectively analyzed 307 patients (mean age 65.6±12.7 years, 78% males) with reduced LV ejection fraction (LVEF<50%). Liner regressions were performed to assess the relationships between MW indices and LVGLS, SBP, and parameters of inter- (i.e. inter-ventricular mechanical delay>40 msec) and intra-ventricular (i.e. mechanical dispersion>100 msec) dyssynchrony. The study endpoint was a composite of all-cause death/HF-hospitalization. Multivariable models including each MW indices once at a time [global work index (GWI), global constructive work (GCW), global wasted work (GWW) and global work efficiency (GWE)] were compared with the model including LVGLS by C-statistics. Results Mean LVEF was 32±9%, mean LVGLS was -9±3, mean GWI was 800±378 mmHg% and median NT-proBNP was 1.800 pg/ml (IQR: 731–4110). The majority of patients (84%) had SBP< 130 mmHg (mean 117±16 mmHg), and had no inter- (71%) and (68%) intra-ventricular dyssynchrony. Over a median follow-up of 20 months (IQR: 11-34), 82 patients reached the study endpoint. After multivariable adjustment for MAGGIC score, natriuretic peptide levels, LV end-diastolic volume index, left atrial volume index, E/e’ ratio, and TAPSE/PASP ratio, both GWI and GCW were independently associated with adverse outcomes, with identical goodness of fit compared to the model including LVGLS (C-index 0.75 for all). On the contrary, both GWW and GWE were not independently associated with outcomes. While GWI and GCW were strongly correlated with LVGLS (B coefficient<-0.85; Figure), their association with SBP was modest and there was no significant association between them and parameters of intra- and inter-ventricular dyssynchrony. Conclusions In a cohort of stable chronic HFrEF patients on optimal medical and device therapy, with controlled afterload and without dyssynchrony, MW indices showed similar prognostic value to LVGLS. Association between LVGLS and MW indices

Long-term changes in myocardial function after CABG assessed by speckle tracking echocardiography

Abstract Introduction Speckle-tracking echocardiography (STE) is an advanced imaging technique for assessing myocardial function, which is more sensitive and specific than standard parameters in detecting subtle changes in myocardial function. Purpose We evaluated global and regional left ventricular (LV) and left atrial (LA) function changes in patients undergoing coronary artery bypass grafting (CABG) using standard and advanced echocardiographic techniques. Methods The study group included 83 patients (72 men, 11 women; mean age 65,1±8,4 years) scheduled for CABG due to multivessel coronary artery disease (CAD). All patients underwent pre- and postoperative transthoracic echocardiographic examinations (TTE). Offline analysis of global functional parameters was performed, including left ventricular ejection fraction (LVEF), global systolic longitudinal strain (GLS), and global peak longitudinal strain (GPLS). Regional systolic and diastolic left ventricular function was analyzed by measuring peak systolic strain rate (SRS), peak diastolic longitudinal strain rate in the early (SRe) and late phase (SRa), and the post-systolic index (PSI). LA strain was also assessed. During the 2nd examination (7,9±3 days), 68 patients had sufficient image quality for analysis. 42 patients attended the 3rd examination (9±2,3 months). 30 patients attended the 4th examination (60,3±5,1 months). Results were compared to the 1st examination. Nine deaths were recorded in the study group. Results The mean baseline LVEF was 46±10%. During 2nd TTE, we noticed a reduction of LVEF to 41±10% (p=0.0016). LVEF remained reduced during the 3rd TTE, but returned to baseline at the 4th examination (50±8%). There was a significant decrease in global strain parameters observed during 2nd TTE. GLS decreased from -12,63±3,5% to -10,61±5,25% (p<0.0001), and GPLS from -13,46±3,4% to -11,77±4,52% (p<0.0001). Global strain parameters recovered at the 3rd and 4th examinations, with no significant differences from the 1st examination. Regional systolic and diastolic deformation parameters followed a similar trend, though only SRS showed a significant persistent reduction during the 4th TTE (0,73±0,15/s) compared to the 1st (0,82±0,17/s, p=0.0290). CABG did not impact LA function. Conclusion CABG leads to a significant postoperative decrease in global longitudinal LV deformation, which recovers over the long term. Revascularized territories show a similar trend. Recovery of global and regional strain parameters occurs earlier than LVEF recovery. CABG does not significantly impact LA function as assessed by STE.

Cardioprotective effect of crocin in patients with breast cancer receiving anthracycline-based chemotherapy: A randomized, double-blind, placebo-controlled study.

Anthracycline chemotherapy leads to cardiotoxicity in patients with breast cancer. We performed a double-blind randomized controlled trial to assess the efficacy of crocin (crocin tablets) in reducing anthracycline-induced cardiotoxicity in breast cancer patients. Eligible patients were randomly assigned to receive either treatment with crocin tablets or placebo for 6 months. Primary efficacy outcome was the proportion of patients with a drop in left ventricular ejection fraction (LVEF) of at least 10% from baseline until 6 months. We randomized 200 patients; 7 of them had no valid randomization as the change in chemotherapy scheme. A total of 193 eligible participants (mean [SD] age, 50.9 [9.6] years; all women) were randomly assigned to receive crocin tablets or placebo. The incidence of the primary efficacy outcome was 7.2% (7/97) in the crocin group and 17.7% (17/96) in the placebo group (P = 0.027). At 6 months, there were significant differences in the mean change of N-terminal pro-brain natriuretic peptide (NT-pro BNP) between the groups (3.06 [-25.18 to 6.95] vs. 3.06 [-4.85 to 24.98] pg/ml; P = 0.017). The changes in heart rate from baseline to 6 months showed a significant difference as the mean difference of -4.00 (95%CI, -6.95 to -1.05) bpm (P = 0.008). Conclusively, among patients with breast cancer treated with anthracycline-based chemotherapy, crocin tablets reduced the incidence of LVEF reduction. This finding indicated that crocin tablets might be a safe and effective therapy to prevent the cardiotoxicity in this population. (Chictr.org.cn, ID Number: ChiCTR2000041134).

Anticancer-Drug-Related Cardiotoxicity from Adjuvant Goserelin and Tamoxifen Therapy.

Background: Breast cancer is a prevalent malignancy with rising incidence globally. Advances in endocrine therapy have improved outcomes for premenopausal women with hormone receptor-positive breast cancer. However, these treatments may induce menopause-like states, potentially elevating cardiovascular risks, including left ventricular (LV) dysfunction. This study aims to evaluate the impact of one year of adjuvant endocrine therapy with goserelin and tamoxifen on LV function in premenopausal breast cancer patients. Methods: The ISACS cardiovascular toxicity (NCT01218776) is a pilot multicenter registry of breast cancer patients referred to hospitals for routine surveillance, suspected, or confirmed anticancer-drug-related cardiotoxicity (ADRC). Patients may be enrolled retrospectively (1 year) and prospectively. The pilot phase focused on the available data on combined goserelin and tamoxifen therapy for breast cancer and its impact on LV disfunction at 1-year follow-up. Inverse probability of treatment weighting (IPTW) analysis of the ISACS registry was performed assigning 70 patients to combined endocrine therapy (goserelin and tamoxifen). Controls consisted of 120 patients with no adjuvant combined goserelin and tamoxifen therapy. None of the patients developed distant metastasis. Primary outcome measures were as follows: low LV function in women as defined by a left ventricular ejection fraction (LVEF) < 65% and subclinical LV dysfunction as defined by a 10-percentage point decrease in LVEF. Results: In the overall population, combined goserelin and tamoxifen therapy did not affect the mean LV function compared with controls at 3-, 6-, and 12-month follow-up (65.7 ± 2.7% versus 65.3 ± 2.1%, p value = 0.27; 65.5 ± 2.9% versus 65.1 ± 2.5%, p value = 0.34; 65.0 ± 3.2% versus 64.6 ± 3.1%, p value = 0.29, respectively). The mean LVEF reduction in patients who did or did not receive combination therapy for 12 months was small and approximately similar (1.03 ± 2.5% versus 1.16 ± 2.9%, p value = 0.73). Using IPTW analyses, there were no significant associations between combined therapy and low LV function (risk ratio [RR]: 1.75; 95% CI: 0.71-4.31) or subclinical LV dysfunction (RR: 1.50; 95% CI: 0.35-6.53) compared with controls. Conclusions: One year of endocrine therapy with goserelin and tamoxifen does not cause ADRC in patients with invasive breast cancer. Findings are independent of the severity of the disease. Results may not be definitive without replication in studies with larger sample size.

Association of Impaired Relaxation Mitral Inflow Pattern (Grade 1 Diastolic Function) with Long-term Non-Cardiovascular and Cardiovascular Mortality.

Abnormalities of left ventricular (LV) diastolic function are established independent predictors of heart failure (HF) and mortality. To determine whether the association of diastolic function with all-cause mortality is driven by cardiovascular or non-cardiovascular death and if impaired relaxation mitral inflow filling pattern is a risk marker. Diastolic function was graded by the Mayo Clinic algorithm utilizing the well characterized prospective Olmsted County Heart Function Study. Those with reduced LV ejection fraction (EF), ≥moderate valve disease, clinical diagnosis of HF, or indeterminate diastolic function were excluded. Notably all patients with an impaired relaxation pattern (E/A <0.8) are classified as abnormal (grade 1) regardless of ejection fraction, clinical or other echocardiographic abnormalities. Individuals were followed for a median of 19.7 years (IQR 18.9 - 20.6) for mortality outcomes. In a community cohort of 1,005 subjects 63 (57-71) years of age, grade 1 diastolic function was common (26%) and associated with all-cause mortality (HR 4.05, 95% CI 3.22-5.09, p<0.0001). This association persisted in a subgroup of those with impaired myocardial relaxation and no other clinical or echocardiographic abnormalities (HR 2.71, 95% CI 1.89-3.88, p<0.0001). The association of diastolic function with non-cardiovascular death was not significant after adjustment for age, sex, and comorbidities, though there was an association with grade 1 diastolic function and risk of death from dementia (age and sex-adjusted HR 2.30, 95% CI 1.54-3.45, p<0.001). The association of diastolic function and cardiovascular mortality persisted in multivariable model, including for grade 1 diastolic function (HR 2.43, 95% CI 1.16-5.05, p=0.02). Impaired relaxation mitral inflow pattern (Grade 1) is common in older adults in the community and found to be associated with cause-specific death, highlighting this simple echo finding as a potential biomarker of cardiovascular and cognitive risk, and not necessarily a benign finding that is normal with age.

Factors Associated With the Recovery of Left Ventricular Ejection Fraction in Patients With Anthracycline-Induced Left Ventricular Dysfunction.

Neurohormonal blocking drugs, like beta-blockers, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs), are recommended for treating anthracycline-induced left ventricular dysfunction (AILVD). However, there is limited evidence supporting their benefit. Therefore, this study evaluated associations of neurohormonal blockers and other clinical factors with recovery of left ventricular ejection fraction (LVEF) in patients with AILVD. This retrospective chart review assessed patients treated with at least one dose of anthracycline, then had ≥10% LVEF reduction or post-anthracycline LVEF value <50%, and then had a follow-up LVEF measurement ≥90 days later. The primary endpoint was LVEF recovery (highest follow-up LVEF-lowest LVEF post-anthracycline). Variables from univariable tests with P < .1 were incorporated in a multiple linear regression model for independent factors significantly associated with LVEF recovery (P < .05). Out of 104 patients, 83% were female, 86% self-reported white race, 53% had breast cancer, median (IQR) age was 52 (22) years, and LVEF recovery was 14% (16%). The final multivariable model included 2 significant variables: beta-blocker dose after anthracycline exposure (every 25 mg increase in beta-blocker dose was associated with 5.0% increase in LVEF recovery; P = .0005) and the time between the start of the anthracycline and the lowest LVEF post-anthracycline (every 5-year increase in time was associated with 1.8% decrease in LVEF recovery; P = .0379). In patients with AILVD, a higher beta-blocker dose and earlier detection of LVEF reduction post-anthracycline were significantly and independently associated with improved LVEF recovery. These findings need to be validated in a larger, independent cohort.

Phase 3 Open-Label Study Evaluating the Efficacy and Safety of Mavacamten in Japanese Adults With Obstructive Hypertrophic Cardiomyopathy ― The HORIZON-HCM Study ―

Mavacamten, a cardiac myosin inhibitor, significantly improved symptoms and cardiac function vs. placebo in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM) in EXPLORER-HCM. However, the efficacy and safety profiles of mavacamten in Japanese patients are unclear. HORIZON-HCM is a Phase 3 single-arm study in Japanese patients with symptomatic obstructive HCM. The mavacamten starting dose was 2.5 mg; individualized dose titration occurred in Weeks 6-20 based on Valsalva left ventricular outflow tract (LVOT) gradient and resting left ventricular ejection fraction (LVEF). Overall, 38 patients were treated; 36 completed the 30-week primary treatment analysis period. Clinically significant improvements in postexercise LVOT gradient were observed after 30 weeks of treatment (mean change from baseline -60.7 mmHg). Improvements in N-terminal pro B-type natriuretic peptide, New York Heart Association class, and Kansas City Cardiomyopathy Questionnaire-23 Clinical Summary Score were observed over 30 weeks, and mean LVEF was ≥74% at all visits. Treatment-emergent adverse events (TEAEs) and serious TEAEs were reported in 63.2% and 7.9% of patients, respectively; none resulted in treatment discontinuation. One patient experienced a transient asymptomatic reduction in LVEF to <50%. No deaths occurred during the study. In Japanese patients with obstructive HCM, mavacamten was associated with similar improvements in LVOT gradients, cardiac biomarkers, and symptoms to those observed in EXPLORER-HCM. Treatment was well tolerated with no new safety concerns.

Cardiotoxicity in Breast Cancer: Impact of Clinical Classifications and Treatment on Heart Health.

Cardio-oncology has become essential in addressing cardiovascular complications from cancer therapies. While advancements in treatments have improved survival rates, they also increase cardiovascular risks. This study evaluates the cardiotoxic effects of cytostatic treatments, examining the relationship between tumor characteristics, such as histopathology and TNM classification, and cardiovascular complications, aiming to improve cardiotoxicity prevention and management in oncology patients. We conducted a retrospective analysis of cancer patients treated with anthracyclines, HER2-targeted therapies, and radiotherapy. Cardiac function was monitored via echocardiography, focusing on global longitudinal strain and left ventricular ejection fraction (LVEF). Cardiac troponins and natriuretic peptides were measured to detect subclinical cardiotoxicity, with patients stratified by TNM cancer stage and histopathology. Our analysis identified a significant association between certain cytostatic treatments, such as anthracyclines and HER2-targeted therapies, and a reduction in LVEF, particularly in patients with advanced-stage cancer. Biomarker assessments indicated early signs of cardiotoxicity in patients before clinical symptoms emerged. The findings also demonstrated a higher prevalence of cardiovascular complications in patients with pre-existing risk factors. This study highlights the importance of personalized treatment protocols in minimizing cardiotoxicity and improving the quality of life for oncology patients. Regular cardiac monitoring, combined with the use of biomarkers, can help identify high-risk patients early, allowing for timely interventions. Future research should focus on optimizing cardioprotective strategies to mitigate the cardiovascular risks associated with modern cancer therapies. N/A (retrospective study).

Transendocardial injection of expanded autologous CD34+ cells after myocardial infarction: Design of the EXCELLENT trial.

The extent of irreversible cardiomyocyte necrosis after acute myocardial infarction (AMI) is a major determinant of residual left ventricular (LV) function and clinical outcome. Cell therapy based on CD34+ cells has emerged as an option to help repair the myocardium and to improve outcomes. The dose of CD34+ cells and the route of administration are two important factors that will determine the clinical effectiveness of the approach, provided it is robust and feasible. Here, we describe the rationale and design of the multicentre open-label randomized controlled phase I/IIb trial evaluating the safety and the likelihood of efficacy of transendocardial expanded CD34+ cell administration in patients presenting with AMI and a reduced LV ejection fraction. Patients with a large AMI and LV ejection fraction <50% are randomized 3:1 to transendocardial expanded CD34+ cell injection plus standard of care or standard of care alone. Patients randomized to intervention are treated with lenograstim for 5days before 220±10mL blood cell harvest from which autologous CD34+ cells are purified and expanded for 9days using an automated good manufacturing practice compliant platform. The primary endpoint is the incidence of major adverse cardiac events over 6months. The main secondary endpoints are LV end systolic volume index and the viability of the infarcted segments. Autologous CD34+ cell therapy is currently limited by technological constraints. This is the first trial to evaluate the feasibility and potential effect of CD34+ cells after automated expansion and transendocardial administration in patients with large AMI.

Establishment of a HFpEF model using female Dahl salt-sensitive rats: a valuable tool for elucidating the pathophysiology of HFpEF in women.

The pathogenesis of heart failure with preserved ejection fraction (HFpEF) remains unclear, and effective treatments are limited. HFpEF is more prevalent in females, indicating potential gender differences in its pathogenesis. However, no female HFpEF model animals have been established. Hypertension is a major contributor to HFpEF, and sympathetic activation is thought to play a role in both conditions. This study aimed to establish a female HFpEF model using hypertensive Dahl salt-sensitive rats and to assess the presence of sympathetic activation. Seven-week-old female Dahl salt-sensitive rats were fed an 8% high-salt diet (HS group, n = 6), while a low-salt diet group (LS group, n = 9) served as controls. The HS group exhibited increased systolic blood pressure and heart rate. Echocardiography revealed an increased left ventricular (LV) wall thickness, a decreased E/A ratio, and an increased E/e' ratio, all indicative of diastolic dysfunction without reduced LV ejection fraction. Additionally, the HS group showed elevated LV end-diastolic pressure, LV weight, and lung weight, along with histological cardiomyocyte hypertrophy and interstitial fibrosis. Gene expression markers for cardiac hypertrophy and fibrosis were also increased. Renal function was significantly impaired, and plasma norepinephrine levels were elevated, consistent with heightened pre-sympathetic neuronal activity in the brain. In conclusion, high salt loading from 7 weeks of age in female Dahl salt-sensitive rats induced hypertensive HFpEF phenotypes with LV hypertrophy and fibrosis, and sympathetic activation by 16 to 19 weeks of age. This model provides a valuable tool for studying HFpEF pathophysiology in women.

Characterisation of patients who develop atrial fibrillation-induced cardiomyopathy

IntroductionAtrial fibrillation (AF)-induced cardiomyopathy (AIC) is retrospectively defined after normalisation of left ventricular ejection fraction (LVEF) in sinus rhythm. It is unclear why some patients develop AIC.HypothesisPatients with AIC have...

Impact of single chamber and dual chamber permanent pacemaker implantation on left ventricular function: An observational study.

Permanent pacemaker implantation has the potential to impact left ventricular (LV) function and hence quality of life (QoL) in the long term. To assess the effect of single- and dual-chamber pacing on LV function and QoL. This study included 56 patients who underwent permanent pacing: Dual pacing, dual sensing, dual responsive and rate responsive (DDDR) for the initial 3 months and ventricular pacing, ventricular sensing, inhibited response and rate responsive (VVIR) for the next 3 months, and DDDR mode for the last 3 months. Throughout the study period, various echocardiographic parameters, functional status, and QoL were measured to assess the impact of pacing on LV function compared with baseline and at every 3 months interval. A significant change appeared in cardiac function after VVIR pacing which included diastolic properties of LV as shown by increase in isovolumic relaxation time from (85.28 ± 9.54 ms) to (89.53 ± 9.65 ms). At the 3-, 6-, and 9-month follow-up, reduction in LV ejection fraction was observed to be 62.71 ± 4.66%, 61.07 ± 4.41%, and 58.48 ± 3.89%, respectively. An increase in the QoL scores was noted at every follow-up visit. An apparent depressant effect on LV function due to right ventricular pacing, with a higher incidence of adverse outcomes in the VVIR mode. In addition, an upsurge in QoL scores for the study population was noted, which indicates improvement in the QoL of patients post-pacing, irrespective of the mode. Generally, the DDDR mode is a highly preferable pacing mode.

Accuracy of left ventricular mechanical dyssynchrony indices for mechanical characteristics of left bundle branch block using cardiovascular magnetic resonance feature tracking.

More than 90% of patients with left bundle branch block (LBBB) and reduced left ventricular (LV) ejection fraction have LV dyssynchrony and a high probability of response to cardiac resynchronization therapy (CRT). A subgroup of patients with non-specific intraventricular conduction delay (IVCD) have a LBBB-like LV activation pattern when studied using invasive mapping and advanced echocardiographic techniques. These patients also frequently benefit from CRT but these patients have proven difficult to identify using ECG criteria. Cardiovascular magnetic resonance (CMR) imaging indices of dyssynchrony may identify patients with IVCD who may benefit from CRT but their relative accuracies for identification of LV dyssynchrony remains unknown. We compared the LV dyssynchrony classification accuracy of two commonly available CMR indices in a study population of patients with severely reduced LV ejection fraction and no scar, and either LBBB or normal conduction (normal QRS duration and axis, controls). In LBBB (n=44) and controls (n=36), using CMR feature-tracking circumferential strain, dyssynchrony was quantified as the circumferential uniformity ratio estimate (CURE) and the systolic stretch index (SSI). Deidentified CMR image-data were made publicly available. Both CURE and SSI quantified more severe dyssynchrony in LBBB compared to controls (p<0.001 for both). SSI more frequently discriminated LBBB and normal conduction LV activation patterns than CURE (area under the receiver-operating characteristics curve [95% confidence interval] 0.96 [0.92-1.00] for SSI vs 0.76 [0.65-0.86] for CURE, p<0.001). SSI is superior to CURE for discriminating synchronous and dyssynchronous LV activation and should be further studied in the setting of non-LBBB conduction abnormalities.

Anthracyclines-induced cardiotoxicity in patients with early breast cancer carrying germline BRCA1/2 mutation: the BRCAN study.

BRCA1/2 genes play a critical role in genome stability and DNA repair. In animal models, loss of cardiomyocyte-specific BRCA1/2 is associated with DNA damage, apoptosis, cardiac dysfunction, and mortality following anthracycline exposure. However, whether these preclinical findings translate to humans remains unclear. Assess the impact of germline BRCA1/2 (gBRCA1/2) status on anthracyclines-induced cardiotoxicity (AIC) in patients with early breast cancer and no prior anti-HER2 therapy. This single-center retrospective/prospective cohort study focused on early breast cancer patients, treated with anthracycline-based chemotherapy in the neo/adjuvant setting, no prior anti-HER2 therapy, and known gBRCA1/2 status, normal baseline left ventricular ejection fraction (LVEF), and no previous cardiovascular disease. Follow-up assessments involved myocardial dysfunction blood biomarkers (MDBB), transthoracic echocardiography (TTE), and quality of life (QoL) questionnaires. The primary objective was LVEF changes comparing BRCA1/2 mutation carriers (gBRCA1/2m) vs non-carriers (gBRCA1/2wt). Secondary objectives included differences in MDBB and QoL. A total of 137 patients were included (103 gBRCA1/2wt and 34 gBRCA1/2m). Baseline characteristics were similar between groups. Compared to baseline, LVEF% reduction was -4.7[-12.0, 0.0] vs -9.5[-18.0, -5.0] in gBRCA1/2wt vs gBRCA1/2m, (P = .027). After adjusting for confounders, the difference in reduction in LVEF remained statistically significant at -4.5 [95%CI, -8.6, -0.4; P = .032]. No differences between MDBB (C-reactive protein, hsTnI, NT-proBNP, D-Dimer, ST-2, or Galectine-3) or QoL (MLHFQ and EQ5-D index) were detected. gBRCA1/2m patients could represent a higher-risk population for AIC. gBRCA1/2 status should be one of the factors to consider in deciding on adjuvant anthracycline necessity. This population could benefit from a cardio-oncology closer follow-up and cardioprotective strategies.

Abstract 4118387: Artificial Intelligence-Enhanced Echocardiogram Assessment Helps Distinguish Cardiomyopathy from Beat-to-Beat Variation in Atrial Fibrillation

Background: Atrial fibrillation (AF) can be associated with reductions in left ventricular ejection fraction (LVEF) that improve upon conversion of AF to sinus rhythm. Such LVEF changes during AF may be due to LVEF measurement error from beat-to-beat variations related to AF itself. More precise artificial intelligence (AI)-enhanced LVEF assessment could help distinguish between such LVEF “pseudo-reduction” during AF and true cardiomyopathy, thus potentially preventing unnecessary downstream workup and treatment. Methods: Using a transthoracic echocardiogram database at a large academic medical center, we identified all patients whose LVEF fell below 50% while in AF who had subsequent LVEF recovery to over 50% within 90 days after converting from AF to sinus rhythm. For echocardiograms in AF, we compared the clinically assessed LVEF with AI-enhanced LVEF assessment by EchoNet-Dynamic, a validated deep learning algorithm. Results: In our cohort of 84 patients, the mean age was 74 years old, 36.9% were female, and 26.2% non-White. The mean LVEF recovery was 19.3% (95% CI 17.1-21.5%) after converting from AF to sinus rhythm with a mean duration of 27.4 days between the AF and sinus rhythm echocardiograms (Figure 1). For AF echocardiograms, the LVEF when reassessed by deep learning was 8.4% (6.3-10.5%) higher than the original clinical read, resulting in 30.3% of patients being reclassified as no longer having a reduced LVEF less than 50% while in AF. Among these patients with LVEF reductions during AF, 27.4% and 19.0% were given a new or worsened heart failure with reduced ejection fraction (HFrEF) diagnosis, 15.5% underwent ischemic testing, and 17.9% were started on new HFrEF medications. Discussion: LVEF reductions during AF can lead to new HFrEF diagnosis, workup, and treatment. However, such LVEF reductions may be temporary and partially explained by undermeasurement of LVEF during AF. AI-enhanced LVEF assessment may help reduce such measurement errors during AF and thereby prevent overdiagnosis of HFrEF. Further research is needed to understand the clinical significance of true but temporary LVEF reductions during AF.

Five‐year outcomes with self‐expanding versus balloon‐expandable TAVI in patients with left ventricular systolic dysfunction

The importance of transcatheter heart valve (THV) design on clinical outcome in patients with aortic stenosis (AS) and left ventricular (LV) systolic dysfunction remains unknown. We aimed to compare 5-year outcomes of patients with severe AS and reduced LV ejection fraction (LVEF), undergoing transcatheter aortic valve implantation (TAVI) with balloon-expandable vs. self-expanding THVs. In a retrospective analysis from the Bern TAVI registry, patients with LVEF <50% who underwent TAVI with either balloon-expandable or self-expanding THVs were included. A 1:1 propensity-score matching was performed to account for baseline differences between groups. A total of 759 patients were included between August 2007 and December 2022, and propensity-score matching resulted in 134 pairs. Technical success was achieved in over 85% of patients, and was similar in both groups. Self-expanding THVs were associated with a lower mean transvalvular gradient (7.1 ± 3.7 mmHg vs. 9.9 ± 4.3 mmHg; P < .001) and a higher incidence of ≥mild-to-moderate paravalvular regurgitation (36.3% vs. 11.3%; P < .001) compared to balloon-expandable THVs. At 5 years, patients treated with a self-expanding THV had higher all-cause mortality than those with a balloon-expandable THV (67.8% vs. 55.8%, HRadjusted: 1.44; 95% CI: 1.02-2.03; P = .037). There were no significant differences in other clinical outcomes up to 5 years between groups. In the setting of LV systolic dysfunction, patients treated with a self-expanding THV had higher risk of 5-year mortality compared to patients treated with a balloon-expandable THV. https://www. gov. NCT01368250.

Abstract 4137311: Inhibition of IL-33 by tozorakimab in patients with diabetic kidney disease: Cardiovascular insights from FRONTIER-1

Introduction: Interleukin-33 (IL-33) is a potent mediator of injury-induced local inflammation. Soluble ST2 (sST2), a decoy receptor of IL-33, is a prognostic serum biomarker for heart failure (HF). Here, we evaluated the impact of tozorakimab, an IL-33-neutralizing monoclonal antibody, on sST2-related secondary cardiac endpoints. Methods: FRONTIER-1 was a 24-week phase 2B study (NCT04170543) in patients with diabetic kidney disease (DKD). Key cardiac exclusion criteria were: 1) NYHA Class 3/4; 2) Left ventricular ejection fraction (LVEF) &lt; 40%; 3) B-type natriuretic peptide (BNP) &gt; 200 pg/mL. Local echocardiography (LVEF) was performed at Screening and Week 24. For exploratory analysis, echocardiography recordings were evaluated by a core laboratory. Throughout the study, BNP and sST2 were assessed and adverse events (AE) recorded. Safety and tolerability were evaluated for all dosed participants (Safety Analysis Population, SAP). Results: 573 participants were included in the SAP (139 = placebo / 434 = tozorakimab). Baseline characteristics were balanced across treatment groups. Tozorakimab was generally well tolerated and the incidences of AE, serious AE (SAEs), discontinuations, and death were similar to placebo. In the placebo group, cardiac disorder AE were reported in 6.5%, and SAE in 2.2%. Decline in LVEF of &gt; 10% was seen in 5 participants (4.3%). None developed BNP &gt; 200 pg/mL or clinical signs of HF. 1 participant (0.7%) presented with clinical symptoms of HF (SAE) without significant changes in LVEF or BNP. On tozorakimab, cardiac disorder AE/SAE were less frequent (3.7%/1.8%). Decline in LVEF of &gt; 10% was observed in 31 participants (8.3%), with 3 showing BNP elevation to 200–308 pg/mL. Two of these participants (0.5%) developed clinical signs of HF with LVEF 55%/30% and BNP &lt; 200 pg/mL. No further AE related to HF were reported for tozorakimab. Central analysis of LVEF revealed a substantial variability of site-based measurements indicating LVEF reductions &gt; 10 % in 2 (3.7%) participants on placebo and 6 (2.9%) on tozorakimab. Furthermore, central exploratory analysis demonstrated a slight increase in LVEF from baseline (1.62%, 95% CI: 0.22, 3.03) and a reduction in average E/e' (-0.47, 95% CI: -0.93, -0.01) for tozorakimab, but not placebo. Trends in BNP and sST2 over time were comparable. Conclusion: This study suggests a favorable cardiac safety profile for tozorakimab in patients with DKD. IL-33 inhibition did not elevate serum sST2 significantly.

Abstract 4137996: Effects of Empagliflozin on diuresis in heart failure: Results from the CINNAMON-study and in-vivo experiments

Background and Purpose: Heart failure is associated with renal dysfunction suggesting a pathophysiological link between heart and kidney. Empagliflozin, a SGLT2 inhibitor, showed beneficial effects on both cardiovascular and renal endpoints. However, mechanistically, it is unclear if empagliflozin-dependent kidney protection is mediated via inhibition of tubular SGLT2 or more indirectly via improved cardiac function. We hypothesized that Empagliflozin treatment improves left ventricular ejection fraction (LVEF) independent of diuretic effect of renal SGLT2 inhibition. Methods: We evaluated NTproBNP, hematocrit, hemoglobin and bodyweight in patients with HF with reduced (n=32) and preserved ejection fraction (n=59) after 30 and 180 days (prospective, single-arm CINNAMON-study, DRKS00031101). Furthermore, we conducted transverse aortic constriction (TAC) or sham surgery in C57BL/6J (wildtype, WT) and SGLT2 deficient mice (SGLT2 -/- ). Animals received either Empagliflozin (10 mg/kg bodyweight) or vehicle by daily oral gavage. Water intake and output was evaluated by metabolic cages at 10 weeks and cardiac function by echocardiography. Results: Empagliflozin treatment reduced NT-proBNP levels and increased hematocrit and hemoglobin levels especially in patients with reduced ejection fraction (Fig. A-C). Surprisingly, there was no change in body weight (Fig. D), which would be expected if the diuretic effects were dominant. In mice after 10 weeks, echocardiography confirmed TAC induced pressure-overload, leading to reduced LVEF. Empagliflozin attenuated changes in LVEF (Fig. G) and improved diastolic dysfunction (isovolumetric relaxation time, data not shown). To test if direct inhibition of SGLT2 in the heart and kidney is mechanistically involved, TAC surgery was repeated in SGLT2-deficient mice (SGLT2-KO). In fact, exposure to TAC resulted in comparable reduction of LVEF in SGLT2-KO and Empagliflozin prevented this deterioration similar to WT mice (Fig. G vs. I). Surprisingly, Empagliflozin did not increase drinking and urine volume neither in wildtype nor in SGLT2 deficient mice, suggesting a mechanism of cardioprotection independent of diuretic effects. Conclusion and Outlook: This is the first study investigating the role of SGLT2 in Empagliflozin treated patients and mice with heart failure. Importantly, empagliflozin treatment prevented deterioration of LVEF independent of the presence of SGLT2 and diuresis.

Mavacamten: Real-World Experience From 22 Months of the Risk Evaluation and Mitigation Strategy (REMS) Program.

Mavacamten is the only cardiac myosin inhibitor approved by the U.S. Food and Drug Administration for the treatment of patients with symptomatic New York Heart Association class II-III obstructive hypertrophic cardiomyopathy. Under the Risk Evaluation and Mitigation Strategy program for mavacamten, patients are required to be monitored for the development of systolic heart failure and reduction of left ventricular ejection fraction (LVEF) to <50%. We report results from the mavacamten Risk Evaluation and Mitigation Strategy database (April 28, 2022 to February 27, 2024). Data on health care providers and pharmacy certification, patient monitoring (from Patient Status Forms, based partly on echocardiograms), and screening for drug interactions before each dispense were collected. Of the 6299 patients who received ≥1 dose of mavacamten, 60.0% were women; 64.6% were aged >60 years. Of the 5573 patients with submitted Patient Status Forms, 256 (4.6%) developed LVEF <50%, and 71 (1.3%) experienced heart failure requiring hospitalization. On the 29 111 status forms in these patients, each representing an assessment of an echocardiogram, LVEF <50% was reported on 276 (0.9%), and heart failure requiring hospitalization was reported on 86 (0.3%). Of the 1929 patients with ≥1 year of treatment, 78 (4.0%) had an LVEF reduction to <50%, and 4 (0.2%) experienced LVEF <50% and heart failure requiring hospitalization but later resumed treatment. Of the 3228 patients initiated on 5 mg/d mavacamten and were treated for at least 6 months, 2391 (74.1%) remained at 5 or 10 mg/d. At 3 and 6 months following mavacamten treatment initiation, 57.2% and 70.3%, respectively, demonstrated post-Valsalva left ventricular outflow tract gradient <30 mm Hg. We describe the feasibility and experience of the first 22 months of the Risk Evaluation and Mitigation Strategy program for prescribing mavacamten in >6000 patients with symptomatic obstructive hypertrophic cardiomyopathy. The need for temporary interruption for LVEF <50% was low, including for patients on therapy ≥1 year, with even fewer LVEF reductions associated with heart failure requiring hospitalization.

Evaluation of early cardiotoxicity in HER2-positive breast cancer patients receiving radiotherapy and concurrent trastuzumab.

Overexpression of human epidermal growth factor receptor 2 (HER-2) is associated with aggressive disease in breast cancer. Trastuzumab and radiotherapy are standard treatments for patients with HER-2 + breast cancer, but they may increase the risk of cardiotoxicity. This study aimed to assess early cardiotoxicity in patients receiving radiotherapy (RT) and concurrent trastuzumab. The study included 116 patients with HER-2 + breast cancer who received concurrent treatment with trastuzumab and RT (52 right-side; 64 left-side). Five left ventricular ejection fraction (LVEF) measurements were performed: one before treatment and four subsequent measurements taken at three-month intervals. LVEF was also assessed before (preRT-EF) and after (postRT-EF) radiotherapy. The baseline LVEF was 62.27 ± 5.5%, while the 12-month LVEF was 59.8 ± 5.8% (p < 0.05). In subgroups, post-RT LVEF values ​​were significantly lower than pre-RT LVEF values (p < 0.05). No significant difference was found between the reduction in LVEF for patients receiving 50Gy and 60Gy doses. Moreover, the contribution of regional lymph node irradiation to the decrease in LVEF could not be demonstrated. A positive correlation was found between the total trastuzumab dose and the decrease in LVEF from preRT to postRT. Additionally, a positive correlation was observed between the total taxane dose and the reduction in LVEF from baseline to 9months, both in the overall group and in the left breast cancer group. In our study,it was found that not only trastuzumab but also taxane-based agents could be cardiotoxic. However, no connection was found between RT doses and the decrease in LVEF.