Decline In Left Ventricular Ejection Fraction Research Articles

Longitudinal modeling of cardiac function to identify trajectories with differential risk of heart failure

Abstract Background Impairments in left ventricular (LV) systolic and diastolic function are common precursors of clinical heart failure (HF) and underlie HF risk. Little data exist regarding trajectories of cardiac function in mid- to late-life, when HF risk is greatest, and the extent to which such trajectories may differentially relate to risk of HF with preserved ejection fraction (HFpEF) or HF with reduced ejection fraction (HFrEF). Purpose To (1) identify multidimensional trajectories of cardiac function from mid- to late-life using serial echocardiographic data, (2) apply the resulting models to predict trajectory membership in a separate sample, and (3) determine associations between assigned trajectory and incident HFpEF and HFrEF. Methods We used a Bayesian nonparametric trajectory approach to jointly model longitudinal measures of LV ejection fraction (LVEF) and E/A ratio among 747 participants in two longitudinal cohort studies (the Atherosclerosis Risk in Communities [ARIC] study and Jackson Heart Study [JHS]) who underwent ≥2 echocardiograms in 2000-04 (mean age 65±5 years), 2011-2013 (age 75±5 years), and 2018-19 (age 81±5 years). Using the trajectories inferred from this modeling, we applied Bayes theorem to assign 4,419 ARIC-only participants to their most likely trajectory using single time-point measures of LVEF and E/A ratio acquired in 2011-2013 (age 75±5 years). These assignments were treated as a categorical variable in subsequent analysis. In ARIC-only participants, we used Cox proportional hazards models adjusted for age, sex, obesity, hypertension, diabetes, chronic kidney disease, and coronary heart disease to assess the relationship between assigned trajectory and incident HF. Results In the discovery set (n=747), we identified six trajectories of cardiac function based jointly on longitudinal changes in LVEF and E/A ratio (Figure 1). The pink (prevalence 50%) and light green (17%) trajectories showed increasing LVEF and decreasing E/A ratio with increasing age, while the red trajectory (22%) demonstrated a lack of increase in LVEF. The dark green trajectory (4%) demonstrated progressive LVEF decline, the orange trajectory (2%) steep LVEF decline and rise in E/A ratio, and the blue trajectory (4%) rising E/A ratio despite increasing in LVEF. Analysis of the ARIC-only participants (n=4,419) showed that trajectory membership was differentially associated with risk of incident HFpEF and HFrEF (Figure 2). Compared to the pink trajectory, membership in the orange trajectory was associated with incident HFpEF and HFrEF, the red and the dark green trajectory associated with HFrEF alone, and the blue trajectory with HFpEF alone. Conclusion(s) These results demonstrate the feasibility of identifying trajectories of cardiac function with multidimensional longitudinal data and may have implications for HF risk prediction.

Abstract 17444: Racial and Ethnic Disparities in Anthracycline Cardiotoxicity

Introduction: There are limited data on anthracycline cardiotoxicity in racially and ethnically diverse populations. Aims: Our study sought to examine the incidence of cardiotoxicity and the changes in left ventricular ejection fraction (LVEF) in cancer survivors treated with anthracycline in a multiracial/ethnic community. Methods: We included consecutive adult patients who underwent anthracycline-based chemotherapy from 2016 to 2019 for any type of cancer. Patients with preexisting heart failure were excluded. The endpoint was the development of cardiotoxicity (defined as clinical HF or drop in LVEF≥10% to LVEF<53%). Results: Our retrospective cohort included 925 patients (22% Non-Hispanic White (NHW), 25% Non-Hispanic Black (NHB), 31% Hispanic, and 2% Asian). Hypertension, diabetes, and hyperlipidemia were more prevalent in NHB, Hispanic, and Asian patients than in NHW patients. The mean cumulative anthracycline dose was 197±99 mg/m 2 and the mean LVEF was 64±5.7%, both similar across racial and ethnic groups. During a median follow-up of 21 months, 116 patients (13%) developed cardiotoxicity. The incidence of cardiotoxicity was significantly higher in NHB (16%), Hispanic (15%), and Asian (18%) patients compared to NHW patients (7%) (p=0.045). Of the 116 patients with cardiotoxicity, 21 patients had reduced ejection fraction (LVEF<50%) and 81 had preserved ejection fraction (LVEF≥50%). Significantly more Hispanic patients developed cardiotoxicity with reduced ejection fraction (33.3%) compared to NHW (14.3%) and NHB (6.1%) patients (p=0.014). The mean decline in LVEF was higher in NHB patients (4% ± 9%) and Hispanic patients (6% ± 10%) than in NHW patients (3% ± 7%). Conclusions: In a large racially and ethnically diverse cohort of cancer survivors treated with anthracycline-based chemotherapy, NHB and Hispanic patients had an increased risk of cardiotoxicity and a greater decline in LVEF compared to their White counterparts.

Abstract 12139: Left Ventricular Myocardial Work in Patients With Chagas Disease From a Quaternary Hospital in Brazil

Background: Left ventricular (LV) function assessment in patients (pts) with Chagas disease (ChD) is challenging. LV ejection fraction (LVEF) as a marker of myocardial contractility in these pts has issues, and alterations in myocardial deformation (MD) may occur in early stages of cardiac disease (CD) before the decline of LVEF. LV global longitudinal strain (GLS) is a good parameter to evaluate LV MD, but is dependent on afterload. LV myocardial work (MW) is a technique which integrates afterload to the calculation of GLS Purpose: To analyze LV function using MW in pts with ChD Methods: 39 pts with positive serology for ChD, (74,4% women, age 68,8 ± 9,7) followed in a quaternary Brazilian hospital, were divided in groups of stages of CD: G1 - normal Echocardiography (Echo) and ECG, G2 - alterations in ECG a/o Echo, normal LVEF, G3 - reduced LVEF. LV MW was measured integrating GLS with non-invasive blood pressure as an afterload index, for generation of pressure-strain loops by specific software(fig.1). Global work index (GWI), global constructive work (GCW), global wasted work (GWW) and global work efficiency (GWE) were measured. Results: 11 pts (28,2%) were in G1, 14 (35,9%) in G2, and 14 (35,9%) in G3. In overall population median values of MW were within normal ranges: GWI = 1760mmHg% (>968), GCW = 2046mmHg% (>1550), GWW= 178mmHg% (<331), GWE = 92 (>83). Values of GWI, GCW and GWE were significantly lower and GWW was higher in G3, compared to G1 and G2, translating into less LV mechanical efficiency (ME) in these pts with more advanced CD (table 1). Despite LVEF and GLS similar between G1 and G2, values of GCW were 12% lower in G2 compared to G1, which could point to a tendency of early alterations in these pts, although not reaching statistical significance (p > 0,05). Conclusion: In pts with advanced stages with Chagas CD (G3) there were significant alterations in parameters that evaluate ME, with reduced values of GWI, GCW and GWE, with higher GWW

Abstract 12697: Identifying Patients at Low Risk for Cancer Therapy Related Cardiac Dysfunction in Patients Treated With Trastuzumab for HER 2+ Breast Cancer

Introduction: Frequent monitoring every 3 months for Cancer Therapy-Related Cardiac Dysfunction (CTRCD) is recommended in patients who receive trastuzumab (tras) for cancer therapy. Aims: We examined the frequency and predictors of asymptomatic and symptomatic CTCRD in a contemporary cohort of patients with breast cancer treated with tras with or without anthracyclines (AC). Methods: Breast cancer patients who received tras with/without AC and had at least one baseline and one follow-up echocardiogram (echo) performed at our tertiary cancer center (2013-2022) were included. CTCRD was defined as left ventricular ejection fraction (LVEF) decline (Simpson’s bi-plane quantitative assessment) of at least 10% to < 50%. Risk factors for CTCRD were examined using univariable and multivariable Fine-Gray models. Results: The cohort included 502 patients with mean ± SD age 52.1±13.2 years, mean baseline LVEF 61.2±4.1%, and a median follow-up of 52.6 months. Patients had a mean of 5.5 ± 2.7 echocardiograms; 25 patients (5%) had CTCRD as defined above during follow-up, 3.4% (95% CI, 1.8-5.9) in the Tras only and 8.7% (95% CI, 4.7-14.5) in Tras + AC group. Only 8 patients (1.6%) developed new clinical HF at any time during follow-up, 6 of whom were associated with a concomitant decline in LVEF. Increasing age (HR, 95% CI, 1.03 1.01-1.06), baseline LVEF <55% (HR 7.3, 2.9-18.2), history of HF (HR 6.2, 1.5-25.2) and AC therapy (HR 4.5, 1.8-11.4) were independently associated with CTCRD. On follow-up, 1.1% of Tras-only vs 2.7% of Tras + AC group had a persistently decreased LVEF. In a low-risk group without any of the risk factors for CTCRD, only 1 % of patients had CTCRD without clinical HF. Conclusions: The incidence of asymptomatic and symptomatic CTCRD was low in patients receiving tras only. Patients without any risk factors receiving tras only could be considered for less frequent monitoring of asymptomatic CTCRD.

Abstract 16049: Hydrogen Sulfide Attenuates Duchenne Cardiomyopathy via Suppression of Sterile Inflammation

Background: Duchenne muscular dystrophy (DMD) is a lethal, X-linked recessive disease caused by mutations in dystrophin. There is currently no cure for DMD, and the main cause of death is dilated cardiomyopathy. Hydrogen sulfide (H 2 S) is a gaseous molecule produced endogenously, and disruptions in basal H 2 S levels have been associated with various pathophysiological conditions, including heart failure. In this study, we investigated whether H 2 S could prevent cardiac dysfunction in a mouse model of DMD. Methods: Male mdx 4cv /mTR KO mice received early treatment (ET) with the H 2 S donor, SG1002 (40 mg/kg/day in chow starting at the time of weaning) or no treatment (NT), and wildtype C57BL (WT) mice were used as control. Left ventricular ejection fraction (LVEF) was assessed by transthoracic echocardiography. Skeletal and cardiac fibrosis was determined by picrosirius red staining. NLRP3 inflammasome activity was measured through apoptosis speck like protein (ASC) staining in cardiac muscle tissue. Results: NT mice exhibited significant LVEF decline by 4 months compared to ET and WT mice and declined further by 12 months (n=15-17, NT: 45.2% ± 7.9 vs ET: 57.1% ± 8.9% and WT: 56.5% ± 7.0%, P<0.001). In addition, ET mice showed significantly reduced fibrosis compared to NT mice in the myocardium (n=5-8, 2.62% ± 0.87% vs 11.32% ± 4.70%, respectively, P=0.002), diaphragm (n=11-14, 15.84% ± 9.0% vs 31.14% ± 7.1%, respectively, P<0.001), and gastrocnemius (n=12-17, 7.60% ± 3.14% vs 13.48% ± 5.97%, respectively, P=0.004) at 12 months. ASC aggregation score was significantly higher in cardiac tissue samples (Fig 1) from NT mice at 12 months compared with WT mice. ET attenuated the increase in cardiac ASC aggregation at 12 months compared with NT mice (P<0.001). Conclusions: Our results demonstrate that early treatment with SG1002 preserves cardiac function in a mouse model of DMD and suggest a potential therapeutic role of NLRP3 inflammasome suppression as a protective strategy in DMD.

Abstract 18324: Artificial Intelligence ECG as a Novel Method to Detect Cardiotoxicity After Anthracyclines

Introduction: Cardiotoxicity is a serious side effect of anthracycline treatment, most commonly manifesting as a reduction in left ventricular ejection fraction (LVEF) on cardiac imaging. Cost-effective alternatives to cardiac imaging are currently not available. Artificial intelligence (AI) models have been developed to detect a reduced LVEF from 12-lead electrocardiograms (ECGs) in the general population. Hypothesis: AI-ECG model can detect a reduced LVEF after anthracycline therapy (i.e. cardiotoxicity). Methods: We included an unbiased oncological population of 989 female breast cancer patients receiving (neo)adjuvant anthracycline chemotherapy. Average follow-up time was 9.83±4.2 years. Patients with incomplete transthoracic echocardiography (TTE) data, HER-2-directed therapy, significant comorbidities, upfront metastatic disease, second primary malignancy or pre-existing cardiovascular disease were excluded from the analyses. Patients with LVEF decline for reasons other than anthracycline-induced cardiotoxicity were also excluded. Primary readout was the diagnostic performance of AI-ECG by area under the curve (AUC) for various levels of LVEF <50%. Results: Using 1,877 ECGs from 703 unique patients, the AI-ECG model detected an LVEF <50% and ≤35% after anthracycline therapy with an AUC of 0.93 and 0.94, respectively. Conclusions: These data support the use of AI-ECG for cardiomyopathy (cardiotoxicity) screening after anthracycline-based chemotherapy. This technology could serve as a gatekeeper to more costly testing and could enable patients to monitor themselves over long periods of time.

Does Dual Anti-HER2 Therapy Increase Early Cardiac Toxicity in Comparison with Trastuzumab Alone in Breast Cancer Patients Receiving Adjuvant Radiotherapy? A Multicenter Retrospective Study

Adjuvant trastuzumab in combination with RT has proved its safety in terms of cardiac events. Dual anti-HER2 therapy with pertuzumab is currently standard adjuvant therapy in N+ and high-risk N0 early breast cancer (BC) patients. Our study aims to find if it increases early cardiac toxicity compared with trastuzumab alone in BC patients receiving adjuvant radiotherapy. Operable BC patients who received adjuvant radiotherapy (RT) and trastuzumab with or without pertuzumab between January 2017 and September 2020 in 7 Chinese centers were retrospectively reviewed. The cardiac examination included ultrasonography, electrocardiogram (ECG), NT-proBNP, and cTnI before RT and during follow-up. The cardiac event was any new-onset symptomatic heart disease or abnormality in the cardiac examination after RT. In total, 711 patients with a median age of 52 years were included, of whom 567 (79.7%) patients were treated with trastuzumab-only and 144 (20.3%) patients received dual anti-HER2 therapy. Adjuvant RT was given concurrently in 140/144 (97.2%) of dual anti-HER2 therapy and 562/567 (99.1%) of trastuzumab alone, respectively. With a median follow-up of 11 months, no patients developed symptomatic heart diseases. Among patients with normal baseline, 17 (2.4%), 86 (12.1%), 18 (2.5%) and 14 (7.3%) developed new-onset diastolic dysfunction, left ventricular ejection fraction (LVEF) decline, abnormal ECG, and abnormal NT-proBNP, respectively. No significant difference was found between the trastuzumab-only and dual anti-HER2 cohort in the incidence of all kinds of new-onset cardiac events (all p > 0.1). Multivariate analysis showed that left-sided (vs right-sided) RT significantly increased the risk of ECG abnormality (HR = 2.32, 95% CI 1.62-3.32, p<0.001). Increased age was an independent risk factor for diastolic dysfunction (HR = 1.1, 95% CI 1.02-1.18, p = 0.0098). Dosimetric analysis showed that patients who developed any cardiac events had increased mean heart dose (397.67±251.08 vs 344.87±236.75 cGy, p = 0.032). A significant increase in risk of cardiac events was found in patients with mean heart dose > 450 cGy (HR = 1.55, 95% CI 1.17-2.05, p = 0.0024), V5 > 26% (HR = 1.51, 95% CI 1.09-2.09, p = 0.013), and V30 > 5.5% (HR = 1.49, 95% CI 1.09-2.04, p = 0.0117), respectively. Further analysis was done in the subgroup of patients treated with left-sided RT, internal mammary nodes RT, or anthracyclines, no difference in risk of cardiac events was found between trastuzumab alone and dual anti-HER2 therapy in concurrent with RT (all p > 0.05). Compared with trastuzumab-only, dual anti-HER2 therapy does not increase early cardiac toxicity in combination with adjuvant RT in BC patients. Cardiac radiation exposure remains the primary risk factor associated with early cardiac toxicity.

Cancer Therapy-Related Cardiac Dysfunction in Patients With Prostate Cancer Undergoing Androgen Deprivation Therapy.

Background The risk of cardiac dysfunction for patients with prostate cancer undergoing androgen deprivation therapy (ADT) in the real-world setting remains unclear. Methods and Results A total of 1120 patients with prostate cancer and a baseline echocardiography scan were identified from Chang Gung Research Database between January 1, 2001 and December 31, 2019. Patients were treated with gonadotropin-releasing hormone agonist therapy, gonadotropin-releasing hormone antagonist therapy, or bilateral orchiectomy. Changes in left ventricular ejection fraction (LVEF) were further assessed in 421 patients using repeated measurements of LVEF before and during ADT treatment. The incidence of cancer therapy-related cardiac dysfunction (CT-RCD) was evaluated and defined as a ≥10% absolute decline in LVEF from baseline to a value of <53%. Among 421 patients undergoing ADT, LVEF declined from 66.3±11.3% to 62.5±13.6% (95% CI of mean difference: -5.0% to -2.7%) after a mean follow-up period of 1.6±0.8 years. CT-RCD occurred in 58 patients (13.7%) with a nadir LVEF of 40.3±9.1% after ADT. Lower baseline LVEF was significantly associated with CT-RCD (odds ratio, 1.07 [95% CI, 1.04-1.10]). The area under the curve of baseline LVEF for discriminating CT-RCD was 75.6%, with the corresponding optimal cutoff value of 64.5% (sensitivity, 79.3%; specificity, 67.2%). Conclusions ADT with gonadotropin-releasing hormone agonist therapy, gonadotropin-releasing hormone antagonist therapy, and bilateral orchiectomy were associated with an increased risk of CT-RCD in patients with prostate cancer. In addition, lower baseline LVEF was a significant predictor of CT-RCD in patients with prostate cancer undergoing treatment with ADT.

The type of suture material affects transverse aortic constriction-induced heart failure development in mice: a repeated measures correlation analysis.

Transverse-aortic constriction (TAC) operation is a widely used animal model to induce hypertrophy and heart failure through left-ventricular pressure overload. In mice, the cardiac response to TAC exhibits considerable variability influenced by factors such as strain, sub-strain, age, sex and vendor. To investigate the impact of suture material (silk versus prolene) and size (6-0 versus 7-0) on the TAC-induced phenotype, we performed surgeries on male C57BL6/N mice at 9 weeks of age defining the aortic constriction by a 27G needle, thereby employing most frequently used methodological settings. The mice were randomly assigned into four separate groups, 6-0 silk, 7-0 silk, 6-0 prolene and 7-0 prolene (10 mice per group). Echocardiography was conducted before TAC and every 4 weeks thereafter to monitor the development of heart failure. Repeated measures correlation analysis was employed to compare disease progression among the different groups. Our findings reveal a significant influence of the chosen suture material on TAC outcomes. Mice operated with prolene showed increased mortality, slower body weight gain, faster left-ventricular mass increase, and a faster decline in left-ventricular ejection fraction, fractional shortening and aortic pressure gradient compared to silk-operated mice. Moreover, despite non significant, using thinner suture threads (7-0) tended to result in a more severe phenotype compared to thicker threads (6-0) across all tested parameters. Collectively, our results highlight the importance of suture material selection in determining the cardiac phenotype induced by TAC and emphasize the need to consider this factor when comparing data across different research laboratories.

Prognostic implications of left ventricular ejection fraction trajectory changes in heart failure.

The latest guidelines recommended to assess the trajectory of left ventricular ejection fraction (LVEF) in patients with heart failure (HF). However, there is limited data on the trajectory of LVEF in real-world settings. In this study, we investigated the frequency and prognostic implications of changes in LVEF trajectory. Patients were divided into intensified LVEF, static LVEF, and worsening LVEF groups based on the transitions of HF types from baseline to follow-up. The intensified and worsening LVEF groups were further subdivided into mild (≤10% absolute changes of LVEF) and significant (>10% absolute changes of LVEF) increase or decrease groups according to the magnitude of change. The incidences and associations of changes in LVEF with patient outcomes were analyzed. Among the 2,429 patients in the study cohort, 38.3% of HF with reduced ejection fraction (HFrEF) and 37.6% of HF with mildly reduced ejection fraction (HFmrEF) showed an improvement in their LVEF. In contrast, a decline in LVEF was observed in 19.3% of HF patients with preserved ejection fraction (HFpEF) and 34.9% of those with HFmrEF. Cox regression analysis showed that the intensified LVEF group was associated with a lower risk of composite endpoints, while the worsening LVEF group yielded opposite findings. Subgroup analysis revealed that compared to those with mild changes in LVEF, baseline HFrEF patients with significant increase showed a lower risk of composite outcome, while baseline HFpEF patients were the opposite. The trajectories of LVEF changes are strongly correlated with outcomes in patients with HF who had prior history of HF admission. The most significant prognostic implications observed in patients with significant LVEF changes. Trajectory LVEF and type of HF changes are useful tools recommended for prognostication.

Atorvastatin for Anthracycline-Associated Cardiac Dysfunction

Anthracyclines treat a broad range of cancers. Basic and retrospective clinical data have suggested that use of atorvastatin may be associated with a reduction in cardiac dysfunction due to anthracycline use. To test whether atorvastatin is associated with a reduction in the proportion of patients with lymphoma receiving anthracyclines who develop cardiac dysfunction. Double-blind randomized clinical trial conducted at 9 academic medical centers in the US and Canada among 300 patients with lymphoma who were scheduled to receive anthracycline-based chemotherapy. Enrollment occurred between January 25, 2017, and September 10, 2021, with final follow-up on October 10, 2022. Participants were randomized to receive atorvastatin, 40 mg/d (n = 150), or placebo (n = 150) for 12 months. The primary outcome was the proportion of participants with an absolute decline in left ventricular ejection fraction (LVEF) of ≥10% from prior to chemotherapy to a final value of <55% over 12 months. A secondary outcome was the proportion of participants with an absolute decline in LVEF of ≥5% from prior to chemotherapy to a final value of <55% over 12 months. Of the 300 participants randomized (mean age, 50 [SD, 17] years; 142 women [47%]), 286 (95%) completed the trial. Among the entire cohort, the baseline mean LVEF was 63% (SD, 4.6%) and the follow-up LVEF was 58% (SD, 5.7%). Study drug adherence was noted in 91% of participants. At 12-month follow-up, 46 (15%) had a decline in LVEF of 10% or greater from prior to chemotherapy to a final value of less than 55%. The incidence of the primary end point was 9% (13/150) in the atorvastatin group and 22% (33/150) in the placebo group (P = .002). The odds of a 10% or greater decline in LVEF to a final value of less than 55% after anthracycline treatment was almost 3 times greater for participants randomized to placebo compared with those randomized to atorvastatin (odds ratio, 2.9; 95% CI, 1.4-6.4). Compared with placebo, atorvastatin also reduced the incidence of the secondary end point (13% vs 29%; P = .001). There were 13 adjudicated heart failure events (4%) over 24 months of follow-up. There was no difference in the rates of incident heart failure between study groups (3% with atorvastatin, 6% with placebo; P = .26). The number of serious related adverse events was low and similar between groups. Among patients with lymphoma treated with anthracycline-based chemotherapy, atorvastatin reduced the incidence of cardiac dysfunction. This finding may support the use of atorvastatin in patients with lymphoma at high risk of cardiac dysfunction due to anthracycline use. ClinicalTrials.gov Identifier: NCT02943590.

Effects of metformin and donepezil on the prevention of doxorubicin-induced cardiotoxicity in breast cancer: a randomized controlled trial

Doxorubicin (DOX) causes deleterious cardiotoxicity. We aimed to investigate the protective roles of metformin and donepezil against DOX-induced cardiotoxicity. In this randomized-controlled trial, 143 female breast cancer patients were enrolled. Metformin (n = 43), donepezil (n = 52), or placebo (n = 48) were prescribed during DOX treatment. The primary endpoint was a proportion of patients with high sensitivity troponin-I (hsTnI) more than the 99th percentile value (> 15.6 ng/L) after DOX treatment. The secondary outcomes were the changes in the hsTnI, N-terminal pro-B-type natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), global longitudinal strain (GLS) and peripheral blood mononuclear cells analysis for mitochondrial respiration. Baseline characteristics were similar between the groups. The primary endpoint occurred in 58.54% of metformin group, 76.92% in donepezil group, and 69.77% in placebo group (p = 0.215). The level of hsTnI increased after receiving DOX with subsequent decline in LVEF and GLS. Metformin and donepezil did not attenuate hsTnI elevation, LVEF or GLS reduction. There was no significant change in NT-proBNP level. Mitochondrial respiratory dysfunction was observed in the placebo and donepezil groups. However, metformin preserved mitochondrial respiration during DOX therapy. In conclusion, co-treatment with metformin or donepezil did not prevent myocardial injury. Metformin had a favorable mitochondrial outcome and warranted future studies.

Heart Failure With Recovered Ejection Fraction in Patients With Nonischemic Cardiomyopathy: Characteristics, Outcomes, and Long-term Follow-up

BackgroundDuration of recovery and long-term outcomes have not been well-described in a large cohort of patients with heart failure with recovered ejection fraction (HFrecEF) owing to nonischemic cardiomyopathy. The aim of the study was to characterize the duration of recovery and long-term outcomes of patients with HFrecEF. Methods and ResultsWe performed a retrospective analysis of our institution's databases. Only patients with nonischemic cardiomyopathy, a chronic HF diagnosis, and a previous left ventricular ejection fraction (LVEF) of ≤35% who had a subsequent LVEF of ≥50% were considered to have recovery. Patients with an LVEF of ≤35% who did not recover served as the comparison group. Included were 2319 patients with an LVEF of ≤35%, of whom 465 (20% [18.4%-21.7%]) met the above criteria for recovery (HFrecEF group). Recovery in the HFrecEF group was temporary in most cases, with 50% of patients experiencing a decline in LVEF to <50% within 3.5 [interquartile range 2.4-4.9] years after the day of recovery. Age and sex adjusted death and hospitalization were lower in the HFrecEF group than the HFrEF group (HR 0.29 [interquartile range 0.20–0.41] for death and 0.44 [interquartile range 0.32–0.60] for HF hospitalization, P < .0001 for both). Longer recovery was associated with better survival, with patients spending >5 years in recovery (LVEF of ≥50%) displaying the highest survival rates (83% alive at 10 years after recovery). Survival after recurrence of LV dysfunction was longer for those whose recovery duration was >1 year. ConclusionsPatients with nonischemic HFrecEF display a unique clinical course. Although recovery is temporary in most cases, patients with HFrecEF display lower mortality and hospitalization rates, with the more durable the recovery of LV systolic function, the longer survival can be anticipated.

Comparing Renin-Angiotensin-Aldosterone Blockade Regimens for Long-Term Chemotherapy-Related Cardiac Dysfunction: A Network Meta-Analysis.

Cancer therapies including trastuzumab and anthracyclines are cardiotoxic and cause cardiac dysfunction. To prevent cardiotoxicity, pharmacological agents used in heart failure have been administered concomitantly with cardiotoxic cancer therapy, but few studies to date have performed a head-to-head comparison of these different agents. This systematic review and network meta-analysis of randomized-controlled trials aims to evaluate the efficacy of renin-angiotensin-aldosterone system (RAAS) blockers, namely angiotensin-converting enzyme inhibitors (ACE-Is), aldosterone receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs), in primary prevention against chemotherapy-related cardiac dysfunction in patients receiving anthracyclines and/or trastuzumab. A systematic search was performed in major web databases for studies from inception to 15 September 2022. A Bayesian network meta-analysis model was used to assess the relative effects of competing treatments on the primary outcomes of risk of significant decline in left ventricular ejection fraction (LVEF) and mean LVEF decline. Secondary outcomes included left ventricular diastolic function, global longitudinal strain, and cardiac biomarkers. This study is registered with PROSPERO, CRD42022357980. Nineteen studies reported the effects of 13 interventions (N = 1905 patients). Only enalapril (RR 0.05, 95% CI 0.00-0.20) was associated with reduced risk of patients developing significant decline in LVEF relative to placebo. Subgroup analysis showed that the beneficial effect of enalapril was driven by protection against anthracycline-associated toxicity. In addition, no RAAS-inhibiting agents showed efficacy in protection against treatment with both anthracycline and trastuzumab. The use of RAAS inhibition therapy did not conclusively impact on other markers of cardiac function, including left ventricular diastolic function and cardiac biomarkers.

Prevention of Cancer Therapy-Related Cardiac Dysfunction With Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blocker: A Systematic Review of Randomised Controlled Trials

Cancer therapy-related cardiac dysfunction (CTRCD) is an important complication of selected chemotherapy agents associated with decline in left ventricular ejection fraction (LVEF) or clinical heart failure. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) have established benefits in heart failure with reduced ejection fraction, but their efficacy for preventing and treating CTRCD remains controversial. This systematic review aimed to assess the efficacy of ACEI and ARB in the prevention of CTRCD. PubMed, Embase, and Cochrane were systematically searched. Studies of interest were randomised controlled trials of patients with normal LVEF and active malignancy receiving chemotherapy, randomised to receive either an ACEI or ARB compared with a control group. The outcome of interest was the change in LVEF from baseline. Death, clinical heart failure, and adverse drug reactions were also recorded. A total of 3,731 search records were screened and 12 studies were included, comprising a total of 1,645 participants. Nine studies assessed the prevention of anthracycline-induced CTRCD, of which five studies showed a beneficial effect (1%–14% higher LVEF in treated groups), while four studies showed no beneficial effect. Three studies assessed the prevention of trastuzumab-induced CTRCD, of which one study showed a beneficial effect (4% higher LVEF) in a subset of participants. There is mixed evidence regarding the efficacy of ACEI or ARB in preventing the decline in LVEF in patients undergoing chemotherapy with either anthracyclines or trastuzumab, with a small but clinically meaningful benefit observed in some studies.

Pharmacological cardioprotective strategy for non-metastatic patients affected by breast cancer receiving an anthracycline-based chemotherapy: Final results of the phase 3 SAFE trial.

12079 Background: Several studies have evaluated cardioprotective strategies to prevent myocardial dysfunction in patients receiving cardiotoxic therapies. However, the optimal approach still represents a controversial issue. We aim to determine whether pharmacological cardiac prevention could reduce subclinical heart damage in breast cancer (BC) patients treated with anthracycline-based chemotherapy. Methods: The SAFE trial is a four-arm, randomised, phase 3, double-blind, placebo-controlled study. Patients were eligible for trial inclusion if they had indication to primary or postoperative systemic therapy using an anthracycline-based regimen. Patients with prior diagnosis of cardiovascular disease were excluded. Cardioprotective therapy (bisoprolol (B), ramipril (R), or both drugs (B+R), as compared to placebo) was administered for 1 year from the initiation of chemotherapy or until the end of trastuzumab therapy in case of HER2 positive patients. Doses for all groups were systematically up-titrated, up to the daily target dose of B (5 mg, once daily), R (5 mg, once daily), and placebo, if tolerated. The primary endpoint was defined as detection of any subclinical impairment (worsening ≥10%) in myocardial function and deformation measured with standard and 3-dimensional (3D) echocardiography, left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS). Results: 262 women (median 48 years; range24-75 years) were enrolled and treated in the study. We analysed patients who had completed the pre-planned cardiological assessment at 24 months. All patients received an anthracycline-based chemotherapy, 215 patients received at least 3 cycles of anthracyclines (range 1-6) and 128 patients had postoperative radiation therapy. At Univariate logistic analysis to evaluate the risk of GLS worsening &gt; 10% at 24 months, Odds ratios (OR) for improvement were 0.055, 0.083 and 0.060 for B, R and B+R, respectively (P &lt; 0.0001), if compared to placebo arm. At Univariate logistic analysis to evaluate the risk of 3DLVEF worsening &gt; 10% at 24 months, OR for improvement were 0.019, 0.048 and 0.054 for B, R and B+R, respectively (P &lt; 0.0001), if compared to placebo arm. Study drugs were well tolerated with no serious adverse events, the ramipril plus bisoprolol arm showed significantly more toxic effects and had a significantly higher rate of allocated treatment discontinuation as compared to the other arms. Conclusions: Cardioprotective pharmacological strategies in patients affected by BC receiving an anthracycline-based chemotherapy are well tolerated and seem to protect against cancer therapy-related LVEF decline and heart remodelling. Clinical trial information: NCT2236806 .

Replication of genetic associations of chemotherapy-related cardiotoxicity in the adjuvant NSABP B-31 clinical trial.

The cardiotoxic effects of doxorubicin, trastuzumab, and other anticancer agents are well known, but molecular genetic testing is lacking for the early identification of patients at risk for therapy-related cardiac toxicity. Using the Agena Bioscience MassARRAY system, we genotyped TRPC6 rs77679196, BRINP1 rs62568637, LDB2 rs55756123, RAB22A rs707557, intergenic rs4305714, LINC01060 rs7698718, and CBR3 rs1056892 (V244M) (previously associated with either doxorubicin or trastuzumab-related cardiotoxicity in the NCCTG N9831 trial of anthracycline-based chemotherapy ± trastuzumab) in 993 patients with HER2+ early breast cancer from the NSABP B-31 trial of adjuvant anthracycline-based chemotherapy ± trastuzumab. Association analyses were performed with outcomes of congestive heart failure (N = 29) and maximum decline in left ventricular ejection fraction (LVEF) using logistic and linear regression models, respectively, under an additive model with age, baseline LVEF, and previous use of hypertensive medications as covariates. Associations of maximum decline in LVEF in the NCCTG N9831 patients did not replicate in the NSABP B-31 patients. However, TRPC6 rs77679196 and CBR3 rs1056892 were significantly associated with congestive heart failure, p < 0.05, with stronger associations observed in patients treated with chemotherapy only (no trastuzumab) or in the combined analysis of all patients relative to those patients treated with chemotherapy + trastuzumab. TRPC6 rs77679196 and CBR3 rs1056892 (V244M) are associated with doxorubicin-induced cardiac events in both NCCTG N9831 and NSABP B-31. Other variants previously associated with trastuzumab-related decline in LVEF failed to replicate between these studies.

Myocardial Function after Coronary Artery Bypass Grafting in Patients with Preoperative Preserved Left Ventricular Ejection Fraction-The Role of the Left Ventricular Longitudinal Strain.

Background and Objectives: The role of coronary artery bypass grafting (CABG) on postoperative left ventricular (LV) function in patients with preoperatively preserved left ventricular ejection fraction (LVEF) is still being discussed and only a few studies address this question. This study aimed to assess LV function after CABG in patients with preoperatively preserved LVEF using left ventricular longitudinal strain assessed by 2D speckle tracking imaging (STI). Materials and Methods: Fifty-nine consecutive adult patients with coronary artery disease (CAD) referred for a first-time elective CABG surgery were enrolled in the final analysis of this prospective single-center clinical study. Transthoracic echocardiography (TTE), with conventional measures and STI measures, was performed within 1 week before CABG as well as 4 months after surgery. Patients were divided into groups based on their preoperative global longitudinal strain (GLS) value. Differences in systolic and diastolic parameters between groups were analyzed. Results: Preoperative GLS was reduced (GLS < -17%) in 39% of the patients. Parameters of systolic LV function were significantly reduced in this group of patients compared to the patient group with GLS% ≥ -17%. In both groups, 4 months after CABG there was a decline in LVEF but statistically significant only in the group with GLS% ≥ -17% (p = 0.035). In patients with reduced GLS, there was a statistically significant postoperative improvement (p = 0.004). In patients with preoperative normal GLS, there was not a significant change in any strain parameters after CABG. There was an improvement in diastolic function parameters measured by Tissue Doppler Imaging (TDI) in both groups. Conclusions: There is improvement in LV systolic and diastolic function after CABG in patients with preserved preoperative LVEF measured by STI and TDI. GLS might be more sensitive and effective than LVEF for monitoring improvements in myocardial function after CABG surgery in patients with preserved LVEF.

PO-05-148 VENTRICULAR DYSFUNCTION IN SARCOIDOSIS CARDIOMYOPATHY: INFLAMMATION IS NOT ALWAYS THE ONE TO BLAME

Clinical presentation A 63-year-old female was admitted after repeated syncopal events. She had a previous history of type 1 diabetes and hypertension. ECG on admission showed sinus rhythm with prolonged PR interval (320ms) and normal QRS duration. Imaging work up Coronary angiography revealed patent arteries. Echocardiography showed regional wall motion abnormalities but preserved left ventricular ejection fraction (LVEF). Cardiac magnetic resonance displayed patchy contrast retention following a non-coronary distribution. Whole-body positron emission tomography showed intense, multifocal tracer uptake in the myocardium and in the thoracic lymph nodes, in a pattern consisting with sarcoidosis. Diagnosis and Initial Treatment A clinical diagnosis of cardiac sarcoidosis (CS) was made. Following the implantation of a biventricular defibrillator, she was discharged from the hospital, and systemic immunosuppression with 30 mg prednisone daily was initiated. Follow-up Six months after diagnosis, interval PET showed reduction in the degree of myocardial inflammation, and no major change in the extent of myocardial scarring as based on myocardial perfusion (Table 1). Nevertheless, LVEF had dropped from 53% to 36%. Device interrogation revealed a high burden of PVCs. PVC-mediated cardiomyopathy was suspected, and amiodarone was initiated. Also because of uncertainty for the precipitous decline of LVEF and concern that it was multifactorial, additional immunosuppression with infliximab was instituted. After four months with amiodarone (but only one dose of infliximab), the PVC burden was reduced to 1%, biventricular pacing improved to target, and LVEF was restored to normal. These outcomes are maintained two years on. Interpretation

Pegylated liposomal doxorubicin (Duomeisu®) monotherapy in patients with HER2-negative metastatic breast cancer heavily pretreated with anthracycline and taxanes: a single-arm, phase II study

PurposeTo evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) heavily pretreated with anthracycline and taxanes.MethodsIn this single-arm, phase II study, patients with HER2-negative MBC previously treated with anthracycline and taxanes as second- to fifth chemotherapy received PLD (Duomeisu®, generic doxorubicin hydrochloride liposome) 40 mg/m2 every 4 weeks until disease progression, unacceptable toxicity, or completion of six cycles. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), and safety.ResultsOf 44 enrolled patients (median age, 53.5 years; range, 34–69), 41 and 36 were evaluable for safety and efficacy, respectively. In total, 59.1% (26/44) of patients had ≥ 3 metastatic sites, 86.4% (38/44) had visceral disease, and 63.6% (28/44) had liver metastases. Median PFS was 3.7 months (95% confidence interval [CI] 3.3–4.1) and median OS was 15.0 months (95% CI 12.1–17.9). ORR, DCR, and CBR were 16.7%, 63.9%, and 36.1%, respectively. The most common adverse events (AEs) were leukopenia (53.7%), fatigue (46.3%), and neutropenia (41.5%), with no grade 4/5 AEs. The most common grade 3 AEs were neutropenia (7.3%) and fatigue (4.9%). Patients experienced palmar-plantar-erythrodysesthesia (24.4%, 2.4% grade 3), stomatitis (19.5%, 7.3% grade 2), and alopecia (7.3%). One patient displayed a left ventricular ejection fraction decline of 11.4% from baseline after five cycles of PLD therapy.ConclusionPLD (Duomeisu®) 40 mg/m2 every 4 weeks was effective and well-tolerated in patients with HER2-negative MBC heavily pretreated with anthracycline and taxanes, revealing a potentially viable treatment option for this population.Trial registration Chinese Clinical Trial Registry: ChiCTR1900022568.