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Patients with acute myocardial infarction (MI) are at risk for developing heart failure (HF) and subsequently are at an increased risk of mortality. Sodium-glucose cotransporter-2 inhibitors have been proven to improve outcomes in patients with HF with reduced ejection fraction, and, in the case of empagliflozin, in HF with preserved ejection fraction even without diabetes, but their efficacy and safety in the post-MI population has not yet been evaluated. The EMPACT-MI trial will evaluate the safety and efficacy of empagliflozin compared with placebo in patients hospitalized for MI with or at high risk of new onset HF, in addition to standard care. EMPACT-MI is a streamlined, multinational, randomized, double-blind, placebo-controlled trial randomizing 5,000 participants at approximately 480 centers in 22 countries. Eligible patients presenting with spontaneous MI must have new signs or symptoms of pulmonary congestion requiring treatment or new left ventricular dysfunction (LVEF<45%), and at least 1 additional risk factor for development of future HF. Eligible and consenting patients are randomized to empagliflozin 10mg or placebo daily in addition to standard of care within 14 days of hospital admission for MI. The primary composite end point is time to first hospitalization for HF or all-cause mortality. EMPACT-MI will inform clinical practice regarding the role of empagliflozin in patients after an MI with high-risk for the development of future HF and mortality.

Pertuzumab, an anti-HER2 antibody, recognizes a different epitope of HER2 than does trastuzumab and behaves differently. In patients with metastatic breast cancer, the combination of the two antibodies plus docetaxel significantly increased progression-free survival. Approximately 20% of all breast cancers have gene amplification or overexpression (or both) of human epidermal growth factor receptor 2 (HER2), 1 a tyrosine kinase transmembrane receptor, resulting in a more aggressive phenotype and a poor prognosis. 2 Treatment with the anti-HER2 humanized monoclonal antibody trastuzumab in addition to chemotherapy, as compared with chemotherapy alone, significantly improves progression-free and overall survival among patients with HER2-positive metastatic breast cancer. 3 , 4 Trastuzumab binds to subdomain IV of the HER2 extracellular domain and exerts its antitumor effects by blocking HER2 cleavage, 5 stimulating antibody-dependent, cell-mediated cytotoxicity 6 and inhibiting ligand-independent, HER2-mediated mitogenic signaling. 7 However, in most patients . . .

Anthracycline (ANT) is a topoisomerase-interacting agent that is used in most malignancy treatments. We investigated the efficacy of enalapril (angiotensin-converting enzyme inhibitor) in the prevention of ANT-induced cardiomyopathy. In this randomized, single-blind, and placebo-controlled study, 69 patients with a newly diagnosed malignancy for which ANT therapy was planned were randomly assigned to either a group receiving enalapril ( n  = 34) or placebo ( n  = 35). Echocardiography studies were performed before chemotherapy and at 6 months after randomization. Additionally, troponin I and creatinine kinase-MB (CK-MB) were measured 1 month after the initiation of chemotherapy. In the enalapril group, the mean left ventricular ejection fraction (LVEF) ( p  = 0.58) was the same at baseline and 6 months after randomization. Conversely, LVEF significantly decreased in the control group ( p  < 0.001). Additionally, LV end systolic volume and left atrial diameter were significantly increased compared with the baseline measures in the control group. According to the tissue Doppler study, the mitral annuli early diastolic ( e ′) and peak systolic ( s ′) velocities were significantly reduced, and the E (the peak early diastolic velocity)/ e ′ ratio was significantly increased in the control group. Furthermore, the TnI and CK-MB levels were significantly higher in the control group than in the enalapril group. Enalapril appears efficacious in preserving systolic and diastolic function in cancer patients treated with ANTs.

Background Anthracyclines are widely used in the treatment of childhood cancer. One of the well-recognized side-effects of anthracycline therapy is dose-dependent cardiomyopathy that may progress to heart failure (HF) years after completion of cancer-directed therapy. This study will evaluate the efficacy of low-dose beta-blocker (carvedilol) for HF risk reduction in childhood cancer survivors at highest risk for HF. The proposed intervention has the potential to significantly reduce chronic cardiac injury via interruption of neurohormonal systems responsible for left ventricular (LV) remodeling, resulting in improved cardiac function and decreased risk of HF. The intervention is informed by previous studies demonstrating efficacy in pediatric and adult non-oncology populations, yet remains unstudied in the pediatric oncology population. Methods/Design The primary objective of the trial is to determine impact of the intervention on echocardiographic markers of cardiac remodeling and HF risk, including: LV wall thickness/ dimension ratio (LVWT/D; primary endpoint), as well as LV ejection fraction, volume, and blood biomarkers (natriuretic peptides, galectin-3) associated with HF risk. Secondary objectives are to establish safety and tolerability of the 2-year course of carvedilol using: 1) objective measures: hepatic and cardiovascular toxicity, treatment adherence, and 2) subjective measures: participant self-reported outcomes. Two hundred and fifty survivors of childhood cancer (diagnosed <21 years of age), and previously treated with high-dose (≥300 mg/m 2 ) anthracyclines will be enrolled in a randomized, double-blind, placebo controlled trial. After baseline assessments, participants will be randomized in a 1:1 ratio to low-dose carvedilol (maximum dose: 12.5 mg/day) or placebo. Carvedilol or placebo is up-titrated (starting dose: 3.125 mg/day) according to tolerability. Discussion When completed, this study will provide much-needed information regarding a physiologically plausible pharmacological risk-reduction strategy for childhood cancer survivors at high risk for developing anthracycline-related HF. Trial registration ClinicalTrials.gov; NCT02717507

Adriamycin though considered as an effective anticancer drug, leads to irreversible cardiomyopathy (CMP) and congestive heart failure (CHF). The aim of this study was to determine the protective effect of carvedilol in adriamycin (ADR)-induced cardiomyopathy (CMP) in cancer patients. Patients with lymphoreticular malignancy in whom ADR therapy was planned were randomized into two groups: carvedilol and control. Twenty seven patients each were enrolled in carvedilol and control groups. In the carvedilol group, 12.5 mg once daily oral carvedilol was given during six months. The patients were evaluated by echocardiography before and after chemotherapy. Left ventricular ejection fraction (EF) and systolic and diastolic diameters were calculated. At six months of follow up, six patients in the carvedilol group and five in the control group had died. The mean EF (63.19 vs. 63.88%) and fraction shortening (FS) (34 vs. 34.6) of the carvedilol group were similar at follow up, but in the control group, the mean EF (67.27 vs. 60.82%, P =0.003) and FS (38.48 vs. 34.6, P<0.05) at control echocardiography were significantly lower. In carvedilol group, both systolic and diastolic diameters were not changed, but in control group, systolic diameters were significantly increased compared with basal measures (left ventricular end systolic diameter = 28.26±5.50 mm vs. 31.25± 6.50 mm; P< 0.05). Prophylactic use of carvedilol in patients receiving anthracycline protected systolic functions of the left ventricle. Carvedilol can be a potential drug which can ameliorate ADR-induced CMP.

Not much is known about the effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on echocardiographic parameters of left ventricular (LV) systolic function in patients with heart failure and reduced ejection fraction (HFrEF). We prospectively included 59 outpatients with HFrEF: 41 patients received SGLT2i with OMT (SGLT2i+ group), whereas eighteen patients received OMT without SGLT2i (SGLT2i− group). Myocardial work index (MWI), 3D ejection fraction (3D LVEF), and global longitudinal strain (GLS) were measured at baseline and after 3 months following treatment. At 3-month follow-up, the SGLT2i+ group showed significantly greater improvement in MWI than the SGLT2i− group. In both groups, there was a significant improvement in 3D LVEF and LV GLS, circulating NT-proBNP levels, and NYHA functional class, with significantly greater improvement in the SGLT2i+ group. In conclusion, the addition of SGLT2i to fully optimized background medical therapy resulted in a greater improvement of LV systolic function among outpatients with HFrEF. Graphical abstract

Trastuzumab (TZB) is an established therapy for HER2-positive breast cancer. The use of TZB is commonly associated with cardiotoxicity manifesting as asymptomatic decrease in left ventricular ejection fraction (LVEF) or overt heart failure. Several studies demonstrated favorable effects of angiotensin-converting enzyme (ACE) inhibitors and β-blockers (BBs) in the prevention of chemotherapy-induced cardiotoxicity. We hypothesize that patients, randomized to receive an ACE inhibitor or a BB during trastuzumab therapy for breast cancer, will maintain a higher LVEF than patients randomized to placebo. We designed a prospective, multicenter, randomized, phase II placebo-controlled clinical trial to evaluate the effects of an ACE inhibitor (lisinopril) and a BB (carvedilol phosphate–extended release) on cardiotoxicity in patients with breast cancer who are receiving adjuvant or neoadjuvant TZB therapy. The primary objectives include (1) comparison of incidence of cardiotoxicity and (2) comparison of LVEF as a continuous variable in between the arms. Cardiotoxicity was defined as an absolute decrease in LVEF from baseline of ≥10% at follow-up or an absolute decrease of ≥5% in LVEF from baseline for individuals with <50% LVEF at follow-up. The target accrual is 468 participants, representing patients both with and without anthracycline exposure. The enrollment is completed. The trial is co-sponsored by University of South Florida and National Cancer Institute. The LVEF is being evaluated by echocardiography or multigated acquisition scan. If we can demonstrate that the use of an ACE inhibitor or a BB can reduce the degree of TZB-induced cardiotoxicity, it is hoped that patients will receive complete and uninterrupted TZB therapy for breast cancer without compromising cardiac function.

Oxidative stress and RAAS play an important role in the occurrence of anthracyclines-induced cardiotoxicity. Telmisartan, an angiotensin II type 1 receptor blocker, inhibits activation of superoxide sources and induces anti-inflammatory effects. The possible role of telmisartan in preventing myocardial damage induced by epirubicin (EPI) was investigated. Forty-nine patients free from cardiovascular diseases affected by a variety of solid cancers were examined. Eligible patients were randomized to receive telmisartan (40 mg/d; TEL, n = 25) or placebo (PLA, n = 24) starting 1 week before chemotherapy. Patients were studied by means of echocardiography, tissue Doppler, and strain and strain rate (SR) imaging. We also measured plasma levels of inflammatory and oxidative stress markers. All parameters were assessed at baseline and 7 days after every new EPI dose of 100 mg/m 2. An impairment of the SR peak was observed at the EPI dose of 200 mg/m 2, with no significant differences between TEL and PLA (1.41 ± 0.31 vs 1.59 ± 0.36/s). At growing cumulative doses of EPI, SR normalized only in TEL, showing a significant difference in comparison to PLA at EPI doses of 300 mg/m 2 (1.69 ± 0.42 vs 1.34 ± 0.18/s, P < .001) and 400 mg/m 2 (1.74 ± 0.27 vs 1.38 ± 0.24/s, P < .001). Moreover, a significant increase in reactive oxygen species and interleukin-6 was found in PLA; but these remained unchanged in TEL. We confirmed that EPI-induced cardiotoxicity is primarily related to the inactivation of the cardiac antioxidant defenses. In addition, we showed that telmisartan can reduce EPI-induced radical species, antagonize the inflammation, and reverse the early myocardial impairment.

The use of antracycline (ANT) in breast cancer has been associated with adverse cardiac events. Two-dimensional (2D) strain imaging (SI) can provide a more sensitive measure of altered left ventricular (LV) systolic function. We aimed to evaluate the preventive effect of carvedilol administration assessed by SI in a patient with breast cancer treated with ANT. Patients receiving ANT were randomly assigned to the carvedilol- or placebo-receiving group. Each received an echocardiographic examination with conventional 2D echocardiography, pulsed tissue Doppler, and 2D SI prior to and 6 months post ANT treatment. During the 6-month follow-up period there were no patient deaths or interrupted chemotherapy treatments due to doxorubicin-induced cardiotoxicity. Both left ventricular ejection fraction (LVEF) and fractional shortening (FS) were within normal limits for all patients before and after ANT therapy. EF, FS and LV dimensions were measured using M-mode echocardiography and found to be similar in both groups before and after ANT therapy. The mean EF, FS, and LV echocardiograph baseline and control dimensions were similar in both groups after 6 months. Though baseline SI parameters were similar between the groups, there was a significant decrease in LV basal septal and basal lateral peak systolic strain in the control group compared to the carvedilol group. These results indicate that carvedilol has a protective effect against the cardiotoxicity induced by ANT.

Anthracyclines have a profound effect on breast cancer. However, at higher dosages, there are many toxic side effects associated with their use; these include bone marrow suppression, alopecia, gastrointestinal reactions and cardiotoxicity. Pegylated liposomal doxorubicin (PEG-LG) has been demonstrated to achieve equivalent efficacy to conventional doxorubicin, with significantly lower cardiotoxicity. We conducted an open-label, multicenter, single-armed clinical trial useing an NAC regimen based on four cycles of PEG-LD 40 mg/m 2 plus cyclophosphamide (CPM) 600 mg/m 2 on day 1 of a 21 day schedule, followed by four cycles of docetaxel (DTX) 85 mg/m 2 on day 1 of a 21 day schedule. The primary endpoint analysed was the pathological complete response rate (pCR) in the breast, while treatment toxicities and safety were also assessed. The results showed that the breast pCR rate was 18.75% (95% CI 11.5–26.0%). Among the different molecular cancer types, the triple negative breast cancer patients had the highest pCR, at 43.75%. No significant decrease in left ventricular ejection fraction was observed. Our data tends to draw the conclusion that this regimen is a viable option for the neoadjuvant treatment of patients with LABC, especially in the triple-negative subtype and patients with heart abnormalities. We believe the efficacy and the safety of this regimen is likely to be the same based on published data from other studies but that this cannot be certain without a randomized trial.