Doxorubicin Induced Apoptosis Enhances Monocyte Infiltration and Adverse Cardiac Remodeling in Diabetic Animals

Diabetic cancer patients treated with Doxorubicin (DOX), a potent chemotherapeutic drug induces cardiac toxicity. However, molecular mechanisms of cardiac toxicity in this specific disease progression in patients and animal models are completely unknown. Therefore, we designed a study to understand the effects of doxorubicin induced cardiac toxicity in diabetic animals and involved pathophysiological mechanisms. C57BL/6J mice were divided into DOX and diabetic (STZ) treated four groups; control, STZ, DOX and DOX+STZ. At Day 14, animals were sacrificed, echocardiography was used to examine heart function, heart and blood samples were collected to investigate apoptotic mechanisms (Caspase 3, BAX, Bcl2), inflammation and cardiac remodeling. Our data shows a significant (p<0.05) increase in glucose levels, apoptotic markers, monocyte infiltration at the site of apoptosis and triggered inflammatory immune response (TNF-α and IL-6), in DOX+STZ animals compared to control and experimental groups. We also observed significant (p<0.05) increase in myofibrillar area, fibrosis and significantly decreased (p<0.05) cardiac function in DOX-treated diabetic animals compared with controls. In conclusion, our data suggest that DOX-induces significantly increased apoptosis, fibrosis and structural alterations in diabetic hearts compared to non-diabetic animals.

Amphotericin B Induced Anaphylactic Reaction and Electrolyte Imbalance: A Case Report

Amphotericin B, a polyene antifungal antibiotic derived from a strain of Streptomyces nodosus. It acts by binding to sterols in the cell membrane of susceptible fungi, with a resultant change in the permeability of the membrane. Amphotericin B can cause allergic reactions, electrolyte imbalance and severe side effects, such as chest discomfort accompanied by dyspnea, flushing, agitation, tachypnea, tachycardia, hypoxemia, hypotension, or hypertension, are likely to develop following the injection of Amphotericin B. Anaphylaxis, cardiac toxicity and respiratory failure have also been associated to different formulations of Amphotericin B as life-threatening acute events. This case report is on a 57-year-old male patient who was admitted with a condition of left diabetic foot with non-healing medial supra heel ulcer and fungal infection on the site of wound. The patient was given Amphotericin B in emulsion form due to the high priority of fungal infection and the need for antifungal medicine, which led to anaphylactic reaction and electrolyte imbalance, which were treated immediately and the same preparation was continued with a low infusion rate. When infusion is discontinued, antihistamines can assist to alleviate the symptoms. In this case, it is recommended that the patient's condition and clinical parameters should be closely followed after the medicine has been administered.

Activation of PPARα by Fenofibrate Attenuates the Effect of Local Heart High Dose Irradiation on the Mouse Cardiac Proteome

Radiation-induced cardiovascular disease is associated with metabolic remodeling in the heart, mainly due to the inactivation of the transcription factor peroxisome proliferator-activated receptor alpha (PPARα), thereby inhibiting lipid metabolic enzymes. The objective of the present study was to investigate the potential protective effect of fenofibrate, a known agonist of PPARα on radiation-induced cardiac toxicity. To this end, we compared, for the first time, the cardiac proteome of fenofibrate- and placebo-treated mice 20 weeks after local heart irradiation (16 Gy) using label-free proteomics. The observations were further validated using immunoblotting, enzyme activity assays, and ELISA. The analysis showed that fenofibrate restored signalling pathways that were negatively affected by irradiation, including lipid metabolism, mitochondrial respiratory chain, redox response, tissue homeostasis, endothelial NO signalling and the inflammatory status. The results presented here indicate that PPARα activation by fenofibrate attenuates the cardiac proteome alterations induced by irradiation. These findings suggest a potential benefit of fenofibrate administration in the prevention of cardiovascular diseases, following radiation exposure.

Sesamol Supplementation Mitigates Isoproterenol-Induced Cardiac Toxicity in Rats by Stabilizing Cardiac Mitochondrial and Lysosomal Enzymes

The current investigation was intended to evaluate the antimyocardial ischemic effects of sesamol on lactate dehydrogenase (LDH) isoenzymes, DNA damage, and mitochondrial and lysosomal enzyme activities in isoproterenol (ISO)-induced myocardial infarction (MI) in male albino Wistar strain rats. Rats that received ISO (85 mg/kg body weight (B.W) subcutaneously) for the first 2 consecutive days showed significant reduction in the activities of tricarboxylic acid (TCA) cycle enzymes (isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, malate dehydrogenase, and succinate dehydrogenase) and respiratory chain enzymes (cytochrome c oxidase and nicotinamide adenine dinucleotide hydrogen (NADH) dehydrogenase) in the heart mitochondria. The activities of the lysosomal enzymes (α-and β-glucosidases, α and β-galactosidases, β-glucuronidase and β-N-acetyl glucosaminidase and cathepsin-B and cathepsin-D) were increased significantly in the heart homogenate of ISO-induced MI rats. ISO injection also increased the % of tail DNA, tail length, and tail moment and decreased the % of head DNA. Pretreatment with sesamol (50 mg/kg B.W) every day for a period of 9 days prevented the above abnormalities induced by ISO. In conclusion, it can be inferred that administration of sesamol has a potent beneficial role against ISO-induced damage to the mitochondria, lysosomes, and DNA, thereby preventing MI.

636 Global cardiovascular assessment in patients with PH+ chronic myeloid leukaemia treated with TKI: long-term follow-up

Aims Patients affected by Philadelphia chromosome+ chronic myeloid leukaemia (Ph+CML) undergoing to therapy with tyrosine kinase inhibitors (TKIs) are prone to develop cardiovascular complications, which have relevant prognostic implications. Speckle-tracking echocardiography, allowing strain and myocardial work analyses, can be useful in the early detection of cardiac toxicity. Aim of our study was to assess the cardiotoxic effects of TKIs. Methods We evaluated, at baseline and during FU, 20 patients affected by Ph+ CML (59.7 ± 12.2 years, 13 males), treated Imatinib (52.6%), Nilotinib (36.8%), Ponatinib (5.3%), Dasatinib (5.3%). We measured systolic and diastolic blood pressure (SBP-DBP) and calculated corrected QT interval (QTc). In addition, we analysed echocardiographic parameters including left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), global work index (GWI), global constructive work (GCW), global wasted work (GWW), global work efficiency (GWE), and peak left atrial longitudinal strain (PALS). Cardiovascular (CV) events that we considered were symptomatic or asymptomatic LV dysfunction, acute coronary syndrome (ACS), peripheral artery disease (PAD), and arrhythmias. Results Follow-up (FU) time was 3.4 ± 1 years. Most of patients (63.2%) had cardiovascular risk factors, including arterial hypertension (50%), type2 diabetes mellitus (15%), dyslipidaemia (40%) and cigarette smoking (15%). At the end of FU, SBP was unchanged (128.9 ± 19.6 mmHg vs. 129.1 ± 9.8 mmHg; P=NS) whereas DBP increased (69.4 ± 8.5 mmHg vs. 75 ± 7.7 mmHg; P = 0.004); moreover QTc was longer than baseline (404.4 ± 20.1 ms vs. 424.3 ± 29.8 ms; P &lt; 0.001) and LVEF showed a significant decrease (62.2 ± 3.9% at baseline vs. 59.3 ± 4.8% at FU; P = 0.003); similarly, GCW (2444.1 ± 540mmHg% vs. 2234.7 ± 179.4 mmHg%; P = 0.034), GWI (2158.1 ± 589.6 mmHg% vs. 1923.1 ± 174.5 mmHg%; P = 0.022) and PALS (36.3 ± 17.1% vs. 32.8 ± 9.7%; P = 0.002) decreased during cancer therapy. On the other hand, GLS (−18.6 ± 3.1% vs. −19.4 ± 1.1%; P=NS), GWE (94.3 ± 4.1% vs. 93.6 ± 3.6%; P=NS) and GWW (120.6 ± 94.3 mmHg% vs. 106.3 ± 68.9 mmHg%; P=NS) did not change significantly. CV events were observed in 66.7% of the study population. These were mostly represented by ACS, atrial arrhythmias and symptomatic LV dysfunction (30.7% for each) and, to a lesser extent, PAD (7.6%). By comparing patients with events (group A) with those without events (group B) we found that differently from group B, group A showed during FU a significant increase of DBP (from 66 ± 5.2 mmHg to 71.2 ± 6.1 mmHg, P = 0.010; vs. group B= from 76 ± 12.mmHg to 78 ± 4.1 mmHg, P=NS) and a significant QTc prolongation (from 415.7 ± 16.1 ms to 441 ± 29.8 ms, P &lt; 0.001; vs. group B= from 390.4 ± 19.3 ms to 405.6 ± 23.3 ms, P=NS); as to echocardiographic parameters, we found, in patients with CV events, a significant decrease of: LVEF (from 62.7 ± 4.7% to 58.8 ± 4.3%, P = 0.004; vs. group B from 61.4 ± 2.8% to 60 ± 1.7%, P=NS), GCW (from 2566.2 ± 669.6 mmHg% to 2230.1 ± 199.4 mmHg%, P = 0.021, vs. group B 2194 ± 167.5 mmHg% to 2212.6 ± 160mmHg%, P=NS) and PALS (from 36.1 ± 17% to 29.6 ± 6.6%, P = 0.022 vs. group B from 32.7 ± 8% to 35 ± 8.5%, P = 0.003). Of these parameters, only PALS was significant independent predictor of CV events on logistic regression analysis (OR 0.82 CI 95 0.69–0.98, P = 0.034). Conclusions Advanced echocardiographic parameters, including myocardial work and left atrial strain analysis, are particularly valuable in the early detection of TKI-induced cardiac toxicity. PALS could be an useful tool to predict outcome in these patients.

710 Advanced echocardiographic analysis to identify cardiac toxicity after TKI exposure in patients with CML

Aims Worsening of cardiac function with increased arrhythmic risk is common in cancer patients undergoing chemotherapy. Impaired LV global longitudinal strain (GLS) in these patients despite preserved ejection fraction is a common issue. Recently, myocardial work by speckle-tracking echocardiography has been used to overcome GLS limitations in various conditions, but little is known about its usefulness in the detection of cardiac toxicity. Moreover, left atrial (LA) toxicity may occur early in the course of cancer therapy. The main aim of the study was to assess the cardiotoxic effects of tyrosine kinase inhibitors (TKIs) on patients with Philadelphia chromosome-positive chronic myeloid leukaemia (Ph+ CML) by using novel echocardiographic tools as myocardial work and atrial strain analysis. Methods and results We retrospectively enrolled Ph+ CML patients treated with TKIs followed at the cardio-oncology outpatient clinic of our hospital from December 2018 to March 2019 who underwent clinical evaluation with ECG and echocardiogram (TTE) before and after 1 year of treatment with TKIs. Healthy subjects were enrolled in the control group matched for gender, age and cardiovascular risk factors. Myocardial work was derived from the strain-pressure relation, integrating in its calculation the non-invasive arterial pressure. LA longitudinal strain (reservoir, conduit, and booster) was obtained from an optimized apical 4-chamber view of the LA. The study recruited 32 patients in Ph+ CML group and 32 healthy controls. 39% of patients were treated with Imatinib, 29.3% with Nilotinib, 4.9% with Dasatinib and 4.9% with Ponatinib. Main results are detailed in Table 1. At 1-year follow-up there was a significant reduction compared to baseline in global constructive work (2555.22 ± 564.33 vs. 2119.31 ± 700.19; P = 0.0001), global work efficiency (96.13 ± 1.90 vs. 94.00 ± 2.96; P = 0.002), and global work index (2340.75 ± 579.57 vs. 1938.46 ± 680.23; P = 0.001), and a non-significant reduction in global wasted work (P = 0.393). Regarding left atrial strain analysis at the 1-year follow-up there was a statistically significant reduction in LA contractile strain (booster= 14.63 ± 1.408 vs. 12.38 ± 1.581; P = 0.018). LA contractile strain reduction was also observed in the comparison with controls (12.38 ± 2.99 vs. 14.91 ± 3.09; P = 0.009). Any other significant difference was detected between baseline and FU TTE data in the Ph+ CML group. Conclusions New imaging methods for the study of cardiotoxicity provide an additional tool for early prediction of potential adverse effects of antineoplastic drugs. TKIs therapy leads to an impairment of atrial contractility, which can be detected by atrial strain e myocardial work analysis.