5 research outputs found
The role of hypoxic preconditioning in protection against the cardiotoxic effects of the anthracycline compound Doxorubicin
Introduction: Anthracyclines (ANTC) are potent chemotherapy agents, but may cause chronic irreversible cardiac failure. Recent data suggest cardiac damage due to ANTC begins early and may be a continuum. Cardioprotective modalities effective against acute injury may therefore provide prolonged benefit. Hypoxic Preconditioning (HP), i.e., subjecting cardiomyocytes to sub-lethal hypoxia and reoxygenation before a prolonged lethal ischaemic insult, protects cardiomyocytes by activating the pro-survival Reperfusion Injury Salvage Kinase (RISK) pathway. We examined the hypothesis that HP can protect cardiomyocytes against toxicity of the ANTC compound Doxorubicin (Dox). / Methods: A toxic concentration of Dox was identified in an in vitro model of cardiotoxicity established in isolated adult rat ventricular myocytes (ARVM), using Propidium iodide (PI) permeability and altered morphology including cell-membrane blebbing as markers of celldeath. An in vitro hypoxic preconditioning (HP) protocol was characterised, and the effect of this HP-stimulus on cell-death with subsequent Dox-treatment was assessed. Induction of the RISK pathway by HP was investigated by pre-inhibiting the Phosphoinositide 3-kinase (PI3K)/Akt cascade and the Mitogen Activated Protein Kinase (MAPK) Extracellular signal-regulated Kinase (ERK) 1/2 pathway with 10µM LY294002 (LY) and 30µM PD98059 (PD) respectively. The role of oxidative stress in Dox-toxicity was probed using N-acetyl cysteine, a known Reactive Oxygen Species (ROS)-scavenger. Fluorescence of 30 nM Tetramethylrhodamine methyl ester (TMRM) was used to assess the mitochondrial transmembrane potential (ΔΨm). Laser-induced ROS generation with 3 µM TMRM was used to assess mitochondrial permeability transmembrane pore (mPTP) induction after Dox-treatment, with 1µM Ciclosporine A (CsA) as a positiveprotective control against mPTP induction. Dox-induced cell-death was also reassessed as an agent to protect against mPTP induction. / Results and Discussion: 7.5 μM Dox resulted in significant increase in cell-death (p<0.05) after 18h (44.2 + 4.7% Dox vs 18.7 + 1.5 % Control). HP protected cardiomyocytes from Dox (35.4 ± 1.7% Dox; 14.7 ± 1.5% Dox HP). LY, but not PD, abrogated this HP-induced protection (Dox HP: 16.9 + 1.5%; Dox HP LY: 38.5 + 3.3%; Dox HP PD: 15.9 + 1.3%). ROS-scavenging failed to rescue cardiomyocytes from Dox-toxicity. Dox failed to alter ΔΨm or mPTP-induction. However, although the protective effect of presence of CsA on mPTP-induction was abrogated in cells pre-treated with Dox, concomitant treatment with dox and CsA could not protect ARVMs from dox-toxicity. / Conclusions and future directions: HP protects cardiomyocytes against cell-death due to Dox. Cell-death data suggest this protection is mediated via the PI3K/Akt pathway. The role of MAPK ERK 1/2 against Dox-toxicity in vitro is unclear. Dox-toxicity appears to be independent of oxidative stress, variations in ΔΨm, or vulnerability of the mPTP-induction. Further work to delineate mechanisms of toxicity, and the downstream components of HP-induced protection is necessary
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Arrhythmic Burden and Outcomes in Pulmonary Arterial Hypertension.
Pulmonary arterial hypertension (PAH) is a devastating, life-limiting disease driven by small vessel vascular remodeling leading to a rise in pulmonary vascular resistance (PVR). Patients present with a range of symptoms including shortness of breath, exercise intolerance, palpitations or syncope. Symptoms may be related to vascular disease progression or arrhythmia secondary to the adaptation of the right heart to pressure overload. Arrhythmic burden is high in patients with left heart disease and guideline-based treatment of arrhythmias improves quality of life and prognosis. In PAH the incidence and prevalence of arrhythmias is less well-defined and there are no PAH-specific guidelines for arrhythmia management. We undertook a literature search identifying 13 relevant papers; detection of arrhythmias was acquired from 12-lead electrocardiogram (ECG) or Holter monitors. In all forms of pulmonary hypertension (PH) the prevalence of supraventricular arrhythmias (SVA) was 26-31%, ventricular arrhythmias (VA) 24% and a 5-year incidence of SVA ~13.2-25.1%. Prevalence and incidence of arrhythmias in PAH is less clear due to limited study numbers and the heterogenous nature of the patient population studied. For arrhythmia treatment, only single-arm studies of therapeutic strategies were reported using antiarrhythmic drugs (AAD), direct current cardioversion (DCCV) and ablation. Periods between ECG or Holter have not been investigated, highlighting the possibility that significant arrhythmias may be undetected. Advances in monitoring allow long-term surveillance via implanted/non-invasive monitors. Use of such technologies may provide an accurate estimate of incidence and prevalence of arrhythmias in patients with PAH, further defining relationships to adverse outcomes, and therapeutic options
Cerebral Protection Device Deployment Via Left Radial Artery During TAVI in Presence of Truncus Bicaroticus
Patients with anomalous aortic arch undergoing transcatheter aortic valve implantation may require modifications to the deployment protocols of cerebral protection device systems. We share the first reported case, to our knowledge, of a cerebral protection device via the left radial artery and using a distal basket alone in a patient with truncus bicaroticus and arteria lusoria. (Level of Difficulty: Intermediate.