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Background: Doxorubicin is an essential cancer treatment, but its usefulness is hampered by the occurrence of cardiotoxicity. Nevertheless, the pathophysiology underlying doxorubicin-induced cardiotoxicity and the respective molecular mechanisms are poorly understood. Recent studies have suggested involvement of cellular senescence. Objectives: The aims of this study were to establish whether senescence is present in patients with doxorubicin-induced cardiotoxicity and to investigate if this could be used as a potential treatment target. Methods: Biopsies from the left ventricles of patients with severe doxorubicin-induced cardiotoxicity were compared with control samples. Additionally, senescence-associated mechanisms were characterized in 3-dimensional dynamic engineered heart tissues (dyn-EHTs) and human pluripotent stem cell-derived cardiomyocytes. These were exposed to multiple, clinically relevant doses of doxorubicin to recapitulate patient treatment regimens. To prevent senescence, dyn-EHTs were cotreated with the senomorphic drugs 5-aminoimidazole-4-carboxamide ribonucleotide and resveratrol. Results: Senescence-related markers were significantly up-regulated in the left ventricles of patients with doxorubicin-induced cardiotoxicity. Treatment of dyn-EHTs resulted in up-regulation of similar senescence markers as seen in the patients, accompanied by tissue dilatation, decreased force generation, and increased troponin release. Treatment with senomorphic drugs led to decreased expression of senescence-associated markers, but this was not accompanied by improved function. Conclusions: Senescence was observed in the hearts of patients with severe doxorubicin-induced cardiotoxicity, and this phenotype can be modeled in vitro by exposing dyn-EHTs to repeated clinically relevant doses of doxorubicin. The senomorphic drugs 5-aminoimidazole-4-carboxamide ribonucleotide and resveratrol prevent senescence but do not result in functional improvements. These findings suggest that preventing senescence by using a senomorphic during doxorubicin administration might not prevent cardiotoxicity.
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Objective: Increased epicardial adipose tissue (EAT) has been identified as a risk factor for the development of coronary artery disease (CAD). However, the exact role of EAT in the development of CAD is unclear. This study aims to compare EAT volumes between healthy controls and individuals with stable CAD and a history of myocardial infarction (MI). Furthermore, associations between clinical and biochemical parameters with EAT volumes are examined. Methods: This retrospective cross-sectional study included 171 participants from the United Kingdom Biobank (56 healthy controls; 60 stable CAD; 55 post MI), whom were balanced for age, sex and body mass index (BMI). EAT volumes were quantified on end-diastolic cardiac magnetic resonance (CMR) imaging short-axis slices along the left and right ventricle and indexed for body surface area (iEAT) and iEAT volumes were compared between groups. Results: iEAT volumes were comparable between control, CAD and MI cases (median [IQR]: 66.1[54.4-77.0] vs. 70.9[55.8-85.5] vs. 67.6[58.6-82.3] mL/m2, respectively (p > 0.005 for all). Increased HDL-cholesterol was associated with decreased iEAT volume (ß = -14.8, CI = -24.6 to -4.97, p = 0.003) and suggestive associations (P-value < 0.05 and ≥ 0.005) were observed between iEAT and triglycerides (ß = 3.26, CI = 0.42 to 6.09, p = 0.02), Apo-lipoprotein A (ß = -16.3, CI = -30.3 to -2.24, p = 0.02) and LDL-cholesterol (ß = 3.99, CI = -7.15 to -0.84, p = 0.01). Conclusions: No significant differences in iEAT volumes were observed between patients with CAD, MI and healthy controls. Our results indicate the importance of correcting for confounding by CVD risk factors, including circulating lipid levels, when studying the relationship between EAT volume and CAD. Further mechanistic studies on causal pathways and the role of EAT composition are warranted.
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INTRODUCTION: Myocardial injury is one of the most notorious complications of a hypertensive crisis. Key electrocardiograph signs used to detect cardiac injury such as ST segment changes and cardiac arrhythmias usually indicate acute ongoing end-organ damage. Lack of early signs to predict end-organ damage might lead to a delay in the initiation of therapy and selection of the incorrect therapeutic strategy. CASE PRESENTATION: We describe five cases of tall, hyper acute symmetrical T-waves alone or accompanied by other electrocardiograph abnormalities in five healthy participants: three women aged 52, 60 and 62-years and two men aged 49 and 66-years, during a tyramine-monoamine oxidase-inhibitor interaction, phase I clinical trial. T-wave changes appeared early during the course of the hypertensive crisis and were attributed to subendocardial ischemia. The changes were transient and reverted to baseline in parallel with a fall in blood pressure. CONCLUSION: Recognition of tall symmetrical T-waves in early phases of hypertensive crisis heralds commencement of myocardial damage. This calls for prompt medical intervention to avoid an impending irreversible myocardial injury. It is our belief that these findings will add new insight into the management of hypertensive crisis and will open avenues of further investigation.
