Translational Proteomics Analysis of Anthracycline-Induced Cardiotoxicity From Cardiac Microtissues to Human Heart Biopsies

Anthracyclines, including doxorubicin, idarubicin, and epirubicin, are common antitumor drugs as well as well-known cardiotoxic agents. This study analyzed the proteomics alteration in cardiac tissues caused by these 3 anthracyclines analogs. The in vitro human cardiac microtissues were exposed to drugs in 2 weeks; the proteomic data were measured at 7 time points. The heart biopsy data were collected from heart failure patients, in which some patients underwent anthracycline treatment. The anthracyclines-affected proteins were separately identified in the in vitro and in vivo dataset using the WGCNA method. These proteins engage in different cellular pathways including translation, metabolism, mitochondrial function, muscle contraction, and signaling pathways. From proteins detected in 2 datasets, a protein-protein network was established with 4 hub proteins, and 7 weighted proteins from both cardiac microtissue and human biopsies data. These 11 proteins, which involve in mitochondrial functions and the NF-κB signaling pathway, could provide insights into the anthracycline toxic mechanism. Some of them, such as HSPA5, BAG3, and SH3BGRL, are cardiac therapy targets or cardiotoxicity biomarkers. Other proteins, such as ATP5F1B and EEF1D, showed similar responses in both the in vitro and in vivo data. This suggests that the in vitro outcomes could link to clinical phenomena in proteomic analysis.

Scaffolds and Extracellular Vesicles as a Promising Approach for Cardiac Regeneration after Myocardial Infarction

Clinical studies have demonstrated the regenerative potential of stem cells for cardiac repair over the past decades, but their widespread use is limited by the poor tissue integration and survival obtained. Natural or synthetic hydrogels or microcarriers, used as cell carriers, contribute to resolving, in part, the problems encountered by providing mechanical support for the cells allowing cell retention, survival and tissue integration. Moreover, hydrogels alone also possess mechanical protective properties for the ischemic heart. The combined effect of growth factors with cells and an appropriate scaffold allow a therapeutic effect on myocardial repair. Despite this, the effects obtained with cell therapy remain limited and seem to be equivalent to the effects obtained with extracellular vesicles, key actors in intercellular communication. Extracellular vesicles have cardioprotective effects which, when combined proangiogenic properties with antiapoptotic and anti-inflammatory actions, make it possible to act on all the damages caused by ischemia. The evolution of biomaterial engineering allows us to envisage their association with new major players in cardiac therapy, extracellular vesicles, in order to limit undesirable effects and to envisage a transfer to the clinic. This new therapeutic approach could be associated with the release of growth factors to potentialized the beneficial effect obtained.

Abstract 12952: Global Longitudinal Strain is Simple, Effective & Sensitive Assessment of Cardiac Chamber Function in Patients With Acute-phase Myocarditis

Introduction: Myocarditis is an inflammatory disease process with growing clinical relevance in the current COVID-19 pandemic. Acute-phase myocarditis is known to result in subclinical changes in left ventricular (LV) function despite normal LV ejection fraction (LVEF), as assessed by myocardial deformation indices. The presence of right ventricular (RV) and left atrial (LA) subclinical dysfunction however has not been well described in current literature. Hypothesis: Myocarditis patients have subclinical impairment of LV, RV and LA function as assessed by global longitudinal strain (GLS) on speckle tracking echocardiography. Methods: Consecutive patients with clinical diagnosis of myocarditis admitted to our institution during 2013-2018 were assessed (n=76). Patients who did not meet appropriate diagnostic criteria (n=14), had impaired LVEF or prior cardiac disease (n=8) or poor transthoracic echocardiogram images (n=14) were excluded from analysis. Clinical and echocardiographic parameters were compared to age- , gender- and risk factor- matched controls. GLS was performed by two independent observers using vendor independent software (TomTec Arena, Germany v4.6). Results: The final cohort consisted 40 patients with myocarditis (age 44.3±16.7, 60% male) and 40 matched controls (44.5±16.6, 60% male). No significant differences in baseline clinical characteristics were observed between groups. No differences in LVEF, indexed LV mass, RV fractional area change, indexed LA volume or TR pressure gradient (p>0.05 for all) were demonstrated between the two groups. Patients with myocarditis had a lower mean LV strain (GLS%: -16.4±2.9 vs -19.7±2.7, p=0.0001), a lower mean RV Free Wall Strain (FWS) (GLS%: -22.1±4.1 vs -26.2±6.9, p=0.03) and a lower mean LA reservoir strain (GLS%: 27.5±4.6 vs. 33.7±6.3, p<0.0001) when compared to controls. Conclusions: Our results demonstrate the presence of significant subclinical global myocardial dysfunction despite normal traditional echocardiographic indices, in patients with acute-phase myocarditis. Routine assessment of GLS may identify such patients for early targeted cardiac therapy.

Modified mRNA as a Therapeutic Tool for the Heart

Despite various clinical modalities available for patients, heart disease remains among the leading causes of mortality and morbidity worldwide. Genetic medicine, particularly mRNA, has broad potential as a therapeutic. More specifically, mRNA-based protein delivery has been used in the fields of cancer and vaccination, but recent changes to the structural composition of mRNA have led the scientific community to swiftly embrace it as a new drug to deliver missing genes to injured myocardium and many other organs. Modified mRNA (modRNA)–based gene delivery features transient but potent protein translation and low immunogenicity, with minimal risk of insertional mutagenesis. In this review, we compared and listed the advantages of modRNA over traditional vectors for cardiac therapy, with particular focus on using modRNA therapy in cardiac repair. We present a comprehensive overview of modRNA’s role in cardiomyocyte (CM) proliferation, cardiac vascularization, and prevention of cardiac apoptosis. We also emphasize recent advances in modRNA delivery strategies and discuss the challenges for its clinical translation.

Drug-Induced Melanoma: Irbesartan Induced Cutaneous Melanoma! First Description in the World Literature!

BACKGROUND: Melanoma appears to be a malignant disease, whose development can be potentiated by different drug groups. More and more data are in favour of the claim that commonly used antihypertensive drugs also contain the risk of developing melanoma. The most evidence is that angiotensin receptor blockers may be carcinogenic. Two representatives from this group, valsartan and irbesartan, produced by certain pharmaceutical companies are being withdrawn from the market due to finding content of NDMA and NDEA, which are believed to be potent carcinogens. Another representative of this group, losartan, according to in vitro data, potentiates cell adhesion and invasion of human melanoma cells. CASE REPORT: We present a 45-year-old man with arterial hypertension. For year and a half/two years, the patient is on systemic therapy with Aspirin and Irbesartan/Hydrochlorothiazide. The patient also reported about the presence of a pigmented lesion in the abdominal area, which occurred 5-6 years ago, before the onset of cardiac therapy. According to him, there was a change in the colour and size of the lesion within the framework of cardiac therapy (from 1.5-2 years). Innovative one step melanoma surgery was performed, and the lesion was radically removed with a 1 cm operational safety margin in all directions within one operative session. The subsequent histological verification found the presence of thin melanoma. CONCLUSION: Drug-induced melanoma turned out to be a problem of significant importance. The group of angiotensin receptor blockers should be investigated more thoroughly and in detail on the probability of potentiating carcinogenesis. We describe an interesting case showing the progression of pigment lesion to melanoma as a possible result of irbesartan therapy, i.e. we share a theory that differs from that of drug-induced de novo melanomas. It should not be overlooked the fact that another widely used drug-Aspirin, is also likely to potentiate the development of melanoma. Furthermore, the case is indicative of the use of one step melanoma surgery in a melanoma patient with a thickness less than 1 mm.