Cancer treatments can have significant cardiovascular adverse effects that can cause cardiomyopathy and heart failure with reduced survival benefit and considerable decrease in the use of antineoplastic therapy. The purpose of this study is to assess the role of TLR2 and TLR4 gene expression as an early marker for the risk of doxorubicin-induced cardiomyopathy in correlation with early diastolic dysfunction in patients treated with doxorubicin. Our study included 25 consecutive patients who received treatment with doxorubicin for hematological malignancies (leukemia, lymphomas or multiple myeloma), aged 18-65 years, with a survival probability>6 months and with left ventricular ejection fraction>50%. Exclusion criteria consisted of the following: previous anthracycline therapy, previous radiotherapy, history of heart failure or chronic renal failure, atrial fibrillation, and pregnancy. In all patients, in fasting state, a blood sample was drawn for the assessment of TLR2 and TLR4 gene expression. Gene expression was assessed by quantitative reverse transcription PCR (qRT-PCR) using blood collection, RNA isolation, cDNA reverse transcription, qRT-PCR and quantification of the relative expression. At enrollment, all patients were evaluated clinically; an ECG and an echocardiography were performed. The average amount of gene expression units was 0.113 for TLR4 (range 0.059-0.753) and 0.218 for TLR2 (range 0.046-0.269). The mean mRNA extracted quantity was 113 571 ng/μl. As for the diastolic function parameters, criteria for diastolic dysfunction were present after 6 months in 16 patients (64%). In these patients, the mean values for TLR4 were 0.1198625 and for TLR2 were 0.16454 gene expression units. As for the diastolic function parameters, criteria for diastolic dysfunction were present after 6 months in 16 patients (64%). In these patients, the mean value for TLR2 was 0.30±0.19 and for TLR4 was 0.15±0.04. The corresponding values for the patients who did not develop diastolic dysfunction were 0.16±0.07 for TLR2 (P=0.01) and 0.11±0.10 for TLR4 (P=0.2). Our study suggests that TLR4 and TLR2 expression is higher in patients under doxorubicin therapy who develop diastolic dysfunction. This may suggest a predisposition to myocardial involvement, a higher sensitivity to doxorubicin cardiac effects.

Current data indicate the existence of post-acute COVID-19 syndrome frequently expressing as cardiovascular and respiratory health issues. The long-term evolution of these complications is not yet fully known or predictable. Among the most common clinical manifestations of post-acute COVID-19 syndrome are dyspnea, palpitations, and fatigue, in most cases being transient and without underlying any morphological or functional changes. A single-center retrospective observational study was performed on cases that had presented with new-onset cardiac symptoms post-COVID-19 infection. Records of three male patients without pre-existing chronic cardiovascular pathology who had presented for dyspnea, fatigue, and palpitations around four weeks post-COVID-19 acute phase were studied in detail. The three post-COVID-19 cases exhibited arrhythmic complications after completely healing from the acute phase of the infection. Palpitations, along with chest pain, and possible aggravation or appearance of dyspnea, with syncopal episodes, were found to be present. All the three cases were non-vaccinated against COVID-19 infection. Isolated case reports showing arrhythmic complications such as atrial fibrillation and ventricular tachycardia on a small number of patients with these complications indicate the need for arrhythmic evaluation of large groups of patients in the post-acute stage of the COVID-19 syndrome for a better understanding of the phenomenon and implicitly better care of these patients. It would also be useful to evaluate large groups of patients divided into vaccinated/non-vaccinated against COVID-19 categories to determine whether vaccination per se can provide protection in the occurrence of these types of complications.

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Because oxidative stress after administration of doxorubicin was identified as playing a central role in cardiac dysfunction, we hypothesized that the expression (or overexpression) of TLR2 and TLR4 contributes to the pathogenesis of doxorubicin-induced cardiac dysfunction. Toll-like receptors (TLRs) are members of the interleukin-1 receptor family (IL1) and are involved in the ability to react to the molecular trigger associated with pathogenic microorganisms. Recent studies have shown that TLR receptors are activated by endogenous signals, such as heat shock proteins and oxidative stress, which can contribute to congestive heart failure. Until recently, the best detection method for cardiotoxicity induced by anthracyclines was myocardial biopsy. Other early screening and early diagnosis methods (biomarkers-cardiac troponins and natriuretic peptide) have not yet proven their efficacy. Our proposed method is a new, revolutionary one that does not imply any kind of physical (and psychic) aggression on the patient: the targeted genetic (TLR2/TLR4) analysis of the human peripheral blood (which is a minimally invasive procedure).

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