Oral supplementation of inositols effectively recovered lithium-induced cardiac dysfunctions in mice.

This study investigates the effects of inositol (INO) supplementation on cardiac changes caused by Li in mice. The study involved 4 groups of C57BL6 mice (n=10 each): (i) mice orally administered with Li2CO3 for 8 weeks, then 4 additional weeks without (Li_group) or (ii) with INO supplementation (Li_INOdelayed_group) (total of 12 weeks); (iii) mice given Li2CO3 and INO supplementation concurrently for 12 weeks (Li+INO_group); (iv) one group left untreated (C-group). The INO was administered as a mixture of myo-inositol and d-chiro-inositol (80:1) in drinking water. The mice were characterised for heart morphology, function, electrical activity, arrhythmogenic susceptibility, and multiorgan histopathology (heart, liver and kidney). Cardiomyocyte size, protein expression of key signalling pathways related to hypertrophy, and transcription levels of ion channel subunits and hypertrophy markers were evaluated in the ventricle tissue. The study found that INO supplementation reduced the Li-induced cardiac adverse effects, including systolic impairment and increased susceptibility to arrhythmias. The positive effect on arrhythmias might be attributed to the restored expression levels of the potassium channel subunit Kv 1.5. Additionally, INO improved cardiomyocyte hypertrophy, possibly by inhibiting the Li-induced activation of the ERK1/2 signalling pathway and by restoring the normal expression level of BNP, and alleviated injury in the liver and kidney. The effect was preventive if INO supplementation was taken concurrently with Li and therapeutic if INO was administered after Li-induced cardiac impairments were established. These results provide new insights into the cardioprotective effect of INO and suggest a potential treatment approach for Li-induced cardiac disease.

The Protective Effect of Flavonoids in the Diet on Autophagy-Related Cardiac Impairment.

The compounds known as flavonoids, commonly found in fruits, vegetables, legumes, medicinal herbs, chocolate, and coffee and tea beverages, have been extensively researched for their impact on cardiovascular health. Flavonoids, with their demonstrated potential, have shown promising effects in regulating blood vessel function and apoptotic processes, as well as in improving lipid profiles. While their powerful antioxidant properties were initially thought to be the main reason behind these effects, recent studies have uncovered new insights into the positive effects of flavonoids on cardiovascular health, and researchers have now identified several signaling pathways and mechanisms that also play a role. Of particular interest are the studies that have highlighted the role of autophagy in maintaining the physiological functions of cardiomyocytes and protecting them from harm. Recent publications have linked the dysregulation of autophagic processes with the development of cardiomyopathies, heart failure, and other cardiovascular diseases. This review aims to present the latest, novel findings from preclinical research regarding the potential beneficial effects of flavonoids on various heart conditions associated with altered autophagy processes.

Lithium Treatment Induces Cardiac Dysfunction in Mice.

Lithium (Li) salts are commonly used as medications for bipolar disorders. In addition to its therapeutic value, Li is also being increasingly used as a battery component in modern electronic devices. Concerns about its toxicity and negative impact on the heart have recently been raised. We investigated the effects of long-term Li treatment on the heart, liver, and kidney in mice. Sixteen C57BL/6J mice were randomly assigned to receive oral administration of Li carbonate (n = 8) or act as a control group (n = 8) for 12 weeks. We evaluated the cardiac electrical activity, morphology and function, and pathways contributing to remodelling. We assessed the multi-organ toxicity using histopathology techniques in the heart, liver, and kidney. Our findings suggest that mice receiving Li had impaired systolic function and ventricular repolarisation and were more susceptible to arrhythmias under adrenergic stimulation. The Li treatment caused an increase in the cardiomyocytes' size, the modulation of the extracellular signal-regulated kinase (ERK) pathway, along with some minor tissue damage. Our findings revealed a cardiotoxic effect of Li at therapeutic dosage, along with some histopathological alterations in the liver and kidney. In addition, our study suggests that our model could be used to test potential treatments for Li-induced cardiotoxicity.

Applications of Deep Learning Algorithms to Ultrasound Imaging Analysis in Preclinical Studies on In Vivo Animals.

BACKGROUND AND AIM: Ultrasound (US) imaging is increasingly preferred over other more invasive modalities in preclinical studies using animal models. However, this technique has some limitations, mainly related to operator dependence. To overcome some of the current drawbacks, sophisticated data processing models are proposed, in particular artificial intelligence models based on deep learning (DL) networks. This systematic review aims to overview the application of DL algorithms in assisting US analysis of images acquired in in vivo preclinical studies on animal models. METHODS: A literature search was conducted using the Scopus and PubMed databases. Studies published from January 2012 to November 2022 that developed DL models on US images acquired in preclinical/animal experimental scenarios were eligible for inclusion. This review was conducted according to PRISMA guidelines. RESULTS: Fifty-six studies were enrolled and classified into five groups based on the anatomical district in which the DL models were used. Sixteen studies focused on the cardiovascular system and fourteen on the abdominal organs. Five studies applied DL networks to images of the musculoskeletal system and eight investigations involved the brain. Thirteen papers, grouped under a miscellaneous category, proposed heterogeneous applications adopting DL systems. Our analysis also highlighted that murine models were the most common animals used in in vivo studies applying DL to US imaging. CONCLUSION: DL techniques show great potential in terms of US images acquired in preclinical studies using animal models. However, in this scenario, these techniques are still in their early stages, and there is room for improvement, such as sample sizes, data preprocessing, and model interpretability.

Clinical management of drug-induced cardiotoxicity in patients with HER-2+ breast cancer: current recommendations and future outlook.

INTRODUCTION: Human epidermal growth factor receptor two (HER2) target therapies have drastically revolutionized the treatment of HER2-positive breast cancer. Starting with trastuzumab, early phase III trials have already highlighted its significant cardiotoxicity, which is also present, albeit to a lesser extent, in the new generation drugs. Also given the growing population of patients with cardiovascular diseases, it is vital to set up proper long-term follow-up to prevent morbidity related to the development of cardiotoxicity. AREAS COVERED: This review discusses the mechanisms of action underlying the cardiotoxicity of HER2 targeted therapies and the main clinical evidence on the toxicity of these drugs. In addition, the patterns of patient assessment prior to the initiation of therapy with HER2 targeted therapies are discussed, as well as the main evidence concerning the follow-up and management of cardiotoxicity. EXPERT OPINION: The mechanisms of cardiotoxicity of new HER2 drugs need further study and, likewise, methods to prevent, monitor and identify HER-2-induced cardiotoxicity need to be implemented. Although some studies highlight the validity of cardiac biomarkers as predictive factors for cardiotoxicity, their actual usefulness and timing is still debated. Further studies are needed to assess the effectiveness of possible pharmacological primary prevention.

Bidirectional Relationship Between Cancer and Heart Failure: Insights on Circulating Biomarkers.

Cancer and heart failure are the two leading causes of death in developed countries. These two apparently distinct clinical entities share similar risk factors, symptoms, and pathophysiological mechanisms (inflammation, metabolic disturbances, neuro-hormonal and immune system activation, and endothelial dysfunction). Beyond the well-known cardiotoxic effects of oncological therapies, cancer and heart failure are thought to be tied by a bidirectional relationship, where one disease favors the other and vice versa. In this context, biomarkers represent a simple, reproducible, sensitive and cost-effective method to explore such relationship. In this review, we recapitulate the evidence on cardiovascular and oncological biomarkers in the field of cardioncology, focusing on their role in treatment-naïve cancer patients. Cardioncological biomarkers are useful tools in risk stratification, early detection of cardiotoxicity, follow-up, and prognostic assessment. Intriguingly, these biomarkers might contribute to better understand the common pathophysiology of cancer and heart failure, thus allowing the implementation of preventive and treatment strategies in cardioncological patients.

In Vivo Murine Models of Cardiotoxicity Due to Anticancer Drugs: Challenges and Opportunities for Clinical Translation.

Modern therapeutic approaches have led to an improvement in the chances of surviving a diagnosis of cancer. However, this may come with side effects, with patients experiencing adverse cardiovascular events or exacerbation of underlying cardiovascular disease related to their cancer treatment. Rodent models of chemotherapy-induced cardiotoxicity are useful to define pathophysiological mechanisms of cardiac damage and to identify potential therapeutic targets. The key mechanisms involved in cardiotoxicity induced by specific different antineoplastic agents are summarized in this state-of-the-art review, as well as the rodent models of cardiotoxicity by different classes of anticancer drugs, along with the strategies tested for primary and secondary cardioprotection. Current approaches for early detection of cardiotoxicity in preclinical studies with a focus on the application of advanced imaging modalities and biomarker strategies are also discussed. Potential applications of cardiotoxicity modelling in rodents are illustrated in relation to the advancements of promising research topics of cardiotoxicity. Created with BioRender.com.

Myo-inositol and d-chiro-inositol oral supplementation ameliorate cardiac dysfunction and remodeling in a mouse model of diet-induced obesity.

Obesity is an independent risk factor to develop cardiac functional and structural impairments. Here, we investigated the effects of supplementation of inositols on the electrical, structural, and functional cardiac alterations in the mouse model of high fat diet (HFD) induced obesity. Three groups of C57BL6 mice (n = 16 each) were studied: j) HFD feeding; jj) HFD feeding + inositols from week 9 to 13; jjj) standard diet feeding. Study observation period was 13 weeks. Inositols were administered as mixture of myo-inositol and d-chiro-inositol in the drinking water. Effects of inositols were evaluated based on electrical, structural, and functional cardiac features, autonomic sympatho-vagal balance and arrhythmogenic susceptibility to adrenergic challenge. Heart samples were collected for histological evaluations and transcriptional analyses of genes involved in defining the shape and propagation of the action potential, fatty acid metabolism and oxidative stress. Inositol supplementation significantly restored control values of heart rate and QTc interval on ECG and of sympatho-vagal balance. Moreover, it blunted the increase in left ventricular mass and cardiomyocyte hypertrophy, reversed diastolic dysfunction, reduced the susceptibility to arrhythmic events and restored the expression level of cardiac genes altered by HFD. The present study shows, for the first time, how a short period of supplementation with inositols is able to ameliorate the HFD-induced electrical, structural and functional heart alterations including ventricular remodeling. Results provide a new insight into the cardioprotective effect of inositols, which could pave the way for a novel therapeutic approach to the treatment of HFD obesity-induced heart dysfunction.

The role of metabolic diseases in cardiotoxicity associated with cancer therapy: What we know, what we would know.

Metabolic diseases, such as obesity and type 2 diabetes, are known risk factors for cardiovascular (CV) diseases. Thus, patients with those comorbidities could be at increased risk of experiencing cardiotoxicity related to treatment with Anthracyclines and the other new generation targeted anticancer drugs. However, investigations addressing the mechanisms underlying the development of CV complications and poor outcome in such cohort of patients are still few and controversial. Given the importance of a personalized approach against chemotherapy-induced cardiomyopathy, this review summarizes our current knowledge on the pathophysiology of chemotherapy-induced cardiomyopathy and its association with obesity and type 2 diabetes. Along with clinical evidences, future perspectives of preclinical research around this field and its role in addressing important open questions, including the development of more proactive strategies for prevention, and treatment of cardiotoxicity during and after chemotherapy in the presence of metabolic diseases, is also presented.

Murine model of left ventricular diastolic dysfunction and electro-mechanical uncoupling following high-fat diet.

BACKGROUND/OBJECTIVES: It is well established that obesity is an independent risk factor for cardiac death. In particular various cardiac alterations have been described in obese patients such as long QT on ECG, impaired diastolic filling of the left ventricle (LV), and all-type arrhythmias. In the present study, the above alterations were all reproduced in a mouse model of fat diet-induced obesity. ANIMALS/METHODS: In C57BL6 mice fed on a high fat (n = 20, HF-group) or standard diet (n = 20, C-group) for 13 weeks, balanced by sex and age, we examined heart morphology and function by high-frequency ultrasounds and electric activity by surface ECG. Besides, the autonomic sympathovagal balance (heart-rate variability) and the arrhythmogenic susceptibility to adrenergic challenge (i.p. isoproterenol) were compared in the two groups, as well as glucose tolerance (i.p. glucose test) and liver steatosis (ultrasounds). RESULTS: Body weight in HF-group exceeded C-group at the end of the experiment (+28% p < 0.01). An abnormal ventricular repolarization (long QTc on ECG) together with impaired LV filling rate and increased LV mass was found in HF-group as compared to C. Moreover, HF-group showed higher heart rate, unbalanced autonomic control with adrenergic prevalence and a greater susceptibility to develop rhythm disturbances under adrenergic challenge (i.p. isoprenaline). Impaired glucose tolerance and higher liver fat accumulation were also found in HF mice compared to C. CONCLUSIONS: The described murine model of 13 weeks on HF diet, well reproduced the cardiovascular and metabolic disorders reported in clinical obesity, suggesting its potential utility as translational mean suitable for testing new pharmaco-therapeutic approaches to the treatment of obesity and its comorbidity.