Cardiovascular Toxicity in Cancer Therapy: Protecting the Heart while Combating Cancer.

PURPOSE OF REVIEW: This review explores the cardiovascular toxicity associated with cancer therapies, emphasizing the significance of the growing field of cardio-oncology. It aims to elucidate the mechanisms of cardiotoxicity due to radiotherapy, chemotherapy, and targeted therapies, and to discuss the advancements in human induced pluripotent stem cell technology (hiPSC) for predictive disease modeling. RECENT FINDINGS: Recent studies have identified several chemotherapeutic agents, including anthracyclines and kinase inhibitors, that significantly increase cardiovascular risks. Advances in hiPSC technology have enabled the differentiation of these cells into cardiovascular lineages, facilitating more accurate modeling of drug-induced cardiotoxicity. Moreover, integrating hiPSCs into clinical trials holds promise for personalized cardiotoxicity assessments, potentially enhancing patient-specific therapeutic strategies. Cardio-oncology bridges oncology and cardiology to mitigate the cardiovascular side-effects of cancer treatments. Despite advancements in predictive models using hiPSCs, challenges persist in accurately replicating adult heart tissue and ensuring reproducibility. Ongoing research is essential for developing personalized therapies that balance effective cancer treatment with minimal cardiovascular harm.

Proinflammatory Effect of Endothelial Microparticles Is Mitochondria Mediated and Modulated Through MAPKAPK2 (MAPK-Activated Protein Kinase 2) Leading to Attenuation of Cardiac Hypertrophy.

Objective- This study investigates the functional significance of mitochondria present in endothelial microparticles (EMP) and how MK2 (MAPKAPK2 [MAPK-activated protein kinase 2]) governs EMP production and its physiological effect on cardiac hypertrophy. Approach and Results- Flow cytometric analysis, confocal imaging, oxygen consumption rate measurement through Seahorse were used to confirm the presence of functionally active mitochondria in nontreated EMP (EMP derived from untreated control cells), lipopolysaccharide, and oligomycin treatment increased mitochondrial reactive oxygen species activity in EMP (EMP derived from cells treated with lipopolysaccharide and EMP derived from cells treated with oligomycin, respectively). The dysfunctional mitochondria contained in EMP derived from cells treated with lipopolysaccharide and EMP derived from cells treated with oligomycin induced the expression of proinflammatory mediators in the target endothelial cells leading to the augmented adhesion of human monocytic cell line on EA.hy926 cells. Multiphoton real-time imaging detected the increased adherence of EMP derived from cells treated with oligomycin at the site of carotid artery injury as compared to EMP derived from untreated control cells. MK2 regulates EMP generation during inflammation by reducing E-selectin expression and regulating the cytoskeleton rearrangement through ROCK-2 (Rho-associated coiled-coil containing protein kinase 2) pathway. MK2-deficient EMP reduced the E-selectin and ICAM-1 (intracellular adhesion molecule-1) expression on target endothelial cells leading to reduced monocyte attachment and reduced cardiac hypertrophy in mice. Conclusions- MK2 promotes the proinflammatory effect of EMP mediated through dysfunctional mitochondria. MK2 modulates the inflammatory effect induced during cardiac hypertrophy through EMP.

Antihypertensive Drugs Aliskiren, Nebivolol, and Olmesartan Reduce Hypertension by Reducing Endothelial Microparticles and Regulating Angiogenesis.

The accelerated generation of endothelial microparticles (EMPs) and impaired angiogenesis are the markers of vascular pathology during various cardiovascular and inflammatory conditions including hypertension. Because studies comparing the effects of antihypertensive agents on these 2 parameters are limited, this study was designed to compare the effects of 3 antihypertensive agents: aliskiren, nebivolol, and olmesartan, on the EMP generation and angiogenesis. Changes in the hemodynamic parameters and serum EMP count were determined after 3 weeks of the drug treatments [aliskiren (30 mg/kg), nebivolol (10 mg/kg), or olmesartan (5 mg/kg) per orally] in L-NAME-induced rat model of hypertension. The 3 drugs prevented the rise in blood pressure and EMP count to a similar extent. Furthermore, nebivolol was found to possess more potent and concentration-dependent antiangiogenic activity compared with aliskiren, whereas olmesartan was devoid of such an effect. The EMPs generated by virtue of the respective drug treatments were found to be involved in mediating the antiangiogenic effect of nebivolol and aliskiren. In addition, olmesartan treatment also resulted in the increased eNOS expression. The results of this study show that the antihypertensive drugs, viz. aliskiren, nebivolol, and olmesartan, regulate the vascular health by their differential effects on the EMP generation and angiogenesis.

Generation of induced pluripotent stem cell line from a patient suffering from arterial calcification due to deficiency of CD73 (ACDC).

Arterial calcification due to deficiency of CD73 (ACDC) is an adult onset, rare genetic vascular disorder signified by calcium deposition in lower extremity arteries and joints of hands and feet. Mutations in NT5E gene has been shown to be responsible for the inactivation of enzyme CD73 causing calcium buildup. Here, we report a iPSC line generated from a patient showing signs of ACDC and carrying a missense mutation in NT5E (c.1126A→G,p.T376A) gene. This iPSC line shows normal morphology, pluripotency, karyotype, and capability to differentiate into three germ layers, making it useful for disease modeling and investigating pathological mechanisms of ACDC.

Generation of two iPSC lines from dilated cardiomyopathy patients with pathogenic variants in the SCN5A gene.

Dilated cardiomyopathy (DCM) is a disorder of cardiac ventricular dilation and contractile dysfunction that often progresses to heart failure. Multiple genes have been associated with DCM, including SCN5A which has been linked to 2 % of all DCM cases. Peripheral mononuclear blood cells from DCM patients with SCN5A variants (c.2440C>T and c.665G>A) were utilized to generate two human induced pluripotent stem cell (iPSC) lines. Both lines exhibited typical iPSC morphology, expressed pluripotency markers, normal karyotypes, and trilineage differentiation capabilities. These lines offer valuable resources for investigating the mechanism of SCN5A-associated DCM, facilitating studies of ion channel protein involvement in the disease.

Generation of two iPSC lines from vascular Ehlers-Danlos Syndrome (vEDS) patients carrying a missense mutation in COL3A1 gene.

Vascular Ehlers-Danlos Syndrome (vEDS) is an inherited connective tissue disorder caused by COL3A1 gene, mutations that encodes type III collagen, a crucial component of blood vessels. vEDS can be life-threatening as these patients can have severe internal bleeding due to arterial rupture. Here, we generated induced pluripotent stem cell (iPSC) lines from two vEDS patients carrying a missense mutation in the COL3A1 (c.226A > G, p.Asn76Asp) gene. These lines exhibited typical iPSC characteristics including morphology, expression of pluripotency markers, and could differentiate to all three germ layer. These iPSC lines can serve as valuable tools for elucidating the pathophysiology underlying vEDS.

Involvement of HIF1α/Reg protein in the regulation of HMGB3 in myocardial infarction.

AIMS: Myocardial ischemia and infarction are the number one cause of cardiovascular disease associated mortality. Cardiomyocyte death during ischemia leads to the loss of cardiac tissue and initiates a signaling cascade between the infarct zone and the area at risk of the myocardium. Here, we sought to determine the involvement of one of the damage-associated molecular patterns HMGB3 in myocardial ischemia and infarction. METHODS AND RESULTS: We used the left anterior descending coronary artery ligation model to study the involvement of HMGB3 in myocardial ischemia and infarction. Our results indicated the presence of HMGB3 at a low level under normal conditions, while myocardial injury caused a robust increase in HMGB3 levels in the heart. Further, intra-cardiac injection of mabHMGB3 had improved cardiac function at day 3 by downregulating HMGB3 levels. In contrast, injection of recombinant rat HMGB3 for 7 days during the adaptation phase of myocardial ischemia improved cardiac functional parameters by increasing regenerative protein family expression. Further, to mimic the disease condition, neonatal rat ventricle cardiomyocytes and fibroblasts were exposed to hypoxia; we observed a significant upregulation in the HMGB3, HIF1α, and Reg1α levels. Endothelial cells exposed to recombinant HMGB3 increased the tubule length. Further, the mitochondrial oxygen consumption rate was reduced with the acute induction of recombinant HMGB3 on cardiomyocytes and fibroblasts. CONCLUSION: HMGB3 plays a dual role during the progression of myocardial ischemia and infarction. Clinically, post-myocardial infarction HMGB3-induced sterile inflammation needs to be tightly controlled, as it plays both a pro-inflammatory role and improves cardiac function during the cardiac remodeling phase.

iPSC model of congenital heart disease predicts disease outcome.

In this issue of Cell Stem Cell, Xu et al. demonstrate that induced pluripotent stem cell-derived cardiomyocytes from patients with hypoplastic left heart syndrome exhibit mitochondrial dysfunction and can be used for disease modeling. In addition, they show the potential to predict future heart failure and develop therapies.