Obesity, particularly visceral adiposity, has been linked to mitochondrial dysfunction and increased oxidative stress, which have been suggested as mechanisms of insulin resistance. The mechanism(s) behind this remains incompletely understood. In this study, we hypothesized that mitochondrial complex II dysfunction plays a role in impaired insulin sensitivity in visceral adipose tissue of subjects with obesity. We obtained subcutaneous and visceral adipose tissue biopsies from 43 subjects with obesity (body mass index ≥ 30 kg/m²) during planned bariatric surgery. Compared with subcutaneous adipose tissue, visceral adipose tissue exhibited decreased complex II activity, which was restored with the reducing agent dithiothreitol (5 mM) ( P < 0.01). A biotin switch assay identified that cysteine oxidative posttranslational modifications (OPTM) in complex II subunit A (succinate dehydrogenase A) were increased in visceral vs. subcutaneous fat ( P < 0.05). Insulin treatment (100 nM) stimulated complex II activity in subcutaneous fat ( P < 0.05). In contrast, insulin treatment of visceral fat led to a decrease in complex II activity ( P < 0.01), which was restored with addition of the mitochondria-specific oxidant scavenger mito-TEMPO (10 µM). In a cohort of 10 subjects with severe obesity, surgical weight loss decreased OPTM and restored complex II activity, exclusively in the visceral depot. Mitochondrial complex II may be an unrecognized and novel mediator of insulin resistance associated with visceral adiposity. The activity of complex II is improved by weight loss, which may contribute to metabolic improvements associated with bariatric surgery.

Increased cancer survivorship represents a remarkable achievement for modern medicine. Unfortunately, cancer treatments have inadvertently contributed to cardiovascular (CV) damage, significantly threatening the health and quality of life of patients living with, through and beyond cancer. Without understanding the mechanisms, including whether the cardiotoxicity is due to the direct or indirect effects on cardiomyocytes, prevention and management of cardiotoxicity can pose challenges in many patients. To date, the cardiotoxicity profiles of most of the chemotherapy drugs are still poorly understood. To conduct a pilot study to investigate the direct effects of a range of cancer therapies on cardiomyocyte viability. Primary human cardiomyocytes (HCM) were cultured and seeded into 96-well culture plates. A total of 35 different Food and Drug Administration-approved anti-cancer drugs were added to the HCM cells with a concentration of 1uM for 72 hours. The viability of HCMs was determined using CellTitre-Glo. The experiments were repeated at least three times for each drug with HCMs of different passages. We identified 15 anti-cancer agents that significantly reduced HCM viability. These drugs were: (1) anthracyclines (daunorubicin [HCM viability, mean %±standard error, 13.7±3.2%], epirubicin [47.6±5.3%]), (2) antimetabolite (azacitidine [67.1±2.4%]), (3) taxanes (paclitaxel [60.2±3.0%]), (4) protein kinase inhibitors (lapatinib [49.8±7.0%], ponatinib [42.4±9.0%], pemigatinib [68.1±2.3%], sorafenib [52.9±10.6%], nilotinib [64.4±4.5%], dasatinib [38.5±3.6%]), (5) proteasome inhibitors (ixazomib citrate [65.4±7.2%]), (6) non-selective histone-deacetylase inhibitor (panobinostat [19.1±4.1%]), poly adenosine diphosphate-ribose polymerase inhibitor (olaparib [68.2±1.7%]) and (7) vinca alkaloids (vincristine [44.6±7.4%], vinblastine [31.2±3.9%]). In total, 15 of the 35 commercially available anti-cancer drugs have direct cardiotoxic effects on HCM. Some of those, have not been associated with clinical cardiotoxicity, while others, known to be cardiotoxic do not appear to mediate it via direct effects on cardiomyocytes. More detailed investigations of the effects of cancer therapies on various cardiovascular cells should be performed to comprehensively determine the mechanisms of cardiotoxicity.

Background: Bevacizumab, a vascular endothelial growth factor (VEGF) monoclonal antibody commonly used for the treatment of various cancers, is often associated with adverse cardiovascular effects such as hypertension, cardiac and cerebral ischemia, thrombosis, and bleeding events. Factors associated with increased risks of adverse cardiovascular effects with bevacizumab have not been intensively studied. In this study, we determined factors associated with hospital admissions due to cardiovascular complications in patients who received bevacizumab for cancer treatment. Methods and Results: We retrospectively collected data for all patients treated with bevacizumab between the 1st January 2016 and the 31st December 2017 at the Hunter New England Local Health District. Patients’ characteristics and their medical history were obtained from hospital electronic medical records. Outcome data were sourced from the Institutional Cardiac and Stroke Outcomes Unit database. A total of n = 230 patients (mean age 65, males n = 124 (53.9%)) were treated with bevacizumab during the study period. N = 28 patients were admitted to hospital for a major cardiovascular-related event. Higher total treatment dose (p < 0.05), concomitant hypertension (p = 0.005), diabetes (p = 0.04), atrial fibrillation (p = 0.03), and lack of use of statin therapy (p = 0.03) were key contributors to hospital admission. Conclusions: Results of our study highlight the fact that patients with concomitant baseline cardiovascular disease/risk factors are at an increased risk of cardiovascular hospitalization related to bevacizumab treatment. Careful baseline cardiovascular assessment may be an essential step to minimize cardiovascular complications.

Purpose of Review: This study is aimed at reviewing the recent progress in Drp1 inhibition as a novel approach for reducing doxorubicin-induced cardiotoxicity and for improving cancer treatment. Recent Findings: Anthracyclines (e.g. doxorubicin) are one of the most common and effective chemotherapeutic agents to treat a variety of cancers. However, the clinical usage of doxorubicin has been hampered by its severe cardiotoxic side effects leading to heart failure. Mitochondrial dysfunction is one of the major aetiologies of doxorubicin-induced cardiotoxicity. The morphology of mitochondria is highly dynamic, governed by two opposing processes known as fusion and fission, collectively known as mitochondrial dynamics. An imbalance in mitochondrial dynamics is often reported in tumourigenesis which can lead to adaptive and acquired resistance to chemotherapy. Drp1 is a key mitochondrial fission regulator, and emerging evidence has demonstrated that Drp1-mediated mitochondrial fission is upregulated in both cancer cells to their survival advantage and injured heart tissue in the setting of doxorubicin-induced cardiotoxicity. Summary: Effective treatment to prevent and mitigate doxorubicin-induced cardiotoxicity is currently not available. Recent advances in cardio-oncology have highlighted that Drp1 inhibition holds great potential as a targeted mitochondrial therapy for doxorubicin-induced cardiotoxicity.

Cardiovascular disease and cancer are 2 of the leading causes of death worldwide. Although improvements in outcomes have been noted for both disease entities, the success of cancer therapies has come at the cost of at times very impactful adverse events such as cardiovascular events. Hypertension has been noted as both, a side effect as well as a risk factor for the cardiotoxicity of cancer therapies. Some of these dynamics are in keeping with the role of hypertension as a cardiovascular risk factor not only for heart failure, but also for the development of coronary and cerebrovascular disease, and kidney disease and its association with a higher morbidity and mortality overall. Other aspects such as the molecular mechanisms underlying the amplification of acute and long-term cardiotoxicity risk of anthracyclines and increase in blood pressure with various cancer therapeutics remain to be elucidated. In this review, we cover the latest clinical data regarding the risk of hypertension across a spectrum of novel anticancer therapies as well as the underlying known or postulated pathophysiological mechanisms. Furthermore, we review the acute and long-term implications for the amplification of the development of cardiotoxicity with drugs not commonly associated with hypertension such as anthracyclines. An outline of management strategies, including pharmacological and lifestyle interventions as well as models of care aimed to facilitate early detection and more timely management of hypertension in patients with cancer and survivors concludes this review, which overall aims to improve both cardiovascular and cancer-specific outcomes.