Aarif Y. Khakoo

Heart failure associated with sunitinib malate: a multitargeted receptor tyrosine kinase inhibitor.

Sunitinib malate is a novel multitargeted receptor tyrosine kinase inhibitor with established efficacy in the treatment of metastatic renal cell carcinoma and imatinib‐resistant gastrointestinal stromal tumor. This report describes the development of heart failure in cancer patients who received this novel agent.

Cardiomyocyte PDGFR-β signaling is an essential component of the mouse cardiac response to load-induced stress

PDGFR is an important target for novel anticancer therapeutics because it is overexpressed in a wide variety of malignancies. Recently, however, several anticancer drugs that inhibit PDGFR signaling have been associated with clinical heart failure. Understanding this effect of PDGFR inhibitors has been difficult because the role of PDGFR signaling in the heart remains largely unexplored. As described herein, we have found that PDGFR-beta expression and activation increase dramatically in the hearts of mice exposed to load-induced cardiac stress. In mice in which Pdgfrb was knocked out in the heart in development or in adulthood, exposure to load-induced stress resulted in cardiac dysfunction and heart failure. Mechanistically, we showed that cardiomyocyte PDGFR-beta signaling plays a vital role in stress-induced cardiac angiogenesis. Specifically, we demonstrated that cardiomyocyte PDGFR-beta was an essential upstream regulator of the stress-induced paracrine angiogenic capacity (the angiogenic potential) of cardiomyocytes. These results demonstrate that cardiomyocyte PDGFR-beta is a regulator of the compensatory cardiac response to pressure overload-induced stress. Furthermore, our findings may provide insights into the mechanism of cardiotoxicity due to anticancer PDGFR inhibitors.

Modulation of Anthracycline-Induced Cardiotoxicity by Aerobic Exercise in Breast Cancer Current Evidence and Underlying Mechanisms

Anthracycline-containing chemotherapy (eg, doxorubicin) is well known to cause dose-dependent, progressive cardiac damage clinically manifest as decreased left ventricular (LV) ejection fraction and, ultimately, heart failure (HF) (Table 1).1,2 Unfortunately, the only clinically accepted method to minimize injury is dose modification and/or therapy discontinuation.3 An important current challenge in breast cancer management is therefore to maximize the benefits of doxorubicin while minimizing cardiac damage. Identification and examination of new interventions to prevent and/or treat doxorubicin-induced cardiotoxicity are urgently required. View this table: Table 1. Stages of Doxorubicin-Induced Cardiotoxicity Aerobic exercise is a nonpharmacological therapy that promises to attenuate doxorubicin-induced cardiotoxicity. Aerobic exercise is well documented to improve systolic and diastolic function and attenuate pathological cardiac remodeling, resulting in improved exercise tolerance and resistance to fatigue during exertion in patients with HF.4,5 The cardioprotective properties of aerobic exercise in the context of doxorubicin have, in contrast, received scant attention. It is not generally used in cancer patients despite its lack of “side effects” and the paucity of alternative strategies to prevent/treat doxorubicin-associated cardiac damage. As a first step in the possible use of exercise in cancer patients, we reviewed the mechanisms of doxorubicin-induced cardiotoxicity and the available evidence supporting the utility of aerobic exercise to prevent/treat cardiac injury. We also explored the molecular mechanisms that may underlie the cardioprotective properties of aerobic exercise. These findings have implications for future research regarding the application and effectiveness of exercise and doxorubicin treatment in humans. The mechanisms underlying the antitumor function of anthracyclines have been described previously.6–8 Among the proposed mechanisms of cardiac injury, doxorubicin-induced generation of reactive oxygen species (ROS)9,10 is a central mediator of numerous direct and indirect cardiac adverse consequences (for review, see Minotti et al11). In the present report, we …

Coronary Microvascular Pericytes Are the Cellular Target of Sunitinib Malate–Induced Cardiotoxicity

Sunitinib-induced cardiotoxicity is caused by depletion of coronary pericytes due to loss of PDGFR signaling; this side effect can be prevented by thalidomide. Saving Pericytes to Prevent a Broken Heart In the world of targeted cancer therapies, sunitinib is a versatile one, targeting a variety of tyrosine kinase receptors. The breadth of its activity allows it to be effective in multiple different types of cancer but also increases the chances of unintended adverse effects. One such side effect is cardiotoxicity, with frequent reports of left ventricular dysfunction and heart failure in patients treated with sunitinib. Chintalgattu and co-workers have now uncovered the mechanism for this toxicity and demonstrated a way to protect the heart from treatment-induced damage in a mouse model. Pericytes are contractile cells that wrap around small blood vessels and are essential to their function. After sunitinib treatment, pericytes were no longer coating the coronary microvasculature in a mouse model. The blood vessels depleted of pericytes were unusually leaky, and the hearts of treated animals showed clear evidence of cardiac dysfunction. The depletion of pericytes was caused by the inhibition of signaling through platelet-derived growth factor receptor (PDGFR), a known target of sunitinib. The authors also discovered that thalidomide, a small-molecule drug that is already used in humans for the treatment of some cancers, could protect pericytes and prevent sunitinib-induced cardiotoxicity without affecting the antitumor effects of sunitinib. Future studies will be needed to uncover additional mechanism explaining why coronary pericytes in particular are so sensitive to inhibition of PDGFR and how thalidomide can protect these cells from toxicity. Eventually, this research could enable the creation of more specific targeted drugs that inhibit the kinases driving cancer cell proliferation without injuring pericytes and other healthy cells. In the meantime, the current findings of Chintalgattu et al. provide a rationale for testing the combination of thalidomide and sunitinib in human cancer patients to protect the patients’ hearts from injury while continuing to effectively target cancer cells. Sunitinib malate is a multitargeted receptor tyrosine kinase inhibitor used in the treatment of human malignancies. A substantial number of sunitinib-treated patients develop cardiac dysfunction, but the mechanism of sunitinib-induced cardiotoxicity is poorly understood. We show that mice treated with sunitinib develop cardiac and coronary microvascular dysfunction and exhibit an impaired cardiac response to stress. The physiological changes caused by treatment with sunitinib are accompanied by a substantial depletion of coronary microvascular pericytes. Pericytes are a cell type that is dependent on intact platelet-derived growth factor receptor (PDGFR) signaling but whose role in the heart is poorly defined. Sunitinib-induced pericyte depletion and coronary microvascular dysfunction are recapitulated by CP-673451, a structurally distinct PDGFR inhibitor, confirming the role of PDGFR in pericyte survival. Thalidomide, an anticancer agent that is known to exert beneficial effects on pericyte survival and function, prevents sunitinib-induced pericyte cell death in vitro and prevents sunitinib-induced cardiotoxicity in vivo in a mouse model. Our findings suggest that pericytes are the primary cellular target of sunitinib-induced cardiotoxicity and reveal the pericyte as a cell type of concern in the regulation of coronary microvascular function. Furthermore, our data provide preliminary evidence that thalidomide may prevent cardiotoxicity in sunitinib-treated cancer patients.

Does the Renin-Angiotensin System Participate in Regulation of Human Vasculogenesis and Angiogenesis?

Several lines of evidence suggest that hypertension and angiogenesis may be related phenomena but a functional link remains elusive. Here, we propose that the renin-angiotensin system (RAS), in addition to its central role in arterial hypertension, also regulates blood vessel formation during normal development and cancer. This mechanistic hypothesis is based on reports of biochemical, genetic, clinical, and epidemiologic data reviewed herein. Species differences between the RAS of rodents and humans likely account for why such a fundamental role in angiogenesis went unrecognized for so long. If proven correct, this hypothesis carries many implications for the medical practices of cardiology, oncology, and neonatology.

Human mesenchymal stem cells inhibit vascular permeability by modulating vascular endothelial cadherin/β-catenin signaling.

The barrier formed by endothelial cells (ECs) plays an important role in tissue homeostasis by restricting passage of circulating molecules and inflammatory cells. Disruption of the endothelial barrier in pathologic conditions often leads to uncontrolled inflammation and tissue damage. An important component of this barrier is adherens junctions, which restrict paracellular permeability. The transmembrane protein vascular endothelial (VE)-cadherin and its cytoplasmic binding partner β-catenin are major components of functional adherens junctions. We show that mesenchymal stem cells (MSCs) significantly reduce endothelial permeability in cocultured human umbilical vascular endothelial cells (HUVECs) and following exposure to vascular endothelial growth factor, a potent barrier permeability-enhancing agent. When grown in cocultures with HUVECs, MSCs increased VE-cadherin levels and enhanced recruitment of both VE-cadherin and β-catenin to the plasma membrane. Enhanced membrane localization of β-catenin was associated with a decrease in β-catenin-driven gene transcription. Disruption of the VE-cadherin/β-catenin interaction by overexpressing a truncated VE-cadherin lacking the β-catenin interacting domain blocked the permeability-stabilizing effect of MSCs. Interestingly, a conditioned medium from HUVEC-MSC cocultures, but not from HUVEC or MSC cells cultured alone, significantly reduced endothelial permeability. In addition, intravenous administration of MSCs to brain-injured rodents reduced injury-induced enhanced blood-brain barrier permeability. Similar to the effect on in vitro cultures, this stabilizing effect on blood-brain barrier function was associated with increased expression of VE-cadherin. Taken together, these results identify a putative mechanism by which MSCs can modulate vascular EC permeability. Further, our results suggest that the mediator(s) of these vascular protective effects is a secreted factor(s) released as a result of direct MSC-EC interaction.

Therapy Insight: Management of cardiovascular disease in patients with cancer and cardiac complications of cancer therapy

Cardiac disease in patients with cancer or caused by cancer therapy is a clinical problem of emerging importance. Optimum management of cardiovascular disease can mean that patients with cancer can successfully receive therapies to treat their malignancy and can reduce morbidity and mortality due to cardiovascular disease in cancer survivors. The presence of cancer and cancer-related morbidities substantially complicates the management of cardiovascular disease in cancer patients. In this Review, we discuss management strategies for cardiovascular disease in patients with cancer, focusing on the prevention and treatment of congestive heart failure and myocardial infarction.

Rare incidence of congestive heart failure in gastrointestinal stromal tumor and other sarcoma patients receiving imatinib mesylate.

The authors sought to determine the incidence and severity of cardiovascular toxicity caused by imatinib mesylate in gastrointestinal stromal tumor (GIST) and other sarcoma patients, and to explore cardiotoxicity caused by imatinib mesylate using cell culture and in vitro models.

Local Hydrogel Release of Recombinant TIMP-3 Attenuates Adverse Left Ventricular Remodeling After Experimental Myocardial Infarction

Delivery of a hydrogel providing sustained release of recombinant TIMP-3 attenuated adverse ventricular remodeling after myocardial infarction in pigs. Hydrogel-Inhibitor Combo Stops Heart Damage After a heart attack, or myocardial infarction (MI), the heart tries to repair itself. This natural process is well intentioned but results in infarct expansion, scar formation, and, in turn, reduced heart function. To prevent such adverse remodeling, Eckhouse and colleagues designed an injectable hydrogel that inhibits the activity of enzymes directly involved in tissue repair. Matrix metalloproteinases (MMPs) are enzymes that are activated in heart tissue after MI. The authors encapsulated TIMP-3 (tissue inhibitor of metalloproteinase 3) in hyaluronic acid hydrogels. The gel/TIMP-3 combo or a control gel without the inhibitor was injected into the hearts of pigs after a heart attack. Weeks later, heart function, inflammation, and remodeling were evaluated. Animals administered the hydrogel with TIMP-3 had improved heart function [as determined by the left ventricular ejection fraction (LVEF)], improved LV geometry, and reduced infarct size. This local delivery mechanism could be used in the context of surgery, such as during coronary revascularization after a heart attack. Because it has been tested in pigs—which have similar heart anatomy to humans—and because other hydrogels, like alginate, have been tested in the human heart before, it is possible that this gel-inhibitor combination therapy could advance to clinical trials in the near future. An imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) contributes to the left ventricle (LV) remodeling that occurs after myocardial infarction (MI). However, translation of these observations into a clinically relevant, therapeutic strategy remains to be established. The present study investigated targeted TIMP augmentation through regional injection of a degradable hyaluronic acid hydrogel containing recombinant TIMP-3 (rTIMP-3) in a large animal model. MI was induced in pigs by coronary ligation. Animals were then randomized to receive targeted hydrogel/rTIMP-3, hydrogel alone, or saline injection and followed for 14 days. Instrumented pigs with no MI induction served as referent controls. Multimodal imaging (fluoroscopy/echocardiography/magnetic resonance imaging) revealed that LV ejection fraction was improved, LV dilation was reduced, and MI expansion was attenuated in the animals treated with rTIMP-3 compared to all other controls. A marked reduction in proinflammatory cytokines and increased smooth muscle actin content indicative of myofibroblast proliferation occurred in the MI region with hydrogel/rTIMP-3 injections. These results provide the first proof of concept that regional sustained delivery of an MMP inhibitor can effectively interrupt adverse post-MI remodeling.

Mesenchymal Stem Cells Regulate Blood-Brain Barrier Integrity Through TIMP3 Release After Traumatic Brain Injury

The matrix metalloproteinase inhibitor TIMP3 mediates the beneficial effects of mesenchymal stem cells on the blood-brain barrier of the injured mouse brain. Mesenchymal Stem Cells Spill Their Secrets Traumatic brain injury (TBI) is the leading cause of death and disability in children and young adults worldwide and is considered a “silent epidemic” in the United States in both civilian and military populations. Pathological cerebral edema and blood-brain barrier (BBB) permeability are the leading causes of death acutely after TBI with very few therapeutic options. It has been established in animal models that intravenously administered adult bone marrow–derived mesenchymal stem cells (MSCs) are able to ameliorate BBB permeability in mice after TBI. In new work, Menge et al. identify the mechanism responsible for this beneficial effect and identify the mediator as a soluble factor produced by MSCs called TIMP3. In a mouse model of TBI, Menge et al. show that down-regulation of TIMP3 expression in intravenously administered human MSCs abrogates their protective effects on the BBB and endothelial cell stability after TBI. Furthermore, the authors demonstrate that administering intravenous recombinant human TIMP3 alone to mice after TBI can fully recapitulate the protective effects of MSCs on vascular stability and BBB integrity, indicating that TIMP3 may be a key factor regulating integrity of the BBB. Although much more work needs to be done, TIMP3 could be a useful cell-free therapeutic for treating the breakdown of BBB integrity and cerebral edema that occurs after TBI. Mesenchymal stem cells (MSCs) may be useful for treating a variety of disease states associated with vascular instability including traumatic brain injury (TBI). A soluble factor, tissue inhibitor of matrix metalloproteinase-3 (TIMP3), produced by MSCs is shown to recapitulate the beneficial effects of MSCs on endothelial function and to ameliorate the effects of a compromised blood-brain barrier (BBB) due to TBI. Intravenous administration of recombinant TIMP3 inhibited BBB permeability caused by TBI, whereas attenuation of TIMP3 expression in intravenously administered MSCs blocked the beneficial effects of the MSCs on BBB permeability and stability. MSCs increased circulating concentrations of soluble TIMP3, which blocked vascular endothelial growth factor-A–induced breakdown of endothelial cell adherens junctions in vitro and in vivo. These findings elucidate a potential molecular mechanism for the beneficial effects of MSCs on the BBB after TBI and demonstrate a role for TIMP3 in the regulation of BBB integrity.