274 research outputs found
Cardiotoxicity with vascular endothelial growth factor inhibitor therapy
Angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signaling pathway (VSP) have been important additions in the therapy of various cancers, especially renal cell carcinoma and colorectal cancer. Bevazicumab, the first VSP to receive FDA approval in 2004 targeting all circulating isoforms of VEGF-A, has become one of the best-selling drugs of all times. The second wave of tyrosine kinase inhibitors (TKIs), which target the intracellular site of VEGF receptor kinases, began with the approval of sorafenib in 2005 and sunitinib in 2006. Heart failure was subsequently noted, in 2–4% of patients on bevacizumab and in 3–8% of patients on VSP-TKIs. The very fact that the single-targeted monoclonal antibody bevacizumab can induce cardiotoxicity supports a pathomechanistic role for the VSP and the postulate of the “vascular” nature of VSP inhibitor cardiotoxicity. In this review we will outline this scenario in greater detail, reflecting on hypertension and coronary artery disease as risk factors for VSP inhibitor cardiotoxicity, but also similarities with peripartum and diabetic cardiomyopathy. This leads to the concept that any preexisting or coexisting condition that reduces the vascular reserve or utilizes the vascular reserve for compensatory purposes may pose a risk factor for cardiotoxicity with VSP inhibitors. These conditions need to be carefully considered in cancer patients who are to undergo VSP inhibitor therapy. Such vigilance is not to exclude patients from such prognostically extremely important therapy but to understand the continuum and to recognize and react to any cardiotoxicity dynamics early on for superior overall outcomes
Vascular toxicities with VEGF inhibitor therapies-focus on hypertension and arterial thrombotic events
The vascular endothelial growth factor (VEGF) signaling pathway (VSP) fulfills a cardinal role in endothelial cells and its inhibition has profound cardiovascular impact. This is true not only for the normal vasculature but also for the tumor vasculature when VSP inhibitors are used as anti-angiogenic therapies. Generalized endothelial dysfunction predisposes to vasoconstriction, atherosclerosis, platelet activation, and thrombosis (arterial more than venous). All of these have been reported with VSP inhibitors and collectively give rise to vascular toxicities, the most concerning of which are arterial thromboembolic events (ATE). VSP inhibitors include antibodies, acting extracelluarly on VEGF, such as bevacizumab and tyrosine kinases inhibitors, acting intracellularly on the kinase domain of VEGF receptors, such as sunintib and sorafenib. The addition of bevacizumab and VSP tyrosine kinase inhibitor therapy to the cancer treatment regimen is associated with a 1.5–2.5-fold and 2.3–4.6-fold increase risk of ATEs, respectively. Risk factors for ATEs while on VSP inhibitor therapy include age older than 65 years, previous thromboembolic events, history of atherosclerotic disease, and duration of VSP inhibitor therapy. In clinical practice, hypertension remains the most commonly noted vascular manifestation of VSP inhibition. Optimal blood pressure goals and preferred therapeutic strategies toward reaching these goals are not defined at present. This review summarizes current data on this topic and proposes a more intensive management approach to patients undergoing VSP inhibitor therapy including Systolic Blood PRessure Intervention Trial (SPRINT) blood pressure goals, pleiotropic vasoprotective agents such as angiotensin converting enzyme inhibitors, amlodipine, and carvedilol, high-dose statin therapy, and aspirin
Recent advances in hypertension and cardiovascular toxicities with vascular endothelial growth factor inhibition
No abstract available
Potential Role of the Ubiquitin-Proteasome System in Atherosclerosis Aspects of a Protein Quality Disease
Misfolded or damaged proteins are recognized intracellularly by protein quality mechanisms. These include chaperones and the ubiquitin-proteasome system, which aim at restoration of protein function and protein removal, respectively. A number of studies have outlined the functional significance of the ubiquitin-proteasome system for the heart and, as of recently, for the vascular system. This review summarizes these recent findings with a focus on atherosclerosis. In particular, this paper reflects on the viewpoint of atherosclerosis as a protein quality disease
Simvastatin preserves the structure of coronary adventitial vasa vasorum in experimental hypercholesterolemia independent of lipid lowering
The Ubiquitin–Proteasome System and Cardiovascular Disease
Over the past decade, the role of the ubiquitin–proteasome system (UPS) has been the subject of numerous studies to elucidate its role in cardiovascular physiology and pathophysiology. There have been many advances in this field including the use of proteomics to achieve a better understanding of how the cardiac proteasome is regulated. Moreover, improved methods for the assessment of UPS function and the development of genetic models to study the role of the UPS have led to the realization that often the function of this system deviates from the norm in many cardiovascular pathologies. Hence, dysfunction has been described in atherosclerosis, familial cardiac proteinopathies, idiopathic dilated cardiomyopathies, and myocardial ischemia. This has led to numerous studies of the ubiquitin protein (E3) ligases and their roles in cardiac physiology and pathophysiology. This has also led to the controversial proposition of treating atherosclerosis, cardiac hypertrophy, and myocardial ischemia with proteasome inhibitors. Furthering our knowledge of this system may help in the development of new UPS-based therapeutic modalities for mitigation of cardiovascular disease
Endothelin-1 receptor blockade prevents renal injury in experimental hypercholesterolemia
Endothelin-1 receptor blockade prevents renal injury in experimental hypercholesterolemia.BackgroundThe potent vasoconstrictor endothelin-1 is involved in regulation of renal function, and is up-regulated in hypercholesterolemia (HC), a risk factor for renal disease that increases oxidative stress and impairs renal hemodynamic responses. However, the involvement of endothelin (ET) in this disease process is yet unknown.MethodsRegional renal hemodynamics and function in vivo were quantified in pigs at baseline and during infusion of acetylcholine using electron beam computed tomography after a 12-week normal diet (N = 6), HC diet (N = 6), and HC diet orally supplemented (4mg/kg/day) with the selective ET receptor-A (ET-A) blocker ABT-627 (HC+ET-A, N = 6). Plasma levels of 8-epi-PGF2-α-isoprostanes, markers of oxidative stress, were measured using enzyme immunoassay, and renal tissue was studied ex vivo using Western blotting, electrophoretic mobility shift assay, and immunohistochemistry.ResultsTotal and low-density lipoprotein (LDL) cholesterol were similarly increased, but isoprostanes were decreased in HC+ET-A compared to HC alone. Basal renal perfusion was similar among the groups, while glomerular filtration rate (GFR) increased in HC+ET-A compared to HC. Stimulated perfusion and GFR were blunted in HC, but normalized in HC+ET-A. Moreover, ET blockade increased expression of endothelial nitric oxide synthase, and decreased endothelial expression of the oxidized-LDL receptor LOX-1, as well as tubular immunoreactivity of inducible nitric oxide synthase, nitrotyrosine, nuclear factor-κB, transforming growth factor-β, and tubulointerstitial and perivascular trichrome staining.ConclusionET-A blockade improves renal hemodynamic and function in HC, and decreases oxidative stress, and renal vascular and tubulointerstitial inflammation and fibrosis. These findings support a role for the endogenous ET system in renal injury in HC and atherosclerosis
final results of a noninterventional study
Background Data are limited regarding routine use of everolimus after initial
vascular endothelial growth factor (VEGF)–targeted therapy. The aim of this
prospective, noninterventional, observational study was to assess efficacy and
safety of everolimus after initial VEGF-targeted treatment in patients with
metastatic renal cell carcinoma (mRCC) in routine clinical settings. Methods
Everolimus was administered per routine clinical practice. Patients with mRCC
of any histology from 116 active sites in Germany were included. The main
objective was to determine everolimus efficacy in time to progression (TTP).
Progression-free survival (PFS), treatment duration, tumor response, adherence
to everolimus regimen, treatment after everolimus, and safety were also
assessed. Results In the total population (N = 334), median follow-up was 5.2
months (range, 0–32 months). Median treatment duration (safety population, n =
318) was 6.5 months (95% confidence interval [CI], 5–8 months). Median TTP and
median PFS were similar in populations investigated. In patients who received
everolimus as second-line treatment (n = 211), median (95% CI) TTP was 7.1
months (5–9 months) and median PFS was 6.9 months (5–9 months). Commonly
reported adverse events (safety population, n = 318) were dyspnea (17%),
anemia (15%), and fatigue (12%). Limitations of the noninterventional design
should be considered. Conclusions This study reflects routine clinical use of
everolimus in a large sample of patients with mRCC. Favorable efficacy and
safety were seen for everolimus after previous therapy with one VEGF-targeted
agent. Results of this study confirm everolimus as one of the standard options
in second-line therapy for patients with mRCC. Novartis study code,
CRAD001LD27: VFA registry for noninterventional studies
(http://www.vfa.de/de/forschung/nisdb/ webcite)
Hypertension and prohypertensive antineoplastic therapies in cancer patients
The development of a wide range of novel antineoplastic therapies has improved the prognosis for patients with a wide range of malignancies, which has increased the number of cancer survivors substantially. Despite the oncological benefit, cancer survivors are exposed to short- and long-term adverse cardiovascular toxicities associated with anticancer therapies. Systemic hypertension, the most common comorbidity among cancer patients, is a major contributor to the increased risk for developing these adverse cardiovascular events. Cancer and hypertension have common risk factors, have overlapping pathophysiological mechanisms and hypertension may also be a risk factor for some tumor types. Many cancer therapies have prohypertensive effects. Although some of the mechanisms by which these antineoplastic agents lead to hypertension have been characterized, further preclinical and clinical studies are required to investigate the exact pathophysiology and the optimal management of hypertension associated with anticancer therapy. In this way, monitoring and management of hypertension before, during, and after cancer treatment can be improved to minimize cardiovascular risks. This is vital to optimize cardiovascular health in patients with cancer and survivors, and to ensure that advances in terms of cancer survivorship do not come at the expense of increased cardiovascular toxicities
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