Collaborative cardiovascular management of patients with chronic myeloid leukemia on tyrosine kinase inhibitors.

Tyrosine kinase inhibitors (TKIs) of the BCR-ABL fusion protein have dramatically changed the mortality of chronic myeloid leukemia (CML) but they carry a risk of serious vascular morbidity. While TKIs do not cure CML, daily oral administration of a TKI can control CML and TKIs are chronic medications. Interestingly, vascular complications can occur at any time a patient is on a TKI. Therefore, it is imperative that all care team members and patients are aware of and watching for possible vascular complications. In the following review, a case of arterial thrombosis secondary to the TKI ponatinib is presented as well as a discussion of thrombotic and vascular adverse events reported with TKIs. TKIs are metabolized through the cytochrome P450 system and important drug interactions to consider are reviewed. Finally, we present a multidisciplinary approach to the management of patients with CML on TKIs.

[A case of recurrent cerebral infarction during treatment with oral tyrosine kinase inhibitors for chronic myelogenous leukemia].

A 76-year-old man, diagnosed with chronic myeloid leukemia in 2010, had been on nilotinib for 7 years. He presented with right hemiparesis in September 2017. He had no history of hypertension, diabetes, hyperlipidemia, heart disease, or smoking. Brain MRI revealed a border-zone infarction of the left cerebral hemisphere and a rapidly progressing severe left internal carotid artery (ICA) stenosis. He was initiated on clopidogrel and bosutinib instead of nilotinib. He presented with right hemiparesis once again in December 2017. Brain MRI revealed the border-zone infarction of the left cerebral hemisphere and a more progressed, severe bilateral ICA stenosis. A carotid ultrasound demonstrated iso-intense and concentrically narrowed ICA on both sides. Carotid artery stenting of the left ICA was performed in February 2018, and clopidogrel was replaced by cilostazol to provide a drug-induced rush. Carotid artery stenting of the right ICA was performed in June 2018 and cervical angiogram demonstrated that there were no residual artery stenoses in the bilateral stent. In recent years, several case reports suggest that tyrosine kinase inhibitors (TKIs) are associated with progressive artery stenosis and cause cerebral infarction. Brain imaging tests should be conducted to evaluate arterial stenosis progression for patients with a history of taking TKI when an arterial vascular event occurs.

Intracranial stenting for nilotinib treatment-associated cerebrovascular stenosis in chronic myeloid leukemia.

One of the second-generation tyrosine kinase inhibitors (TKIs), nilotinib, is increasingly used for imatinib-resistant or intolerant chronic myeloid leukemia (CML). Nilotinib is considered well tolerated with few side effects including hyperglycemia, hyperbilirubinemia and elevated levels of pancreatic enzymes. However, there is growing evidence that nilotinib accelerates atherosclerosis and causes peripheral arterial occlusive disease such as stroke, transient ischemic attack (TIA) and cardiovascular diseases. Herein, we report a case of a 74-year-old male CML patient with intracranial stenosis of the internal carotid artery developed during treatment with nilotinib successfully cured by the intracranial stent, Wingspan.

Platelet activation independent of pulmonary inflammation contributes to diesel exhaust particulate-induced promotion of arterial thrombosis.

BACKGROUND: Accelerated thrombus formation induced by exposure to combustion-derived air pollution has been linked to alterations in endogenous fibrinolysis and platelet activation in response to pulmonary and systemic inflammation. We hypothesised that mechanisms independent of inflammation contribute to accelerated thrombus formation following exposure to diesel exhaust particles (DEP). METHODS: Thrombosis in rats was assessed 2, 6 and 24 h after administration of DEP, carbon black (CB; control carbon nanoparticle), DQ12 quartz microparticles (to induce pulmonary inflammation) or saline (vehicle) by either intra-tracheal instillation (0.5 mg, except Quartz; 0.125 mg) or intravenous injection (0.5 mg/kg). Thrombogenicity was assessed by carotid artery occlusion, fibrinolytic variables and platelet-monocyte aggregates. Measures of inflammation were determined in plasma and bronchoalveolar lavage fluid. Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI)-1 were measured following direct in vitro exposure of human umbilical vein endothelial cells (HUVECs) to DEP (10-150 µg/mL). RESULTS: Instillation of DEP reduced the time to thrombotic occlusion in vivo, coinciding with the peak of DEP-induced pulmonary inflammation (6 h). CB and DQ12 produced greater inflammation than DEP but did not alter time to thrombotic occlusion. Intravenous DEP produced an earlier (2 h) acceleration of thrombosis (as did CB) without pulmonary or systemic inflammation. DEP inhibited t-PA and PAI-1 release from HUVECs, and reduced the t-PA/PAI-1 ratio in vivo; similar effects in vivo were seen with CB and DQ12. DEP, but not CB or DQ12, increased platelet-monocyte aggregates. CONCLUSION: DEP accelerates arterial thrombus formation through increased platelet activation. This effect is dissociated from pulmonary and systemic inflammation and from impaired fibrinolytic function.

Expression of Egr1 and p53 in human carotid plaques and apoptosis induced by 7-oxysterol or p53.

Egr-1 and p53 are involved in pathology of both atherosclerosis and cancer. However, it is unknown whether p53 and Egr1 are interactively involved in apoptosis in atherosclerosis. We found that in human carotid plaques, the expression of p53 was inversely correlated with Egr1. In U937 cells, 7ß-hydroxycholesterol and 7-ketocholesterol induced production of reactive oxygen species (ROS), transient up-regulation of Egr1 followed by late induction of p53 and apoptosis. Cells with nuclear fragmentation induced by 7-oxysterol or p53 showed increased levels of p53, but decreased levels of Egr1. In conclusion, ROS induced by 7-oxysterols may function as an early initiator of Egr1 expression. The late induced p53 by 7-oxysterols contributes to apoptotic cell death and is linked to the reduction of Egr1 levels, which resembles the differential expression of p53 and Egr1 in human atheroma progression.

Cisplatin-associated occlusion of the internal carotid artery.

BACKGROUND: Cisplatin is a highly effective antineoplastic agent used also in germ cell cancer. Thromboembolic complications like pulmonary embolism, myocardial infarction and stroke have occasionally been reported. CASE REPORT: A 46-year-old man with seminoma and without any cerebrovascular risk factors developed an acute stroke with complete right-sided hemiparesis and global aphasia, during the second cycle of cisplatin-based chemotherapy. After exclusion of an intracerebral bleeding, a systemic thrombolysis was performed. Further diagnostics revealed an acute occlusion of the left carotid internal artery with infarction in the territory of the middle cerebral artery. The patient slowly recovered; however, a moderate aphasia and partial hemiparesis persisted whereas the tumor was in complete remission. Months later, the patient developed symptomatic epilepsy. CONCLUSIONS: Ischemic stroke associated with cisplatin-based chemotherapy is rare, but may be disabling or even fatal. With regard to the literature, several precautions are discussed to minimize the risk of these major side effects.

Venous and arterial thrombo-embolic complications of hormonal treatment in a male-to-female transgender patient.

We present a male-to-female (MTF) transgender patient admitted with a pulmonary embolism. The patient had been treated with high-dose oestrogens since the age of 16. Following a prolonged period of hypotension, our patient sustained cerebral border zone infarcts. There was evidence of bilateral carotid stenosis on Doppler ultrasound. We discuss the treatment and vascular complications of gender dysphoria.

Inhibitory avoidance memory retention in the elevated T-maze is impaired after perivascular manipulation of the common carotid arteries.

Perivascular manipulation promoted by the positioning of a silicone collar around the common carotid arteries causes local inflammation and has been suggested as an animal model of atherosclerosis. This manipulation induces biochemical and morphological changes that are similar to those observed in the early stage of atherosclerosis in humans. Based on evidences showing that atherosclerosis is associated with cognitive deficits in humans, we presently investigated the temporal consequences of the bilateral positioning of silicone collars around the common carotid arteries (n = 15) on inhibitory avoidance memory retention in male Wistar rats tested in the elevated T-maze. The effects of this procedure were compared to those observed in sham-operated animals (n = 15) and to those observed in animals submitted to permanent bilateral occlusion of the common carotid arteries (n = 16). Additionally we studied the effects of the pretreatment with the non-selective anti-inflammatory drug indomethacin (n = 13) or the selective COX-2 inhibitor celecoxib (n = 12) and compared the effects to those of the pretreatment with vehicle (n = 11). The results showed that the silicone collar implants induced deficits in memory retention when animals were tested 2 and 4, but not 15 or 30, days after surgery. Permanent bilateral occlusion of the common carotid arteries impaired avoidance retention up to 30 days after surgery. Pretreatment with indomethacin (2 mg/kg/day) or celecoxib (5 mg/kg/day) post surgery and up to 3 days thereafter did not prevent memory deficits caused by silicone collar implants. Our data suggest that the prostanoids that participate in the inflammatory process triggered by the placement of the silicone collar do not seem responsible for the deficit in memory retention observed during the first days after collar placement.

Functional P2Y2 nucleotide receptors mediate uridine 5'-triphosphate-induced intimal hyperplasia in collared rabbit carotid arteries.

BACKGROUND: Extracellular uridine 5'-triphosphate (UTP) induces mitogenic activation of smooth muscle cells (SMCs) through binding to P2Y2 nucleotide receptors. P2Y2 receptor mRNA is upregulated in intimal lesions of rat aorta, but it is unclear how this G-protein-coupled receptor contributes to development of intimal hyperplasia. METHODS AND RESULTS: This study used a silicone collar placed around rabbit carotid arteries to induce vascular injury and intimal thickening. Collar placement caused rapid upregulation of P2Y2 receptor mRNA in medial SMCs before appearance of neointima. Fura-2 digital imaging of single SMCs was used to measure changes in myoplasmic calcium concentration (Ca(m)) in response to P2Y receptor agonists. In contrast to UDP, activation by UTP or adenosine 5'-triphosphate (ATP) greatly increased Ca(m), which indicates upregulation of functional P2Y2 receptors at which UTP and ATP are equipotent agonists. The number of responsive cells was significantly greater for freshly dispersed SMCs from collared arteries than for controls. Perivascular infusion of UTP (100 micromol/L) within the collar significantly enhanced neointimal development. Intimas that resulted from UTP exposure were infiltrated by macrophages. Moreover, increased expression of osteopontin occurred in response to in situ application of UTP. ATP or UTP also stimulated osteopontin expression in cultured SMCs in a dose-dependent manner. Furthermore, P2Y2 antisense oligonucleotide inhibited osteopontin expression induced by UTP. CONCLUSIONS: These findings indicate for the first time a role for the UTP/ATP receptor, P2Y2, in development of intimal hyperplasia associated with atherosclerosis and restenosis.

Different mechanisms of increased luminal stenosis after arterial injury in mice deficient for urokinase- or tissue-type plasminogen activator.

BACKGROUND: Tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) are thought to play critical roles in vascular remodeling after injury, with tPA mediating intravascular clot lysis and uPA modulating cell migration within the vessel wall. In human vascular disease, however, thrombus organization and neointimal formation are closely interrelated processes. This study examines the differential roles of tPA and uPA in these processes in mice. METHODS AND RESULTS: Carotid artery injury and thrombosis were induced in wild-type (WT), uPA-deficient (uPA(-/-)), and tPA-deficient (tPA(-/-)) mice with the use of ferric chloride. The expression of uPA and tPA was significantly upregulated in the vessel wall of WT mice 1 week after injury, and compared with WT mice, uPA(-/-) and tPA(-/-) mice had lower carotid patency rates after injury. At 3 weeks, only 55% of uPA(-/-) mouse vessels were patent compared with 81% in tPA(-/-) mice and 100% in WT mice (P=0.014). Morphometric analysis of injured arterial segments revealed severe luminal stenosis (62+/-28%) in uPA(-/-) mice compared with their tPA(-/-) (16+/-12%) and WT (6.3+/-3.6%, P<0.001) counterparts. Moreover, although the vascular walls of WT mice and, particularly, tPA(-/-) mice developed a cell-rich multilayered neointima and media, the lumen of uPA(-/-) vessels remained obstructed with acellular unorganized thrombotic material, and their medial areas did not expand. CONCLUSIONS: These results indicate that the roles of uPA and tPA in the arterial response to injury are different and more complex than previously assumed and emphasize the critical role of thrombus organization and resolution in neointimal formation and vascular pathology.

Cerebral vasculopathy and multiple infarctions in a woman with carcinomatous meningitis while on treatment with intrathecal methotrexate.

We report on a 33-year-old woman with carcinomatous meningitis due to carcinoma of the breast who developed multiple cerebral infarctions within four days after intrathecal chemotherapy with methotrexate. MR angiography revealed a narrowing of basal cerebral arteries, which is consistent with vasculopathy. The vasculopathy was probably due to carcinomatous meningitis itself, an acute toxic effect of methotrexate, or a combination of both.

Nitric oxide synthase gene therapy rapidly reduces adhesion molecule expression and inflammatory cell infiltration in carotid arteries of cholesterol-fed rabbits.

BACKGROUND: Hypercholesterolemia reduces nitric oxide bioavailability, manifested by reduced endothelium-dependent vascular relaxation, and also induces vascular adhesion molecule expression and inflammatory cell infiltration. We have previously shown that gene therapy with NO synthase in hypercholesterolemic rabbits substantially reverses the deficit in vascular relaxation. In the present study, we show that NO synthase gene therapy rapidly and substantially reduces vascular adhesion molecule expression, lipid deposition, and inflammatory cell infiltration. METHODS AND RESULTS: Thirty male New Zealand White rabbits were maintained on a 1% cholesterol diet for 11 to 13 weeks, then underwent carotid artery gene transfer with Ad.nNOS or Ad.betaGal (recombinant adenoviruses expressing neuronal NO synthase or beta-galactosidase, respectively), or received medium alone in a sham procedure. Arteries were harvested at 1 and 3 days after gene transfer, and the following parameters were determined by immunohistochemical and image-analysis techniques: intercellular adhesion molecule-1, vascular cell adhesion molecule-1, lipid deposition by oil red O staining, lymphocyte infiltration (CD43-positive cells), and monocyte infiltration (RAM-11-positive cells). In Ad.nNOS-treated arteries, all markers were significantly decreased relative to Ad. betaGal or sham-treated arteries within 3 days after gene transfer. Ad.nNOS had a particularly striking impact on monocyte infiltration; as early as 24 hours after gene transfer, Ad.nNOS-treated arteries had >3-fold fewer monocytes than Ad.betaGal- or sham-treated arteries. CONCLUSIONS: NO synthase gene therapy rapidly ameliorates several markers of atherosclerosis in the cholesterol-fed rabbit.

Histological changes in the rat common carotid artery following simultaneous topical application of cotton sheet and cyanoacrylate glue.

Histological changes in and around the arterial walls of rats were investigated following simultaneous topical application of cotton sheet and cyanoacrylate glue. The bilateral common carotid arteries were exposed using sterile techniques, and the test materials were applied to the right artery. The left artery served as a control. Changes in arterial histology were evaluated at 2 weeks, 1 month, 2 months, and 3 months after surgery. Extensive inflammation consisting primarily of histiocytes and multinuclear giant cells was observed around the materials, but tended to decrease by 3 months. Necrosis in the media and fibrosis in the adventitia initially appeared around 2 weeks, and became advanced by 2-3 months. At 2-3 months, disruption of elastic fibers and marked fibrosis in the media were seen, and endothelial proliferation in the intima appeared. Intimal proliferation was observed at both the experimental and other sites of the vessels. The present results suggest that simultaneous use of the test materials can cause the arterial occlusive lesions observed following aneurysmal surgery.