Dasatinib induces endothelial dysfunction leading to impaired recovery from ischaemia.

Chronic myeloid leukaemia (CML) management is complicated by treatment-emergent vascular adverse events seen with tyrosine kinase inhibitors (TKIs) such as nilotinib, dasatinib and ponatinib. Pleural effusion and pulmonary arterial hypertension (PAH) have been associated with dasatinib treatment. Endothelial dysfunction and impaired angiogenesis are hallmarks of PAH. In this study, we explored, at cellular and whole animal levels, the connection between dasatinib exposure and disruption of endothelial barrier integrity and function, leading to impaired angiogenesis. Understanding the mechanisms whereby dasatinib initiates PAH will provide opportunities for intervention and prevention of such adverse effects, and for future development of safer TKIs, thereby improving CML management.

Reticulated livedoid skin patterns after soft-tissue filler-related vascular adverse events.

BACKGROUND: For the treatment of vascular adverse events caused by filler injections, duplex ultrasound imaging may be used. The findings of duplex ultrasound examination and the clinical features of reticulated livedoid skin patterns were compared with the hemifaces anatomy. OBJECTIVE: The objective of this study was to link the reticulated livedoid skin patterns to the corresponding duplex ultrasound findings and the facial perforasomes. METHODS: Duplex ultrasound imaging was used for the diagnosis and treatment of vascular adverse events. The clinical features and duplex ultrasound findings of 125 patients were investigated. Six cadaver hemifaces were examined to compare the typical livedo skin patterns with the vasculature of the face. RESULTS: Clinically, the affected skin showed a similar reticulated pattern in each facial area corresponding with arterial anatomy and their perforators in the cadaver hemifaces. With duplex ultrasound, a disturbed microvascularization in the superficial fatty layer was visualized. After hyaluronidase injection, clinical improvement of the skin pattern was seen. Normalization of blood flow was noted accompanied by restoration of flow in the corresponding perforator artery. The skin patterns could be linked to the perforators of the superficial fat compartments. CONCLUSION: The livedo skin patterns seen in vascular adverse events may reflect the involvement of the perforators.

A structured approach with Swiss cheese model to reduce vascular adverse events of filler injections.

BACKGROUND: Filler injection is among the most popular nonsurgical aesthetic procedures worldwide. Though relatively noninvasive, filler injection can lead to severe vascular adverse events. Even though the incidence is rare, it may cause devastating and irreversible outcomes. A Swiss cheese model has been widely applied for risk analysis and management approach in medical field. AIMS: In this review article, we adopt the Swiss cheese model and create a structured approach to prevent severe vascular complications caused by filler injections. METHODS: We reviewed the current literature regarding the knowledge and techniques of preventing vascular adverse events in the filler injection. RESULTS: We propose four structured strategies in this model to reduce the risk of severe vascular adverse events of filler injections, including clinical facial anatomy, safe filler injection principles, real time imaging and auxiliary instruments, and implication of checklist. CONCLUSION: This review provides clinicians a structured approach before and during the filler injection procedure to reduce the risk of vascular adverse events and improve its safety and outcome.

Cardiovascular Safety of Ozanimod in Patients With Ulcerative Colitis: True North and Open-Label Extension Analyses.

BACKGROUND & AIMS: Evaluating cardiovascular safety of sphingosine 1-phosphate (S1P) receptor modulators is warranted due to S1P receptor expression on cardiomyocytes and vascular endothelial cells. This analysis reports the cardiovascular safety of ozanimod, an S1P receptor modulator, in patients with moderately to severely active ulcerative colitis from the phase 3 True North (TN) and open-label extension (OLE). METHODS: All patients who received ozanimod in TN (n = 796) and all eligible TN patients who entered the OLE (n = 823) were included. Cardiovascular-related adverse events were evaluated in patients with up to 146 weeks of ozanimod exposure (2219 patient-years), which included 52 weeks during TN. RESULTS: On TN day 1, first-dose ozanimod resulted in a 0.2 beats per minute mean decrease in heart rate from pretreatment to hour 6; 2 patients experienced bradycardia, which resolved without treatment modification. Mean systolic and diastolic blood pressure increases of 5.1 and 2.2 mm Hg, respectively, were observed at TN week 52. No second-degree Mobitz type II atrioventricular block events were reported; 1 third-degree atrioventricular block unrelated to ozanimod occurred in the OLE. Cardiac and vascular treatment-emergent adverse events were infrequent (3.8% [31 of 823] and 8.5% [70 of 823]); no ozanimod-related cardiovascular deaths occurred. The incidences of deep-vein thrombosis (0.2%; 2 of 823), pulmonary embolism (0.2%; 2 of 823), and ischemic stroke (0.4%; 3 of 823) in the OLE were low. CONCLUSIONS: No new cardiovascular safety signals were identified, consistent with findings from previous ozanimod studies. There were few major adverse cardiovascular events or thromboembolic events, which were unrelated or unlikely related to ozanimod. Ozanimod has a well-tolerated cardiovascular safety profile when prescribed in accordance with the label. Clinical trial registry website and trial numbers: ClinicalTrials.gov numbers: NCT02435992 and NCT02531126.

New Concepts in Cardio-Oncology.

Cancer and cardiovascular disease are the two major causes of morbidity and mortality in worldwide. Discovering new therapeutic agents for the management of breast cancer (BC) has increased the numbers of cancer survivors but with the risk of cardiovascular adverse events (CV-AEs). All drugs can potentially damage the cardiovascular system, with different types of clinical manifestations from ischemic myocardial disease to vasculitis, thrombosis or pericarditis. An early detection of CV-AEs guarantees an earlier treatment, which is associated with better outcomes. Cardio-oncology field enlarged its studies to improve prevention, monitoring and treatment of all cardiotoxic manifestations related to old or modern oncological agents. A multidisciplinary approach with a close partnership between oncologists and cardiologists is essential for an optimal management and therapeutic decision-making. The aim of this chapter is to review all types of cardiotoxic manifestations related to novel and old agents approved for treatment of BC patients including chemotherapy, anti-HER2 agents, cyclin-dependent kinase 4/6 inhibitors, PolyADP-ribose polymerase (PARP) inhibitors, antiangiogenic drugs and immunotherapy. We also focused our discussion on prevention, monitoring, treatment, and management of CV-AEs.

Nilotinib related acute myocardial infarction with nonobstructive coronary arteries: a case report and literature review.

BACKGROUND: Myocardial Ischemia with No Obstructive Coronary Artery Disease (MINOCA) is a common cause of type 2 acute myocardial infarction (AMI) which requires careful differential diagnosis. Coronary artery spasm (CAS) syndrome is one etiology that can lead to MINOCA. Nilotinib, a targeted treatment for chronic myeloid leukemia (CML), has been reported to be related with increased risk of adverse vascular events. CASE PRESENTATION: A 67-year-old male patient was admitted to hospital with acute chest pain. He had a past medical history of CML and a history of treatment with nilotinib for 12 months. Coronary angiography (CAG) showed no significant stenosis. Since the onset of angina was generally in the early morning, and ECG and echocardiography suggested right coronary artery (RCA) disease, an ergonovine provocation test was performed to confirm the diagnosis of CAS. After intracoronary administration of ergonovine, middle and distal RCA showed over 90% vasoconstriction. Nilotinib related MINOCA, CAS and CML were diagnosed. Lifestyle changes (cessation of smoking), anti-spasmodics, statin treatment and adjustment of the nilotinib dose (from 200 mg bid, to 150 mg bid) were recommended for this patient. Six-month's follow-up showed good recovery with no onsets of angina. CONCLUSIONS: Physicians should be vigilant to adverse vascular events when treating patients who have been prescribed nilotinib. It is suggested that in patients with MINOCA who have a history of treatment with nilotinib, CAS-induced MINOCA should be included in the differential diagnosis. Further studies are needed to clarify the mechanism and to find better management.

Tyrosine Kinase Inhibitors and Vascular Adverse Events in Patients with Chronic Myeloid Leukemia: A Population-Based, Propensity Score-Matched Cohort Study.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) have shown long-term survival benefits in patients with chronic myeloid leukemia (CML). Nevertheless, significant concern has been raised regarding long-term TKI-associated vascular adverse events (VAEs). The objective of this retrospective cohort study was to investigate the incidence of VAEs in Taiwanese patients with CML treated with different TKIs (imatinib, nilotinib, and dasatinib) as well as potential risk factors. MATERIALS AND METHODS: We conducted a retrospective cohort study using the Taiwan Cancer Registry Database and National Health Insurance Research Database. Adult patients diagnosed with CML from 2008 to 2016 were identified and categorized into three groups according to their first-line TKI treatment (imatinib, nilotinib, and dasatinib). Propensity score matching was performed to control for potential confounders. Cox regressions were used to estimate the hazard ratio (HR) of VAEs in different TKI groups. RESULTS: In total, 1,111 patients with CML were included in our study. We found that the risk of VAEs in nilotinib users was significantly higher than that in imatinib users, with an HR of 3.13 (95% confidence interval (CI), 1.30-7.51), whereas dasatinib users also showed a nonsignificant trend for developing VAEs, with an HR of 1.71 (95% CI, 0.71-4.26). In multivariable logistic regression analysis, only nilotinib usage, older age, and history of cerebrovascular diseases were identified as significant risk factors. The annual incidence rate of VAEs was highest within the first year after the initiation of TKIs. CONCLUSION: These findings can support clinicians in making treatment decisions and monitoring VAEs in patients with CML in Taiwan. IMPLICATIONS FOR PRACTICE: This study found that patients with chronic myeloid leukemia (CML) treated with nilotinib and dasatinib may be exposed to a higher risk of developing vascular adverse events (VAEs) compared with those treated with imatinib. Thus, this study suggests that patients with CML who are older or have a history of cerebrovascular diseases should be under close monitoring of VAEs, particularly within the first year after the initiation of tyrosine kinase inhibitors.

[Management of vascular adverse events during tyrosine kinase inhibitors in patients with chronic myeloid leukemia].

In 2000, imatinib became the first tyrosine kinase inhibitor (TKI) approved for the treatment of chronic myeloid leukemia (CML); this was soon followed by second generation (nilotinib, dasatinib, and bosutinib) and third generation (ponatinib) TKIs, all of which are currently available for the treatment of CML. Their emergence has revolutionized treatment strategies for CML, leading to a new era that has seen the 10-year overall survival rate for CML patients exceed 80%; despite the impact of TKIs on CML prognosis, only 10 to 20% of CML patients maintain treatment-free remission after TKI cessation. Moreover, prolonged treatment produces various adverse effects, such as serious vascular adverse events including stroke, myocardial infarction, and peripheral arterial occlusive disease. The pathophysiological mechanisms underlying those effects remain unclear, and protocols for managing such life-threatening events have not been established. Thus, I conducted a narrative review of the literature to clarify the current state of knowledge. Based on that review and my experiences during daily clinics, I herein present a discussion on the incidence, diagnosis, and management of TKI-induced vascular adverse events.

Isolated pulmonary vasculitis associated with nilotinib use: A case report.

An association between tyrosine-kinase inhibitor therapy for chronic myeloid leukemia and vascular adverse events including peripheral arterial disease, coronary artery disease, and pulmonary hypertension has been described. We present a patient who developed isolated pulmonary artery vasculitis resulting in left pulmonary artery stenosis, in addition to left coronary artery stenosis while on nilotinib. While monitoring for cardiovascular events is important, clinicians should also recognize possible drug-induced vasculitis during chronic nilotinib therapy.

Effects of high-intensity focused ultrasound treatment on peripancreatic arterial and venous blood vessels in pancreatic cancer.

The present study aimed to evaluate the safety of high-intensity focused ultrasound (HIFU) treatment on peripancreatic arterial and venous blood vessels in patients with pancreatic cancer. This trial included 15 patients with pancreatic cancer (9 females and 6 males; age, 39-81 years; median age, 62 years). All patients underwent preoperative computed tomography (CT) or magnetic resonance imaging (MRI) and color Doppler flow imaging (CDFI) to assess the vascular hemodynamics of peripancreatic arterial and venous blood vessels pre-treatment. These patients were re-examined within 1 week post-HIFU treatment. Then, vascular adverse events were observed and followed up clinically. Prior to HIFU treatment, vessel involvement was recorded in 13 patients, including tumor lesions invading 19 veins and 14 arteries, which refers to the growth of pancreatic tumor lesions surrounding blood vessels, or tumor growth into blood vessels. In addition, 9 veins and 13 arteries were <1 cm from the lesions. The hemodynamic parameters of peripancreatic vessels were measured using CDFI, including mean blood flow velocity, peak systolic blood flow velocity, vascular resistance index, vascular pulsatility index, vascular diameter, vascular blood flow and other indicators, to assess vascular perfusion in CT/MRI. There were no significant differences in preoperative and postoperative hemodynamic data (P>0.05). Overall, HIFU demonstrated no negative effects on peripancreatic arterial and venous blood vessels in patients with pancreatic cancer, even with tumor lesions wrapped in blood vessels. In addition, no complications of vascular stenosis and vascular adverse events were observed in the present study.

Ponatinib Activates an Inflammatory Response in Endothelial Cells via ERK5 SUMOylation.

Ponatinib is a multi-targeted third generation tyrosine kinase inhibitor (TKI) used in the treatment of chronic myeloid leukemia (CML) patients harboring the Abelson (Abl)-breakpoint cluster region (Bcr) T315I mutation. In spite of having superb clinical efficacy, ponatinib triggers severe vascular adverse events (VAEs) that significantly limit its therapeutic potential. On vascular endothelial cells (ECs), ponatinib promotes EC dysfunction and apoptosis, and inhibits angiogenesis. Furthermore, ponatinib-mediated anti-angiogenic effect has been suggested to play a partial role in systemic and pulmonary hypertension via inhibition of vascular endothelial growth factor receptor 2 (VEGFR2). Even though ponatinib-associated VAEs are well documented, their etiology remains largely unknown, making it difficult to efficiently counteract treatment-related adversities. Therefore, a better understanding of the mechanisms by which ponatinib mediates VAEs is critical. In cultured human aortic ECs (HAECs) treated with ponatinib, we found an increase in nuclear factor NF-kB/p65 phosphorylation and NF-kB activity, inflammatory gene expression, cell permeability, and cell apoptosis. Mechanistically, ponatinib abolished extracellular signal-regulated kinase 5 (ERK5) transcriptional activity even under activation by its upstream kinase mitogen-activated protein kinase kinase 5α (CA-MEK5α). Ponatinib also diminished expression of ERK5 responsive genes such as Krüppel-like Factor 2/4 (klf2/4) and eNOS. Because ERK5 SUMOylation counteracts its transcriptional activity, we examined the effect of ponatinib on ERK5 SUMOylation, and found that ERK5 SUMOylation is increased by ponatinib. We also found that ponatibib-mediated increased inflammatory gene expression and decreased anti-inflammatory gene expression were reversed when ERK5 SUMOylation was inhibited endogenously or exogenously. Overall, we propose a novel mechanism by which ponatinib up-regulates endothelial ERK5 SUMOylation and shifts ECs to an inflammatory phenotype, disrupting vascular homeostasis.

Features of vascular adverse events in Japanese patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors: a retrospective study of the CML Cooperative Study Group database.

This study investigated the incidence rate and features of vascular adverse events (VAEs) in Japanese patients with chronic myeloid leukemia (CML) who were treated with tyrosine kinase inhibitors (TKIs). The analysis included 369 CML patients in the chronic or accelerated phases, selected from the CML Cooperative Study Group database; 25 events in 23 (6.2%) of these patients were VAEs. At the time of VAE incidence, nine patients were on treatment with imatinib, 12 with nilotinib, three with dasatinib, and one with bosutinib. VAE incidence comprised 13 cases of ischemic heart disease (IHD), eight of cerebral infarction (CI), and four of peripheral arterial occlusive disease (PAOD). IHD incidence rate in the study population was higher than that in the age-matched general population, particularly in nilotinib-treated patients, while CI incidence rate was almost equivalent. Compared with the Suita score, the SCORE chart and the Framingham score risk assessment tools detected more patients with high or very high risk of VAEs. In conclusion, incidence of IHD requires closer monitoring in nilotinib-treated patients. More detailed investigations for determining the most useful tool to predict VAE incidence and long-term analysis of therapy-related VAE cases are needed for improving safety during TKI therapy.

[Clinical characteristics of vascular adverse events and significance of peripheral artery disease as a risk factor in chronic myeloid leukemia patients treated with nilotinib].

Vascular adverse events (VAEs) in chronic myeloid leukemia (CML) patients treated with nilotinib (NIL) has become a; however, studies on strategies to prevent VAEs remain limited. Therefore, the present study investigated VAEs in 19 CML patients treated with NIL at our hospital. The median age of the patients was 65 years and median follow-up period was 55 months after the initiation of NIL. VAEs occurred in 8 patients (peripheral artery disease (PAD), n=6; cerebral infarction (CI), n=3; coronary artery disease (CAD), n=4). The median elapsed time from the initiation of NIL to VAEs was 42 months. The 4-year cumulative incidence of VAEs was 23.5%. Majority of the patients with VAEs were smokers (P=0.074). All the six patients with PAD were diagnosed on the basis of the ankle-brachial index (ABI<0.9) in the asymptomatic phase; 4 of these patients had other VAEs (CI, n=1; CAD, n=2; CI and CAD, n=1). However, antecedent asymptomatic PAD was diagnosed even before CAD was diagnosed in two patients. Nevertheless, in cardiology, extensive studies have indicated that asymptomatic PAD is a risk factor for the development of cardiovascular events. In conclusion, for the effective management of CML patients treated with NIL, a routine screening with ABI to diagnose asymptomatic PAD may be beneficial in preventing severe VAEs.

Two in one is better than one plus one: comparison of adverse events between combining electrophysiological examination and coronary angiography versus performing them consecutively.

PURPOSE: In some patients, both an electrophysiological examination (EPS) and a coronary angiography (CA) are necessary. It might be preferable to choose a combined approach of EPS and CA versus performing them consecutively. The purpose of this study is to evaluate the type and rate of adverse events between both approaches. METHODS: Patients were eligible if they underwent a CA and an EPS in a combined approach or in a time interval of at most 2 months. In all patients, clinical adverse events were recorded. RESULTS: A total of 1184 patients were included. CA and EPS were performed in a combined procedure (comb) in 492 patients, whereas they were performed consecutively in 692 patients (cons). The acute major complication rate was 0.67%, showing no differences between both groups. In the comb 6.9% and in the cons 6.6% of vascular complications were observed (p = 0.20). The rates of AV fistula and hematoma needing transfusion showed a significantly higher rate in the cons group (p = 0.018 and p = 0.045, respectively). In a multivariate logistic regression analysis, age was a significant predictor for groin complications. After propensity matching, AV fistula occurred significantly more often in the cons group (p = 0.002). CONCLUSION: Overall, serious adverse events were rare and there were no differences between the combined approach of EPS and CA and the consecutive approach; however, the occurrence of AV fistula and groin hematoma needing transfusion occurred significantly less in the combined procedure group. Therefore, a combined approach is preferable to a consecutive one.

Risk factors and mechanisms contributing to TKI-induced vascular events in patients with CML.

Vascular adverse events (VAE) are an emerging problem in patients with chronic myeloid leukemia (CML) receiving second-generation BCR-ABL1 tyrosine kinase inhibitors (TKI). Relevant VAE comprise peripheral, cerebral, and coronary artery changes in patients receiving nilotinib, venous and arterial occlusive events during ponatinib therapy, and pulmonary hypertension in patients receiving dasatinib. Although each TKI binds to a unique profile of molecular targets in leukemic cells and vascular cells, the exact etiology of drug-induced vasculopathies remains uncertain. Recent data suggest that predisposing molecular factors, pre-existing cardiovascular risk factors as well as certain comorbidities contribute to the etiology of VAE in these patients. In addition, direct effects of these TKI on vascular endothelial cells have been demonstrated and are considered to contribute essentially to VAE evolution. In the current article, we discuss mechanisms underlying the occurrence of VAE in TKI-treated patients with CML, with special emphasis on vascular and perivascular target cells and involved molecular (vascular) targets of VAE-triggering TKI. In addition, we discuss optimal patient selection and drug selection through which the risk of occurrence of cardiovascular events can hopefully be minimized while maintaining optimal anti-leukemic effects in CML, thereby following the principles of personalized medicine.

Tyrosine kinase inhibitor associated vascular toxicity in chronic myeloid leukemia.

Tyrosine kinase inhibitors (TKIs) have revolutionized the management and outcomes of chronic myeloid leukemia (CML) patients. Improved disease control and prolonged life expectancy now mandate focus on improving TKIs' safety profile. Recently, vascular adverse events (VAEs) have emerged as a serious consequence of some of the newer TKIs. In this review, we describe the clinical spectrum of TKI-associated VAE, and examine the unique vascular safety profile of the main TKIs currently used in the treatment of CML: imatinib, nilotinib, dasatinib, bosutinib and ponatinib. The issue of TKI-related platelet dysfunction is discussed as well. We describe the contemporary research findings regarding the possible pathogenesis of the VAE. Finally, the different aspects of TKI-associated VAE management are addressed, including prevention methods, monitoring strategies and treatment options.