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Review

Arterial stiffness in hematologic malignancies

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Pages 1381-1388 | Published online: 03 Mar 2017

Abstract

Malignant and cardiovascular disorders are the top causes of mortality worldwide. This article reviews the main literature data and mechanisms linking hematologic malignancies and arterial stiffness, focusing on recent experimental and clinical results. Several links were found in hematologic malignancies between complete blood count and arterial stiffness. Chemotherapy, especially anthracyclines, cyclophosphamide and tyrosine kinase inhibitors, as well as radiotherapy and hematopoietic stem cell transplantation are the main known causes of arterial stiffness increase in hematologic malignancies. The mechanisms of arterial stiffness elevation in hematologic malignancies include an increased oxidative stress, impaired vascular wall homeostasis, endothelial dysfunction and apoptosis of endothelial cells, overexpression of inflammatory cytokines, accelerated atherosclerosis, increased blood viscosity and unstable platelet aggregates. Guidelines regarding cardiovascular health screening and cardiovascular risk scores are necessary for hematologic cancer survivors in order to improve prognosis and quality of life of the patients.

Introduction

Malignant and cardiovascular disorders are among the leading causes of mortality worldwide. The number of long-term cancer survivors is increasing, considering the advancement in diagnostic tools and therapy.Citation1,Citation2 Cardiovascular disorders may increase mortality in cancer survivors, but the latency of the development of cardiovascular disorders has hampered large studies.Citation3 The main cardiovascular abnormalities occurring in cancer survivors include heart failure, coronary heart disease, myocardial infarction, cardiomyopathy, pericarditis, conduction abnormalities, valvular disorders, hemorrhagic or ischemic stroke and vascular abnormalities, including peripheral arterial disease and venous thromboembolism.Citation3Citation6 The increased risk of premature cardiac disease in cancer survivors is due to the overlap in risk factors for cancer and cardiovascular disease and the cardiotoxic effects of therapy.Citation7 Metastases of several cancers are also associated with an increased risk of coronary heart disease.Citation5 Stroke is common among cancer patients, especially those with leukemia, and several cancer-related causes of stroke have been suggested, such as treatment-related side effects, compression or invasion of blood vessels, hemostatic activation or an alteration in blood viscosity due to the tumor, nonbacterial thrombotic endocarditis and cytokines and chemokines produced by tumor cells, inducing a proinflammatory reaction with prothrombotic and atherosclerotic effects, but there is no consensus about cancer as an independent risk factor for stroke.Citation6

Arterial stiffness, the expression of reduced elastic properties of the arteries, predicts cardiovascular events. It is one of the earliest detectable signs of adverse structural and functional changes within the vessel wall.Citation8 Changes in blood vessels occur much earlier than the clinical disease.Citation9 Arterial stiffness may be assessed using pulse wave velocity (PWV) or augmentation index. Increased arterial stiffness is related to arteriosclerosis, atherosclerosis, increased vascular fibrosis, loss of elastic fibers and extensive vessel wall calcificationCitation10 and may serve as a screening method for the detection of pre-clinical cardiovascular disease.

Aim

It is critical to identify, as early as possible, any sign of cardiovascular disorders in cancer survivors.

The aim of the present article was to review the main literature data and mechanisms linking hematologic malignancies and arterial stiffness, focusing on recent experimental and clinical results.

Complete blood count

Complete blood count, an inexpensive, convenient and accessible test, has been recently associated with increased arterial stiffness, early arterial aging and cardiovascular risk in patients with hematologic malignancies.Citation11

Anemia, common in chronic diseases, is an independent risk factor for cardiovascular complications, considering hypoxia, volume overload causing progressive cardiac enlargement and reduced blood viscosity causing a hyperdynamic state.Citation12,Citation13 Hemoglobin affects peripheral vascular resistance due to the effect on blood viscosity and caliber of peripheral arterioles.Citation14 Montero et alCitation15 concluded that arterial stiffness is strongly and inversely associated with the total volume of red blood cells in healthy individuals, suggesting that arterial stiffness may be involved in the regulation of erythropoiesis. Mozos and MihaescuCitation11 found a negative correlation between hemoglobin level and PWV in patients with hematologic malignancies, but blood viscosity could have been elevated in patients with a high leukocyte count, considering that leukocytes have a higher viscosity than erythrocytes.Citation16 Not only anemia but micro- and macrocytosis were also found to be predictors of arterial stiffness and early arterial aging in hematologic malignancies.Citation11

Increased white blood cell (WBC) count, as a consequence of the hematologic malignancy or a marker of systemic inflammation, was associated with atherosclerotic cardiovascular disease and arterial stiffness in several studies.Citation17,Citation18 Experimental inflammation increases arterial stiffness, suggesting a causative role, and anti-inflammatory therapy can reduce arterial stiffness.Citation18 Neutrophil to lymphocyte ratio, calculated from complete blood count, is an inexpensive, accessible marker of inflammation, which may also be used in risk stratification of patients with cardiovascular diseases, including peripheral arterial occlusive diseases.Citation19,Citation20 It is also a marker of advanced, aggressive cancer, evidenced by increased tumor stage, nodal stage and number of metastatic lesions.Citation21

Significant correlations and associations were found between WBC count and arterial stiffness, related, probably, to the high blood viscosity, especially in chronic granulocytic leukemia.Citation16 Elevated blood viscosity was found to be a component of vascular shear stress, responsible for the rapid growth of atherosclerotic plaque and increasing plaque instability.Citation22

Mean platelet volume, a marker of platelet activation, was previously positively correlated with arterial stiffness in healthy Chinese subjects and also in patients with hematologic malignancies.Citation11,Citation23

In hematologic malignancies, arterial function, especially PWV and arterial age, should be assessed in patients with anemia, micro- and macrocytosis, leukocytosis (increased neutrophil, basophil, monocyte, lymphocyte) and platelet count ().Citation11

Table 1 Arterial stiffness in hematologic malignancies

Leukemia

Leukemia is defined by uncontrolled proliferation of malignant nonfunctional blasts in the bone marrow, followed by their release in the general circulation. Childhood leukemia survivors have increased arterial stiffness, indicating risk of premature atherosclerosis and cardiovascular disorders, and efforts should be directed in order to early identify, monitor and manage cardiovascular risk factors in these patients.Citation24 Chemotherapy itself may increase leukemia cell stiffness in acute lymphoblastic and myeloid leukemia, enabling vascular complications due to cell aggregation and obstruction of capillary-sized channels.Citation25

Lymphocytes of chronic lymphocytic leukemia patients have a smaller cell volume, a higher stiffness and a higher median transit time compared to lymphocytes in healthy patients.Citation26 Tyrosine kinase inhibitors, effective in therapy of patients with chronic myeloid leukemia, may cause vascular events.Citation27

Lymphoma

Lymphomas are defined by neoplastic proliferation of lymphoid cells, with the Sternberg–Reed cells as histological diagnosis elements in Hodgkin’s lymphoma. Non-Hodgkin’s lymphomas are more common, and immune mechanisms are frequently involved in the occurrence of vasculitis.Citation28 Cardiovascular diseases may be responsible for mortality after secondary malignancies in survivors of Hodgkin’s and non-Hodgkin’s lymphoma.Citation29,Citation30 Arterial stiffness was increased in Hodgkin’s lymphoma survivors who underwent radiotherapy.Citation31

Multiple myeloma

Multiple myeloma, the malignancy of plasma cells, characterized by bone marrow infiltration, osteolysis and injuries caused by paraproteinemia, is also associated with arterial stiffness.

Taniguchi et alCitation32 reported a case of a patient with multiple myeloma undergoing therapy with vincristine–Adriamycin (doxorubicin)–dexamethasone, with progressive increase of arterial stiffness and multivessel coronary vasospasm, related to cumulative chemotherapy-induced endothelial damage and dysfunction.

An increased blood viscosity, an impaired platelet and coagulation function were also described in multiple myeloma due to the circulating monoclonal immunoglobulinsCitation33 and could be related to increased arterial stiffness. The thromboembolic risk is increased in multiple myeloma patients, especially due to novel antimyeloma agents, such as thalidomide associated with dexamethasone.Citation33

Chemotherapy

Several vascular disorders are associated with chemotherapy, such as Raynaud’s phenomenon, hypertension, myocardial infarction, stroke, peripheral vascular disease, hepatic veno-occlusive disease, vascular toxicity and angiogenesis inhibition.Citation4,Citation34Citation36 Alkylating agents, platinum compounds and anthracyclines have been considered as vascular toxicants.Citation34 Experimental, in vivo evaluation of chemotherapy-induced vascular toxicity is challenging.Citation34 Assessment of PWV and augmentation indices and monitoring of cardiovascular risk factors may identify asymptomatic subjects at high risk of cardiovascular events who could benefit from cardiovascular monitoring and cardioprotective approaches during and after chemotherapy, considering that cardiovascular disorders may appear after 10–15 years of treatment completion.Citation37 Acute vascular complications may occur as a result of vascular toxicity induced by chemotherapy, and they may progress into chronic conditions, such as atherosclerosis, responsible for the increased cardiovascular morbidity.Citation34

Anthracycline therapy, the cornerstone in the treatment of several malignant disorders, especially breast cancer and hematologic malignancies, significantly improves the survival rate. Anthracyclines are known for their cardiotoxic effect, causing cardiac myocyte dysfunction or injury, left ventricular dilatation and diastolic dysfunction.Citation38Citation40 The anthracyclines generally used are doxorubicin, epirubicin, pirarubicin and idarubicin.Citation41 Cardiotoxicity has limited the use of anthracyclines, with cumulative dose limitations, considering that all are cardiotoxic to varying degrees, depending on the dosage, method of administration, age, cardiovascular history and previous and concomitant therapy.Citation41

Several studies revealed structural arterial remodeling, increased arterial stiffness and endothelial dysfunction after anthracycline therapy in patients with hematologic malignancies (). A significant increase in aortic stiffness was found very soon, within 4 months of anthracycline therapy initiation, in a study including patients with lymphoma or leukemia, regardless of age, sex, diabetes, hypertension, hyperlipidemia or coadministration of other cytostatics.Citation30 The rapid increase in PWV (1 month) suggests an acute process (endothelial dysfunction, increase in smooth muscle tone) rather than a chronic one (atherosclerosis, increased collagen synthesis).Citation42 Daskalaki et alCitation41 studied 70 patients with lymphomas who underwent therapy with anthracyclines, reporting a progressive, dose-dependent decrease in aortic distensibility, and negative predictors of aortic distensibility were baseline age, systolic blood pressure, left atrial diameter and left ventricular ejection fraction. A decreased brachial artery reactivity, a measure of endothelial dysfunction, assessed by high-resolution ultrasound, was found in patients receiving doxorubicin or daunorubicin compared to controls.Citation43 It is known that vasodilator changes in the brachial artery correlate well with coronary endothelial function,Citation44 but the type of lymphoma did not correlate with the magnitude of aorta impairment.Citation41 A positive correlation was found between doses of anthracyclines and reduction in thoracic aortic distensibility,Citation30 but other authors did not confirm the correlation.Citation9,Citation42 In survivors of childhood cancer, who completed anthracycline therapy for a malignant disorder, aortic PWV was significantly higher compared to age- and sex-matched healthy controls, but no correlation was found between aortic PWV and the dose of anthracycline.Citation9 Jenei et alCitation45 compared 96 long-term survivors of different childhood cancer types and 72 age-, sex-, body weight- and blood pressure-matched controls, who underwent echocardiography and flow-mediated dilatation (FMD), revealing a greater FMD response and a lower stiffness index in healthy controls compared to anthracycline- or only chemotherapy-treated patients. Higher triglyceride level, higher cumulative anthracycline dose and lower age at the start of therapy were independently associated with impairment of FMD response and aortic stiffness.Citation45 Mozos and MihaescuCitation11 did not find significant associations between anthracycline use and PWV and early arterial aging in patients with hematologic malignancies, but only 5 patients underwent therapy with doxorubicin in the mentioned study. Currently, anthracyclines are limited to cumulative doses of ≤450 mg/m2 in order to reduce the incidence of cardiovascular events.Citation42 Drafts et alCitation42 demonstrated that 6 months after initiation of low- to moderate-dose anthracycline therapy, subclinical abnormalities of cardiac and vascular functions occurred, in parallel with worsening of quality of life. There may be thresholds of susceptibility to vascular dysfunction due to anthracycline therapy, and further research is needed in order to clarify the reversibility of the increase in arterial stiffness.Citation4 Long-term persistence of their effects on vascular stiffness is not well known, but considering that increased PWV was recorded at least 1 year after chemotherapy completion, probably structural and functional vascular changes after anthracyclines persist for, at least, 1 year.Citation9

Table 2 Chemotherapy and arterial stiffness

Blood vessel walls were affected after doxorubicin administration due to decrease in endothelial-dependent relaxation, cell toxicity causing apoptosis of endothelial cells and possible early events in end-organ injury.Citation34,Citation43,Citation46 The acute vascular effect of doxorubicin begins shortly after administration, with no recovery during the next 8 minutes of real-time imaging, and depends on the size of blood vessels (more prominent in smaller vessels).Citation34 Doxorubicin-induced acute vascular toxicity may also involve increased platelet–endothelial cell adhesion, mediated by glycoprotein IIb/IIIa; enhanced procoagulant activity of macrophages and endothelial cells; impaired membrane fluidity and protein C anticoagulant pathway and facilitated activation of tissue factor, resulting in microthrombi formation and compromised blood flow.Citation47 Antiplatelet and anti-coagulant agents may protect the vessels against the detrimental effects of doxorubicin, but there is no clinical evidence for massive acute thrombotic events in the population treated with doxorubicin.Citation47 The explanation is a platelet paradox effect of doxorubicin, enhancing platelet adhesion to endothelial cells on one hand and inhibiting platelet aggregation on the other hand, resulting in unstable endothelium-bound surface platelet aggregates that could reduce blood flow but not cause complete vessel occlusion.Citation47 Reactive oxygen species are involved in directly induced platelet cytotoxicity after doxorubicin, resulting in thrombocytopenia following therapy,Citation47Citation49 but may also be toxic to endothelial cells.Citation47 Thrombocytopenia is also caused by bone marrow toxicity of doxorubicin.Citation11 Endothelial cells exposed to doxorubicin exhibit a dose-related apoptosis in vitro and in vivo, mediated by caspase activation, with changes in the expression of the apoptosis-related genes.Citation50 Apoptosis, caused by doxorubicin, damages the vessels, causing excoriation, thrombosis and denudation of the endothelium in rabbit arteries.Citation50,Citation51

Spironolactone, an aldosterone antagonist, able to block the renin–angiotensin–aldosterone system, has positive effect on cardiac fibrosis and remodeling, reducing cardiotoxicity of anthracyclines.Citation39 Considering the add-on therapy effects of mineralocorticoid receptor blockers in improving arterial stiffness in hypertensive patients and their effects on the attenuation of vascular inflammation and fibrosis,Citation10 future research should focus also on the vascular benefits in patients with hematologic malignancies undergoing chemotherapy. In hypertensive patients treated with doxorubicin, drugs blocking the renin–angiotensin–aldosterone system are able to reduce not only blood pressure but also arterial stiffness.Citation41

Arterial stiffness elevation due to anthracyclines is related to increased oxidative stress, impaired vascular collagen turnover and vascular wall homeostasis due to nuclear cellular actions of anthracyclines, endothelial dysfunction with rapid depletion of systemic NO levels, apoptosis of endothelial cells, overexpression of inflammatory cytokines and increased platelet–endothelial cell adhesion enabling microthrombi formation.Citation4,Citation11,Citation30,Citation41,Citation47,Citation52

Cyclophosphamide, an alkylating agent, may cause endothelial injury, enabling extravasation of toxic metabolites, ischemic injury of cardiomyocytes, coronary vasospasm and intracapillary microemboli.Citation53 Endothelial damage may be also due to cumulative chemotherapy, associated with inactivation of endogenous NO synthase; reactive oxygen species derived from chemotherapy and impaired cell repair.Citation32 Ding et alCitation54 reported intravenous cyclophosphamide use as an independent risk factor for increased arterial stiffness in patients with systemic lupus erythematosus.

Tyrosine kinase inhibitors are very effective in the therapy of patients with chronic myeloid leukemia,Citation27 but are commonly associated with cardiotoxicity.Citation7 Vascular events, especially peripheral arterial occlusive disease, have been described in patients receiving nilotinib, bosutinib and ponatinib, especially if they had preexisting cardiovascular risk factors.Citation27 Little is known about the incidence and predisposing factors of vascular events in long-term tyrosine kinase inhibitor-treated patients with chronic myeloid leukemia; probably, vascular events occur in a dose-dependent manner.Citation27 Nilotinib may exert direct proatherogenic and antiangiogenic effects on endothelial cells, causing arterial stenosis and blocking recanalization and reperfusion after occurrence of arterial stenosis, and increases cholesterol and fasting glucose levels, despite high efficacy in treatment of patients with chronic myeloid leukemia.Citation27,Citation55 The proatherogenic effect of nilotinib has been confirmed by assessing the ankle brachial index in patients with chronic myeloid leukemia.Citation56 Ponatinib counteracts endothelial cell growth and survival, but little is known about the molecular targets responsible for the effects on vascular endothelial cells.Citation27

Radiotherapy

Several studies reported increased arterial stiffness due to radiotherapy in cancer,Citation57Citation59 related to total body irradiation.Citation60 Radiotherapy may also increase the activity of nuclear factor kappa B, associated with atherosclerosis.Citation61

Radiotherapy is also associated with increased arterial stiffness in patients with Hodgkin’s lymphoma, treated at an older age (after 35–40 years), related to accelerated atherosclerosis, endothelial dysfunction, presence of fibrous tissue, increased proteoglycan content and degeneration of the elastic fibers, induced by radiotherapy especially in smaller diameter arteries.Citation31 Mediastinal radiotherapy can impair PWV, but not radiotherapy of the cervical lymph nodes in Hodgkin’s lymphoma.Citation3 Aortic distensibility is inversely correlated with radiotherapy dose.Citation57

Krystal et alCitation62 evaluated 68 childhood cancer survivors, including patients who had lymphoma and leukemia, and found significantly higher values for PWV than that in controls, not related to radiation therapy or chemotherapy exposure. Vatanen et alCitation59 demonstrated that long-term childhood cancer survivors treated with total body irradiation during early childhood display signs of early arterial aging during adulthood, including decreased arterial lumen size and an increased carotid intima-media thickness.

Metabolic syndrome, including central obesity, insulin resistance, hypertension, dyslipidemia and impaired carbohydrate metabolism, was found in children and adult cancer survivors, related to exposure to steroids, cranial radiation therapy, total body irradiation and hypogonadism.Citation60

Hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation, a curative option in several hematologic malignancies, is associated with an increased risk of health conditions, such as cardiovascular and endocrine disorders, metabolic syndrome and subsequent malignancies, requiring systematic and targeted follow-up.Citation60,Citation63 Early arterial mechanical changes were found at young age after allogenic stem cell transplantation in children, including lower distensibility of the common carotid artery, which decreased with time passed after transplantation.Citation63

Cardiovascular consequences of increased arterial stiffness

An increased arterial stiffness causes a premature return of the reflected pulse wave in late systole, increasing central systolic blood pressure, pulse pressure and afterload of the left ventricle (causing left ventricular hypertrophy), and impairs coronary perfusion.Citation9 An increased stiffness of the aorta is an independent predictor of cardiovascular events in the adult population, and assessing arterial stiffness in patients with hematologic malignancies, before and after therapy, enables prevention of cardiovascular complications. Poor vascular health was mentioned also in childhood and very young survivors of acute lymphoid leukemia.Citation64

Conclusion

Hematologic malignancies impair vascular function and structure. Several cytostatics and radiotherapy are additional factors for the increased number of cardiovascular disorders in cancer survivors. Therefore, it is important to monitor arterial stiffness in patients with hematologic malignancies, especially if they are undergoing therapy with anthracyclines, cyclophosphamide or tyrosine kinase inhibitors; radiotherapy and stem cell transplantation or if they have cardiovascular risk factors. Vascular safety is an emerging challenge in patients with hematologic malignancies, and it is important to assess vascular stiffness before therapy, to consider the risk profile, to monitor metabolic and cardiovascular parameters and to develop protective mechanisms against toxic vascular effects of chemotherapy in order to prevent discontinuation of therapy.

Understanding the mechanisms linking arterial stiffness and hematologic malignancies enables development of prophylactic measures, multidisciplinary management and early intervention if necessary and may improve outcomes in oncology patients. Management of hematologic cancer survivors should include a multidisciplinary team, comprising a cardiologist and a hematologist, and long-term follow-up of patients is recommended. Complete blood count, a useful, inexpensive, widely available tool for management of patients with hematologic malignancies, can also provide useful information for cardiovascular complications.

Further studies to clarify the mechanisms and reversibility of chemotherapy-induced vascular toxicity are needed, enabling control of long-term vascular complications in cancer survivors. Guidelines regarding cardiovascular health screening and cardiovascular risk scores are necessary in cancer survivors in order to improve prognosis and quality of life of the patients.

Disclosure

The authors report no conflicts of interest in this work.

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