Καρδιαγγειακές Επιπλοκές στον Ογκολογικό Ασθενή Αρτηριακή και Πνευμονική Υπέρταση

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1 Καρδιαγγειακές Επιπλοκές στον Ογκολογικό Ασθενή Αρτηριακή και Πνευμονική Υπέρταση Τσούγκος Ηλίας Διευθυντής Β Καρδιολογικής κλινικής ENHC Επ. Καθηγητής Καρδιολογίας EUC

2 The spectrum of cardiovascular complications of cancer therapy ANS dysfunction Myocardial dysfunction / Heart failure Coronary artery disease Pericardial disease Arterial hypertension Cancer therapy Pulmonary hypertension Arrhythmias Peripheral vascular disease Thromboembolic disease Valvular disease

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7 Mechanisms of chemotherapy cardiotoxicity Direct toxic effects: Cardiomyocytes (anthracyclines, trastuzumab) Loss (death/apoptosis) Dysfunction (mitochondria, contraction proteins) Endothelial cells (5-FU) Indirect toxic effects: Hypercoagulability (VEGF inh, alkylating agents) Hypertension (VEGF inh) Arrhythmias, AFib (ifosfamide, gemcitabine, melphalan) Albini et al, J Natl Cancer Inst 2010

8 Hypertention influences CVD and the neoplastic process Hypertension Angiogenic endothelial growth factor oxidative stress Vascular endothelial growth factor Liver and Kidney Cancer Both diastolic and systolic heart failure Bloom et al, Circ Heart Fail 2016

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13 Pulmonary Hypertension and Cancer: Etiology,Diagnosis, and Management Pulmonary hypertension is caused by cancer and its therapeutic agents including chemotherapy, radiotherapy, and even the targeted therapies. Ironically, some of the cancer therapies that cause one type of pulmonary hypertension (PH) could potentially be employed in the treatment of another PH type. In short, the relationship between cancer, cancer therapy, and PH is an interesting one requiring further attention, education, and research.

14 Pulmonary Hypertension and Cancer: Etiology,Diagnosis, and Management McLaughlin VV, J AmColl Cardiol (18):

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19 Pulmonary hypertension in cancer patients

20 Pulmonary hypertension in cancer patients Chronic thromboembolic pulmonary hypertension Epidimiology: Majority of cancers associated with thromboembolic events are clinically evident and have been previously diagnosed at the time of the event The five most common sites for cancer diagnosed at the time of venous thromboembolism included the following: 1. lung (17%), 2. pancreas (10%), 3. colon and rectum (8%), 4. kidney (8%), and 5. prostate (7%) Aitiology: Tumor cells and host vascular cells have been shown to express proteaseactivated receptor proteins that interact with coagulation factors (such as tissue factor and thrombin) which leads to the induction of genes related to angiogenesis, cell survival, and cell adhesion and migration Fatima A, MD Curr Treat Options Cardio Med (2017)

21 Pulmonary hypertension in cancer patients Pulmonary hypertension related to other pulmonary artery obstructions PH can also be caused by direct compression from tumor or tumor invasion of the pulmonary artery. PH related to this obstructive mechanism is included in the PH group 4 due to other pulmonary artery obstructions. The cancer-related etiologiesof direct compression are rare and include: 1. pulmonary angiosarcoma and 2. intravascular large B cell lymphoma. Fatima A, MD Curr Treat Options Cardio Med (2017)

22 Pulmonary hypertension in cancer patients Pulmonary hypertension with unclear and/or multifactorial mechanisms Group 5 PH is a category of miscellaneous causes of PH with unclear pathogenesis. This class includes rare systemic disorders that have lung involve mentsuch as 1. lymphangioleiomyomatosis (LAM) 2. neurofibromatosis type 1 (NF1) 3. metastatic cancer or its complications,such as in pulmonary tumor thrombotic microangiopathy (PTTM) Mechanism: 1. Proliferation of abnormal smooth muscle-like cells along lymphatics in the lungs and abdomen 2. Hypoxia and reduced pulmonary vascular capacitance caused by the cystic lesions Fatima A, MD Curr Treat Options Cardio Med (2017)

23 Pulmonary hypertension associated with cancer therapy

24 Pulmonary hypertension associated with cancer therapy Chemotherapy-induced PH is an important consideration in the cancer patient. Chemotherapeutic agents have long been implicated in PH involving both the lung parenchyma (i.e., pulmonary fibrosis) and the pulmonary vasculature (i.e., pulmonary obstruction due to dasatinib-mediated PAH and alkylating agents causing PVOD) Hoeper MM J Am Coll Cardiol. 2013

25 Pulmonary hypertension associated with cancer therapy The role of dasatinib in PAH Dasatinib is presently approved for first-line treatment of Philadelphia-positive chronic myelogenous leukemia (CML) and for all phases of Philadelphiapositive CML with resistance or intolerance to prior therapy Dasatinib is a second-generation tyrosine kinase inhibitor and acts as a broad inhibitor of PDGFR, Dasatinib was shown to have potent inhibitory effects on pulmonary smooth muscle cells and vascular remodeling Initial case series from the French PH registry suggested that chronic treatment with dasatinib in patients with chronic myelogenous leukemia was associated with the onset of severe PAH, marked by severe symptoms and hemodynamic compromise. Although clinical improvement was generally observed after withdrawal of dasatinib, some patients remained symptomatic and showed persistent hemodynamic impairment severalmonths after discontinuation of this agent Hoeper MM J Am Coll Cardiol. 2013

26 Pulmonary hypertension associated with cancer therapy The role of proteasome inhibitors in PH Proteasome inhibitors are highly effective chemotherapeutic agents that act by targeting the ubiquitin-proteasome pathway that is responsible for degradation of the regulatory proteins and maintaining normal cellular homeostasis. Bortezomib is a reversible proteasome inhibitor that is used for the treatment of multiple myeloma and mantle cell lymphoma. development of PH in 2% of patients

27 The role of chemotherapy in PVOD Pulmonary veno-occlusive disease (PVOD) is a rare subgroup of PH (group 1 ) characterized by progressive obstruction of the small pulmonary veins leading to pulmonary venous remodeling and a dismal prognosis Several chemotherapeutic agents, including alkylating agents (cyclophosphamide, mitomycin, procarbazine, carmustine, and cisplatin), plant alkaloids (vincristine, etoposide, and docetaxel), antimetabolites (doxorubicin, daunorubicin, and bleomycin), and cytotoxic antibiotics agents (cytarabine and methotrexate), have been suggested from the French PH Network to induce PVOD. Hoeper MM J Am Coll Cardiol. 2013

28 General approach to diagnosis of pulmonary hypertension incancer

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30 General approach to the treatment of pulmonary hypertension in cancer

31 Treatment of pulmonary hypertension Management of PH in cancer patients is highly variable and depends on the underlying cause of PH as well as treatment of the underlying malignancy Regardless of the etiology, general management is similar for all PH patients and focuses on improving symptoms and quality of life, mitigating disease progression, and improving mortality Diuretics oxygen, digoxin, anticoagulation, vaccination, and exercise therapy This includes treatment with prostanoids, endothelin receptor antagonists, phosphodiesterase 5 inhibitors

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35 The role of radiotherapy and bone marrow transplantation in PVOD The role of cancer therapy in PH due to left heart disease Hoeper MM J Am Coll Cardiol. 2013

36 Role of system-wide endothelial dysfunction in HFPEF pathophysiology Oxidative Medicine and Cellular Longevity 2017

37 Systemic and myocardial signaling in HFPEF Circulation July 5; 134(1):

38 Pathophysiologic mechanisms contributing to increased myocardial stiffness in HFPEF Heart Failure Clin 10 (2014)

39 Extracellular matrix and cardiomyocytes determine myocardial stiffness and interact via matricellular proteins European Heart Journal (2011) 32,

40 The 3 Independent Determinants of LV Early Diastolic Lengthening Velocity and Schematic Drawing of Diastolic LV Filling J Am Coll Cardiol Img 2015;8:

41 Summary of mechanisms of exercise intolerance in HFPEF Circ J 2014; 78: 20 32

42 Abnormalities in diastolic reserve, contractility, heart rate, and peripheral vasodilation in HFPEF European Heart Journal (2011) 32,

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44 Estimated and projected cancer survivors in USA de Moor JS et al. Cancer Epidemiol Biomarkers Prev 2013

45 Childhood cancer survivors in UK Skinner et al. Lancet Oncol 2006 Kroll et al. Cancer Stats Monograph 2004

46 Causes of death in cancer survivors Causes of death in 1807 cancer survivors followed for 7 years Other 16% Heart disease 33% Cancer 51% Ning et al. Cancer Res 2012

47 Cumulative incidence of cardiomyopathy in breast cancer survivors Years since chemotherapy Doyle et al, J Clin Oncol 2005

48 Effects of anthracyclines in long-term survivors of childhood cancer 62 long-term survivors of childhood cancer mean age 15 years 8 years post-anthracycline, CMR revealed: LVEF <45%: 18% ; LVEF 45-55%: 61% RV dysfunction: 27% J Am Coll Cardiol 2013

49 Mechanisms and forms of heart disease in cancer

50 Cancer Determinants Pre-existing of cardiovascular Cancer injury in cancer RF and patients CVD therapy

51 Effects of cancer therapy: Radiation-induced cardiac injury Groarke et al, Eur Heart J 2014

52 Cancer Determinants Pre-existing of cardiovascular Cancer injury in cancer RF and patients CVD therapy

53 Effect of CV disease and risk factors: The Multiple-Hit Hypothesis Jones et al, J Am Coll Cardiol 2007

54 Obesity Alcohol Diabetes Mellitus Physical Activity Cancer and CVD Hypertens ion Diet Shared risk factors Hyperlipi demia Tobacco

55 Inflammation in CVD Inflammation in Cancer Oxidative Stress and Reactive Oxygen Species Biological Mechanisms Common to CVD and Cancer

56 Participation of inflammation in all stages of atherosclerosis. Peter Libby Am J Clin Nutr 2006;83:456S-460S 2006 by American Society for Nutrition

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58 Participation of inflammation in all stages of cancer Inflammation within the tumor microenvironment has effects that promote malignant transformation of cells, carcinogenesis, and it s progression. Furthermore, as tumors grow, their survival depends on the release of chemicals that signal immune cells to the tumor.

59 Body-mass index and incidence of cancer: a systematic review and metaanalysis of prospective observational studies The Lancet The results of this meta-analysis demonstrate a significant association between obesity and some of the 13 cancers for men and many of the 13 cancers for women. Obesity was significantly and positively associated with 5 of the possible 11 cancers relevant to men including, colon, gallbladder, malignant melanoma, pancreatic, and renal Dr Andrew G et al Published: 16 February 2008

60 Hyperinsulinemia Hyperglycemia Diabetes mellitus IGF influences CVD and the neoplastic process Inflammation The hormone resistin links obesity to diabetes Steppan C et al Nature 2001

61 Diabetes mellitus influences CVD and the neoplastic process Hyperinsulinemia and IGF Tumor cells express both insulin receptors and IGF receptors Decreases hepatic synthesis of sex hormones Promotes cell proliferation Breast and endometrial cancer Insulin resistance promotes dyslipidemia colorectal cancer prostate cancer breast cancer Atherosclerosis Hyperinsulinemia decreases hepatic synthesis of sex hormone binding globulins, increasing estrogen levels in men and women and testosterone levels in women Jones et al, J Am Coll Cardiol 2007

62 Tumor cells often express receptors that attract cholesterol metabolites necessary to support their growth, thus diminishing circulating levels in the plasma The cholesterol metabolite, 27-hydroxycholesterol, is similar in both structure and action to estradiol (an estrogen) and has been recently implicated in breast cancer The enzyme that produces this metabolite 27-hydroxycholesterol is abundant within tumor-associated macrophages, suggesting a probable role for inflammatory cells in the tumor process as well. Hyperlipidemia, Cancer, and CVD: Is There a Shared Biology? Gabitova L,Clin Cancer Res. 2014

63 Tobacco, Cancer, and CVD: Is There a Shared Biology? Tobacco smoking affects the early stages of atherosclerosis by decreasing levels of nitric oxide, causing vasomotor dysfunction, and increasing oxidative stress, causing endothelial and structural changes. It plays a largely thrombotic role in acute coronary events Moris PB J Am Coll Cardiol. 2015

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65 Tobacco, Cancer, and CVD: Is There a Shared The main carcinogenic mechanism from smoking is repetitive injury to squamous cell epithelium, Biology? exceeding normal regenerative abilities. Tobacco smoking produces a number of irritants, carcinogens, proinflammatory stimuli, and oxidizing agents. These processes stimulate abnormal signaling pathways found within smoking-related cancer and CVD. Moris PBJ Am Coll Cardiol. 2015

66 Diet, Cancer, and CVD: Is There a Shared Biology?

67 Controlling CVD Risk Factors Can Reduce the Risk of Cancer

68 The EPIC study followed participants aged 35 to 65 years. Healthy lifestyle factors were defined as Controlling CVD Risk 1. Never smoking, 2. BMI <30, 3. Physical activity >3.5 hours weekly, 4. Healthy diet. Factors Can After a Reduce mean follow-up of 7.8 the years, participants Risk who of adhered to all 4 healthy lifestyle factors in comparison with none had an adjusted HR 0.22 (95% CI, ) for chronic disease; 0.07 (95% CI, ) for diabetes mellitus; 0.19 (95% CI, ) for myocardial infarction; 0.50 (95% CI, ) for stroke; and 0.64 (95% CI, ) Cancer for cancer.

69 Can Reduce the Risk of Cancer

70 Association of Cardiovascular Health With Subclinical Disease and Incident Events: The Multi Ethnic Study of Atherosclerosis JAMA 2013 Whether Controlling better adherence to the 7 CVD ideal cardiovascular Risk health metrics defined by the AHA was associated with incident cancer. This longitudinal analysis from 1987 to 2006 within the ARIC cohort (45 64 years of age at baseline) identified incident cancer Factors (excluding nonmelanoma Can skin cancer) in 2880 of the participants. Adherence at least 6 of the 7 ideal health metrics (2.7% of the overall population) resulted in a 51% lower risk of incident cancer Reduce the Risk of Cancer

71 Cardiac consultation in cancer: in whom, when and how?

72 In whom? Baseline risk factors for cardiotoxicity ESC 2016

73 Risk factors for anthracycline-induced cardiotoxicity ESC 2016

74 Before cancer therapy Identification of high risk patients Identification and treatment of heart disease or risk factors Use of specific prevention strategies When?

75 Before cancer therapy Identification of high risk patients Identification and treatment of heart disease or risk factors Use of specific prevention strategies During cancer therapy Early identification and treatment of cardiovascular complications Modification of cancer therapy if needed When?

76 Before cancer therapy Identification of high risk patients Identification and treatment of heart disease or risk factors Use of specific prevention strategies During cancer therapy Early identification and treatment of cardiovascular complications Modification of cancer therapy if needed After cancer therapy Regular follow-up When?

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78 Cardiac approach to cancer patients Cardinale et al, Curr Cardiol Rep 2016

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80 Effects of cancer itself: Pathophysiology of AFib in cancer Farmakis, Parissis, Filippatos J Am Coll Cardiol 2014

81 Before cancer therapy ESC 2016

82 Before cancer therapy ESC 2016

83 Trials on primary prevention (RCT selection) Trial Agent N Design/Fup Results Cardinale (2006) Enalapril 114 RCT/12mo No LVEF MACE incidence Pituskin (2015) Bisoprolol Perindopril Gulati (2015) Candesartan 120 RCT/2-16mo 99 RCT/12mo No LVEF No LVEF Akpek (2015) Spironolactone 83 RCT/6mo No LVEF No TNI and BNP Acar (2011) Atorvastatin 40 RCT/6mo No LVEF Cardinale et al, Curr Cardiol Rep 2016

84 During cancer therapy Tools for detecting cardiotoxicity ESC 2016

85 Echo monitoring 2625 pts receiving anthracycline chemo (breast Ca or NHL) Close monitoring (3-monthy during chemo and 1 st year, 6-monthly for 4 years, yearly afterwards) 9% LVEF decline (decrease >10% and <50%) 2% HF NYHA III-IV 0.3% hospitalized for AHF (0.2% died of AHF) Cardinale et al, Circulation 2015

86 Mean time to LVEF decline: 3.5 months 98% of cases within 1 st year 5 pts with LVEF decline at 5.5 years: 4 had CAD, 1 had additional Rth 1 year before Time course of LVEF decline post-anthracycline Cardinale et al, Circulation 2015

87 Troponin predicts cardiac events and LVEF decline TnI measured soon after chemotherapy (early TnI) and 1 month later (late TnI). Cardinale et al, Circulation 2004

88 ΝT-proBNP predicts LVEF decline Cardinale & Sandri, Prog Cardiovasc Dis 2010

89 2D strain predicts LV dysfunction early Stoodley et al, Eur J Echocard 2011 Α decrease in longitudinal strain after the 3 rd cycle of epirubicin was the best predictor of cardiotoxicity after treatment Florescu et al, J Am Soc Echocardiogr 2014

90 CMR-LGE in anthracycline-induced cardiomyopathy Mid-wall or subepicardial LGE Prevalence 0-100% Thavendiranathanet al, Circ Cardiovasc Imaging 2013

91 Assessment of myocardial fibrosis in anthracycline-induced cardiomyopathy ECV values (mean/sd) were increased in the basal, mid, and apical short-axis images. Myocardial fibrosis is diffuse and may be missed by LGE Extracellular volume fraction (ECV) with pre- and post-contrast T1 mapping may illustrate diffuse myocardial injury Thavendiranathanet al, Circ Cardiovasc Imaging 2013

92 Effects of ACEi and BB on anthracycline-induced cardiotoxicity 201 pts, LVEF <45% due to anthracycline chemotherapy Enalapril +/- carvedilol Response rates: 42% LVEF incr. >50% - 13% LVEF incr. >10% but <50% - 45% LVEF incr. <10% but <50% Time of therapy onset a crucial determinant of response Cardinale et al, JACC 2010

93 Effects of ACEi and BB on anthracycline-induced cardiotoxicity 2625 pts receiving anthracycline chemo (breast Ca or NHL) Enalapril and carvedilol or bisoprolol: 82% LVEF recovery: 11% full recovery (pre-chemo value) 71% partial recovery (increase >5% and >50%) Mean time to LVEF recovery: 8 months Cardinale et al, Circulation 2015

94 Effects of ACEi on cardiotoxicity due to highdose chemotherapy 473 pts receiving high-dose chemo regimens 24% had TnI increase and responded to ACEi Cardinale et al, Circulation 2006