Role of Echocardiography and Cardiac Biomarkers in Early Detection of Hematopoietic Stem Cell Transplantation Associated Cardiotoxicity
Authors: Oliver Ana Carolina , Superchi Roberto , Federico Superchi , Matilde Canabal , Silvana Jubin , Errecarte Carolina , Ada Caneiro , Pierri Silvia , Galeano Sebastian , Riva Eloisa , Laura Bello , Gai Regis , Andrew Miller , Muxi Pablo J. , Mosquera Ricardo Fabian 
Published: November 2019

Introduction:
Cardiovascular disease is the first cause of death worldwide; in Uruguay it corresponds to 30%. Classical risk factors are: age, smoking, male gender, diabetes, hypertension, hyperuricemia and dyslipidemia. In the last decades, the increasing use of chemotherapy and radiotherapy in oncology have augmented cardiovascular side effects. The improvement in response and overall survival of hematologic patients allow a longer time to develop cardiovascular complications. Cardiotoxicity has been studied extensively in the setting of breast cancer and anthracyclines use.However, within Hematopoietic Stem Cell Transplantation (HSCT) this is still being in research. The estimated incidence is 5-10 % but the data is little and unsystematic. The primary objective of this trial is to assess subclinical myocardial damage using biomarkers and echocardiography and identify patients at high risk of developing cardiotoxicity after HSCT.
Methods:
This is a prospective, single center trial that started on April 2017. Population: adult patients admitted in the British Hospital Transplant Unit, Montevideo Uruguay to receive either an autologous or allogeneic HSCT. Inclusion criteria: 18 years old or older, Eastern Cooperative Oncology Group performance status 0-1. Patients who signed informed consent. Exclusion criteria: baseline left ventricular ejection fraction (LVEF) <50%, systemic amyloidosis. We have performed serial measurements of cardiac biomarkers (pro-BNP, Troponin T, Troponin I and CPK) at the admission, day 1, day 14 and day 30 after HSCT. Echocardiograms at admission and at day 30 were performed by the same physicians. Biomarkers and echocardiogram were repeated at day 100 if there were alterations in normal values of biomarkers or myocardial dysfunction measured by the echocardiography in day 30.
Results:
Between May 2017 and April 2019 we have perform 96 HSCT, of those, all 96 consented to enter into the study. Male gender 57 (60%). Median age 56 years old (18-74). Diseases: Multiple myeloma: 42, Non Hodgkin Lymphoma 27, Hodgkin Lymphoma 12, Acute Myeloid Leukemia 11, Solid tumors 2, Aplasia 1, Renal Amyloidosis 1. Type of transplant: Autologous were 85 and Related Allogenic 11 patients.
82 patients (85,5%) have been studied with the 4 biomarkers determinations and the 2 echocardiograms proposed by the study. Causes for which patients were not studied: 3 because they died before the time points, and 11 because violation of protocol. Forty nine (51%) patients had one biomarker elevated at Day 30, so they would have to be studied at Day 100. Of them 49% performed the echocardiogram studies at D100 and 45% the biomarkers.
Biomarkers: The evolution of the biomarkers during transplant is shown in figure 1. Pro-BNP is the biomarker that has more significant changes: 71% of transplanted patients has pro-BNP elevated at day 14; at day 30 53% persists with this biomarker elevated. At day 100, Troponin T and I 0% elevated, CPK 4% and pro-BNP 75% elevated.
Echocardiogram: no one patient reached the definition of cardiotoxicity in terms of a decrease in LVEF of more than 10% to a value of less than 53%. However, 12 patients (12,5%) had a reduction of the Global Longitudinal Strain (GLS) of more than 15%. Currently, the deformation index strain is an echocardiographic way to detect early cardiac involvement. The decline in rates of deformation precedes the decline in LVEF and persists during subsequent cancer treatment. A relative reduction of 15% or more of GLS has the greatest specificity in predicting subclinical left ventricular dysfunction. In 74 patients we were able to measure the strain at the admission and 81 at day 30. At day 100 there were no significant reduction of LVEF and 3 patients had a relative reduction of GLS more than 15%.
Conclusions:
This is a prospective and systematic analysis of biomarker and echocardiographic changes during HSCT. We found changes in biomarkers and echocardiographic measures during HSCT: pro-BNP is the biomarker that raises during transplant, and it is persistently elevated at day 30 in 53%. GLS has a significant reduction in 12,5% of patients. We hypothesized that this changes can be predictive of clinical cardiotoxicity in the future, therefore, we are planning to enroll 100 more patients to confirm this results and after that, correlate this changes with comorbidities, conditioning regimens and study the development of clinical cardiotoxicity after 1-year post HSCT.

Disclosures
Galeano: Szabo SA: Other: (Equity interest).