Muckienė, Gintarė

Breast cancer is the most common cancer in women worldwide. Anthracyclines (doxorubicin, epirubicin, daunorubicin, idarubicin) are among the most used drugs for the treatment of breast cancer. Unfortunately, anthracyclines cause cardiotoxicity, which is a limiting factor for its use, and the lifetime cumulative dose of anthracyclines is the major risk factor for cardiotoxicity. In our study, we focused on acute and subacute heart damage. One of the main factors is a genetic predisposition, which determines individual susceptibility to anthracycline cardiotoxicity. The main idea of this study was, for the first time, to evaluate drug metabolism-related genes as a risk factor for developing cardiovascular toxicity in breast cancer patients. The main objective of our study was to identify the impact of drug metabolism-related gene SNPs on the development of subclinical heart damage during and/or after doxorubicin-based chemotherapy in breast cancer patients. The data of 81 women with breast cancer treated with doxorubicin-based chemotherapy in an outpatient clinic were analyzed, and SNP RT-PCR tests were performed. The drug metabolism-related gene variants SULT2B1 rs10426377, UGT1A6 rs17863783, CBR1 rs9024, CBR3 rs1056892, NCF4 rs1883112, and CYBA rs1049255 did not reach a statistically important impact on ABCC in multivariate logistic regression analysis. However, we identified that NCF4 rs1883112 had a risk reduction tendency for ABCC (OR = 0.49, 95% CI 0.27–0.87, p = 0.015). Our findings suggest that some SNPs, such as NCF4 rs1883112, may be associated with a reduced risk of cardiotoxicity, while no variants in this study showed a statistically significant increased risk. Even though, NCF4 rs1883112 showed a risk reduction tendency, suggesting the potential for personalized risk stratification. We can conclude that multiple genes are involved in ABCC, with different impacts, and it is unlikely that there is a single driver gene in ABCC pathogenesis.

Jūsų rankose - Lietuvos sveikatos mokslų universiteto vadovėlis „Kardiologijos pagrindai“. Tai platus ir svarus leidinys, apimantis sindrominę diagnostiką, paciento tyrimo metodiką, kardiologijoje naudojamų vaistų klinikinę farmakologiją, vaizdinius širdies ligų tyrimo metodus, genetinius širdies ligų tyrimus bei tam tikrų širdies ir kraujagyslių ligų profilaktiką, diagnostiką, gydymą ir reabilitaciją. Vadovėlį rengė LSMU Kardiologijos klinikos, Vidaus ligų klinikos, Širdies, krūtinės ir kraujagyslių chirurgijos klinikos, Reabilitacijos klinikos, Anesteziologijos klinikos, Genetikos ir molekulinės medicinos klinikos, Onkologijos ir hematologijos klinikos, Fiziologijos ir farmakologijos instituto bei Kardiologijos instituto darbuotojai, iš viso 68 autoriai, todėl kiekvieną skyrių rašė geriausi tos srities specialistai. Pastarasis dešimtmetis medicinoje išsiskyrė įrodymais grįstos medicinos įsigalėjimu, diagnostikai bei gydymui naudojamų technologijų sudėtingumu ir įvairove, labai greitu mokslo bei technikos naujovių įdiegimu į kasdieninę klinikinę praktiką. Todėl tikslinga atnaujinti kardiologijos vadovėlį, kuris taptų ne vien priemone studentams mokyti, bet ir kiekvieno gydytojo rezidento, vidaus ligų gydytojo, kardiologo parankine knyga. Laikas bėga labai greitai, todėl net rengiant šį vadovėlį keitėsi daugelio ligų diagnostikos bei gydymo rekomendacijos, nes greita mokslo pažanga ir nauji duomenys nuolat keičia mūsų požiūrį į daugelį dalykų, kurie atrodė aiškūs ir nusistovėję. Todėl siūlome skaitytojui priimti skaitomą medžiagą kaip geriausią šiuo metu turimą informaciją ir kardiologinės patologijos sampratą, tačiau kartu palikti protą atvirą naujovėms, kurios gali ateiti plečiantis mūsų žinioms visose medicinos srityse. Dėkojame visiems, prisidėjusiems prie vadovėlio „Kardiologijos pagrindai“ išleidimo: autoriams, recenzentams, kalbos redaktorei, leidėjams, o ypač rėmėjams, be kurių pagalbos šis leidinys nebūtų išvydęs dienos šviesos.

BACKGROUND/OBJECTIVES: The 6-minute walking test (6MWT) is an easily performed, widely available and well-tolerated test for assessing the functional capacity of patients with HF in everyday clinical practice. The measurement properties of the 6MWT, such as reliability and validity, have been studied in patients with chronic heart failure, coronary artery disease, and cancer. However, little is currently known about the 6MWT and cardiotoxicity. The study was aimed at assessing the incidence of cancer therapy-related cardiovascular toxicity, identified the role of 6MWT as early predictor of early onset cardiotoxicity.

METHODS: We performed a prospective study of 85 patients with breast cancer, treated with doxorubicin-based chemotherapy in the Department of Oncology and Hematology. 2D echocardiography and speckle tracking echocardiography were performed before anticancer treatment was started and after the treatment. We defined anthracycline-induced subclinical cardiotoxicity if a decline in global longitudinal strain (GLS) by >15% from baseline was observed and based on that patients were divided into two groups– patients with subclinical cardiotoxicity and patients without subclinical cardiotoxicity. The 6MWT was developed by the American Thoracic Society comprehensive guidelines. The 6MWT was performed in a long straight hospital corridor, over a 30-m distance. Statistical analysis was performed with „IBM SPSS statistics 27.0" program. Statistical significance level p<0.05.

RESULTS: In the study population statistically significant GLS reduction was detected before and after the anticancer treatment (-21±0.53 vs. -18.1± 1.18, p<0.01). Of 85 women (mean age, 54.5 (9.3) years) subclinical left ventricle dysfunction was identified in 51 (60%). We found a significant negative correlation between baseline 6MWT and cardiotoxicity (r=0.3 and p=0.02). The baseline 6MWT results were significantly lower among patients with subclinical cardiotoxicity (494.3 ± 40.5 m vs 629.8 ± 60.1 m, p<0.001). The diagnostic validity of 6 MWT as a cardiotoxicity biomarker was evaluated using the non-parametric ROC curve (Pic. 1). We obtained an optimal cut-off point of 6MWT of ≤540m. (AUC=0.98; p < 0.001).

CONCLUSIONS: Baseline 6MWT may be used as independed prognostic predictor of subclinical anthracycline-induced cardiotoxicity.

Krūties vėžys yra vienas dažniausiai moterims diagnozuojamų vėžių. Krūties vėžio gydymo pažanga pagerino pacienčių išgyvenamumą, tačiau kartu padidino sergamumą ir mirštamumą, nulemtus šalutinio chemoterapijos poveikio. Amerikos klinikinės onkologijos asociacijos (angl. American Society of Clinical Oncology, ASCO) paskelbtose gairėse teigiama, kad širdies disfunkcija, kaip vienas iš dažniausių nepageidaujamų poveikių klinikinėje praktikoje gydant onkologinius ligonius, turi neigiamą poveikį gydymo veiksmingumui, gyvenimo kokybei ir išgyvenamumui. Vienas svarbiausių, o kartu ir sunkiausių, antraciklinų šalutinis poveikis – širdies pažaida, galinti sukelti tiek besimptomę širdies pažaidą, tiek sunkų stazinį širdies nepakankamumą (ŠN). Vienas pagrindinių tikslų – ankstyvas širdies pažaidos nustatymas ir tinkamas šių pacientų gydymas – gali pagerinti rezultatus ir sumažinti ŠN progresavimą. Darbo tikslas – nustatyti vaistų nuo vėžio sukeltos ankstyvosios besimptomės širdies pažaidos prognozinius klinikinius, echokardiografinius, biocheminius ir genetinius veiksnius pacientėms, sergančioms krūties vėžiu, kurioms gydyti skiriama chemoterapija doksorubicino pagrindu. Darbo uždaviniai: 1) Įvertinti klinikinių, echokardiografinių ir biocheminių rodiklių pokyčius gydymo metu bei jų sąsajas su ankstyvosios širdies pažaidos atsiradimu pacientėms, sergančioms krūties vėžiu, kurioms skiriama chemoterapija antraciklinų pagrindu; 2) Nustatyti kairiojo skilvelio (KS) ilgosios ašies, 6 minučių ėjimo mėginio (6 MĖM) ir NT-proBNP rezultatų prognozinę reikšmę vaistų nuo vėžio sukeltai širdies pažaidai atsirasti; 3) Nustatyti su vaistų pernaša susijusių ABCB1 rs1045642 ir ABCC1 rs4148350 bei rs3743527 vieno nukleotido polimorfizmų ryšį su vaistų nuo vėžio sukelta besimptome širdies pažaida. Išvados: 1) Kardiotoksinė pažaida buvo nustatyta 22 (25,9 proc.) tiriamosioms. Pacientėms, kurioms gydymo fone išsivystė KS pažaida, stebėtas didesnis KS ilgosios ašies f-jos pablogėjimas, lyginant su pacientėmis, kurioms pažaida neišsivystė: bendroji išilginė įtampa (BIĮ) sumažėjo iki –16,53 ± 1,07 proc. palyginti su –18,48 ± 0,94 proc. (po keturių chemoterapijos kursų). Stebėtas reikšmingas 6 minučių ėjimo mėginio (6 MĖM) rezultatų sumažėjimas (508,64 ± 56,0 m palyginti su 556,98 ± 61,98 m) ir NT-proBNP koncentracijos padidėjimas (207,84 ± 93,33 ng/l palyginti su 133,6 7± 56,52 ng/l) po gydymo. Nustatėme reikšmingas koreliacijas tarp KS išstūmio frakcijos (KS IF) pokyčio ir BIĮ, dviburio vožtuvo žiedo judesio amplitudės (DVŽJA), 6 MĖM bei NT-proBNP rezultatų, gautų po dviejų chemoterapijos kursų; 2) Nustatyta, kad BIĮ ≤ –18,0 proc. (jautrumas 72,7 proc., specifiškumas 92, proc.), DVŽJA ≤ 13,7 mm (jautrumas 77,3 proc., specifiškumas 52,4 proc.), NT-proBNP > 125 ng/l (jautrumas 90,0 proc., specifiškumas 56,9 proc.), 6 MĖM ≤ 515 m (jautrumas 54,5 proc., specifiškumas 85,7 proc.) ribinės vertės prognozuoja ankstyvos (po keturių chemoterapijos kursų) kardiotoksinės pažaidos išsivystymą; 3) Nustatėme reikšmingą ryšį tarp ABCC1 rs4148350 genotipų bei T alelio nešiojimo ir kardiotoksiškumo atsiradimo. Nustatyta, kad rs4148350 TG genotipas, palyginti su referentiniu GG genotipu, kardiotoksiškumo atsiradimą didina 8 kartus. Tyrimo rezultatai parodė, kad rs4148350 T alelio nešiojimas, palyginti su ne nešiojimu, susijęs su 5 kartus didesne kardiotoksiškumo išsivystymo rizika.

Background/objectives: The literature data on the use of biomarkers for anthracycline-induced cardiotoxicity risk stratification before cancer therapy is still limited. N-terminal pro-brain natriuretic peptide (NT-proBNP) is one of biomarkers for cardiovascular disease (CVD) risk stratification. A few studies have shown the role of NT-proBNP measurement at baseline to predict future anthracycline-induced cardiotoxicity. The study was aimed at assessing the incidence of cancer therapy-related cardiovascular toxicity, identified the role of NT-proBNP as early predictor of early onset cardiotoxicity. Methods: We performed a prospective study of 85 patients with breast cancer, treated with doxorubicin-based chemotherapy in the Department of Oncology and Hematology. 2D echocardiography and speckle tracking echocardiography were performed before anticancer treatment was started and after the treatment. We defined anthracycline-induced subclinical cardiotoxicity if a decline in global longitudinal strain (GLS) by >15% from baseline was observed and based on that patients were devided into two groups– patients with subclinical cardiotoxicity and patients without subclinical cardiotoxicity. Blood samples were obtained from all patients at the beginning of the study and tested for NTproBNP. Statistical analysis was performed with „IBM SPSS statistics 27.0" program. Statistical significance level p<0.05.Results: In the study population statistically significant GLS reduction was detected before and after the anticancer treatment (-21±0.53 vs. -18.1± 1.18, p<0.01). Of 85 women (mean age, 54.5 (9.3) years) subclinical left ventricle dysfunction was identified in 51 (60%). There was a significant positive correlation between baseline level of NT-proBNP and cardiotoxicity (r=0,3, p=0,02). The baseline levels of NT-proBNP were significantly higher among patients with subclinical cardiotoxicity (142.4±90.5 ng/l vs. 96.7±76.3 ng/l, p =0.008). The diagnostic validity of NT-proBNP as a cardiotoxicity biomarker was evaluated using the non-parametric ROC curve (Pic. 1). We obtained an optimal cut-off point of NT-proBNP of >62.1 ng/l (AUC=0.68; p < 0.001; OR: 6,74; 95% CI: 2,29–19,8). Conclusions: Baseline NT-pro BNP may be used as independed prognostic predictor of subclinical anthracycline-induced cardiotoxicity.

Background. Cardiac side effects associated with anthracycline-based treatment may seriously compromise the prognosis of patients with breast cancer (BC). Evidence shows that genes that operate in drug metabolism can influence the risk of anthracycline-induced cardiotoxicity (AIC). ATP-binding cassette (ABC) transporters could serve as one of the potential biomarkers for AIC risk stratification. We aimed to determine the link between single-nucleotide polymorphisms (SNPs) in several ABC genes (ABCB1 rs1045642, ABCC1 rs4148350, ABCC1 rs3743527) and cardiotoxicity. Methods. The study included 71 patients with BC, who were treated with doxorubicin-based chemotherapy. Two-dimensional echocardiography and speckle-tracking echocardiography were performed. AIC was defined as a new decrease of 10 percentage points in the left ventricular ejection fraction (LVEF). SNPs in ABCB1 and ABCC1 genes were evaluated using real-time PCR. Results. After a cumulative dose of 236.70 mg/m2 of doxorubicin, 28.2% patients met the criteria of AIC. Patients who developed AIC had a larger impairment in left ventricular systolic function compared to those who did not develop AIC (LVEF: 50.20 ± 2.38% vs. 55.41 ± 1.13%, p < 0.001; global longitudinal strain: −17.03 ± 0.52% vs. −18.40 ± 0.88%, p < 0.001). The ABCC1 rs4148350 TG genotype was associated with higher rates of cardiotoxicity (TG vs. GG OR = 8.000, 95% CI = 1.405–45.547, p = 0.019). Conclusions. The study showed that ABCC1 rs4148350 is associated with AIC and could be a potential biomarker to assess the risk of treatment side effects in patients with BC.

Background. The most important anthracycline side effect is cardiotoxicity, resulting in congestive heart failure (HF). Early detection of cardiac dysfunction and appropriate treatment can improve outcomes and reduce the progression of HF. The aim of our study was to evaluate changes in clinical data, echocardiographic parameters, and NT-proBNP, as well as their associations with early anthracycline-induced cardiotoxicity (AIC) in patients treated with anthracycline-based chemotherapy. Methods and Materials. Patients with breast cancer were prospectively assessed with echocardiography, as well as NT-proBNP testing at baseline, (T0), after two cycles (T1) and four cycles (T2) of chemotherapy. AIC was defined as a new decrease in the LVEF of 10 percentage points, to a value below the lower limit of normal. Results. We evaluated 85 patients aged 54.5 ± 9.3 years. After a cumulative dose of 237.9 mg/m2 of doxorubicin, 22 patients (25.9%) met the criteria of AIC after chemotherapy. Patients who subsequently progressed to cardiotoxicity had demonstrated a significantly larger impairment in LV systolic function compared to those who did not develop cardiotoxicity (LVEF: 54.0 ± 1.6% vs. 57.1 ± 1.4% at T1, p < 0.001, and 49.9 ± 2.1% vs. 55.8 ± 1.6% at T2, p < 0.001; GLS: −17.8 ± 0.4% vs. −19.3 ± 0.9% at T1, p < 0.001, and −16.5 ± 11.1% vs. −18.5 ± 0.9% at T2, p < 0.001, respectively). The levels of NT-proBNP increased significantly from 94.8 ± 43.8 ng/L to 154.1 ± 75.6 ng/L, p < 0.001. A relative decrease in GLS ≤ −18.0% (sensitivity: 72.73%; specificity: 92.06%; AUC, 0.94; p < 0.001) and a relative increase in NT-proBNP > 125 ng/L (sensitivity: 90.0%; specificity: 56.9%; AUC, 0.78; p < 0.001) from baseline to T1 predicted subsequent LV cardiotoxicity at T2. Conclusions. Decrease in GLS and elevation in NT-proBNP were significantly associated with AIC, and these could potentially be used to predict subsequent declines in LVEF with anthracycline-based chemotherapy.

Introduction. Cancer therapy-related cardiac dysfunction is one of the most common adverse events of chemotherapy, within the treatment of oncological patients, leading to an important increase of morbidity and mortality. Speckle tracking echocardiography can detect early cardiotoxic effects of anthracycline group agents. Global longitudinal strain (GLS) is the optimal parameter of deformation for the early detection of sub-clinical left ventricle (LV) dysfunction. The American Society of Echocardiography and the European Association of Cardiovascular Imaging have agreed that deformity changes precede LV dysfunction. A reduction > 15% in GLS, immediately after or during anthracycline treatment, was the most useful parameter to predict cardiotoxicity. Aims: The aim of the study was to identify the impact of risk factors and comorbidities such as arterial ypertension, diabetes mellitus, dyslipidaemia, smoking, cardiovascular family history for subclinical cardiotoxicity after doxorubicin-based chemotherapy in breast cancer patients. Methods: Prospective study was done. 49 female patients with breast cancer treated with doxorubicin in the Oncology and Hematology department of LUHS Kaunas Clinics were enrolled. 2D echocardiography and STE were performed before anticancer treatment was started and after the treatment. A relative percentage reduction of GLS > 15% from baseline was assessed as subclinical LV dysfunction. Results: Of 49 women (mean age, 54.1 ± 10.4 years), sub-clinical LV dysfunction was identified in 21 (42.9%). Statistically significant GLS reduction was detected if compare GLS before and after the anticancer treatment: -20.8 [20.6 – 21.0], and -18.2 [17.55 – 18.95], p<0.01. Hypertension was identified as a risk factor for LV dysfunction occurrence (OR: 12.0; 95% CI: 2.977–48.378; p < 0.001). However, there were no relations between cardiovascular family history, dyslipidaemia, diabetes mellitus, smoking and left ventricular systolic dysfunction. Conclusions: Hypertension is associated with increased risk of anthracycline-induced cardiotoxicity, which indicates that corresponding protective strategies should be used during and after anthracycline treatment.

The non-Hodgkin’s lymphomas are a diverse group of lymphoid neoplasms that collectively rank fifth in cancer incidence and mortality. Patients treated with mediastinal radiotherapy and/or anthracycline-containing chemotherapy are known to have increased risks of coronary heart disease, valvular heart disease, and heart failure. This may be the result of cancer treatment cardiotoxicity or may be due to accelerated development of cardiovascular disease. We presented 41-year-old male who was admitted to the hospital because of congestive heart failure. He has a medical history of non-Hodgkin’s lymphoma treated with anthracycline-based chemotherapy and mediastinal radiotherapy almost 20 years ago. Echocardiography showed significant aortic valve stenosis, thickened and fibrotic pericardium. Coronary angiography showed diffuse three-vessel coronary artery disease. The patient was referred for surgical treatment. Aortic valve replacement, coronary artery bypass grafting and pericardiectomy were successfully performed, symptoms of heart failure reduced.

Pirmą kartą širdies funkcijos sutrikimai, sukelti vaistų nuo vėžio, buvo aprašyti jau 1960 metais. Jie siejami su antraciklinų atsiradimu onkologijoje. Kairiojo skilvelio (KS) disfunkcija ir širdies nepakankamumas (ŠN) yra gana dažnas ir pavojingas nepageidaujamas onkologinių ligų gydymo poveikis. Labiausiai ištirtas doksorubicino kardiotoksiškumas, kuriam būdingas kumuliacinis,t. y. nuo dozės priklausomas, progresuojantis miokardo pažeidimas. Tai gali būti besimptomis kairiojo skilvelio išstūmio frakcijos (KSIF) sumažėjimas, o kartais pažeidimas – negrįžtamas, su sunkaus ŠN simptomais. Norėdami apsaugoti pacientus nuo ŠN ir jo pasekmių (invalidumo, gyvenimo kokybės pablogėjimo, pavojingų širdies aritmijų rizikos), gydytojai turi mažinti šių medikamentų dozes, o tai, žinoma, gali lemti ne itin sėkmingą onkologinės ligos gydymą. Todėl vienas svarbiausių tikslų – kuo anksčiau pastebėti vaistų nuo vėžio sukeltą širdies pažaidą ir laiku skirti profilaktinį ŠN gydymą. Siekiant išvengti ar sustabdyti ŠN atsiradimą, progresavimą, labai svarbu identifikuoti didelės kardiotoksinio poveikio rizikos pacientus (1 lentelė). Rizikos veiksnius vertina gydytojas onkologas, tačiau didelės rizikos pacientams rekomenduojama ir kardioonkologijos specialisto konsultacija. Kardiotoksiškumas įtariamas ir nustatomas vadovaujantis širdies vaizdiniais tyrimais.Tyrimų pasirinkimas priklauso nuo centro galimybių ir patirties, bet turėtų būti vadovaujamasi keliais esminiais principais: [...].