
==== Front
Cardiooncology
Cardiooncology
Cardio-oncology
2057-3804
BioMed Central London

39252141
258
10.1186/s40959-024-00258-6
Research
Association of anthropometric variables with therapy-induced cardiotoxicity in women with breast cancer: a pilot study for a randomized clinical trial
Merolillo Karini 1
Solari Maria Inês González 1
Cohen Tayani Palma 2
Lutz Andreas 2
de Carvalho Patricia 2
Cañellas Fabio 2
Rech Diogo 2
de Carvalho Otávio 2
Zelmanowicz Alice 3
Lehnen Alexandre Machado amlehnen@gmail.com

1
Nardi Nance 1
Leguisamo Natalia Motta 13
1 grid.419062.8 0000 0004 0397 5284 Instituto de Cardiologia do Rio Grande do Sul/Fundação Universitária de Cardiologia (IC/FUC), Av. Princesa Isabel, 370, Porto Alegre, CEP 90620-001 Rio Grande do Sul Brazil
2 Irmandade Santa Casa de Misericórdia de Porto Alegre (ISCMPA), Porto Alegre, RS Brasil
3 https://ror.org/00x0nkm13 grid.412344.4 0000 0004 0444 6202 Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS Brasil
4 9 2024
4 9 2024
2024
10 5721 5 2024
19 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Background

Doxorubicin (DOX) has been widely used in the treatment of breast cancer, but it is directly associated with late-onset cardiovascular disease (CVD). Whether anthropometric, food intake or other risk factors together with DOX-based chemotherapy can increase the risk of developing cardiotoxicity remains uncertain. We examined the association between anthropometric variables with doxorubicin-induced cardiotoxicity in women with breast cancer.

Methods

Twenty-six women (53.7 ± 9.6 y) undergoing DOX-based chemotherapy (408.3 ± 66.7 mg/m2) participated in the study. We collected data on body composition (bioimpedance), dietary intake (24 h) and cardiac function (echocardiographic assessment of left ventricular ejection fraction, LVEF). All measurements were taken at baseline, one month of treatment completion and one-year follow-up after start of treatment. DOX-induced cardiotoxicity was defined as ≥ 10% absolute decrease in LVEF. Thus, the participants were then grouped as DOX-induced (DIC) or non-DOX-induced (non-DIC) cardiotoxicity. Data are shown as mean ± SD (standard deviation). We performed comparisons between the two groups using Student’s t-test for independent samples or Generalized Estimating Equations (groups + 3 evaluation time points) with Bonferroni post-hoc test. Lastly, the correlations were analyzed using Pearson correlation; p < 0.05 for all tests.

Results

At baseline the participants’ body mass index (BMI) was 29.9 ± 7.9 kg/m2 and LVEF was 67.4 ± 6.2%. Seven of them (26.9%) developed therapy-induced cardiotoxicity (ΔLVEF − 3.2 ± 2.6%; p < 0.001). Postmenopausal status and family history of CVD were more prevalent in the DIC group than non-DIC group. We found no consistent BMI changes in the groups over time. Interestingly, the non-DIC group showed a small increase in visceral fat at treatment completion and increased waist circumference at one-year follow-up compared to baseline. These same changes were not seen in the DIC group. We also observed a pattern of correlation of some anthropometric variables with LVEF: the more unfavorable the body composition the more pronounced the LVEF decrease at one-year follow-up, though not associated with cardiotoxicity.

Conclusions

Our study did not provide sufficient evidence to support that anthropometric variables, food intake or other risk factors increase the risk of developing cardiotoxicity. However, there are apparent trends that need to be further investigated in larger samples.

Supplementary Information

The online version contains supplementary material available at 10.1186/s40959-024-00258-6.

Keywords

Doxorubicin
Body composition
Food consumption
Cardiotoxicity
issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcBackground

Breast cancer is the second most common cancer and a leading cause of death among women worldwide [1]. Current survival rates have increased with improved diagnosis and treatment [2]. However, population-based studies have demonstrated that breast cancer survivors are more likely to develop late-onset cardiovascular disease (CVD) [3] which has been associated with anticancer therapies [4]. Furthermore, anticancer therapy has been identified as an independent risk factor for the development of CVD similarly to other risk factors including obesity and smoking [4]. Of the cost-effective antineoplastic agents available for the treatment of breast cancer, doxorubicin (DOX) has been directly associated with late-onset cardiac dysfunction, including arrhythmias, ischemic and thrombotic events and heart failure [4, 5].

Cardiac dysfunction related to the use of antineoplastic agents, also known as cardiotoxicity, occurs when these agents affect the heart resulting in ventricular systolic dysfunction and is chiefly characterized by a decrease in left ventricular ejection fraction (LVEF) [6]. In light of growing evidence showing that antineoplastic agents are associated with the development of CVD, cardio-oncology guidelines have been set out [7] proposing new diagnostic and clinical concepts. However, antineoplastic agents have been associated with a wide variety of clinical manifestations of cardiovascular toxicity. It is challenging to predict or estimate the degree of DOX-induced cardiac dysfunction in patients with breast cancer [7]. There are several methods for the assessment of cardiac function. Global systolic longitudinal strain (GLS) is a major method of measuring cardiac function through echocardiography and an early marker of subclinical or clinical cardiotoxicity in patients undergoing chemotherapy [8].

It is thus crucial to identify factors that can potentially increase the risk of CVD as an effect of anticancer therapy or not to be able to predict cardiovascular outcomes in patients undergoing treatment [9]. Current cardio-oncology guidelines recommend all patients undergoing anticancer therapy to maintain an ideal body weight due to an increased risk of cardiac dysfunction associated with therapy [7]. Body mass index (BMI) is a metric commonly used to define and classify obesity. However, nutritional assessment of patients with cancer should include body composition measurements, especially abdominal fat deposition, because they are directly associated with increased risk of CVD [10, 11]. In addition, these patients should follow a balanced diet (including macronutrients and micronutrients) as it creates a favorable environment for chemotherapy.

To deepen our understanding on the association between body weight, DOX-based therapy and cardiotoxicity, this study aimed to examine the association between anthropometric variables, food consumption and cardiac function in women with breast cancer undergoing systemic chemotherapy with DOX. Secondarily, we investigated the relative risk (RR) for each potential risk factor to be associated with cardiotoxicity. We hypothesize that there is an association between poor body composition (increased relative or absolute body fat, reduced muscle mass, high deposition of visceral adipose tissue) and unbalanced food consumption with therapy-induced cardiotoxicity in women with breast cancer undergoing DOX treatment.

Methods

This study following the principles of the Declaration of Helsinki. We performed a prospective cohort study between January 2019 and December 2020 at the medical oncology outpatient clinic of Hospital Santa Rita (HSR) in the city of Porto Alegre, southern Brazil. Cardiac imaging assessments were carried out at Hospital São Francisco. Both hospitals belong to Santa Casa de Misericórdia Hospital Compound in Porto Alegre. This study was approved by the research ethics committees of Instituto de Cardiologia do Rio Grande do Sul/Fundação Universitária de Cardiologia (protocol nr. 3,119,951) and Santa Casa de Misericórdia Hospital Compound (protocol nr. 3,061,585).

Sample characteristics

We used convenience sampling due to specific characteristics of volunteers (disease status) as well as special circumstances associated with the COVID-19 pandemic. Our sample comprised female patients over 18 years of age with pathologic diagnosis of primary breast cancer and indication of adjuvant or neoadjuvant anthracycline-based chemotherapy (adriamycin/doxorubicin). Patients with metastatic cancer at diagnosis; prior cancer chemotherapy or radiation therapy; and/or indication of non-anthracycline chemotherapy regimens (docetaxel and cyclophosphamide) were excluded. Those patients with established CVD, including acute myocardial infarction, stroke, coronary artery disease or valvular heart disease, were also excluded.

Unfortunately, half of this study was conducted under special circumstances due to the COVID-19 pandemic which affected our ability to evaluate a larger sample of volunteers. Participants who were already being followed up completed their assessments by the end of the year 2020. The last patient evaluated completed the study protocol in December 2020. Brazil was hit hard by the pandemic and we decided to terminate the study in the beginning of 2021.

Study flowchart

All volunteers were asked to sign a free informed consent form to participate. The study participants were evaluated at three time points: before starting anthracycline-based therapy (baseline); one month after the last dose of anthracycline (one month of treatment completion); and one year after the beginning of treatment (one-year follow-up). We collected data on demographic and clinical characteristics from medical records and some variables were self-reported, including menopause status, skin color, and level of education; body composition (anthropometric and bioimpedance measurements); dietary intake (24-hour dietary recall [24 h]) and cardiac function (echocardiographic assessment of left ventricular ejection fraction [LVEF] and global systolic longitudinal strain [GLS]) at the three time points evaluated.

Anthracycline-based chemotherapy cycles were repeated every 21–28 days. The participants were provided outpatient care at the clinic according to the local protocol and the Brazilian Ministry of Health guidelines [12].

Anthropometric variables

Body composition assessments were performed in a consultation room at the clinic for the comfort and convenience of the volunteers. Bioelectrical impedance analysis (BIA) and anthropometric methods were used to measure body composition. Body weight and height were measured using a digital scale with a portable stadiometer (Sanny©). Body circumference measures (neck, waist, abdomen, hip and calf) were taken with a two-meter inelastic tape (Cescorf©) with a precision of 0.1 cm. Anatomy landmarks followed the guidelines proposed by the International Society for the Advancement of Kinanthropometry (ISAK) and standardized measurement methods [13].

BIA measurements were taken when participants were not during their menstrual period (if applicable). They were instructed not drink alcohol 48 h prior to testing; not drink tea, coffee or mate infusion 24 h prior to testing; not consume any foods or drinks three hours prior to testing; urinate at least 30 min prior to testing; and remove all metal objects (rings, chains, bracelets, piercings and earrings). All measurements were taken using a tetrapolar device (Omron© HBF-514 C) following a protocol as proposed by Gallagher et al. [14]. Data were collected for total body weight, BMI, body fat percentage (BF%), skeletal muscular mass percentage (MM%) and visceral adipose tissue (VAT). Classification and acceptability of the data collected were based on the procedure described in the manual for the BIA equipment (Omron© HBF-514 C).

Dietary intake assessment

We assessed dietary intake using the 24-hour recall (24 h) for three non-consecutive days at all time points evaluated (baseline, one month of treatment completion and one-year follow-up). We collected information for the first 24 h in a face-to-face visit and then through phone or video interview for all other 24 h.

Dietary information was collected using the multiple-pass 24 h method as recommended [15]: (1) a quick list, when the participants were asked to remember and report all foods and beverages consumed on the day prior to the interview; (2) a list of non-reported food items, when they were asked about sweets, coffee and soft drinks consumed; (3) times and places where they consumed the food and beverage items listed; (4) details about the method of food preparation and amounts consumed; (5) final review to make sure all food items consumed throughout the day were reported. We chose to use the 24 h for dietary assessment to minimize recall bias and consequently errors in calculating dietary intake as it assesses foods consumed on the day prior to the interview.

We calculated dietary calorie and macronutrient and micronutrient intakes using Dietbox© v6.6.1. Mean and dispersion measures were calculated for each macronutrient and micronutrient based on values obtained in every 24 h. The analysis of nutrient intake adequacy was based on the Dietary Reference Intakes [16].

Cardiac function assessment

Skilled evaluators from the study hospitals performed all echocardiographic assessments using an ultrasound device (Philips Epiq 7c). The primary outcome of this study was LVEF calculated using the Simpson method as recommended by the American Society of Echocardiography [17]. GLS measurements were made in the apical views in at least three heartbeats with two-dimensional imaging and frame rates between 40 and 80 frames/second.

The primary outcome was subclinical or clinical cardiac dysfunction defined as an absolute decrease in LVEF by ≥ 10% [8] or a relative decrease in GLS by ≥ 15% [18, 19] compared to baseline following the first cycle of DOX chemotherapy.

Lifestyle assessment

We assessed the following lifestyle variables at baseline to rank potential risk factors for doxorubicin-induced cardiotoxicity: physically active (those engaging in physical activity for at least 150 min per week) [20]; smoking (current smokers were those smoking ≥ 5 cigarettes/day for more than 15 days) [21]; and consistent excessive alcohol use (defined as a consumption ≥ 14 units of alcohol per week) [22].

Statistical analysis

We used mean and standard deviation or medians and interquartile range for quantitative variables and absolute and relative frequencies for categorical variables. We calculated median age and used it as a cutoff (below and above median) as an analysis factor. We performed Student’s t-test for paired samples to compare variation of the means within the group and the Mann-Whitney test when the data was not normally distributed. For comparison of proportions, we applied Pearson’s chi-square or Fisher’s exact tests. For comparison of variables over time, the Generalized Estimating Equations (GEE) method with Bonferroni post-hoc test was used. We calculated the relative risk (RR) as the ratio of the absolute risk of exposed and the absolute risk of non-exposed and related 95% confidence intervals to validate RR. We assessed any associations between numerical variables using Pearson or Spearman correlation coefficients. The significance level was set at 5% (p < 0.05). All analyses were performed using SPSS v27.0.

Results

Sample characteristics

Table 1 shows the characteristics of the sample studied. A total of 26 volunteers participated in the study, median age of 56 years and mean age of 53.7 ± 9.6 years (range 33–63 years). Most were overweight (29.9 ± 7.9 kg/m2) and postmenopausal (n = 18/26; 69.2%) at baseline. The most commonly used regimen was neoadjuvant therapy with a cumulative DOX dose of 408.3 ± 66.7 mg/m2. The participants showed normal cardiac function at baseline: LVEF was 67.4 ± 6.2% and GLS was − 22.1 ± 2.6.

Table 1 Demographic and clinical characteristics of the study participants (n = 26)

Age (years) – mean ± SD	53.7 ± 9.6	
Skin color – n (%)		
 white	24 (92.3)	
 brown	1 (3.8)	
 black	1 (3.8)	
Level of education – mean ± SD		
 Incomplete primary education	1 (3.8)	
 Completed primary education	7 (26.9)	
 Completed secondary education	13 (50.0)	
 Completed higher education	5 (19.2)	
Family history of breast cancer – mean ± SD		
 No	11 (44.0)	
 Yes	14 (56.0)	
Breast cancer molecular subtype – mean ± SD		
 Luminal A (ER + or PR+/HER2-/Ki-67 < 14%)	3 (12.0)	
 Luminal B (ER + or PR+/HER2-/Ki-67 ≥ 14%)	9 (36.0)	
 Luminal HER* (ER + or PR+/HER2+)	4 (16.0)	
 HER2+ (ER- and PR-/HER2+)	1 (4.0)	
 Triple negative (ER-/PR-/HER2-)	8 (32.0)	
Family history of CVD – mean ± SD		
 No	8 (30.8)	
 Yes	18 (69.2)	
BMI (kg/m2) – mean ± SD	29.85 ± 7.85	
Comorbidities – n (%)		
 Arterial hypertension	13 (50.0)	
 Type 2 diabetes mellitus	4 (15.4)	
 Dyslipidemia	2 (7.7)	
CV drug use – n (%)		
 Antihypertensive agents	13 (50)	
 Diuretics	6 (23)	
 Anticoagulant agents	3 (11.5)	
 Statins	6 (23)	
 Antidiabetic agents	4 (15.3)	
Smoking status† – n (%)		
 Never smoked	22 (84.6)	
 Former smoker	1 (3.8)	
 Current smoker	3 (11.5)	
Sedentary lifestyle – n (%)		
 No	3 (11.5)	
 Yes	23 (88.5)	
Excessive alcohol use† – n (%)		
 No	24 (92.3)	
 Yes	2 (7.7)	
Menopausal status – n (%)		
 Premenopausal	8 (30.8)	
 Postmenopausal	18 (69.2)	
Type of treatment – n (%)		
 Adjuvant	10 (38.5)	
 Neoadjuvant	16 (61.5)	
Other type of treatment‡ – n (%)		
 Radiotherapy (No/Yes)	21 (84.0) / 5 (19.2)	
 Endocrine therapy + trastuzumabe (No/Yes)	22 (84.6) / 4 (15.4)	
Total cumulative dose of DOX – mean ± SD	408.3 ± 66.7	
BMI, body mass index; CVD, cardiovascular disease; CV, cardiovascular; DOX, doxorubicin. ER, estrogen receptor; PR, progesterone receptors. * Luminal HER is also known as a subtype of Luminal B positive for HER2 defined as “+++ by immunohistochemistry” or “++ by silver-enhanced in situ hybridization” [50]. † See definition in Lifestyle Assessment section. ‡ Radiotherapy was started only after DOX treatment completion and endocrine therapy was administered in four Luminal HER patients

Cardiotoxicity and risk factors

Seven participants (26.9%) developed subclinical or clinical cardiac dysfunction (decrease in LVEF by ≥ 10% or decrease in GLS ≥ 15% compared to baseline) within one year of DOX treatment (Table 2). To examine any potential associations between nutritional status and DOX-induced cardiotoxicity (DIC), they were then grouped as DIC or non-DIC (non-DOX-induced cardiotoxicity).

Table 2 Doxorubicin-induced cardiotoxicity and potential risk factors

	DIC (n = 7)
n (%)	non-DIC (n = 19)
n (%)	p-value	
LVEF (%)	-13.2 ± 2.6	2.4 ± 4.9	< 0.001 t	
Age (years)	55.9 ± 11.9	52.9 ± 8.9	0.505t	
 Less than 56 (median)	3 (42.9)	12 (63.2)		
 ≥ 56 (median)	4 (57.1)	7 (36.8)		
Menopausal status			0.007	
 Premenopausal	2 (28.6)	6 (31.6)		
 Postmenopausal	5 (71.4)	13 (68.4)		
Family history of CVD			0.007	
 No	2 (28.6)	6 (31.6)		
 Yes	5 (71.4)	13 (68.4)		
Sedentary lifestyle			< 0.001	
 No	1 (14.3)	1 (5.3)		
 Yes	6 (85.7)	18 (94.7)		
Smoking status†			0.453	
 Never smoked	5 (71.4)	17 (89.5)		
 Current smoker or former smoker	2 (28.6)	2 (10.5)		
Alcohol use†			0.125	
 No	6 (85.7)	18 (94.7)		
 Alcohol abuse	1 (14.3)	1 (5.3)		
Arterial hypertension			0.092	
 No	3 (42.9)	9 (47.4)		
 Yes	4 (57.1)	10 (52.6)		
Type 2 diabetes mellitus			0.453	
 No	5 (71.4)	17 (89.5)		
 Yes	2 (28.6)	2 (10.5)		
Dyslipidemia	0 (0.0)	2 (10.5)	0.180	
CVD drug use				
 Antihypertensive agents	4 (57.1)	7 (36.8)	0.344	
 Anticoagulant agents	0 (0.0)	1 (5.3)	0.070	
 Statins	1 (14.3)	4 (21.1)	0.754	
 Antidiabetic agents	2 (28.6)	1 (5.3)	0.219	
Cancer staging I-II	7 (100.0)	15 (78.9)	0.549	
DIC, DOX-induced cardiotoxicity; non-DIC, non-DOX-induced cardiotoxicity; LVEF. left ventricular ejection fraction; CVD, cardiovascular disease; CV, cardiovascular; † see definition in Lifestyle assessment; t Student’s t-test for independent samples. All other variables were tested using Pearson chi-square test (p < 0.05)

We compared demographic characteristics, clinical and pathological features of breast cancer and prior history of CVD between the two groups based on the development of subclinical or clinical cardiac dysfunction (DIC vs. non-DIC). Table 2 shows differences found in menopausal status, family history of CVD, and lifestyle factors (sedentary) between the two groups.

Body and dietary assessments at three time points

Table 3 summarizes anthropometric changes over the course of DOX treatment. The non-DIC group showed increased visceral fat at the completion of treatment and increased waist circumference at one-year follow-up compared to baseline. These same changes were not seen in the DIC group.

Table 3 Anthropometric and dietary variables

	DIC (n = 7)	non-DIC (n = 19)	p-value (group)	p-value (time)	p-value (interaction)	
Baseline DOX treatment	Completion of DOX treatment	One-year follow-up	Baseline DOX treatment	Completion of DOX treatment	One-year follow-up	
Body weight (kg)	83.2 ± 24.3	82.0 ± 21.5	81.7 ± 21.0	72.6 ± 15.7	74.0 ± 15.9	73.4 ± 17.0	0.314	0.994	0.271	
BMI (kg/m2)	32.6 ± 9.3	32.2 ± 8.8	31.8 ± 8.3	28.9 ± 6.7	29.6 ± 6.3	28.2 ± 5.6	0.389	0.676	0.208	
 Low weight (n)	0	0	0	0	1	0	---	---	---	
 Normal weight (n)	3	3	3	6	3	5	---	---	---	
 Overweight (n)	0	0	0	6	7	7	---	---	---	
 Obesity I (n)	0	1	0	4	5	3	---	---	---	
 Obesity II (n)	3	1	3	2	1	1	---	---	---	
 Obesity III (n)	1	2	1	1	2	1	---	---	---	
Fat mass (%)	42.5 ± 11.7	40.8 ± 8.6	41.4 ± 10.5	39.4 ± 8.0	39.6 ± 8.2	38.8 ± 6.5	0.628	0.646	0.408	
Muscle mass (%)	23.8 ± 3.6	25.6 ± 3.3	25.4 ± 4.2	26.0 ± 2.6	26.6 ± 3.9	26.0 ± 2.4	0.429	0.054	0.059	
Visceral fat (rating)	11.4 ± 5.2	10.4 ± 4.5	10.9 ± 5.0	8.9 ± 3.7	9.5 ± 3.6*	8.5 ± 2.4	0.375	0.581	0.007	
Neck circumference (cm)	36.7 ± 4.4	37.7 ± 4.8	36.2 ± 5.3	34.9 ± 2.9	35.6 ± 3.6	34.8 ± 2.8	0.330	0.027	0.425	
Waist circumference (cm)	103.7 ± 16.9	102.8 ± 14.4	99.8 ± 16.7	96.2 ± 14.2	97.7 ± 14.4	100.3 ± 10.0*	0.513	0.898	0.002	
Total calorie intake (kcal)	1378.6 ± 362.8	1499.5 ± 352.6	1467.8 ± 361.9	1601.2 ± 467.5	1321.9 ± 424.3	1623.4 ± 434.2	0.569	0.350	0.122	
Carbohydrates (g)	55.4 ± 10.1	50.3 ± 3.2	54.3 ± 4.7	54.4 ± 10.0	53.0 ± 7.7	55.5 ± 5.2	0.636	0.020	0.559	
Proteins (g)	19.0 ± 3.7	17.5 ± 2.9	19.1 ± 4.7	18.4 ± 4.8	17.8 ± 4.0	16.7 ± 3.9	0.340	0.594	0.233	
Lipids (g)	25.6 ± 8.7	32.2 ± 3.4	26.7 ± 5.4	27.3 ± 9.0	29.2 ± 5.9	26.7 ± 7.5	0.868	< 0.001	0.088	
Cholesterol (g)	336.4 ± 217.1	238.9 ± 133.0	289.5 ± 168.3	266.9 ± 171.0	223.8 ± 156.1	238.9 ± 160.4	0.227	0.529	0.906	
Saturated fat (g)	13.3 ± 6.9	20.2 ± 7.9	15.6 ± 5.4	17.9 ± 8.3	16.9 ± 8.3	18.7 ± 8.0	0.578	0.336	0.072	
Sodium (mg)	2123.1 ± 868.4	2734.2 ± 1479.9	1881.7 ± 891.4	1966.9 ± 1142.5	1510.5 ± 933.4	1683.7 ± 847.4	0.085	0.133	0.148	
DIC, DOX-induced cardiotoxicity; non-DIC, non-DOX-induced cardiotoxicity; BMI, body mass index. Data expressed as mean ± standard error or absolute value (n). Generalized estimating equations (GEE) method with Bonferroni post-hoc test was used; * p < 0.05 versus baseline within the group

As for dietary changes, a comparison of the two groups did not show no major changes in total calorie intake (Table 3). Both groups showed reduced carbohydrate intake [p(time) = 0.020] at the completion of treatment, which may have been compensated by an increased consumption of total lipids [p(time) < 0.001]. In addition, carbohydrate and total lipid intake returned to baseline values in both groups at one-year follow-up. Similarly, we found increased neck circumferences at the completion of treatment, but they returned to baseline values at one-year follow-up.

Table 4 illustrates potential correlations between anthropometric variables, dietary intake and LVEF. We found a consistent pattern for all anthropometric variables, i.e., the higher the measures of body composition the greater the decrease in LVEF at one-year follow-up compared to baseline, but not for dietary intake (total calories, carbohydrates, proteins, lipids, dietary cholesterol, saturated fat and sodium).

Table 4 Correlation between anthropometric and dietary variables with left ventricular ejection fraction variation at the completion of doxorubicin treatment and one-year follow-up

Baseline variables	Δ LVEF	
Completion of DOX treatment – baseline	One-year follow-up – baseline	
Anthropometric measures	
 Body surface	–0.384 (p = 0.070)	–0.541 ( p  = 0.011)	
 Body weight	–0.326 (p = 0.130)	–0.509 ( p  = 0.018)	
 BMI	–0.212 (p = 0.331)	–0.475 ( p  = 0.029)	
 Fat mass	–0.154 (p = 0.482)	–0.421 (p = 0.057)	
 Muscle mass	0.316 (p = 0.142)	0.467 ( p  = 0.033)	
 Visceral fat	–0.151 (p = 0.491)	–0.502 ( p  = 0.020)	
 Neck circumference	–0.138 (p = 0.530)	–0.579 ( p  = 0.006)	
 Waist circumference	–0.201 (p = 0.358)	–0.423 (p = 0.056)	
Dietary intake	
 Total calories	–0.324 (p = 0.132)	–0.039 (p = 0.868)	
 Carbohydrates	0.137 (p = 0.532)	0.400 (p = 0.072)	
 Proteins	–0.276 (p = 0.203)	–0.233 (p = 0.310)	
 Lipids	–0.021 (p = 0.925)	–0.336 (p = 0.137)	
 Cholesterol*	–0.144 (p = 0.513)	–0.201 (p = 0.382)	
 Saturated fat*	–0.292 (p = 0.176)	–0.028 (p = 0.904)	
 Sodium*	0.084 (p = 0.702)	–0.149 (p = 0.519)	
LVEF, left ventricular ejection fraction; DOX, doxorubicin; BMI, body mass index; Pearson “r” correlation except for (*) where Spearman “r” correlation was used (p < 0.05)

Additional analysis

We calculated the relative risk (RR) for each potential risk factor and related 95% CIs. Although the RR calculated for some variables seemed associated with cardiotoxicity, the associations were not verified in the analysis of 95% CIs for the following variables: age > 56 years (RR 1.82, 95% CI 0.51; 6.53); menopausal status (RR 1.11, 95% CI 0.27; 4.56); history of CVD (RR 1.11, 95% CI 0.27; 4.56); physically inactive (RR 0.50, 95% CI 0.11; 2.35); smoking (RR 2.20, 95% CI 0.63; 7.65); excessive alcohol use (RR 2.00, 95% CI 0.42; 9.42); arterial hypertension (RR 1.14, 95% CI 0.32; 4.12); type 2 diabetes (RR 2.20, 95% CI 0.63; 7.65).

Discussion

In the present study we examined the association of anthropometric variables with DOX-induced cardiotoxicity in women with breast cancer undergoing treatment. We found that 26.9% of the participants developed cardiac dysfunction having a decrease in LVEF by ≥ 10% or a decrease in GLS by ≥ 15% at one-year of follow-up of anthracycline-based chemotherapy. But we found no evidence supporting an association of anthropometric variables or food intake with therapy-induced cardiotoxicity. Thus, we reject our initial hypothesis that poor body composition and/or unbalanced food consumption is potentially associated with the development or the severity of DOX-induced cardiotoxicity. Yet, this is a pilot study conducted in a small sample of 26 volunteers and our results should be interpreted with caution.

Until recently cancer was not considered to be related to CVD. However, current data show these conditions share several risk factors, which suggests a common biological pathway [23]. Obesity and visceral adiposity have been directly associated with increased risk of CVD in both the general population and cancer survivors [24]. Yet, they may develop as a result of cancer treatment affecting body composition, specifically leading to increased central adiposity and reduced fat-free mass [25]. But our results did not demonstrate a clear association of poor body composition with therapy-induced cardiac dysfunction. A possible explanation is the small sample used in this study largely because of special circumstances and restrictions imposed due to the COVID-19 pandemic. In addition, food consumption showed no variation in macronutrient and total calorie intake between the groups over time.

A population-based study and a meta-analysis reported that obesity assessed by BMI was an independent risk factor for therapy-induced cardiotoxicity in women with breast cancer undergoing anthracycline and/or trastuzumab treatment [26, 27]. A significant proportion of the participants in our study were overweight (n = 6/26) or obese (n = 11/26) as well as physically inactive (n = 24/26). Regarding their body composition, there was an absolute change in body weight with consequent change in BMI over time. Those women who developed cardiac dysfunction showed reduced BMI compared to baseline immediately after treatment completion while those without cardiac dysfunction showed increased BMI. A similar pattern was seen for BF% and VAT. However, the women in the DIC group showed increased MM% soon after treatment completion compared to baseline. This finding is not clinically relevant and can be associated with changes in eating habits during a stressful life event or a special concern to maintain or excessively increase calorie intake to avoid weight loss [28].

To further the analysis of body composition, we included a dietary assessment in this study. We found the participants changed their eating habits over a period of 12 months, especially regarding macronutrient and micronutrient intake (mostly average consumption of calories, carbohydrates, lipids and sodium) though without marginal significance. From the diagnosis of cancer and the beginning of chemotherapy they became more concerned about their diet and make changes to include more healthy foods and less processed foods and chemical additives. However, they struggled to maintain healthy eating habits over the course of treatment due to emotional distress and side effects of treatment as cancer patients undergoing chemotherapy are likely to present symptoms such as nausea, vomiting, taste changes, among others [29]. A meta-analysis on different methods for assessing changes in weight, body composition and lifestyle among women with breast cancer reported quantitative and qualitative changes compared to women with no breast cancer. This finding provides insights and help understand the changes in this patient population [30].

We compared body composition and dietary variables between DIC and non-DIC groups and found no significant changes at the completion of treatment regardless of cardiotoxicity, i.e., cancer treatment did not affect body composition and dietary variables. In contrast, a recent study demonstrated that, different from the classic relationship between obesity and increased CV risk, a reduction in BMI—though not in waist circumference—was associated with a decrease in LVEF over the course of anthracycline-based treatment among women with breast cancer. The authors reported that every 1 kg/m2 reduction in BMI was associated with a 0.4% decrease in LVEF [31].

Evidence has shown that the associations between BMI and cardiotoxicity or even cancer mortality are usually nonlinear [26]. Although severe obesity has been clearly associated with lower survival rates, studies have showed a U-shaped association between BMI and unfavorable outcomes. A probable explanation is that BMI likely incompletely captures key measures of body composition, especially when skeletal muscle is not assessed. Fat and lean body mass can be measured using computed tomography, dual-energy radiograph absorptiometry (DEXA), A-mode ultrasound, BIA, and other technologies [32]. Although our results assessed by BIA did not show any differences in fat or lean mass between the groups (DIC and non-DIC), we found a delayed moderate correlation at the one-year follow-up from baseline between muscle mass and LVEF (0.467; p = 0.033) and a moderate inverse correlation between visceral fat and LVEF (–0.502; p = 0.020). Even though these findings are irrespective of cardiotoxicity, they affect quality of life and thus have significant clinical relevance. In relation to adiposity, some mechanisms by which overweight or obesity promote anthracycline-induced cardiotoxicity involve adiponectin downregulation [33, 34], which has been demonstrated in obese patients [35]. In addition, adiponectin-KO mice showed exacerbated left ventricle contractile dysfunction after doxorubicin injection, whereas exogenous adiponectin improved doxorubicin-induced left ventricular dysfunction in wild-type and adiponectin-KO mice [33]. While increased adiposity, mostly visceral, created an unfavorable environment for cardiac performance in our sample—a decrease in LVEF regardless of cardiotoxicity—, skeletal muscle played a role that is consistent with the current focus on inflammatory and immunological pathways for both the cardiac environment and overall cancer survival rates [32]. Skeletal muscle secretes myokines including interleukin (IL)-6, IL-8, IL-15, and leukemia inhibitory factor [36]. Therefore, higher muscle mass may decrease the impact of systemic inflammation [37] and suppress tumor growth [38]. Several studies have suggested that systemic inflammation may lead to ongoing muscle loss in cancer patients and has been associated with cancer survival [39]. Besides, skeletal muscle is a limiting factor in oxygen consumption associated with cardiac performance and is a secondary factor contributing to a decrease in LVEF [40]. Significant reductions in resting cardiac and skeletal muscle energy and increased skeletal muscle degradation have been demonstrated in patients with breast cancer after the administration of anthracycline chemotherapy [41]. Collectively, this evidence shows the importance of preserving muscle mass for improving survival and quality of life of patients undergoing chemotherapy.

As for the volunteers’ lifestyle habits, those who developed cardiotoxicity showed at least two risk factors associated, including sedentary behavior, being a current or former smoker and/or excessive alcohol use. Besides, four of these women had a BMI > 30 kg/m2. Our research group showed in an animal model that exercise training is a cardioprotective approach against DOX-induced cardiomyopathy, especially prior to DOX exposure [42]. The cardioprotective effects of aerobic exercise training are mediated by preserving sympathetic vagal function and improving DNA repair capacity of peripheral blood mononuclear cells [43]. As for smoking, considering the association between smoking and breast cancer risk [44] and that active smoking—or environmental tobacco exposure—is associated with approximately 80% increase in the risk of ischemic heart disease [45], it is expected that women with breast cancer undergoing chemotherapy who are smokers would more likely develop cardiotoxicity. In fact, Jin et al. [46] showed that smoking was associated with reduced LVEF during anthracycline chemotherapy (OR 1.91; 95% CI 1.24 to 2.95; p = 0.003). Likewise, heavy alcohol use is associated with an increased risk of cardiotoxicity compared to low alcohol intake among these women [47].

Although we were not able to demonstrate that body composition plays a role on the development of DOX-induced cardiotoxicity, health providers should be aware that excess weight gain is not only a stressor but also an additional risk for CVD, diabetes and arterial hypertensin in individuals with cancer [7, 48]. Furthermore, BMI is not the only measure to assess CV risk, but other measures of body composition should be considered to screen those individuals more likely to benefit from CV prevention care [24].

Our study presents some limitations. The measures adopted during the COVID-19 pandemic, such as non-hospital patient care management, social distancing and other care-related restriction measures, significantly affected participation in our study. Losses derived from deaths during treatment and patient refusal to participate as data collection involved physical contact were also issues faced during that highly unusual time caused by the pandemic. Therefore, the small sample size was the main limitation of this study that may have affected its power to verify our primary hypothesis concerning the association between changes in body composition and development of DOX-induced cardiac dysfunction. Many variables showed a relative risk associated with cardiotoxicity, but the great variability resulting from a small sample affected 95% CIs and did not allow to confirm an association of the risk factors evaluated. Another important limitation of our study is the lack of further information on lifestyle habits and nutritional survey. These women were in a fragile state while undergoing chemotherapy and dealing with uncertainties during the COVID-19 pandemic and thus we were careful not to overwhelm them with long questionnaires and surveys.

Conclusions

To the best of our knowledge, only one study in the literature used BIA to assess the correlation between body composition measures and cardiac dysfunction in women with breast cancer undergoing antineoplastic treatment [49]. Despite its small sample, the present study provides insights on the value of BIA as a non-invasive, objective method to assess body composition. Likewise, food consumption showed no association with the outcomes evaluated.

The comparison of body composition between the two groups of participants (DIC and non-DIC) at the completion of DOX treatment did not support the hypothesis that this measure plays a role on the development of cardiac dysfunction. Further studies with larger samples are needed to support our findings.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Acknowledgements

Authors thank to Carla Finger for her English assistance.

Author contributions

K.M. was involved in conception and design of the study, data collection, data analysis and interpretation, as well as drafting the manuscript. M.I.G.S. worked on the conception and design of the study, and data collection. T.C., A.L., P.C., and O.C. were involved in patient’s recruitment and data collection. F.C. and D.R. performed and analyzed echocardiography exams. A.Z. worked on conception and design of the study. A.M.L. and N.N. made data analysis and interpretation, as well as critical review of manuscript. N.M.L. was involved in all steps of manuscript. Also, all authors have read and approved the manuscript.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Data availability

Data is provided within the manuscript or supplementary information files.

Declarations

Ethics approval and consent to participate

This study following the principles of the Declaration of Helsinki. This study was approved by the research ethics committees of Instituto de Cardiologia do Rio Grande do Sul/Fundação Universitária de Cardiologia (protocol nr. 3,119,951) and Santa Casa de Misericórdia Hospital Compound (protocol nr. 3,061,585). Also, all volunteer participants read and signed a free informed consent form.

Consent for publication

Not Applicable.

Competing interests

The authors declare no competing interests.

Abbreviations

BF% Body fat percentage

BIA Bioelectrical impedance analysis

BMI Body mass index

CVD Cardiovascular disease

DOX Doxorubicin

GLS Global systolic longitudinal strain

ISAK International Society for the Advancement of Kinanthropometry

LVEF Left ventricular ejection fraction

MM% Skeletal muscular mass percentage

RR Relative risk

VAT Visceral adipose tissue

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References

1. Han H Guo W Shi W Yu Y Zhang Y Ye X Hypertension and breast cancer risk: a systematic review and meta-analysis Sci Rep 2017 7 44877 10.1038/srep44877 28317900
Han H, Guo W, Shi W, Yu Y, Zhang Y, Ye X, et al. Hypertension and breast cancer risk: a systematic review and meta-analysis. Sci Rep. 2017;7:44877. 10.1038/srep4487728317900 10.1038/srep44877
2. Miller KD Nogueira L Mariotto AB Rowland JH Yabroff KR Alfano CM Cancer treatment and survivorship statistics, 2019 CA Cancer J Clin 2019 69 5 363 85 10.3322/caac.21565 31184787
Miller KD, Nogueira L, Mariotto AB, Rowland JH, Yabroff KR, Alfano CM, et al. Cancer treatment and survivorship statistics, 2019. CA Cancer J Clin. 2019;69(5):363–85. 10.3322/caac.2156531184787 10.3322/caac.21565
3. Kawahara LT Costa I Barros CCS Almeida GC Bittar CS Rizk SI Cancer and Cardiovascular diseases during the COVID-19 pandemic Arq Bras Cardiol 2020 115 3 547 57 10.36660/abc.20200405 33027380
Kawahara LT, Costa I, Barros CCS, Almeida GC, Bittar CS, Rizk SI, et al. Cancer and Cardiovascular diseases during the COVID-19 pandemic. Arq Bras Cardiol. 2020;115(3):547–57. 10.36660/abc.2020040533027380 10.36660/abc.20200405
4. Mehta LS Watson KE Barac A Beckie TM Bittner V Cruz-Flores S Cardiovascular Disease and breast Cancer: where these entities Intersect: A Scientific Statement from the American Heart Association Circulation 2018 137 8 e30 66 10.1161/CIR.0000000000000556 29437116
Mehta LS, Watson KE, Barac A, Beckie TM, Bittner V, Cruz-Flores S, et al. Cardiovascular Disease and breast Cancer: where these entities Intersect: A Scientific Statement from the American Heart Association. Circulation. 2018;137(8):e30–66. 10.1161/CIR.000000000000055629437116 10.1161/CIR.0000000000000556
5. Florescu M Cinteza M Vinereanu D Chemotherapy-induced cardiotoxicity Maedica (Bucur) 2013 8 1 59 67 24023601
Florescu M, Cinteza M, Vinereanu D. Chemotherapy-induced cardiotoxicity. Maedica (Bucur). 2013;8(1):59–67.24023601
6. Corremans R Adao R De Keulenaer GW Leite-Moreira AF Bras-Silva C Update on pathophysiology and preventive strategies of anthracycline-induced cardiotoxicity Clin Exp Pharmacol Physiol 2019 46 3 204 15 10.1111/1440-1681.13036 30244497
Corremans R, Adao R, De Keulenaer GW, Leite-Moreira AF, Bras-Silva C. Update on pathophysiology and preventive strategies of anthracycline-induced cardiotoxicity. Clin Exp Pharmacol Physiol. 2019;46(3):204–15. 10.1111/1440-1681.1303630244497 10.1111/1440-1681.13036
7. Hajjar LA Costa I Lopes M Hoff PMG Diz M Fonseca SMR Brazilian Cardio-Oncology Guideline – 2020 Arq Bras Cardiol 2020 115 5 1006 43 10.36660/abc.20201006 33295473
Hajjar LA, Costa I, Lopes M, Hoff PMG, Diz M, Fonseca SMR, et al. Brazilian Cardio-Oncology Guideline – 2020. Arq Bras Cardiol. 2020;115(5):1006–43. 10.36660/abc.2020100633295473 10.36660/abc.20201006
8. Curigliano G Lenihan D Fradley M Ganatra S Barac A Blaes A Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations Ann Oncol 2020 31 2 171 90 10.1016/j.annonc.2019.10.023 31959335
Curigliano G, Lenihan D, Fradley M, Ganatra S, Barac A, Blaes A, et al. Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Ann Oncol. 2020;31(2):171–90. 10.1016/j.annonc.2019.10.02331959335 10.1016/j.annonc.2019.10.023
9. Lenneman CG Sawyer DB Cardio-Oncology: an update on cardiotoxicity of Cancer-Related treatment Circ Res 2016 118 6 1008 20 10.1161/CIRCRESAHA.115.303633 26987914
Lenneman CG, Sawyer DB. Cardio-Oncology: an update on cardiotoxicity of Cancer-Related treatment. Circ Res. 2016;118(6):1008–20. 10.1161/CIRCRESAHA.115.30363326987914 10.1161/CIRCRESAHA.115.303633
10. Kotwinski P Smith G Cooper J Sanders J Ma L Teis A Body surface area and baseline blood pressure predict subclinical anthracycline cardiotoxicity in women treated for early breast Cancer PLoS ONE 2016 11 12 e0165262 10.1371/journal.pone.0165262 27911951
Kotwinski P, Smith G, Cooper J, Sanders J, Ma L, Teis A, et al. Body surface area and baseline blood pressure predict subclinical anthracycline cardiotoxicity in women treated for early breast Cancer. PLoS ONE. 2016;11(12):e0165262. 10.1371/journal.pone.016526227911951 10.1371/journal.pone.0165262
11. Larsson SC Back M Rees JMB Mason AM Burgess S Body mass index and body composition in relation to 14 cardiovascular conditions in UK Biobank: a mendelian randomization study Eur Heart J 2020 41 2 221 6 10.1093/eurheartj/ehz388 31195408
Larsson SC, Back M, Rees JMB, Mason AM, Burgess S. Body mass index and body composition in relation to 14 cardiovascular conditions in UK Biobank: a mendelian randomization study. Eur Heart J. 2020;41(2):221–6. 10.1093/eurheartj/ehz38831195408 10.1093/eurheartj/ehz388
12. BRASIL Ministério da Saúde Secretaria De Atenção à Saúde. Protocolos clínicos e diretrizes terapêuticas em Oncologia/Ministério Da Saúde, Secretaria De Atenção à Saúde 2014 Brasília Ministério da Saúde
BRASIL Ministério da Saúde. Secretaria De Atenção à Saúde. Protocolos clínicos e diretrizes terapêuticas em Oncologia/Ministério Da Saúde, Secretaria De Atenção à Saúde. Brasília: Ministério da Saúde; 2014.
13. Marfell-Jones M Stewart A de Ridder J International standards for anthropometric assessment 2012 Wellington, New Zealand International Society for the Advancement of Kinanthropometry
Marfell-Jones M, Stewart A, de Ridder J. International standards for anthropometric assessment. Wellington, New Zealand: International Society for the Advancement of Kinanthropometry; 2012.
14. Gallagher D Heymsfield SB Heo M Jebb SA Murgatroyd PR Sakamoto Y Healthy percentage body fat ranges: an approach for developing guidelines based on body mass index Am J Clin Nutr 2000 72 3 694 701 10.1093/ajcn/72.3.694 10966886
Gallagher D, Heymsfield SB, Heo M, Jebb SA, Murgatroyd PR, Sakamoto Y. Healthy percentage body fat ranges: an approach for developing guidelines based on body mass index. Am J Clin Nutr. 2000;72(3):694–701. 10.1093/ajcn/72.3.69410966886 10.1093/ajcn/72.3.694
15. de Holanda LB Azevedo Barros Filho AJRPdP Métodos Aplicados em inquéritos Alimentares 2006 24 1 62 70
de Holanda LB. Azevedo Barros Filho AJRPdP. Métodos Aplicados em inquéritos Alimentares. 2006;24(1):62–70.
16. DRI. Institute of Medicine (US). Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. DRI Dietary Reference Intakes: Applications in Dietary Assessment. Washington (DC)2000.
17. Rudski LG Lai WW Afilalo J Hua L Handschumacher MD Chandrasekaran K Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography J Am Soc Echocardiogr 2010 23 7 685 713 10.1016/j.echo.2010.05.010 20620859
Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr. 2010;23(7):685–713. 10.1016/j.echo.2010.05.010. quiz 786 – 688.20620859 10.1016/j.echo.2010.05.010
18. Barroso GMHM Teles JCOC Silva PVdJ, Fonseca KYS Aragão VAS Aquino MM Subclinical Systolic Dysfunct Dur Chemother Breast Cancer 2021 35 220 9
Barroso GMHM, Teles JCOC, Silva PVdJ, Fonseca KYS, Aragão VAS, Aquino MM, et al. Subclinical Systolic Dysfunct Dur Chemother Breast Cancer. 2021;35:220–9.
19. Di Lisi D Manno G Novo G Subclinical cardiotoxicity: the emerging role of myocardial work and other Imaging techniques Curr Probl Cardiol 2021 46 6 100818 10.1016/j.cpcardiol.2021.100818 33756178
Di Lisi D, Manno G, Novo G. Subclinical cardiotoxicity: the emerging role of myocardial work and other Imaging techniques. Curr Probl Cardiol. 2021;46(6):100818. 10.1016/j.cpcardiol.2021.10081833756178 10.1016/j.cpcardiol.2021.100818
20. Bull FC Al-Ansari SS Biddle S Borodulin K Buman MP Cardon G World Health Organization 2020 guidelines on physical activity and sedentary behaviour Br J Sports Med 2020 54 24 1451 62 10.1136/bjsports-2020-102955 33239350
Bull FC, Al-Ansari SS, Biddle S, Borodulin K, Buman MP, Cardon G, et al. World Health Organization 2020 guidelines on physical activity and sedentary behaviour. Br J Sports Med. 2020;54(24):1451–62. 10.1136/bjsports-2020-10295533239350 10.1136/bjsports-2020-102955
21. BRASIL Abordagem e Tratamento do Fumante - Consenso. 2001. Rio de Janeiro: INCA; 2001.
22. Andrade LOMd, Barreto I, Fonseca CDd, Duncan BB, Schmidt MI. GIUGLIANI ERJ. Medicina ambulatorial: condutas de atenção primária baseadas em evidências. 2004.
23. Koene RJ Prizment AE Blaes A Konety SH Shared Risk factors in Cardiovascular Disease and Cancer Circulation 2016 133 11 1104 14 10.1161/CIRCULATIONAHA.115.020406 26976915
Koene RJ, Prizment AE, Blaes A, Konety SH. Shared Risk factors in Cardiovascular Disease and Cancer. Circulation. 2016;133(11):1104–14. 10.1161/CIRCULATIONAHA.115.02040626976915 10.1161/CIRCULATIONAHA.115.020406
24. Brown JC Caan BJ Prado CM Weltzien E Xiao J Cespedes Feliciano EM Body Composition and Cardiovascular events in patients with colorectal Cancer: a Population-based Retrospective Cohort Study JAMA Oncol 2019 5 7 967 72 10.1001/jamaoncol.2019.0695 31095251
Brown JC, Caan BJ, Prado CM, Weltzien E, Xiao J, Cespedes Feliciano EM, et al. Body Composition and Cardiovascular events in patients with colorectal Cancer: a Population-based Retrospective Cohort Study. JAMA Oncol. 2019;5(7):967–72. 10.1001/jamaoncol.2019.069531095251 10.1001/jamaoncol.2019.0695
25. Freedman RJ Aziz N Albanes D Hartman T Danforth D Hill S Weight and body composition changes during and after adjuvant chemotherapy in women with breast cancer J Clin Endocrinol Metab 2004 89 5 2248 53 10.1210/jc.2003-031874 15126549
Freedman RJ, Aziz N, Albanes D, Hartman T, Danforth D, Hill S, et al. Weight and body composition changes during and after adjuvant chemotherapy in women with breast cancer. J Clin Endocrinol Metab. 2004;89(5):2248–53. 10.1210/jc.2003-03187415126549 10.1210/jc.2003-031874
26. Guenancia C Lefebvre A Cardinale D Yu AF Ladoire S Ghiringhelli F Obesity as a risk factor for anthracyclines and trastuzumab cardiotoxicity in breast Cancer: a systematic review and Meta-analysis J Clin Oncol 2016 34 26 3157 65 10.1200/JCO.2016.67.4846 27458291
Guenancia C, Lefebvre A, Cardinale D, Yu AF, Ladoire S, Ghiringhelli F, et al. Obesity as a risk factor for anthracyclines and trastuzumab cardiotoxicity in breast Cancer: a systematic review and Meta-analysis. J Clin Oncol. 2016;34(26):3157–65. 10.1200/JCO.2016.67.484627458291 10.1200/JCO.2016.67.4846
27. Kabore EG Guenancia C Vaz-Luis I Di Meglio A Pistilli B Coutant C Association of body mass index and cardiotoxicity related to anthracyclines and trastuzumab in early breast cancer: French CANTO cohort study PLoS Med 2019 16 12 e1002989 10.1371/journal.pmed.1002989 31869400
Kabore EG, Guenancia C, Vaz-Luis I, Di Meglio A, Pistilli B, Coutant C, et al. Association of body mass index and cardiotoxicity related to anthracyclines and trastuzumab in early breast cancer: French CANTO cohort study. PLoS Med. 2019;16(12):e1002989. 10.1371/journal.pmed.100298931869400 10.1371/journal.pmed.1002989
28. Demark-Wahnefried W Aziz NM Rowland JH Pinto BM Riding the crest of the teachable moment: promoting long-term health after the diagnosis of cancer J Clin Oncol 2005 23 24 5814 30 10.1200/JCO.2005.01.230 16043830
Demark-Wahnefried W, Aziz NM, Rowland JH, Pinto BM. Riding the crest of the teachable moment: promoting long-term health after the diagnosis of cancer. J Clin Oncol. 2005;23(24):5814–30. 10.1200/JCO.2005.01.23016043830 10.1200/JCO.2005.01.230
29. Muscaritoli M Arends J Bachmann P Baracos V Barthelemy N Bertz H ESPEN practical guideline: Clinical Nutrition in cancer Clin Nutr 2021 40 5 2898 913 10.1016/j.clnu.2021.02.005 33946039
Muscaritoli M, Arends J, Bachmann P, Baracos V, Barthelemy N, Bertz H, et al. ESPEN practical guideline: Clinical Nutrition in cancer. Clin Nutr. 2021;40(5):2898–913. 10.1016/j.clnu.2021.02.00533946039 10.1016/j.clnu.2021.02.005
30. van den Berg MM Winkels RM de Kruif JT van Laarhoven HW Visser M de Vries JH Weight change during chemotherapy in breast cancer patients: a meta-analysis BMC Cancer 2017 17 1 259 10.1186/s12885-017-3242-4 28403873
van den Berg MM, Winkels RM, de Kruif JT, van Laarhoven HW, Visser M, de Vries JH, et al. Weight change during chemotherapy in breast cancer patients: a meta-analysis. BMC Cancer. 2017;17(1):259. 10.1186/s12885-017-3242-428403873 10.1186/s12885-017-3242-4
31. Reding K, O’Connell NS, Cheng R, Nguyen J, Ladd A, Jordan J, et al. LVEF decline in relation to body composition among women treated for breast cancer: WF-97415. American Society of Clinical Oncology; 2022.
32. Cespedes Feliciano E Chen WY Clinical implications of low skeletal muscle mass in early-stage breast and colorectal cancer Proc Nutr Soc 2018 77 4 382 7 10.1017/S0029665118000423 29860952
Cespedes Feliciano E, Chen WY. Clinical implications of low skeletal muscle mass in early-stage breast and colorectal cancer. Proc Nutr Soc. 2018;77(4):382–7. 10.1017/S002966511800042329860952 10.1017/S0029665118000423
33. Maruyama S Shibata R Ohashi K Ohashi T Daida H Walsh K Adiponectin ameliorates doxorubicin-induced cardiotoxicity through akt protein-dependent mechanism J Biol Chem 2011 286 37 32790 800 10.1074/jbc.M111.245985 21784858
Maruyama S, Shibata R, Ohashi K, Ohashi T, Daida H, Walsh K, et al. Adiponectin ameliorates doxorubicin-induced cardiotoxicity through akt protein-dependent mechanism. J Biol Chem. 2011;286(37):32790–800. 10.1074/jbc.M111.24598521784858 10.1074/jbc.M111.245985
34. Nakamura K Fuster JJ Walsh K Adipokines: a link between obesity and cardiovascular disease J Cardiol 2014 63 4 250 9 10.1016/j.jjcc.2013.11.006 24355497
Nakamura K, Fuster JJ, Walsh K. Adipokines: a link between obesity and cardiovascular disease. J Cardiol. 2014;63(4):250–9. 10.1016/j.jjcc.2013.11.00624355497 10.1016/j.jjcc.2013.11.006
35. Marinou K Tousoulis D Antonopoulos AS Stefanadi E Stefanadis C Obesity and cardiovascular disease: from pathophysiology to risk stratification Int J Cardiol 2010 138 1 3 8 10.1016/j.ijcard.2009.03.135 19398137
Marinou K, Tousoulis D, Antonopoulos AS, Stefanadi E, Stefanadis C. Obesity and cardiovascular disease: from pathophysiology to risk stratification. Int J Cardiol. 2010;138(1):3–8. 10.1016/j.ijcard.2009.03.13519398137 10.1016/j.ijcard.2009.03.135
36. Pratesi A Tarantini F Di Bari M Skeletal muscle: an endocrine organ Clin Cases Min Bone Metab 2013 10 1 11 4 10.11138/ccmbm/2013.10.1.011
Pratesi A, Tarantini F, Di Bari M. Skeletal muscle: an endocrine organ. Clin Cases Min Bone Metab. 2013;10(1):11–4. 10.11138/ccmbm/2013.10.1.01110.11138/ccmbm/2013.10.1.011
37. Bekkelund SI Jorde R Lean body mass and creatine kinase are associated with reduced inflammation in obesity Eur J Clin Invest 2017 47 11 803 11 10.1111/eci.12802 28796313
Bekkelund SI, Jorde R. Lean body mass and creatine kinase are associated with reduced inflammation in obesity. Eur J Clin Invest. 2017;47(11):803–11. 10.1111/eci.1280228796313 10.1111/eci.12802
38. Pedersen L Idorn M Olofsson GH Lauenborg B Nookaew I Hansen RH Voluntary running suppresses Tumor Growth through Epinephrine- and IL-6-Dependent NK Cell mobilization and redistribution Cell Metab 2016 23 3 554 62 10.1016/j.cmet.2016.01.011 26895752
Pedersen L, Idorn M, Olofsson GH, Lauenborg B, Nookaew I, Hansen RH, et al. Voluntary running suppresses Tumor Growth through Epinephrine- and IL-6-Dependent NK Cell mobilization and redistribution. Cell Metab. 2016;23(3):554–62. 10.1016/j.cmet.2016.01.01126895752 10.1016/j.cmet.2016.01.011
39. Malietzis G Johns N Al-Hassi HO Knight SC Kennedy RH Fearon KC Low muscularity and myosteatosis is related to the host systemic inflammatory response in patients undergoing surgery for Colorectal Cancer Ann Surg 2016 263 2 320 5 10.1097/SLA.0000000000001113 25643288
Malietzis G, Johns N, Al-Hassi HO, Knight SC, Kennedy RH, Fearon KC, et al. Low muscularity and myosteatosis is related to the host systemic inflammatory response in patients undergoing surgery for Colorectal Cancer. Ann Surg. 2016;263(2):320–5. 10.1097/SLA.000000000000111325643288 10.1097/SLA.0000000000001113
40. Bassett DR Jr Howley ET Limiting factors for maximum oxygen uptake and determinants of endurance performance Med Sci Sports Exerc 2000 32 1 70 84 10.1097/00005768-200001000-00012 10647532
Bassett DR Jr., Howley ET. Limiting factors for maximum oxygen uptake and determinants of endurance performance. Med Sci Sports Exerc. 2000;32(1):70–84. 10.1097/00005768-200001000-0001210647532 10.1097/00005768-200001000-00012
41. Gamble DT Ross J Khan H Unger A Cheyne L Rudd A Impaired cardiac and skeletal muscle energetics following anthracycline therapy for breast Cancer Circ Cardiovasc Imaging 2023 16 10 e015782 10.1161/CIRCIMAGING.123.015782 37847761
Gamble DT, Ross J, Khan H, Unger A, Cheyne L, Rudd A, et al. Impaired cardiac and skeletal muscle energetics following anthracycline therapy for breast Cancer. Circ Cardiovasc Imaging. 2023;16(10):e015782. 10.1161/CIRCIMAGING.123.01578237847761 10.1161/CIRCIMAGING.123.015782
42. Ghignatti P Nogueira LJ Lehnen AM Leguisamo NM Cardioprotective effects of exercise training on doxorubicin-induced cardiomyopathy: a systematic review with meta-analysis of preclinical studies Sci Rep 2021 11 1 6330 10.1038/s41598-021-83877-8 33737561
Ghignatti P, Nogueira LJ, Lehnen AM, Leguisamo NM. Cardioprotective effects of exercise training on doxorubicin-induced cardiomyopathy: a systematic review with meta-analysis of preclinical studies. Sci Rep. 2021;11(1):6330. 10.1038/s41598-021-83877-833737561 10.1038/s41598-021-83877-8
43. Ghignatti P Russo MKB Becker T Guecheva TN Teixeira LV Lehnen AM Preventive aerobic training preserves sympathovagal function and improves DNA repair capacity of peripheral blood mononuclear cells in rats with cardiomyopathy Sci Rep 2022 12 1 6422 10.1038/s41598-022-09361-z 35440673
Ghignatti P, Russo MKB, Becker T, Guecheva TN, Teixeira LV, Lehnen AM, et al. Preventive aerobic training preserves sympathovagal function and improves DNA repair capacity of peripheral blood mononuclear cells in rats with cardiomyopathy. Sci Rep. 2022;12(1):6422. 10.1038/s41598-022-09361-z35440673 10.1038/s41598-022-09361-z
44. Ambrose JA Barua RS The pathophysiology of cigarette smoking and cardiovascular disease: an update J Am Coll Cardiol 2004 43 10 1731 7 10.1016/j.jacc.2003.12.047 15145091
Ambrose JA, Barua RS. The pathophysiology of cigarette smoking and cardiovascular disease: an update. J Am Coll Cardiol. 2004;43(10):1731–7. 10.1016/j.jacc.2003.12.04715145091 10.1016/j.jacc.2003.12.047
45. Law MR Morris JK Wald NJ Environmental tobacco smoke exposure and ischaemic heart disease: an evaluation of the evidence BMJ 1997 315 7114 973 80 10.1136/bmj.315.7114.973 9365294
Law MR, Morris JK, Wald NJ. Environmental tobacco smoke exposure and ischaemic heart disease: an evaluation of the evidence. BMJ. 1997;315(7114):973–80. 10.1136/bmj.315.7114.9739365294 10.1136/bmj.315.7114.973
46. Jin H Xu J Sui Z Wang L Risk factors from Framingham risk score for anthracyclines cardiotoxicity in breast cancer: a systematic review and meta-analysis Front Cardiovasc Med 2023 10 1101585 10.3389/fcvm.2023.1101585 36742068
Jin H, Xu J, Sui Z, Wang L. Risk factors from Framingham risk score for anthracyclines cardiotoxicity in breast cancer: a systematic review and meta-analysis. Front Cardiovasc Med. 2023;10:1101585. 10.3389/fcvm.2023.110158536742068 10.3389/fcvm.2023.1101585
47. Lemieux J Diorio C Cote MA Provencher L Barabe F Jacob S Alcohol and HER2 polymorphisms as risk factor for cardiotoxicity in breast cancer treated with trastuzumab Anticancer Res 2013 33 6 2569 76 23749910
Lemieux J, Diorio C, Cote MA, Provencher L, Barabe F, Jacob S, et al. Alcohol and HER2 polymorphisms as risk factor for cardiotoxicity in breast cancer treated with trastuzumab. Anticancer Res. 2013;33(6):2569–76.23749910
48. Zamorano JL Lancellotti P Rodriguez Munoz D Aboyans V Asteggiano R Galderisi M 2016 ESC position paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: the Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC) Eur Heart J 2016 37 36 2768 801 10.1093/eurheartj/ehw211 27567406
Zamorano JL, Lancellotti P, Rodriguez Munoz D, Aboyans V, Asteggiano R, Galderisi M, et al. 2016 ESC position paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: the Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J. 2016;37(36):2768–801. 10.1093/eurheartj/ehw21127567406 10.1093/eurheartj/ehw211
49. Porciuncula Frenzel A Aberici Pastore C Gonzalez MC The influence of body composition on quality of life of patients with breast cancer Nutr Hosp 2013 28 5 1475 82 10.3305/nh.2013.28.5.6705 24160203
Porciuncula Frenzel A, Aberici Pastore C, Gonzalez MC. The influence of body composition on quality of life of patients with breast cancer. Nutr Hosp. 2013;28(5):1475–82. 10.3305/nh.2013.28.5.670524160203 10.3305/nh.2013.28.5.6705
50. Kondov B Milenkovikj Z Kondov G Petrushevska G Basheska N Bogdanovska-Todorovska M Presentation of the molecular subtypes of breast Cancer detected by immunohistochemistry in surgically treated patients Open Access Maced J Med Sci 2018 6 6 961 7 10.3889/oamjms.2018.231 29983785
Kondov B, Milenkovikj Z, Kondov G, Petrushevska G, Basheska N, Bogdanovska-Todorovska M, et al. Presentation of the molecular subtypes of breast Cancer detected by immunohistochemistry in surgically treated patients. Open Access Maced J Med Sci. 2018;6(6):961–7. 10.3889/oamjms.2018.23129983785 10.3889/oamjms.2018.231
