Assessment of right ventricular functions during cancer chemotherapy

Abstract

Aims

Although systolic and diastolic left ventricular functions after cancer chemotherapy are well studied, there are a few investigations about the right ventricular functions. We aimed to investigate the early effects of chemotherapy on right heart, if any, in addition to the association between N-terminal pro-brain natriuretic peptide (NT-proBNP) and right heart echocardiographic indices.

Methods and results

Thirty-seven consecutive patients with newly diagnosed breast cancer who were planned to receive either AC protocol [cyclophosphamide (600 mg/m²) + adriamycin (60 mg/m²)] or CAF protocol [cyclophosphamide (600 mg/m²) + adriamycin (60 mg/m²) + 5-fluorouracil (600 mg/m²)] for six cures were enrolled between February 2009 and June 2010. Echocardiography was performed before the onset of the chemotheurapeutic regimen (T1), on the day after the completion of the first cure (T2), and after the completion of two cures of the regimen (T3). Serum NT-proBNP levels were also measured at T1, T2, and T3. The mean right ventricular fractional area change (RVFAC) was 63.7 ± 3.63, 63.3 ± 3.67, and 61.2 ± 4.41% at T1, T2, and T3, respectively (pT1–T3 and pT2–T3 <0.05). Tricuspid annular plane systolic excursion (TAPSE) has decreased in time (1.82 ± 0.2, 1.78 ± 0.19, and 1.62 ± 0.24 cm; pT1–T2, pT1–T3, and pT2–T3 were 0.002, <0.001, and <0.001, respectively). Tricuspid annular mean E′/A′ ratios were 1.42 ± 0.16, 1.36 ± 0.18, and 1.11 ± 0.32 (pT1–T2 = 0.013, pT1–T3 < 0.001, and pT2–T3 < 0.001). Mean tricuspid annular systolic velocities were 11.35 ± 1.85, 11.0 ± 1.82, and 10.45 ± 1.75 cm/s for T1, T2, and T3; and the differences between T1 and T2, T1 and T3, and T2 and T3 were all significant (P = 0.005, <0.001, and 0.001). Median serum NT-proBNP levels were 82 (60–247), 116 (60–426), and 170 (60–600) pg/mL at T1, T2, and T3. The amount of change in RVFAC and TAPSE between T1 and T3 were found to be correlated with the amount of change in NT-proBNP measurements between T1 and T3 (R: −0.7, P < 0.001; R: −0.62, P < 0.001).

Conclusion

There is a subclinical decrease in right ventricular systolic and diastolic echocardiographic indices, although mostly, in the normal range, in a relatively short time interval after onset of chemotherapy.

Chemotherapy, Right ventricular function, Tissue Doppler echocardiography, Tricuspid annular plane systolic excursion, N-terminal pro-brain natriuretic peptide

Introduction

Chemotherapeutic regimens which contain anthracyclines, cyclophosphamide, fluorouracil, cisplatin, taxanes, and trastuzumab cause early and late cardiotoxicity.¹ Chemotherapy-induced cardiotoxicity includes cardiomyopathy with or without overt congestive heart failure. Impairment in diastolic cardiac function was suggested as an early finding of chemotherapy-induced cardiac damage.² Tissue Doppler echocardiography (TDI), which allows measurement of systolic and diastolic velocities of ventricular walls, has been a useful method recently for earlier detection of local abnormalities in cardiac functions before the heart is globally affected.^3,4

Although the left ventricular systolic and diastolic functions after chemotherapy were well studied, there have been scarce investigations about right ventricular functions whose prognostic value increases in the presence of left ventricular systolic dysfunction.⁵ The right ventricle is functionally and anatomically divided into inflow and outflow tracts⁶ and echocardiographic assessment is difficult due to it's crescentic anatomical and morphological structure. M-mode echocardiography, two-dimensional echocardiography, conventional Doppler echocardiography, and myocardial Doppler tissue imaging are all used to evaluate right heart and provide accurate prognostic information especially when used in combination.⁷

We investigated early effects of cancer chemotherapy, if any, on right heart in a relatively short time period in patients with breast cancer who received anthracycline, cyclophosphamide, and 5-fluorouracil (5-FU) and who have been treated with chemotherapeutics for the first time throughout their lives. We also searched for the relationship between right heart echocardiographic indices and serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) which is a well-known marker of cardiac damage and which have been shown to predict subtle myocardial damage in chemotherapy survivors.^8,9

Methods

Study population

Thirty-seven consecutive patients who were newly diagnosed to have breast cancer at the Medical Oncology department of our university hospital were included between February 2009 and June 2010. The study was conducted according to the recommendations of Declaration of Helsinki on Biomedical Research involving human subjects and was approved by the local Ethics Committee. Written informed consent was obtained from each participant. We did not involve patients older than 50 years of age, because diastolic function of the heart may be impaired by increasing age. We also did not involve patients who had inadequate echocardiographic view since some of the patients have limited access after left-sided breast surgery. Other disclusion criteria were hypertension, diabetes mellitus, established coronary artery disease, rhythm other than sinus, valvular heart disease (more than mild), renal failure (serum creatinine >1.6 mg/dL), and hepatic dysfunction (serum aspartate aminotransferase, alanine aminotransferase >3 times of the upper level). Participants received either AC protocol [cyclophosphamide (600 mg/m²) + adriamycin (60 mg/m²) at each cure] or CAF protocol [cyclophosphamide (600 mg/m²) + adriamycin (60 mg/m²) + 5-FU (600 mg/m²) at each cure]. Each patient was planned to receive six cures of the above-mentioned therapies, 21 days apart. All participants have undergone complete physical examination before the beginning of the chemotherapeutic regimen. Blood samples were obtained for complete blood count, biochemistry, and serum NT-proBNP determination. An electrochemiluminescence immunoassay (Elecsys proBNP, Roche Diagnostics, Mannheim, Germany) was used for the determination of serum NT-proBNP measurement which had a reference range between 0 and 125 pg/mL. NT-proBNP measurements were repeated on the day after the delivery of the first cure of the regimen and after the completion of the first two cures which were applied at every 21 days.

Echocardiographic analysis

All participants have undergone echocardiographic evaluation before the onset of the chemotherapeutic regimen (T1), on the day after the completion of the first cure (T2), and after the completion of two cures of the regimen which corresponds to 45th day after the onset of the therapy (T3). All echocardiographic examinations were performed by the same cardiologist using a Vivid 7 ultrasound (GE-Vingmed Ultrasound AS, Horten, Norway) with a 2.5–3.5 MHz transducer in the left lateral decubitus position. Each examination was recorded and two other cardiologists blinded to the chemotherapeutic status of the patients interpreted the results off-line. Interobserver variability was <5%. Parasternal and apical projections were obtained according to the recommendations of American Society of Echocardiography.¹⁰ All recordings were done with a superimposed electrocardiography. For each parameter, five consecutive cycles were averaged. Standard two-dimensional echocardiographic evaluation for left and right ventricular size and function was performed. Left and right ventricular diameters were measured from a parasternal long-axis view¹¹ by M-mode examination recorded at the speed of 50 mm/s. Left ventricular ejection fraction (EF) was measured from the apical four-chamber view using biplane Simpson's rule.¹⁰ Right ventricular end-diastolic area and end-systolic area were measured from the apical four-chamber view to calculate right ventricular fractional area change (RVFAC).⁷ To determine the motion and excursion of tricuspid annulus (TAPSE), an M-Mode cursor was placed at the junction of the tricuspid valve plane with the right ventricular free wall, using the images of the apical four-chamber view.¹² Pulmonary artery systolic pressure was estimated by calculating the systolic pressure gradient between the right ventricle and the right atrium by the maximum velocity of the tricuspid regurgitant jet using the modified Bernoulli equation and then adding the estimated right atrial pressure based on the size of the inferior vena cava and the change in the calibre of it with respiration to this value.¹³ To measure the pulmonary acceleration time, pulsed Doppler was used to record the right ventricular outflow tract systolic spectral signal, and time-to-peak duration of the spectral signal across the pulmonic valve was measured from the short-axis view.¹⁴ Eccentricity index was measured at diastole and systole as the ratio of the minor axis diameter of the left ventricle parallel to the septum to that perpendicular to it.¹⁵ TDI values of the right and left ventricles were obtained from the apical four-chamber view using a sample volume placed at the lateral corner of the tricuspid annulus; and anterior, inferior, medial, and lateral sections of the mitral annulus.¹⁶ The imaging angle was adjusted to obtain a parallel alignment of the ultrasound beam with the segment of interest. The gains were minimized to reduce background noise and the Nyquist limit was adjusted to <30 cm/s. Peak systolic annular velocity (S′), early (E′), and late (A′) annular diastolic velocities were measured and E′/A′ was calculated.

Statistical analysis

Data analysis was performed by using Statistical Package for Social Sciences (SPSS) version 11.5 software (SPSS Inc., Chicago, IL, USA). For the continuous variables, parametric test conditions were first tested. The Shapiro–Wilk test was used to determine whether the continuous variables were normally distributed. Descriptive statistics were shown as mean ± standard deviation or median (minimum–maximum) where appropriate. While the mean differences between measurement times were compared by repeated measures of ANOVA; the Friedman test was applied for comparisons of the median differences. When the P-values from ANOVA or Friedman's test statistics were statistically significant, Bonferroni's adjusted multiple comparison test or Bonferroni's adjusted Wilcoxon's sign-rank test was used to determine which measurement time differs from which others. Degrees of association between continuous variables were calculated by Spearman's correlation analysis. A P-value <0.05 was considered statistically significant; but for all possible multiple comparison tests, the Bonferroni's correction was applied to control type I error and P < 0.017 was considered significant.

Results

Table 1 shows the basal characteristics of the study population. The mean age of the participants was 41.9 ± 5.2; 97.3% of the patients were female. The ratio of the patients who had undergone breast surgery before chemotherapy was 45% (17/37). The mean duration between the breast surgery and the onset of chemotherapy was 31.17 ± 5.44 days. None of the patients required termination or postponement of the treatment due to cardiotoxicity or any cardiovascular symptom after two cycles have been completed. No significant change was observed in heart rate or blood pressure between the basal values and after the completion of two cycles, and all of the participants remained in sinus rhythm.

Table 1

Basal characteristics of the study population.

	T1	T2	T3	p**T1–T2; p**T1–T3; p**T2–T3
Age (years)	41.9 ± 5.2	—	—
Systolic BP (mmHg)	121.4 ± 11.5	122.0 ± 10.1	121.5 ± 10.0	>0.05; >0.05; >0.05
Diastolic BP (mmHg)	78.2 ± 6.1	77.2 ± 7.2	78.1 ± 5.0	>0.05; >0.05; >0.05
Heart rate(bpm)	67.4 ± 4.4	66.1 ± 4.6	67.0 ± 5.2	>0.05; >0.05; >0.05
Height (m)	1.59 ± 4.8	—	—
Weight (kg)	66.4 ± 5.1	66.3 ± 5.3	64.2 ± 4.3	>0.05; <0.05; <0.05
Tumour site (right/left)	23/14	—	—
Breast surgery (+/−)	17/20	—	—
Hb (g/dL)	12.5 ± 1.27	12.1 ± 1.25	10.7 ± 1.23	<0.001; <0.001; 0.007
WBC (103)*	7.2(4.0–12.3)	7(4–12.4)	4.3(2.6–11.6)	0.023; <0.001; <0.001
Platelet (103)*	318(182–443)	310(175–583)	256(131–529)	0.629; 0.018; 0.008

*Non-significant after Bonferroni's correction. T1, before chemotherapy; T2, first day after the first cure of chemotherapy; T3, after the completion of two cures of chemotherapy.

**P < 0.017 considered significant after Bonferroni's correction.

Table 2 shows the echocardiographic measurements for the right ventricle. The mean RVFAC was 63.7 ± 3.63% before chemotherapy (T1), 63.3 ± 3.67% at T2, and 61.2 ± 4.41% at T3. The difference between T1 and T2 was non-significant, whereas the differences between T1 and T3 and T2 and T3 were significant (P < 0.05 both). Mean TAPSE values were 1.82 ± 0.2, 1.78 ± 0.19, and 1.62 ± 0.24 cm, respectively. The differences between T1 and T2, T1 and T3, and T2 and T3 were all significant (P = 0.002, <0.001, and <0.001, respectively). Mean pulmonary acceleration times decreased with time and differences between T1 and T2, T1 and T3, and T2 and T3 were significant (121.9 ± 14.01, 119.0 ± 12.9, and 111.2 ± 12.5 ms; P = 0.007, <0.001, and <0.001, respectively). Mean diastolic eccentricity indices were 1.11 ± 0.073, 1.13 ± 0.076, and 1.14 ± 0.085, whereas mean systolic eccentricity indices were 1.07 ± 0.067, 1.07 ± 0.069, and 1.09 ± 0.080. For both the diastolic and the systolic eccentricity indices, the differences between T1 and T2, T1 and T3, and T2 and T3 were non-significant. In 20 patients, adequate jet of tricuspid regurgitation was not available so pulmonary artery pressures were not measured.

Table 2

Right ventricular echocardiographic examination

	T1	T2	T3	pT1–T2; pT1–T3; pT2–T3
RVEDD (cm)*	2.8 (2.5–3.4)	2.8 (2.5–3.4)	2.9 (2.5–3.4)	0.005; <0.001; 0.001
RVFAC (%)**	63.7 ± 3.63	63.3 ± 3.67	61.2 ± 4.41	0.11; <0.001; <0.001
RAD (cm)*	3.4 (2.9–4.2)	3.4 (2.8–4.2)	3.4 (3.0–4.3)	1; 0.008; 0.008
RAV (cm³)*	28 (18–44)	28 (18–44)	29 (19–44)	0.28; <0.001; <0.001
TAPSE (cm)*	1.82 ± 0.2	1.78 ± 0.19	1.62 ± 0.24	0.002; <0.001; <0.001
Pulm vel (m/s)**	1.03 ± 0.12	1.01 ± 0.13	0.95 ± 0.14	0.12; <0.001; <0.001
Pulm acc time (ms)**	121.9 ± 14.01	119.0 ± 12.9	111.2 ± 12.5	0.007; <0.001; <0.001
sPAP (mmHg)*	30 (28–39)	32 (29–39)	33 (29–44)	0.016; 0.001; 0.017

RVEDD, right ventricular end-diastolic diameter; RVFAC, right ventricular fractional area change; RAD, right atrial diameter; RAV, right atrial volume; TAPSE, tricuspid annular plane systolic excursion; Pulm vel, pulmonary velocity; Pulm acc time, pulmonary acceleration time; sPAP, systolic pulmonary artery pressure; T1, before chemotherapy; T2, first day after the first cure of chemotherapy; T3, after the completion of two cures of chemotherapy.

*P < 0.017 considered significant after Bonferroni's correction.

**P < 0.05 considered significant.

Table 3 shows the tissue Doppler echocardiographic examination results. Tricuspid annular mean E′/A′ ratios were 1.42 ± 0.16, 1.36 ± 0.18, and 1.11 ± 0.32 and the differences between T1 and T2, T1 and T3, and T2 and T3 were significant (P = 0.013, <0.001, and <0.001, respectively). Mean tricuspid annular systolic velocities were 11.35 ± 1.85, 11.0 ± 1.82, and 10.45 ± 1.75 cm/s, respectively, for T1, T2, and T3 and the differences between T1 and T2, T1 and T3, and T2 and T3 were all significant (P = 0.005, <0.001, and 0.001, respectively).

Table 3

Tissue Doppler echocardiographic measurements from lateral tricuspid annulus

	T1	T2	T3	pT1–T2; pT1–T3; pT2–T3
TAE′ (cm/s)	16.62 ± 1.72	16.18 ± 1.68	13.43 ± 2.63	0.013; <0.001; <0.001
TAA′ (cm/s)	11.75 ± 1.73	11.90 ± 1.77	12.40 ± 1.87	0.115; 0.003; 0.026
TAS′ (cm/s)	11.35 ± 1.85	11.00 ± 1.82	10.45 ± 1.75	0.005; <0.001; 0.001
T E′/A′	1.42 ± 0.16	1.36 ± 0.18	1.11 ± 0.32	0.013; <0.001; <0.001

TAE′, tricuspid annular early diastolic velocity; TAA′, tricuspid annular late diastolic velocity; TAS′, tricuspid annular systolic velocity; T E′/A′, tricuspid annular E′/A′ ratio; T1, before chemotherapy; T2, first day after the first cure of chemotherapy; T3, after the completion of two cures of chemotherapy. P< 0.017 is considered significant after Bonferroni's correction.

There were no significant differences with regard to left ventricular systolic EFs, left ventricular end-diastolic diameter (LVEDD), and left ventricular end-systolic diameters (LVESD) between time intervals (EF: 66.4 ± 2.77, 66.1 ± 2.78, and 65.7 ± 2.66%; LVEDD: 4.38 ± 0.25, 4.38 ± 0.24, and 4.40 ± 0.24 cm; and LVESD: 2.8 ± 0.23, 2.81 ± 0.23, and 2.84 ± 0.23 at T1, T2, and T3, respectively). Table 4 shows the tissue Doppler echocardiographic measurements of the left ventricle measured separately from lateral, medial, inferior, and anterior annuli. Most of the systolic annular velocities were not changed significantly except for the mitral annulus. However, there were slight but significant impairments in the diastolic tissue Doppler indices except for the lateral annulus values.

Table 4

Left ventricular tissue Doppler echocardiographic examination from mitral annulus

	T1	T2	T3	pT1–T2; pT1–T3; pT2–T3
LAE′a (cm/s)	13.00 ± 1.22	12.92 ± 1.38	12.84 ± 1.42	0.206
LAA′b (cm/s)	8.78 ± 1.03	8.86 ± 1.00	8.95 ± 1.29	0.747
LAS′b (cm/s)	7.38 ± 0.79	7.35 ± 0.86	7.24 ± 0.93	0.199
L E′/A′a	1.49 ± 0.18	1.47 ± 0.17	1.45 ± 0.17	0.162
MAE′b (cm/s)	11.27 ± 1.41	11.14 ± 1.53	10.46 ± 1.56	0.059; <0.001; <0.001
MAA′b (cm/s)	8.22 ± 0.95	8.43 ± 1.09	8.51 ± 1.07	0.142
MAS′b (cm/s)	7.00 ± 0.78	6.84 ± 0.93	6.62 ± 0.89	0.058; <0.001; 0.005
M E′/A′a	1.37 ± 0.15	1.33 ± 0.18	1.23 ± 0.19	0.027; <0.001; 0.001
IAE′b (cm/s)	11.81 ± 1.05	11.49 ± 0.93	10.97 ± 1.26	0.008; <0.001; 0.003
IAA′b (cm/s)	8.49 ± 0.84	8.49 ± 0.84	8.62 ± 1.04	0.878
IAS′b (cm/s)	7.24 ± 0.89	7.16 ± 0.76	7.14 ± 0.82	0.338
I E′/A′a	1.40 ± 0.18	1.38 ± 0.20	1.29 ± 0.21	0.257; 0.001; 0.001
AAE′b (cm/s)	11.38 ± 0.89	11.22 ± 1.00	10.57 ± 0.99	0.058; <0.001; 0.001
AAA′b (cm/s)	8.03 ± 0.60	8.19 ± 0.74	8.22 ± 0.95	0.377
AAS′b (cm/s)	6.95 ± 0.91	6.95 ± 0.97	6.76 ± 0.76	0.120
A E′/A′b	1.42 ± 0.11	1.37 ± 0.11	1.30 ± 0.17	0.026; <0.001; 0.003

LAE′, lateral mitral annular early diastolic velocity; LAA′, lateral mitral annular late diastolic velocity; LAS′, lateral mitral annular systolic velocity; L E′/A′, lateral mitral annular E′/A′ ratio; MAE′, medial mitral annular early diastolic velocity; MAA′, medial mitral annular late diastolic velocity; MAS′, medial mitral annular systolic velocity; M E′/A′, medial mitral annular E′/A′ ratio; IAE′, inferior mitral annular early diastolic velocity; IAA′, inferior mitral annular late diastolic velocity; IAS′, inferior mitral annular systolic velocity; I E′/A′, inferior mitral annular E′/A′ ratio; AAE′, anterior mitral annular early diastolic velocity; AAA′, anterior mitral annular late diastolic velocity; AAS′, anterior mitral annular systolic velocity; A E′/A′, anterior mitral annular E′/A′ ratio; T1, before chemotherapy; T2, first day after the first cure of chemotherapy; T3, after the completion of two cures of chemotherapy. P < 0.017 is considered significant after Bonferroni's correction.

^aRepeated measures of ANOVA.

^bFriedman's test.

Median serum proBNP levels were 82 (60–247), 116 (60–426), and 170 (60–600) pg/mL at T1, T2, and T3 (P < 0.001). The amount of changes in RVFAC, TAPSE, and right atrial volume between T1 and T3 were found to be correlated with the amount of change in proBNP measurements between T1 and T3 (R: −0.7, P< 0.001; R: −0.62, P < 0.001; R: 0.55, P < 0.001, respectively). None of the patients had any sign or symptom of clinical heart failure.

Discussion

We have demonstrated that chemotherapeutic drugs cause a decrease in right ventricular systolic and diastolic functions in a relatively short time period, although most echocardiographic indices remain in the normal range and do not cause any clinical sign of right heart failure. Some TDI indices were acutely reduced after the infusion of the first dose of the therapy. In addition, increase in serum NT-proBNP concentrations were found to be correlated with the decrease in RVFAC and TAPSE after two cycles of chemotherapy.

In numerous studies involving mostly anthracyclines, subclinical cardiac damage was demonstrated,¹⁷ and especially diastolic impairment in the left ventricle was shown to precede systolic derangement.^18–20 TDI has been suggested as the preferred method to detect early cardiac damage caused by cancer chemotherapy in many articles.^21,22 However, myocardial deformation parameters (strain and strain rate) have been recently reported to detect the subclinical myocardial damage earlier than myocardial velocity measurements.²³ Jurcut et al.²⁴ reported a significant reduction in radial strain after three cycles of pegylated doxorubicin treatment given every 3 weeks and a significant reduction in both longitudinal and radial strain and strain rates after six cycles of the same regimen. In a study using speckle-tracking echocardiography in addition to TDI, subclinical systolic and diastolic myocardial abnormalities were shown to persist up to 6 years of follow-up.²⁵

Interpretation of myocardial displacement and velocities using TDI which does not require a separate examination or application is feasible and easy for routine use in our institution's clinical practice. TDI which is less affected by the loading conditions is appropriate for patients receiving chemotherapy because these patients are prone to changing fluid and weight status during the course of therapy. We preferred not to use strain rate imaging or speckle-tracking echocardiography because we wanted to be realistic in terms of availability for routine clinical application for every cancer patient.

The study by Ganame et al.²⁶ was similar to our study in terms of the investigation of short-time effects of chemotherapy. After each of the first three doses of low-to-moderate dose anthracycline therapy, cardiac systolic and diastolic functions were acutely impaired as detected by TDI and strain rate imaging. Although some other studies also described subtle myocardial involvement detected by TDI in a short-term interval,²⁷ Appel et al.²⁸ did not find a significant impairment in most of the echocardiographic indices, other than a modest reduction in E/A ratio, by TDI or conventional echocardiography after three cycles of low-dose epirubicin infusion. However, the cardiotoxic effect of epirubicin is about half that of doxorubicin at same doses.²⁹

In histological studies, the cardiotoxic damage was more prominent in the subendocardial part of the cardiac walls.³⁰ The thinner right ventricle should be more sensitive to the toxic effects of chemotherapy, although data are lacking to support this hypothesis. In our study, it was impossible to perform histological analysis to compare the right ventricular and left ventricular involvement; still, it is interesting with regards to being supportive to the above-mentioned hypothesis. There were deteriorations in the systolic and diastolic echocardiographic parameters of the right ventricle, whereas only minimal diastolic impairment in the left ventricular TDI indices was observed meanwhile. This study may lead to prospective non-human studies with histological analysis to test whether the right ventricle is more prone to toxic effects of chemotherapy and affected earlier.

In general, the issue of right ventricular involvement during or after chemotherapy is not adequately studied. Belham et al.³¹ reported that low-dose anthracycline administration was associated with an increase in the left ventricular Tei index (myocardial performance index), whereas there was no significant change in the right ventricular Tei index. Cottin et al.³² evaluated the cardiac functions by radionuclide angiography in 33 women treated with anthracycline therapy and found an impairment in the systolic and diastolic left ventricular radionuclide parameters without any alteration in the right heart functions. Yildirim et al. investigated left ventricular and right ventricular functions using dobutamine stress echocardiography and TDI in asymptomatic paediatric long-term survivors of different types of malignancies who were treated with anthracyclines and detected that right ventricular S_m′, A_m′, and E′/A′were impaired.³³

Poorly defined geometry hinders the assessment of right heart functions using standard methods so we preferred to use both TDI and conventional echocardiography. The results of our study are not concordant with the results of Belham et al. and Cottin et al. We have found that RVFAC was decreased during the ongoing chemotherapy, although it remained in the normal range. TAPSE, which was shown to correlate strongly with radionuclide EF calculation,³⁴ was also found to have a decremental trend during the chemotherapy process. TDI revealed decreasing systolic tricuspid annular velocities and a marked change was observed especially in tricuspid E′/A′ ratio. It is reported in many studies that right ventricular diastolic dysfunction precedes apparent systolic dysfunction. In the analysis of 29 studies with a total number of 1053 participants, the mean E′/A′ value was 1.3 [(95% confidence interval (CI) 1.1–1.3], the lower reference value was 0.5 (95% CI 0.4–0.6), and upper reference value was 1.9 (95% CI 1.7–2.0),³⁵ which means we have detected a modest diastolic impairment in our population. Despite a decrease in right ventricular systolic and diastolic functions, most parameters remain in the normal ranges provided in the recent guideline of American Society of Echocardiography for the echocardiographic assessment of the right heart.³⁵ The reason for the discrepancy between our results and the results of the above-mentioned studies may be due to the difference in echocardiographic indices evaluated. The Tei index is a combined measure of systolic and diastolic performance in patients with primary myocardial systolic dysfunction.³⁶ The Tei index or EF reflects the heart functions globally whereas TAPSE or TDI S′ rather reflect regional myocardial displacement or velocities. Although they are assumed to represent the entire right ventricle, this may not be valid in many disease states.³⁵

We detected a slight significant decrease in pulmonary acceleration time and a slight increase in estimated pulmonary artery pressure, although the echocardiographic threshold for pulmonary hypertension was not reached. It has been known for a long time that a shorter acceleration time reflects an increase in pulmonary artery pressure.³⁷ Lopez-Candales et al.³⁸ have shown that right ventricular outflow signal could also be used to assess the presence of right ventricular dysfunction. Although invasive pulmonary vascular resistance calculation was not performed in this study, we think that this finding reflected a decrease in right ventricular performance rather than an impairment in pulmonary resistance because of the absence of severe manifest left ventricular failure to induce reactive (out of proportion) post-capillary pulmonary hypertension.³⁹ Still, it should be kept in mind that chemotherapeutic agents are among the possible causes of idiopathic pulmonary arterial hypertension by increasing pulmonary vascular resistance, although not frequent.³⁹ Systolic and diastolic eccentricity indices are means to differentiate between right ventricular volume or pressure overload.⁴⁰ Unsurprisingly, we have not detected any impairment in neither of the systolic or diastolic eccentricity indices, as the changes detected on right ventricular indices in the present study were subtle and right ventricular geometry has not been affected.

5-FU is an S phase-specific antimetabolite and the cardiotoxicity related to 5-FU manifests itself by angina pectoris, arrhythmias, or hypotension.⁴¹ In a recent literature review including 377 studies about the cardiotoxic effects of 5-FU, it was reported that 69% of the cardiac events were seen during or within 72 h of the first cycle of 5-FU. Angina occurred in 45% of the patients, whereas myocardial infarction was seen in 22%.⁴² Twelve patients in our study have been treated with 5-FU in addition to adriamycin and cyclophosphamide but only one of them complained of chest pain during the infusion of the drug which recovered when the infusion was ceased. She had non-specific T-wave changes in the electrocardiogram and no cardiac enzyme or troponin elevation was observed.

The major limitation of this study is the short follow-up; however, the purpose is to assess the right ventricular function in the short-term period, during ongoing chemotherapy.

In conclusion, we have demonstrated an impairment in right ventricular echocardiographic indices during chemotherapy in a relatively short time, although this has not caused any clinical deterioration. This investigation may give rise to attention on right heart in cancer patients and may lead to larger trials which also test the possible association of short-term changes in right heart echocardiographic indices with the long-term prognosis. After analysing the possible association between the early impairment in each of the above-mentioned parameters and the long-term prognosis, the parameters which should be preferred for risk assessment would be more clearly identified. However, at the moment, we suggest a combined use of tissue Doppler echocardiography and conventional echocardiography to measure TDI E′/A′, TDI S′, TAPSE, and RVFAC to assess the right heart functions during ongoing chemotherapy starting from the relatively early phases of the treatment.

Conflict of interest: none declared.