Abstract
Background
A large number of chemotherapy‐induced cardiovascular complications were discovered in studies over the last several decades. The focus of the majority of these studies was left ventricular (LV) remodeling. The aim of this article was to provide a comprehensive overview of potential mechanisms of chemotherapy‐induced right ventricular (RV) remodeling and summarize clinical studies on this topic.
Hypothesis
Chemotherapy induces RV structural, functional, and mechanical changes.
Methods
We searched PubMed, MEDLINE, Ovid and Embase databases for studies published from January 1990 up to September 2016 in the English language using the following keyword “chemotherapy,” “heart,” “right ventricle,” “anthracyclines,” and “trastuzumab.”
Results
The existing research show that RV remodeling occurs simultaneously with LV remodeling, which is why RV remodeling should not be neglected in the overall cardiac assessment of patients treated with chemotherapy, and especially those protocols that involve anthracyclines and trastuzumab. Investigations showed that these agents could significantly impact RV structure, function, and mechanics. These medications induce fibrosis of the RV myocardium, RV dilatation, decline in RV systolic function, worsening of its diastolic function, and finally impairment of RV mechanics (strain). The mechanisms of chemotherapy‐induced RV remodeling are still not entirely clear, but it is considered that direct destructive influence of chemotherapy on myocardium, oxidative stress, endothelial dysfunction, and negative impact on pulmonary circulation could significantly contribute to RV impairment.
Conclusions
Chemotherapy induces the impairment of RV structure, function, and mechanics by different complex mechanisms.
Keywords: chemotherapy, cancer, right ventricle
1. INTRODUCTION
The incidence of cancer is constantly increasing, and it is predicted that by 2030 the incidence will increase in 45%.1 However, despite this negative trend, the mortality rate decreased 20% to 30% in the last several decades.2 The introduction of new anticancer drugs significantly improved survival, but also revealed the large spectrum of cardiotoxicity manifestations caused by different chemotherapeutic agents.3
There are many factors that could increase the risk of cardiotoxicity development, such as type of chemotherapeutics, cumulative dosage, age, concomitant or previous irradiation therapy, and comorbidities. However, most chemotherapy‐induced cardiotoxicity mechanisms could be sorted in 1 of 2 groups4: (1) Type 1 is irreversible and induced mostly by anthracyclines. (2) Type 2 is mostly reversible and induced by monoclonal antibodies such as trastuzumab.
The majority of published studies are focused on the impact of chemotherapy on the left ventricle (LV). The rapid development of imaging techniques, particularly echocardiography and magnetic resonance, enabled comprehensive assessment of LV structure, function, and mechanics in cancer patients.5, 6 The current guidelines regarding detection of cardiotoxicity include only LV parameters: ejection fraction (EF) as traditional parameter of LV systolic function and global longitudinal strain as a new parameter of global systolic and mechanical function.7, 8
The data about the influence of chemotherapy on right ventricular (RV) function and mechanics are scarce and conflicting.9, 10, 11, 12 However, the number of studies that underline the predictive significance of RV structure, function, and deformation in patients with different cardiovascular conditions is constantly increasing.13, 14, 15
The aim of this review was to summarize the current knowledge about the impact of chemotherapeutic agents on RV remodeling from potential mechanisms to diagnostics.
2. POTENTIAL CELLULAR MECHANISMS OF RV REMODELING
Investigations showed that chemotherapeutic agents with the most important negative influence on RV structure, function and mechanics, as well as on the pulmonary circulation are anthracyclines, trastuzumab, cyclophosphamide, and dasatinib. We sought to summarize the current knowledge regarding the cellular mechanisms that could be responsible for RV remodeling (Figure 1).
Figure 1.
Different mechanisms of RV remodeling in the cancer patients treated with chemotherapy. Abbreviations: RV, right ventricular.
2.1. Anthracyclines
The widely accepted mechanism that could clarify anthracycline‐mediated cardiac toxicity comprises the production of oxygen species that react with iron and produce highly toxic and highly active hydroxyl radicals, which induces intracellular damage.4, 16 More recently, investigations revealed that anthracycline could also have direct negative impact on cardiomyocytes through the inhibition of topoisomerase II.
The target of anthracyclines is topoisomerase II α, which is very active in cancer cells due to their intensive division that includes replication, transcription, and chromosomal segregation. Adult cardiomyocytes express only topoisomerase II β isoenzyme. These 2 isoenzymes are structurally very similar and have the same catalytic mechanisms, which is why anthracyclines affect both.17 Therefore, topoisomerase II β is essential in anthracycline‐induced cardiomyopathy, and inhibition of this enzyme should provide the best protective effect of anthracycline‐mediated cardiomyopathy. Dexrazoxane is the only effective protective agent against doxorubicin‐induced cardiotoxic effects.18
Myocardial changes induced by anthracyclines (type 1 cardiotoxicity) are dose dependent and mostly irreversible, because they stimulate progression of vacuolar swelling to myofibrillar disarray and finally myocardial cell death.
2.2. Trastuzumab
Trastuzumab is a monoclonal antibody that inhibits receptor tyrosine‐protein kinase erbB‐2 and erbB‐3, receptors of tyrosine kinases. Both human epidermal growth factor receptors are expressed on cancer cells. However, erbB‐2 is also expressed on cardiomyocytes, and its deletion in the cardiomyocytes induced dilated cardiomyopathy in an animal model,19 which confirms its essential role in cardiac development (cardiomyocyte proliferation) and function.20
The incidence of cardiomyopathy is significantly lower in patients treated only with trastuzumab than in patients who received anthracycline.21 Slamon et al showed that cardiac dysfunction of New York Heart Association class III and IV was present in 27% of patients who were treated with anthracycline, cyclophosphamide, and trastuzumab; in 8% of subjects treated with anthracycline or cyclophosphamide; in 13% of participants treated with combined paclitaxel and trastuzumab; and only in 1% of patients who received only paclitaxel.
Trastuzimab‐induced cardiotoxicity (type 2 cardiotoxicity) is not dose‐related, and it is mostly completely reversible upon withdrawal of medication.
2.3. Cyclophosphamide
Cyclophosphamide is the alkylating agent that interferes with DNA replication. The results of the French Pulmonary Hypertension Network showed that some chemotherapeutics could be associated with pulmonary venous occlusive disease.22 The most responsible for pulmonary embolism were cyclophosphamide (43%), mitomycin C (24.3%), and cisplatin (21.6%).22 Interestingly, the majority of embolic events occurred within 1 year from the initiation of chemotherapy. The mechanism of cyclophosphamide‐induced pulmonary hypertension could be endothelial injury caused by oxidative stress.23
2.4. Dasatinib
Dasatinib is an oral tyrosine kinase inhibitor approved for first‐line use in patients with chronic myelogenous and acute lymphoblastic leukemia. However, it has been used for a number of solid cancers including prostate, ovarian, and breast tumors.
The results of the French Pulmonary Hypertension Network showed that dasatinib could also be associated with pulmonary hypertension.22 Investigators reported that most patients were clinically and functionally improved after discontinuation of dasatinib. Unfortunately, some patients died due to hemodynamic complications.
Dasatinib induces endothelial cell damage, oxidative stress, and changes the ratio among the proliferation and antiproliferation of the endothelial and pulmonary arterial smooth muscle cells, which leads to increased susceptibility and pulmonary hypertension.
3. CHEMOTHERAPY‐INDUCED RV REMODELING
Different chemotherapeutics could be responsible for the development of RV structural, functional, and mechanical remodeling in patients with cancer. Considering the results of previous studies that show significant increase of markers of cardiovascular damage, such as troponin or pro‐brain natriuretic peptide, in patients treated with chemotherapy,24 one should not forget the direct negative influence of these agents on the myocardium.
Investigations showed that RV function deteriorated even in naïve, untreated cancer patients, which represents an interesting finding that could be partly explained by the cancer‐related proinflammatory markers (interleukins), reactive oxidative species, and neurohormonal changes that are frequently elevated in cancer patients.25
3.1. RV structure
in an animal model, Milano et al showed that LV and RV wall thickness was decreased in mice treated with doxorubicin or a combination of doxorubicin and trastuzumab.26 There was no statistically significant difference in LV and RV wall thickness for mice treated only with trastuzumab. Interestingly, both groups (doxorubicin and combined doxorubicin and trastuzumab) had significantly higher fibrosis deposition in the RV free wall, as well as increased oxidative stress, than groups treated with placebo or solely trastuzumab.26 These are probably the reasons for the gradual increase of LV and RV volumes from mice treated with placebo, across mice treated only with trastuzumab, and by mice treated with doxorubicin, to mice treated with a combination of doxorubicin and trastuzumab.26 To our knowledge, there are no data regarding the influence of chemotherapy on RV wall thickness changes in cancer patients.
3.2. RV systolic function
Nowadays, echocardiography and magnetic resonance are the preferred techniques for evaluation of RV systolic function in cancer patients. The INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) compared necessity for assisted circulatory support between patients with chemotherapy‐induced cardiomyopathy, nonischemic cardiomyopathy, and ischemic cardiomyopathy.27 The authors reported that severe reduction of RV EF occurred in 27% of patients with chemotherapy‐induced cardiomyopathy, and in 19% of patients assisted circulatory support was required.27
Haarmark et al recently showed that RV systolic function changes even in patients before chemotherapy.28 The investigators reported that LV and RV volumes and EFs were somewhat different in patients with cancer who were not yet treated with chemotherapeutic agents.28 The authors unfortunately did not provide the comparison of these values with healthy subjects. However, it is evident that the values are different when comparing current guidelines and cutoff values for the global population. Thus, the lower cutoff for LV EF is only 50% for both genders, and for RV EF only 29% for men and 28% for women.28
Different studies that compared the same methodology with gold standard cardiac magnetic resonance set cutoff values for LV and RV volumes and EF.29 The authors showed that the cutoff values for diagnosing a ventricular dysfunction or dilatation were: 46% for RV EF and 94 mL for RV end‐diastolic volume.29
The comparison between these 2 studies indicates that RV systolic function is significantly deteriorated in cancer patients, even if they are not treated with chemotherapy. This possibly could be explained by the cancer‐related proinflammatory state characteristic for oncologic patients.
In 1 of the first studies that investigated the influence of anthracycline therapy on RV systolic and diastolic function evaluated by radionuclide angiography, the authors showed that RV EF, RV peak ejection rate, and time to peak ejection rate, as well as RV peak filling rate did not significantly change during the 1‐year follow‐up.30
Lange et al echocardiographically followed 42 female patients with breast cancer, and they did not find significant deterioration in RV diameter, pulmonary systolic pressure, tricuspid annular plane systolic excursion (TAPSE) index of longitudinal RV systolic function, or parameters obtained by tissue Doppler (the peak systolic velocity of the lateral tricuspid annulus obtained by tissue Doppler [s′] and Tei index) 6 months after trastuzumab introduction.31
Another study that used cardiac magnetic resonance in 46 women with breast cancer showed that both LV and RV end‐systolic volume indexes gradually increased from baseline up to 12 months after initiation of anticancer therapy (anthracycline and/or trastuzumab).32 Remarkably, LV and RV end‐diastolic volumes were increased 12 months after therapy but not before. On the other hand, LV and RV EF progressively decreased from baseline to 12 months after introduction of chemotherapy, with the steeper decline of RV EF in comparison with LV EF reduction.32 It should also be mentioned that half of the patients were also treated with radiotherapy.
More recently, a published study including 49 breast cancer patients undergoing anthracycline‐based chemotherapy reported that mean RV fractional area change (FAC), the important parameter of RV radial systolic function, decreased significantly from 48.3% to 42.1% (P = 0.01) during a period of 3 months.10 Similar results were reported by Calleja et al, who followed 40 female patients with breast cancer treated with trastuzumab with or without anthracycline.11 RV FAC declined from 47% to 42% (P = 0.01), whereas pulmonary systolic pressure significantly increased (24 ± 6.4 vs 29 ± 7.5 mm Hg, P = 0.01).11
A study by Tanindi et al involved 37 consecutive patients with newly diagnosed breast cancer who received cyclophosphamide + Adriamycin ± 5‐fluorouracil.9 The authors found significant impairment in RV systolic function even after the first chemotherapy cycle. RV diameter increased, whereas FAC decreased after the second chemotherapy cycle.9 Additionally, pulmonary acceleration time was decreased, whereas pulmonary systolic pressure was increased after 2 cycles.9 Considering that different mechanisms could explain endothelial dysfunction and oxidative stress in pulmonary circulation in patients who receive chemotherapy, it is reasonable to make a connection between pulmonary circulation and chemotherapy‐induced RV remodeling.
Not all investigators agree about the negative influence of chemotherapy on RV function. Belham et al studied 23 patients treated with low‐dose anthracycline (doxorubicin) and revealed no significant change in the RV Tei index after therapy.12 Havsteen et al also did not find any reduction in RV EF after therapy with epirubicin in female patients with breast cancer.33
We should be careful in the interpretation of different RV parameters obtained by various techniques. For instance, a recently published study in which the authors followed female patients with breast cancer treated with trastuzumab revealed that the Tei index and TAPSE were significantly deteriorated after 6 months of therapy, whereas tricuspid s′ and tricuspid isovolumic contraction time did not change.4 In this circumstance, assessment of RV strain would be of a great help. An overview of the existing data is provided in the Table 1.
Table 1.
Investigations regarding the influence of chemotherapy on right ventricular remodeling
| Reference | Sample Size | Age, y | Cancer Type | Chemotherapy | Imaging Technique | RV Systolic Function | RV Diastolic Function | RV Mechanics |
|---|---|---|---|---|---|---|---|---|
| Tanindi et al9 | 37 | 41.9 ± 5.2 | Breast | Cyclo + Adria ± 5‐F | Echocardiography | Impaired (FAC, TAPSE, s′) | Impaired (e′/a′) | Not evaluated |
| Boczar et al10 | 49 | 53.4 ± 3.3 | Breast | Anthracyclines | Echocardiography | Impaired (FAC) | Not evaluated | Impaired (LS) |
| Calleja et al11 | 30 + 30 | 51 ± 8 vs 54 ± 12 | Breast | Trastuzumab ± anthracycline | Echocardiography + nuclear | Impaired (FAC, EF) | Not evaluated | Impaired (LS) |
| Belham et al12 | 23 | 48 ± 20 | Hematologic malignancies or solid tumors | Anthracycline | Echocardiography | Unchanged (Tei index) | Unchanged (Tei index) | Not evaluated |
| Cottin et al30 | 33 | 51 ± 13 | Breast | Anthracycline | Nuclear | Unchanged (EF) | Unchanged (peak filling rate) | Not evaluated |
| Lange et al31 | 42 | 54 (35–73) | Breast | Trastuzumab | Echocardiography | Unchanged (TAPSE, s′, Tei index) |
Unchanged (e′, a′, Tei index) |
Not evaluated |
| Grover et al32 | 46 | 55 ± 10 | Breast | Anthracycline ± trastuzumab | Magnetic resonance | Impaired (EF) | Not evaluated | Not evaluated |
| Havsteen et al33 | 14 + 11 | 50 ± 9 vs 53 ± 14 | Breast | Epirubicin1 | Nuclear | Unchanged (EF) | Not evaluated | Not evaluated |
| Kiliçaslan et al34 | 42 | 50.4 ± 11.6 | Breast | Trastuzumab | Echocardiography |
Impaired (TAPSE, IVCT, s′, Tei index) |
Impaired (IVRT, E/A, E/e′, Tei index) | Not evaluated |
| Nakano et al36 | 9 | 62.3 ± 12.6 | Breast | Trastuzumab | Magnetic resonance | Unchanged (EF) | Not evaluated | Impaired (LS,CS) |
Abbreviations: a′, the peak late diastolic relaxation velocity of the lateral tricuspid annulus obtained by tissue Doppler; CS, circumferential strain; Cyclo + Adria ± 5‐F, Cyclophosphamide + Adriamycin ± 5‐fluorouracil; EF, ejection fraction; FAC, fractional area change; e′, the peak early diastolic relaxation velocity of the lateral tricuspid annulus obtained by tissue Doppler; IVCT, isovolumic contraction time; IVRT, isovolumic relaxation time; LS, longitudinal strain; RV, right ventricular; s′, the peak systolic velocity of the lateral tricuspid annulus obtained by tissue Doppler; E/A, The ratio between early and late diastolic tricuspid flow assessed by pulsed Doppler.
Fourteen females with advanced breast cancer were treated with epirubicin. Previously these patients received cyclophosphamide, methotrexate, and 5‐fluorouracil or cyclophosphamide alone as adjuvant treatment. The control group consisted of 11 females with advanced breast cancer who were treated with only cyclophosphamide.
It should be mentioned that RV EF obtained by echocardiography is affected by different loading conditions and not simple to assess in everyday clinical practice. Therefore, the quickly and easily obtained echo parameters, such as TAPSE, basal RV free wall tissue velocity, and FAC, together with strain measurements, could be the coming standard for RV evaluation by echocardiography. RV EF is more accurately assessed by cardiac magnetic resonance or radionuclide angiography.
3.3. RV diastolic function
The assessment of RV diastolic function is usually performed by echocardiography using pulsed and tissue Doppler. RV diastolic dysfunction in patients treated with chemotherapy could be explained by the direct and indirect effect of chemotherapy on the RV, fibrosis of the RV myocardium, increased pulmonary pressure due to changes in pulmonary circulation caused by endothelial dysfunction and oxidative stress, but also could be the consequence of retrograde transmission of increased LV filling pressure to the RV or reflection of a decrease in RV performance. However, the results from the literature are conflicting.
In study that included newly diagnosed female patients treated with cyclophosphamide and Adriamycin with or without 5‐fluorouracil, investigators found significant deterioration of RV diastolic function estimated by tissue Doppler parameters after the first cycle of chemotherapy.9
Kiliçaslan et al also obtained conflicting results.34 E/e′ ratio is increased after treatment with trastuzumab, which reflects elevation in RV filling pressure that implies deterioration of RV diastolic function. However, tricuspid isovolumic relaxation time and E/A did not change significantly after trastuzumab therapy.
Cottin et al did not show any difference in RV diastolic function in female patients with breast cancer treated with anthracycline therapy.30 However, the authors used radionuclide measurement throughout treatment, which is not suitable for everyday clinical circumstances. Lange et al used tissue Doppler for evaluation of RV diastolic function and did not find deterioration of tricuspid the peak late diastolic relaxation velocity of the lateral tricuspid annulus obtained by tissue Doppler and the peak late diastolic relaxation velocity of the lateral tricuspid annulus obtained by tissue Doppler (parameters of early and late diastolic RV filling) in female patients with breast cancer treated with trastuzumab.31 The summary of the existing studies is showed in the Table 1.
3.4. RV mechanics
The introduction of new imaging tools, such as speckle‐tracking imaging (STI), significantly changed our approach to the assessment of myocardial function. This method provides the insight of myocardial mechanics of the whole thickness of cardiac wall, which overcomes many disadvantages of pulsed and tissue Doppler. STI is relatively angle independent, less load dependent, and more reproducible than tissue Doppler imaging. As a very sensitive method, 2‐dimensional and 3‐dimensional strain analysis has been largely used for the evaluation of subtle signs of chemotherapy‐induced LV dysfunction.6 However, studies that involve the RV are less common.
RV longitudinal strain is a good parameter of RV functional remodeling and is a useful predictor of mortality in patients with pulmonary hypertension, heart failure, pulmonary embolism, congenital heart diseases, cardiomyopathies, and valvular diseases.35 Therefore, the assessment of RV mechanics is very important and should be considered as the part of diagnostic evaluation of the patients treated with chemotherapy (Figure 2).
Figure 2.
Right ventricular longitudinal strain before and after anthracycline chemotherapy in the patient with breast cancer.
Boczar et al used echocardiographic methods to follow 49 patients with breast cancer treated with anthracycline‐based chemotherapy and revealed significant worsening of RV longitudinal strain 3 months after therapy initiation (from −16.2% to −13.81%, P = 0.04).10
Nakano et al involved 9 female patients with breast cancer treated with trastuzumab and reported that RV circumferential strain, assessed by magnetic resonance, decreased after 6 months of therapy (20.9% ± 2.4% vs −19.1% ± 2.3%, P = 0.049), whereas RV longitudinal strain and RV EF remained unchanged during the course of chemotherapy.36 The Table 1 provides an overview of the present data on this topic.
The study that investigated 30 patients with breast cancer treated with trastuzumab ± anthracycline showed that RV longitudinal strain of the entire RV, as well as isolated RV free wall, was significantly lower in patients with developed chemotherapy‐induced cardiomyopathy than in cancer patients before chemotherapy (for global RV: −21.0% ± 3.1% vs −25.7% ± 2.7 %, P < 0.001).11 However, it should be noted that even values of RV longitudinal strain in controls are somewhat lower than in healthy controls (global longitudinal strain for women: −26.7% ± 3.1%).37 Interestingly, the difference is more pronounced for RV free wall longitudinal strain, which implies greater susceptibility of RV myocardium than the interventricular septum for chemotherapy.
Chang et al recently reported that RV free wall longitudinal strain represents an independent predictor of dyspnea in chemotherapy‐treated cancer patients independently of LV and RV systolic and diastolic function.38 Reviewing the mechanisms of exercise intolerance in early‐stage breast cancer patients, Bonsignore et al described that chemotherapy induces angiogenesis inhibition, impairment of central hemodynamics, negative inotropic influence, vascular dysfunction, loss of contractile strength of muscles, and oxygen transport changes in chemotherapy‐treated patients.39
4. TREATMENT APPROACH
To the best of our knowledge, there are no data regarding the treatment of chemotherapy‐induced RV failure. However, there is no reason why the same therapy approach for chemotherapy‐induced LV failure, which implies renin–angiotensin system inhibitors (angiotensin‐converting enzyme [ACE] and angiotensin receptor blocker [ARB]) and β‐blockers, would not be used in the treatment of chemotherapy‐induced RV failure. The role of preventive treatment with ACE inhibitor, ARB, or β‐blocker therapy in patients with a low baseline cardiovascular risk who received anthracyclines remains uncertain, and there is no recommendation at this time.40 There are no data regarding the treatment strategy for isolated RV failure in patients treated with chemotherapy. We recommend that patients with chemotherapy‐induced isolated RV failure should be seen by a cardiologist, preferably in the cardio‐oncology clinic, and their treatment discussed with the oncology team.
5. CONCLUSION
The diagnostic and therapeutic approach to patients with cancer is often very challenging. Detailed evaluation of LV function and mechanics is crucial. However, the adequate assessment of RV function and mechanics should be a mandatory part of every echocardiographic examination, and only visual estimation of RV function should be discouraged. Considering the fact that echocardiography presents widely accepted imaging modality in everyday clinical practice, we strongly recommend evaluation of RV systolic function (TAPSE, FAC, s′) and RV longitudinal strain for monitoring cardiotoxic myocardial effects before, during, and after drug regimens, particularly anthracycline‐ and/or trastuzumab‐based protocols. The patients with chemotherapy‐induced isolated RV failure should be seen by a cardiologist and oncologist, who should make joint decisions regarding further treatment, especially regarding continuation of chemotherapy.
Tadic M, Cuspidi C, Hering D, Venneri L and Danylenko O. The influence of chemotherapy on the right ventricle: did we forget something? Clin Cardiol, 2017;40:437–443. 10.1002/clc.22672
Marijana Tadic, MD, received a training grant from the European Society for Cardiology for 2015.
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