Cardio-oncology: Foundations and value of echocardiography in its study. New horizons of ultrasound in Cardiology
ROBERTO LÓPEZ JIMÉNEZ, ADRIÁN LAMARQUE, EDUARDO MANUEL ESCUDERO
Facultad de Ciencias Médicas, Universidad Nacional de La Plata.
(1900) La Plata, Buenos Aires, Argentina. E-mail
Recibido 04-AGO-18 – ACEPTADO despues de revisión el 24-AGOSTO-2018.
There are no conflicts of interest to disclose.
Cardiotoxicity, which refers to the set of symptoms and signs that result from the effect of antineoplastic therapy on the heart, is one of the main areas of study of Cardio-oncology. The sum of risk factors and the side effects of antineoplastic agents are capable of producing reversible (type 1) or irreversible (type 2) heart damage. A fundamental tool to define cardiotoxicity is echocardiography, which confirms the decrease of the left ventricular ejection fraction. However, the echocardiographic approach has been limited to visualizing the damage produced, but not to preventing its occurrence. Among the new techniques developed, strain rate imaging allows to document changes in ventricular wall motion before they manifest with the fall of systolic function, thus identifying patients who are at risk of presenting cardiovascular complications related to the use of antineoplastic drugs.
Cardio-oncology is the meeting point between cancer and cardiovascular disease . If we consider its area of interaction, it is one of the branches of Cardiology booming for multiple reasons: a) the increase in life expectancy for oncological patients because of the appearance of new drugs; b) the requirement to study cancer survivors as carriers of a mix of risk factors and diseases existing before the disease proper; c) the adverse effects of oncological therapy on the cardiovascular area. So, cardiologists go from being bystanders before the development of heart failure, to integrating a multidisciplinary team seeking to identify and attempting to predict the occurrence of cardiovascular damage, with the aim of changing the natural history of the disease.
Currently, cancer is one of the main causes of morbidity and mortality in the world, only exceeded in numbers by cardiovascular diseases. In the US, it is estimated that there are 15.5 millions of cancer survivors ; on the other hand, Argentina is among the range of countries with a mid-to-high cancer incidence (172.3-242-9 per 100,000 inhabitants) by year 2012, according to data from the International Agency for Research on Cancer (IARC), with breast and prostate cancer being the most frequent ones in women and men respectively (http://globocan.iarc.fr/).
Oncological pathologies may influence the endocrine system function and modify it with the aim of guaranteeing the survival of the aggressor agent . Starting with this concept, antineoplastic therapies have been developed, seeking to modulate hormone response in some types of cancer, not devoid from producing cardiac damage. What was mentioned and the knowledge on the existence of harmful secondary effects by conventional oncological therapies with anthracyclines and radiotherapy on the cardiovascular system, make it necessary to conduct a multidimensional evaluation on the oncological patient.
Cardiotoxicity: definition and classification
The term cardiotoxicity refers to the set of cardiac symptoms and left ventricular ejection fraction (LVEF) impairment, associated to oncological therapy ; it is defined as a drop in LVEF greater than 10%, up to less than 53% . To this date, the evaluation of left ventricular function has focused on measuring ejection fraction, on the basis of its predictor power for morbidity and mortality in a variety of clinical scenarios . However, the way to measure this parameter and its real value have been put into question by emerging techniques, posing the requirement to look for other resources to evaluate subclinical ventricular dysfunction.
Historically, it has been proven that some oncological treatments could possibly generate permanent cardiac dysfunction, with the best example being anthracyclines, capable of causing systolic function depression progressively . Later, drugs were used, the functioning of which was based on the molecular inhibition of signaling, hand in hand with molecular biology booming; however, their advent brought about the development of subclinical dysfunction studied in many cases. From this point, the need arose to classify cardiovascular effects secondary to antineoplastic agents, which are comprised within the concept of cancer therapy-related cardiac dysfunction (CTRCD). Two groups were defined according to their toxicity: type 1 (producers of irreversible damage) and type 2 (responsible for reversible damage); with the best examples for both groups being doxorubicin and trastuzumab, respectively . Figure 1 .
Figure 1. Types of CTRCD and main characteristics .
The drugs belonging to the CTRCD type 1 group are characterized by producing necrosis and/or cell apoptosis, which may express by ventricular remodeling, heart failure and myocardial infarction. On the other hand, the group responsible of CTRCD type 2, produces cell dysfunction (at mitochondrial level or protein level), manifesting as temporary contractile dysfunction or by development of systemic hypertension, with the particular aspect that both alterations could be reversible. In the latter, the drugs anti-HER2 (human epidermal growth receptor 2 antagonist) and anti-VEGF (vascular endothelial growth factor blockers) are included. Understanding the pathophysiological mechanism of dysfunction associated to drugs for cancer is important, as it allows predicting and treating these adverse effects, although it may be difficult to identify the causal mechanism in each patient (Figure 1) .
In CRTCD type 1, the damage is dose-dependent (presence of ultrastructural changes in cardiomyocytes), considering patients receiving a dose above 250-300 mg/m2 of doxorubicin as in high risk of suffering dysfunction [10,11]. Cardiotoxicity by anthracyclines may manifest in two ways: progressive chronic presentation of early onset (if it happens within the first year of administration) or progressive chronic presentation of late onset (after 1 year from receiving the drug). The latter may even start after decades from the drug being in contact with the organism. On the other hand, the acute appearance of left ventricular systolic dysfunction subsequent to the administration of anthracyclines is rare and reversible [10,12].
Alternatively, in CTRCD type 2, the damages are not dose-dependent (absence of ultrastructural changes of cardiomyocytes), and are usually reversible [13,4]. The inhibition of the HER2 signals in cardiomyocytes blocks a response that prevents the dilatation of cardiac chambers under scenarios of stress [13,15]. In spite of being a reversible effect, it may have agonist effects when combined with subtype 1 drugs, which explains the high risk of cardiac dysfunction in patients receiving molecules from both groups .
In regard to the heart rhythm alterations secondary to the administration of oncological drugs, they are in general, transient and associated to hydroelectrolytic disorders. Anthracyclines are associated to premature ventricular and supraventricular contractions, with no hemodynamic repercussions. Taxanes may cause self-limited sinus bradycardia. We should also mention QT prolongation, because of the frequency with which gastrointestinal symptoms are combined in patients with drugs capable of producing QT alterations, entailing a risk of potentially lethal ventricular arrhythmias .
Besides cardiac involvement, vascular disease represents another risk associated to use of antineoplastic agents, with two types of lesions being described. In vascular toxicity type 1, the risk of vascular events persists after the administration of the drug; within the group there are the tyrosine kinase inhibitors such as nilotinib and ponatinib, that have also been associated to systemic hypertension of new onset or difficulty to control it if already present. On the other hand, in vascular toxicity type 2, the risk appears only during the administration of the treatment, with 5-fluorouracil being the most representative drug .
Diagnostic approach and risk stratification
Before starting the oncological treatment, the first step is identifying the patients in high risk of presenting cardiotoxicity . Some common risk factors in patients developing CTRCD are:
Presence of previous heart disease: heart failure, CAD, moderate to severe valve disease, hypertensive heart disease, hypertrophic/restrictive/infiltrative cardiomyopathy, ventricular arrhythmias and atrial fibrillation.
Demographic risk factors: age (<18 years >50 years with trastuzumab, >65 years with anthracyclines), family history (cardiovascular disease, systemic hypertension, diabetes mellitus, hypercholesterolemia).
Previous cancer treatment: use of anthracyclines or radiotherapy in the chest area.
Risk factors related to lifestyle: smoking, alcoholism, obesity, sedentarism.
Once common risk factors are defined, we should know the particular ones according to the group of drug to be used (Figures 2 and 3).
Figure 2. CTRCD type 1: risk factors.
Figure 3. CTRCD type 2: risk factors
The second step consists of choosing the strategy to detect cardiotoxicity , which could be by imaging (echocardiography, magnetic resonance, nuclear imaging) or biomarkers (troponin, natriuretic peptides), taking into account some principles:
Keeping the same imaging technique or biomarker for subsequent monitoring during treatment.
Choosing a modality with good reproducibility.
If an imaging technique is chosen, it is advisable to, besides evaluating left ventricular function, be able to provide additional information (right ventricle and valve function, measurement of pulmonary pressures and ruling out pericardial diseases) and no radiation should be used.
The protocol to follow and the frequency with which monitoring is done will depend on the specific treatment and its duration, total accumulated dose and risk factors of the patient.
Relationship between biomarkers and cardiotoxicity: Current outlook
In spite of the increase in survival reached with the use of some highly effective anticancer drugs, such as trastuzumab and doxorubicin, their risk to generate cardiotoxicity should not be underestimated. It has been described that patients present a risk greater than 7 times of presenting heart failure when using the abovementioned combination, and so the need arises to identify patients with risk of cardiotoxicity. However, the traditional evaluation approach using left ventricular ejection fraction has shown to have a low sensitivity to detect subclinical changes or to predict who will have their cardiac function disturbed by the treatment .
Considering the uncertainty of screening by ventricular ejection fraction, the use of biomarkers emerged to identify patients in risk of cardiac toxicity. Within the group, it has been proven that there is a relationship between the increase in troponin and decrease in left ventricular ejection fraction [18,19], greater risk of cardiovascular events, and response to the treatment for heart failure . During a 20-month follow-up, it was shown that patients with an absolute troponin value greater than 0.08 ng/mL, one month after starting chemotherapy, have a risk of 84% of presenting cardiac events, in comparison to 1% of accumulated risk in those with troponin concentrations of less than 0.08 ng/mL . On the other hand, Sawaya H., et al  demonstrated that in patients with breast cancer HER2+, the presence of high-sensitivity values greater than 30 pg/mL had a positive predictive value of 44% for the development of heart failure.
From the knowledge generated in heart failure trials, natriuretic peptides (BNP, NT-proBNP) have been used as markers to determine subclinical ventricular dysfunction . It has been proven that a sustained increase of these biomarkers is associated to a greater risk of developing (both systolic and diastolic) left ventricular dysfunction, in comparison to the patients presenting transient alteration or who stayed within normal parameters [23-25].
Other markers that have proven to increase in the presence of post-chemotherapy cardiac dysfunction have been: myeloperoxidase (MPO) , interleukin 6 (IL-6) , heart-type fatty acid-binding protein (H-FABP) , and glycogen phosphorylase isoenzyme BB (GPBB) .
However, one of the drawbacks that biomarker assays have presented is the lack of systematization to use them and the drugs with which they have been assessed, as a wide range of antineoplastic agents have been used, and at different times of applying the treatment, all factors limiting the creation of a protocol focused on its use . However, they still have a promising future as a universal, minimally invasive tool, not requiring experience from the observer, with the capability of identifying patients developing cardiotoxicity.
Echocardiography in the evaluation of cardiotoxicity: Use of LVEF to detect cardiotoxicity
Chemotherapy and radiotherapy may place oncological patients in risk of several cardiovascular complications, including heart failure, peripheral artery disease, thromboembolism, pericardial and valve disease . Starting from this premise, the guideline emerged to keep monitoring the patient before, during and after ending the treatment, to be able to diagnose the appearance of CTRCD.
Ejection fraction could be measured by imaging modalities, the effects of which are ionizing (echography, magnetic resonance) or nonionizing (X-rays, CT, radioisotopes). In spite of magnetic resonance being the method of choice for its estimation, echocardiography is the first diagnostic line, as it is an easily accessible test, and also inexpensive and free from radiation ; also, it allows evaluating other structures that could be victims of injury (as the pericardium and valve apparati), and measuring relevant hemodynamic data (stroke volume, ventricular filling pressures, pulmonary artery pressure). The measurement of LVEF has been supplemented with the use of nontoxic contrast, to improve the evaluation in the case of suboptimal echographic images, and wall motion score (WMS) to add predictive value .
The most widely used echocardiographic technique to quantify LVEF is the biplane one . However, it presents several limitations, from the necessary but not always accurate assumption of a left ventricular elliptic shape (that has been partially overcome by using the 3D technique), and the requirement to have to visualize properly defined endocardial edges, up to the inter and intraobserver variability proper of the method .
When analyzing the study of LVEF in the field of cardio-oncology, a drawback of using it to monitor cardiac dysfunction lies in that their changes occur late, when cardiac injury has happened . In spite of this being a universal parameter to guide decision-making, its use could not overcome different challenges posed by the oncological area, which has led to seeking other techniques that would allow diagnosing cardiac dysfunction early and in a reproducible way, so as to be able to start an early treatment and to halt the heart injury.
Imaging techniques to evaluate myocardial deformation: Advantages of strain rate imaging
With echocardiography, it is possible to evaluate cardiac mechanic function. From its structure in three layers (subendocardium, myocardium and subepicardium), techniques have been created that evaluate deformation of a particular segment, compare it to others and are able to identify normality in movement. Doppler tissue imaging (DTI) allows to measure Doppler signals of low frequency, that are generated in the atrioventricular valve annulus and the myocardium. Myocardial velocities in a longitudinal direction can be evaluated in apical views; while those with a radial direction are evaluated in short-axis views. As virtually any myocardial area can be studied, it allows detecting regional alterations and it keeps a good correlation with LVEF, even in oncological patients . However, the measurement of velocities could be affected by a phenomenon where the motion of a segment that has no activity could result from that generated by the activity of neighbor segments (tethering); we should add to this limitation that, because of its uneven distribution (velocity decrease from the base to the apex), it is difficult to establish reference values.
To overcome the disadvantages of DTI, other techniques were created, based on strain and strain rate, which evaluate the magnitude and rate of strain in the cardiac muscle. One of the ways to obtain data to evaluate both is color DTI, which enables the measurement of velocities in all myocardial segments and generating strain values. However, just as with the base technique, it is angle-dependent, requiring training and experience for a proper interpretation .
There is a method to evaluate myocardial strain based on tracking the movement of specific points of the myocardium, called speckle-tracking, which overcomes some of the limitations of DTI (Figure 4). From speckle-tracking, it is possible to evaluate strain in a longitudinal, radial and circumferential sense, regardless of the angle. The most widely used measurement to evaluate left ventricular systolic function is global longitudinal strain (GLS); while the other measurements, global radial strain (GRS) and global circumferential strain (GCS), are less used because they have less reproducibility than the first one. It has been proven that GLS reduction occurs before LVEF decrease becomes evident , which allows to project it as a tool capable of detecting subclinical ventricular dysfunction in patients receiving cardiotoxic drugs .
Figure 4. General aspects of echocardiography with speckle-tracking.
It has been verified that GLS values tend to decrease after chemotherapy, and that strain has a higher sensitivity than LVEF to detect subclinical ventricular dysfunction [22,36,37]. The observations of Thavendiranathan P, et al  showed that GLS presented a decrease between 9 and 19% during or immediately after the use of anthracyclines. Alternatively, in the study conducted by Fallah-Rad N, et al , in patients with breast cancer that develop cardiotoxicity with trastuzumab and anthracyclines, a reduction in GLS was observed during the first 3 months of follow-up, with no changes documented in LVEF. On the other hand, GRS and GCS measurements have presented conflictive evidence due to opposite results. However, based on the location of the fibers studied, GRS decrease was related to the progression in subendocardial lesion into the myocardium, which would entail progression of the disease .
Given the variability in basal strain values between patients, the best ventricular dysfunction predictor is the GLS change compared to its previous value. A >15% reduction of GLS is an indication of subclinical left ventricular dysfunction, while if reduction is <8%, it is consistent with absence of subclinical ventricular dysfunction . In the case that the change is between 8 and 15%, it is considered within a grey area that justifies frequent monitoring to detect if the tendency to decrease in GLS persists (Figure 5) .
Figure 5. 57-year-old woman with breast cancer, receiving therapy with trastuzumab. A (22%) test made before starting the treatment; B (13%) evaluation at 3 months: C (21%) post-treatment monitoring.
The significance of determining a significant strain reduction is that, as a parameter of subclinical left ventricular dysfunction, it would suggest the time to start the administration of cardioprotective drugs (renin-angiotensin-aldosterone system modulators, beta blockers) before a significant LVEF decrease manifests . Currently the SUCCOUR (Strain sUrveillance during Chemotherapy for improving Cardiovascular OUtcomes) study is in development to determine if GLS changes, used as a guide to start a cardioprotective pharmacological treatment, are associated to an improvement in morbidity and mortality in oncological patients receiving chemotherapy .
GLS evaluation is still in a stage of being improved, with the aim of reaching a level of reproducibility and availability allowing to have the technique as part of routine echocardiographic evaluation . To this date, it maintains a role as a support tool, which would enable detecting changes that are beyond the range of view of ejection fraction. Nevertheless, it generates many expectations as a parameter to predict cardiovascular morbidity and mortality in heart failure , making it possible to have in the future, a central role in the evaluation of left ventricular function within the different areas of cardiology, including Cardio-Oncology.
Toxicity evaluation in the right ventricle
The damage by cardiotoxicity is not limited to the left ventricle: the use of anthracyclines and trastuzumab has been related to acute and chronic dysfunction of the right ventricle [44,45]. The characteristic of having less wall thickness compared to the left ventricle, has been posed as the most likely cause of greater sensitivity of the right ventricle to antineoplastic drugs . On the other hand, using dasatinib has been related to the development of pulmonary hypertension , and the right ventricle could also be affected in a secondary way.
Due to its complex geometric configuration, evaluating the right ventricle has been a challenge in echocardiography . The advent of the 3D technique has allowed to overcome the limitations of the 2-dimensional mode in the functional test, with it being closest to the values obtained by magnetic resonance ; however, it is not beyond a universal limitation, such as the need to obtain quality images . In spite of some setbacks, right ventricular echocardiographic evaluation has contributed to the study of CTRCD . Just as with its left counterpart, the use of strain is being developed to evaluate the right ventricular function, having shown a good correlation to systolic function measured by nuclear imaging [50,51]. Although there is right ventricular strain analysis in large populations of oncological patients, it represents one of the items to be improved in a near future, within the evaluation of cardiotoxicity.
Valve, pericardial and arterial disease related to antineoplastic agents
Primary valve disease by cardiotoxicity has been little documented in literature. Although cardiac tumors may damage valve architecture , oncological treatment has been related to degenerative processes , with mitral valve being the most frequent victim, and valve insufficiency being the predominant type of lesion [53,54]. The time span over which mitral valve insufficiency manifests is wide, from 3 months after the use of anthracyclines, to 10 years after having received thoracic radiation ; the latter have been related to the appearance of late lesions (up to 25 years after receiving therapy), consistent in fibrosis and valve insufficiency of left predominance . On the other hand, the lesions were the stenotic component predominates are rare, with most being caused by tumors compressing the valve structures [56,57].
As to the pericardium, its compromise by cardiotoxicity is a common phenomenon , that could be expressed by pericarditis, tamponade or constriction (Figure 6). Echocardiographic evaluation is a significant tool in the follow-up of oncological patients, particularly in those receiving radiotherapy, because of the late documentation of pericardial diseases . In spite of magnetic resonance and CT having a greater capacity to detect effusion and wall thickening, echocardiography enables the hemodynamic evaluation of tamponade, as well as pointing out differences between constrictive pericarditis and other entities (restrictive cardiomyopathy, right ventricular failure, among others) , which may emerge as a consequence of antineoplastic drugs [61,62].
Figure 6. Post-radiotherapy constrictive pericarditis in 35-year-old patient, treated because of Hodgkin’s lymphoma. Left: pericardial thickening manifesting in transesophageal echo (TEE). Right: pericardial mass extracted after surgery.
As an easily accessible tool, echocardiography is the most common method to start the evaluation of cardiac tumors, although magnetic resonance has the advantage of being able to differentiate the type of tissue that constitutes the mass, as well as determining its dissemination . As to the modality of stress echo, it still holds a leading role in the evaluation of CAD, being widely used in patients receiving radiotherapy, because of the accelerated atherosclerosis they suffer [63,64].
Conclusions: Cardio-Oncology, a new road to explore
Any new discipline entails the start of novel approaches and trial and error attempts, while searching to generate knowledge. Cardio-oncology is one of the booming branches within Cardiology, which has led us to reconsider many concepts that we thought of as irrefutable, and to face the universe behind the door of antineoplastic therapy improvement. It has enabled us to get a different view on oncological patients, the antagonism of which lies in cardiovascular disease appearing as a consequence of treatment, which on one hand is capable of extending survival, but at the expense of causing cardiovascular injury, thus posing a new scenario demanding new modalities of diagnosis and early treatment.
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