In the last decades non-communicable diseases have increased, being responsible for about ¾ deaths worldwide. Among these, cardiovascular disease and cancer contribute with 2/3 of them - about 25 million deaths per year [1].
In the United States 15 and 14 million people are estimated with cardiovascular disease (CVD) and a history of cancer, respectively, and this number is rising as the population grows older and better therapies enhance longevity [2]. [3]. Although these diseases are usually thought as 2 independent entities that share similar risk factors, more recent research has proposed mechanisms of cross talk between cancer and cardiovascular disease [4].
Major advances in recent years have expanded the number of available treatments for patients with cancer. Despite this, radiation-therapy or radiotherapy (RT) remains as the most effective, non-surgical curative treatment against the disease; RT employs high-energy radiation to reduce tumor size by damaging cells’ DNA or generating free radicals that eventually damage and destroy cancer cells. In general, about 50% of all cancer patients receive some type of RT during their course of treatment, within this group approximately 60% receive RT with a “curative intent”, meaning the goal is the eradication of the tumor or preventing its future recurrence. Finally, RT is a highly cost-effective methodology, representing only a small fraction of the total cost of cancer care.
Side effects of thoracic radiotherapy: cardiotoxicity & cardio-oncology
Despite its demonstrated effectiveness against cancer RT damages not only malignant cells but also normal cells within our bodies. Consequently, like any other cancer therapy it has side effects that can range from moderate to severe [5]. In particular, thoracic RT has well-documented side-effects upon the cardiovascular system [6], which are commonly known as “cardiotoxicity”. Early studies demonstrated that the exposure to ionizing radiation causes a dose-dependent cardiac damage that may result in a premature death of the patient due to ischemic events, cardiac valve failure/disorders or pericardial injury [7]. In recent years, the prevention, assessment and clinical management of cardiotoxicity in oncological patients has established the basis for a new discipline and an emerging field in oncological medicine called “cardio-oncology” [8]. As described above, radiation to the chest has the potential to cause damage to the heart in a dose-dependent manner. Subsequently, post-RT cardiac dysfunction can progress into heart failure via a complex mechanism that involves damage to the endothelium and microvascular injury [9, 10]. This protocol will assess the dose-dependent cardiotoxic effects of thoracic RT in cancer patients.
Most cardiotoxic effects of thoracic RT manifest years, even decades after exposure
Unlike other cancer therapies that can also cause cardiotoxicity (including anthracyclines & chemotherapeutics), RT-derived cardiac damage is usually manifested after years or even decades from initial exposure [ [11]]. Indeed, studies demonstrate that exposure to radiation can damage the intimal layer of blood vessels also triggering atherogenesis, and over the years these can lead to ischemia. Concomitantly, the damage to small vessels can also affect cardiac contractility [12]. Unfortunately, these effects develop over a prolonged period of time and become clinically apparent only after the cardiac performance is compromised and the reduction in the patient’s heart function can be measured, difficulting its diagnosis. At present, the sensitivity and specificity of the tools employed to measure cardiac function are somewhat imperfect and sometimes over-estimate or under-estimate RT-derived cardiotoxicity.
Strain by speckle tracking (SST) as an early marker of cardiac damage and dysfunction
For years the echocardiogram has been the standard tool to assess cardiotoxicity in cancer patients subjected to thoracic RT. By this method, cardiac function is estimated based on volumetric changes of the left ventricle during the cardiac cycle by Simpson’s method, commonly known as Left Ventricular Ejection Fraction (LVEF) a parameter that is affected by pre and post load conditions. Thus, a 10%-drop in LVEF has been traditionally considered as a parameter to define “cardiotoxicity”. However, as previously pointed out this is a rather “late” event in the progression to heart failure, and by the time these changes occur there are structural modifications on the myocardium often irreversible, or difficult to compensate at best. Recently, a variety of novel echocardiographic techniques have been developed; these are largely based on the transient deformation (shortening) of the myocardial fibers assessed with changes of the “speckle” pattern observed in an echocardiogram during a normal cardiac cycle. Although myocardial deformation during the cardiac cycle is a multidimensional process it can be simplified into three basic strains [13] as shown by Fig.1 (Modified from Bansal) for analysis: (a) longitudinal, (b) radial and (c) circumferential. -Longitudinal strain refers to the shortening of the myocardial fibers along its major axis (longitudinal). -Radial strain denotes the thickening of ventricle wall in reference to its radius -Circumferential strain relates to a reduction in the circumference of a heart cavity (ventricle or atrium) during the cardiac cycle. Figure 1 shows a simplified diagram of the components of myocardial deformation that can be assessed with Strain by Speckle-Tracking echocardiogram (hereafter, simply called SST). In summary, the use of the SST allows a more accurate and much earlier assessment of alterations in myocardial contractility compared to the traditionally used 10%-drop in LVEF and thus previous studies have assessed RT-induced acute myocardial damage by SST in multiple settings and has been suggested as an early indicator of subclinical cardiac dysfunction [14,15,16]. Furthermore, SST alterations predict mortality among acute heart failure patients [17]. Hence, one of the main goals of this proposal is to evaluate SST patterns as early predictors for the development of cardiotoxicity and acute damage during or after thoracic RT treatment across different dosages.
Magnetic resonance imaging (MRI) is a high-resolution technique that allows assessment of acute cardiac damage by RT treatment
Studies demonstrate that MRI provides a higher spatial resolution to accurately visualize myocardial lesions compared to other techniques such as scintigraphy [18]. A study in esophageal cancer patients that received high doses of RT (>60Gy) used MRI to demonstrate that RT induces cardiac fibrosis and edema [19] suggesting this is an effective technique to assess RT-induced cardiac damage. Therefore, our proposal will incorporate MRI analysis pre- and post-RT in cancer patients as an imaging assessment along with SST. MRI will include Cardiac Magnetic Resonance Cinema Imaging (Long axis balance, Balance 4 cameras, Short shaft full balance, Right ventricular balance), Anatomical imaging (Inversion recovery single shot balance, 3D short axis covering the entire heart and aorta with free respiratory trigger), Flow Imagining (2D outflow tract of the aorta and 2D pulmonary artery outflow tract) and Quantitative Imaging (T1 map short axis apical section, T1 map short axis medial section, T1 map short axis basal section, T2 map short axis apical section, T2 map short axis medial section, T2 map short axis basal section).
Other soluble/biochemical factors may also serve as early predictors of cardiotoxicity
In addition to alteration in the SST patterns or MRI, a number of soluble factors have been postulated as markers for cardiac dysfunction and will be assessed as early predictors of cardiotoxicity:
-
1)
High-sensitivity cardiac troponin-T (hscTnT): Troponins are key regulators of cardiac contractility by controlling the calcium-mediated actin-myosin interaction. More specifically, soluble levels of cardiac troponin-T have been traditionally used as a marker for myocyte injury and cardiac dysfunction in acute and chronic heart failure. More recently, a high-sensitivity assay that efficiently detects low cardiac troponin-T concentrations has been developed [20]. Originally used to diagnose acute coronary syndrome, the high-sensitivity cardiac Troponin-T (hscTnT) has gained attention for its predictive value upon cardiovascular disease. In fact, a recent study demonstrated that increasing cardiac radiation doses, given as adjuvant RT, were associated to a rise in hscTnT [21]. Furthermore, elevated hscTnT levels can identify cancer patients with a higher risk to develop cardiac complications derived from anthracycline treatment [22], which, like thoracic RT, can be associated to cardiotoxicity.
-
2)
N-Terminal pro-Brain Natriuretic Peptide (NTproBNP): Brain Natriuretic Peptide (BNP) and its pro-hormone the N-Terminal pro-BNP (NTproBNP) are mainly secreted by cardiomyocytes located in the heart’s left ventricle in response to stretching caused by increases in cardiac filling pressure or volume load. Ventricle or atrium secreted BNP and NTproBNP have been successfully used as markers to diagnose congestive heart failure. Similarly to hscTnT, NTproBNP levels have been used to identify patients at higher risk for cardiac dysfunction; a study demonstrated a correlation between elevated NTproBNP and a reduction of fractional shortening measured by echocardiogram in asymptomatic cancer patients that received anthracyclines. The study proposes NTproBNP as an early serum marker for anthracycline-induced cardiotoxicity [23].
Circulating endothelial cells (CECs) as early predictors of RT-derived cardiotoxicity
Circulating Endothelial Cells (CECs) are a subpopulation of fully-differentiated mature endothelial cells that have detached from the vascular walls. This may occur under certain circumstances such as tumor angiogenesis, derived from smoking, by acute myocardial infarction [24] or hypertension [25]. Although CECs were described over 30 years ago, they were only recently recognized as a reliable marker for endothelial dysfunction [26], and studies have postulated their role on the pathogenesis of ischemic vascular disease [27]. In particular, apoptotic CECs are predictors of cardiac vasculopathy in heart transplanted patients [28] and are well established as indicators of vascular injury and endothelial damage. On the other hand, RT is known to produce endothelial vascular injury through a variety of mechanisms [29]. Hence, our proposal will assess changes in apoptotic CECs prior and after RT in cancer patients. We hypothesize that high-RT doses will increase apoptotic CECs. Our proposal will compare imaging by SST and MRI against soluble/biochemical markers as early predictors of cardiac dysfunction in RT-treated cancer patients.
Measuring the impact of high & low doses of RT on cardiotoxicity
As explained above cardiotoxic damage by RT is dose dependent. Evidently, the success of a RT treatment in eradicating a tumor is determined by the total radiation dose given measured in Gray (Gy), however, this is limited by the tolerance of the surrounding normal tissue [5]. Similarly, previous studies have demonstrated that cardiotoxicity effects are proportional to the radiation dose applied to the patient. In order to quantify the dose-dependent effects of thoracic RT we will stratify our patients into two categories according to the calculated mean heart dose received. Therefore, our proposal will stratify patients receiving low (<10Gy) and high (>10Gy) doses of RT (see Fig. 2 and the methodology section for further details).
Relevance of the proposal
In recent decades, novel more effective therapies against cancer have significantly prolonged patient survival. Consequently, the number of cancer survivors with “late” anti-cancer treatment derived complications is expected to rise in coming years. Among these complications, cardiotoxicity represents a significant risk for premature death [8]. It is estimated that approximately 50% of all oncological patients receive some type of RT during their treatment. As occurs with other therapies, thoracic RT is associated to a risk of developing cardiotoxicity in a percentage of patients. Unfortunately, current standard techniques only allow the detection of cardiac dysfunction at an advanced stage in the progression to heart failure (a 10% drop in LVEF). Here we propose the use of a combination of echocardiogram SST, MRI and serum factors associated cardiac/endothelial dysfunction as early predictors of late cardiotoxicity derived from RT treatment.
Significance for patients
Estimates in the United States indicate that approximately 4 million cancer survivors die from cardiovascular disease derived complications. An earlier identification of patients at a higher risk for late thoracic RT-derived cardiotoxicity may help identify the best candidates for a risk adapted clinical follow-up in order to prevent long-term cardiac complications aiming to minimize the risk of death. Likewise, this will pave the way to testing new interventions to reduce cardiac damage, as it has been the case for anthracycline-induce cardiotoxicity. The SST echocardiogram is a relatively simple, low-cost, non-invasive assay that can be routinely performed by cardiologists in any clinical setting.
