The Effects of Anthracycline-based Chemotherapy on Peripheral Vascular Function

The overall goal of this project is to determine the effects of anti-cancer chemotherapy on reflex control of blood pressure and vascular function. Recent data have demonstrated that cardiovascular disease-related mortality is the 2nd cause of morbidity and mortality for 7-year cancer survivors treated with chemotherapy. This anti-cancer treatment-mediated cardiotoxicity is a progressive process that begins at the molecular level, progresses to myocardial injury and left ventricular dysfunction, cumulating as heart failure and cardiovascular disease-related mortality. In parallel to these cardiac-specific changes, chemotherapy has also been shown to increase the risk for vascular-related abnormalities. However, the impact of adjuvant treatments on the function and structure of the peripheral vascular system remains poorly understood. With normal aging, two of the most important vascular adaptations to arteries, which strongly contribute to the increased risk of vascular-related and general cardiovascular disease, are an increase in large artery stiffness and dysfunction of the vascular endothelium. Therefore, the overall goal of this project is to determine the effects of anthracycline-based chemotherapy on large and small artery function and structure. The central hypothesis is that this type of cancer therapy results in negative vascular consequences as determined by non-invasive evaluation of spontaneous blood pressure control, carotid artery stiffness, and vascular endothelium-dependent vasodilation.

This observational study is designed to increase our understanding of the vascular changes that occur during and following anti-cancer chemotherapy and provide insight into new methods that will decrease cardiovascular disease risk in those treated for cancer.

Cancer remains one of the leading causes of death in modern society. Breast cancer is a prevalent type of cancer in most societies, but due to increasing rates of detection coupled with advanced therapies, of the ≈230,000 people newly diagnosed each year with breast cancer, approximately 90% are expected to live beyond 5 years. Despite the trend in improved cancer-related morality, cancer survivors are at a significantly increased risk for cardiovascular disease (CVD) morbidity and mortality. As such, approximately $800 million is spent annually in providing cardiovascular care for female cancer survivors alone. In a recent study, Daher et al. (2012) reported a Framingham Risk Score of 8.4 and a 10-year risk of general CVD of 7.6% in men and women cancer survivors older than 30 yrs. More importantly, they also determined that the mean vascular age of cancer survivors was 8 years greater than their chronological age, suggesting that sub-clinical manifestation of CVD may be present within the vasculature of some cancer survivors.

The definition and scientific study of cardiotoxicity has, to date, primarily focused solely on the myocardial injury related to adjuvant cancer therapy and the National Cancer Institute has defined it as "toxicity that affects the heart" (http://www.cancer.gov/dictionary/). However, cancer survivors are also at risk for vascular-related abnormalities. Despite this risk, the impact of adjuvant treatments on the function and structure of the peripheral vascular system is still poorly understood. With normal aging, two of the most important vascular adaptations to arteries, which strongly contribute to the increased risk of vascular-related and general CVD, are an increase in large artery stiffness and dysfunction of the vascular endothelium \[15, 16\]. In subjects receiving anthracycline chemotherapy, Chaosuwannaki et al. (2010), Miza-Stec et al. (2013), and Draft et al. (2013) independently demonstrated significant increases in aortic stiffness 4-6 mo following treatment. Likewise, carotid intima-media thickness has been shown to increase within 6 mo of treatment with chemotherapy. This is critical given that arterial stiffness and intima-media thickness both are independently associated with increased risk of cardiovascular disease. In addition, carotid artery stiffness is a key determinant of the sympathetic baroreflex sensitivity in older men and women. This information suggests that decreases in baroreflex sensitivity may be occurring following chemotherapy treatment, which is important given it is a primary mechanism through which the autonomic nervous system regulates arterial blood pressure and that a low baroreflex sensitivity is associated with cardiovascular morbidity and mortality. Specific Aim 1 will address this question.

The vascular endothelium is the first physiological barrier encountered by intravenously administered chemotherapy. Unfortunately, the effects of adjuvant therapy on endothelial function have primarily been studied in childhood cancer survivors or following a single treatment session. Chow et al. (2006) observed a decreased brachial artery flow-mediated dilation (FMD), a measurement of endothelial-dependent dilation, ≈20 mo following anthracycline-based chemotherapy. Similarly, Vaughn et at. (2008) demonstrated a decreased FMD in long-term survivors of testicular cancer. In addition, several reports have demonstrated a decrease in arterial reactivity to various biological vasodilators (e.g., sodium nitroprusside, acetylcholine) following acute chemotherapy and radiation. In contrast to these studies, Jones et al. (2007) reported no difference in FMD in breast cancer patients ≈20 mo post-treatment compared to healthy controls. Increasing our understanding of the effects of chemotherapy on endothelial function is essential, especially since it can be the initial step in the development of cardiovascular disease.

Recently, the skin microcirculation has been used as a model circulation to evaluate the changes in vascular health in a variety of diseases including hypertension, renal disease, diabetes, atherosclerosis, coronary artery disease, and heart failure. This work has been facilitated, in part, by its easy accessibility and high responsiveness to biological vasodilators. Given the paucity of information on endothelial health in cancer patients undergoing anthracycline chemotherapy evaluation of the skin microcirculation provides a non-invasive and useful method of increasing our understanding of cardiotoxicity. Specific Aim 2 will address this problem.

Specific Aim 1: Evaluate the changes in spontaneous blood pressure control and arterial stiffness in patients treated with anthracycline-based chemotherapy.

Hypothesis 1a: Spontaneous baroreflex sensitivity will be significantly decreased in cancer patients and cancer survivors treated with anthracycline-based chemotherapy.

Hypothesis 1b: Changes in baroreflex control of blood pressure will be related to increases in carotid artery stiffness and cardiac changes in left ventricular ejection time.

Specific Aim 2: Evaluate the changes in macrovascular and microvascular vascular function.

Hypothesis 2a: Treatment with anthracycline-based chemotherapy will significantly decrease endothelium-dependent vasodilation in both the large brachial artery and the small microvascular capillaries in the skin.

Hypothesis 2b: Changes in vascular function will be associated with molecular markers of endothelial function and oxidative stress.

Eligibility Criteria:
Inclusion Criteria:

* Give voluntary consent to participate in the study
* (Group 1) Diagnosed Stage I-III breast cancer or lymphoma cancer with a \> 2 year life expectancy
* (Group 1) Current chemotherapy treatment includes anthracyclines
* (Group 2) History of Stage I-III breast cancer or lymphoma cancer with a \> 2 year life expectancy
* (Group 2) 1 - 5 years removed from last date of anthracycline-based chemotherapy

Exclusion Criteria:

* History of clinical cardiovascular disease (Atherosclerotic cardiovascular disease (ASCVD) defined by history of acute coronary syndromes, myocardial infarction (MI), stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemia attack (TIA), or peripheral arterial disease presumed to be of atherosclerotic origin)
* Not met the above criteria
* Unable to provide informed consent