Original ArticleCoronary vasomotor dysfunction portends worse outcomes in patients with breast cancer
Introduction
Coronary vasomotor dysfunction is a manifestation of atherosclerosis affecting the large and small coronary vasculature, which can be present even in the absence of flow-limiting, obstructive epicardial coronary artery disease (CAD).1 Patients with coronary vasomotor dysfunction often present with chest pain, exertional dyspnea, and/or reduced exercise tolerance.2, 3, 4, 5, 6, 7, 8 Cardiac stress positron emission tomography (PET) can be used to measure myocardial flow reserve (MFR), defined as the ratio of global stress over rest myocardial blood flow (MBF). In the absence of obstructive epicardial CAD, MFR is a measure of the hemodynamic abnormalities resulting from diffuse nonobstructive atherosclerosis and microcirculatory dysfunction and can therefore be used to identify patients with subclinical coronary vasomotor dysfunction. Independent of other risk factors, coronary vasomotor dysfunction has been shown to be associated with adverse cardiovascular outcomes.3,8, 9, 10, 11, 12, 13, 14 However, these studies excluded patients with malignancy.
Patients with breast cancer can have concomitant risk factors for cardiovascular disease and may have been exposed to cardiotoxic therapies including anthracyclines, trastuzumab, and thoracic irradiation, which increases their risk of cardiovascular events.15, 16, 17, 18 Both macrovascular and microvascular injury to the endothelium are implicated in cardiotoxicity of cancer therapies, particularly radiation therapy to the chest. Radiation therapy is associated with accelerated atherosclerosis,19 results in vascular endothelial cell damage, and has been linked to reduction in capillary density.20, 21, 22 Cardiopulmonary symptoms are common in patients with breast cancer, and survivors are at increased risk of cardiovascular morbidity and mortality.23, 24, 25, 26 Therefore, many patients with breast cancer are referred for cardiac stress testing to help guide management decisions.16,27
In this study, we aimed to study if coronary vasomotor dysfunction was a marker of risk even in the absence of clinically overt CAD or left ventricular systolic dysfunction in patients with active or prior breast cancer referred for cardiac PET. We hypothesized that MFR is a biomarker of general vascular health in this population and abnormal MFR would be associated with adverse cardiovascular outcomes.
Section snippets
Study Population
The study population included consecutive patients with a diagnosis of breast cancer (prior or currently active at the time of PET) who underwent cardiac PET, including MFR assessment, for evaluation of symptoms (chest pain/dyspnea/syncope/palpitations) or pre-operative assessment between 2006 and 2017 at our center. The cohort was identified using our cardiac PET database and by using ICD-9 and ICD-10 codes to identify patients with breast cancer prior to the date of PET. Patients with a
Characteristics of the Study Cohort
Among the 87 patients in the cohort (median age 69.0 years (IQR 59.0-75.8), 98.9% female), 82.8% (n = 72) had cardiovascular symptoms at the time of PET, 63.2% (n = 55) had hypertension, 56.3% (n = 49) had dyslipidemia, 16.1% (n = 14) had diabetes, and 14.9% (n = 13) had chronic kidney disease (Table 1). Additionally, 14.7% (n = 11) of patients had metastatic disease at the time of their breast cancer diagnosis, 21.7% (n = 18) had recurrence of their breast cancer at some point during their
Discussion
The results from our study support the hypothesis that MFR, a marker of coronary vasomotor dysfunction that is associated with adverse outcomes in patients without cancer, is also associated incident major adverse cardiovascular events in this cohort of patients with breast cancer. These results advance our understanding of the prognostic implications of abnormal MFR and may provide the basis for further evaluation of MFR as a biomarker of general vascular health and clinical risk in this
Conclusions
In patients with breast cancer or survivors of breast cancer referred for cardiac stress PET, coronary vasomotor dysfunction was associated with higher incidence of cardiovascular events. The data from our study suggest that MFR may have value as a biomarker of cardiovascular risk in patients with breast cancer. Further investigation with larger sample sizes may provide more supportive data for the use of MFR as a general biomarker of vascular health/fitness in this population.
New Knowledge Gained
In a retrospective analysis of a cohort of 87 consecutive patients with breast cancer or survivors of breast cancer clinically referred for a cardiac stress PET, coronary vasomotor dysfunction (via myocardial flow reserve (MFR)) was associated with incident major adverse cardiovascular events. MFR may have potential in risk stratification among patients with/survivors of breast cancer.
Disclosures
Dr. Dorbala is a member of an advisory board for Proclara, Pfizer, and General Electric Health Care, and receives grant support from Pfizer. Dr. Blankstein receives research support from Amgen Inc. and Astellas Inc. Dr. Groarke receives research support from Amgen, Inc. Dr. Nohria receives research support from Amgen, Inc. and consulting fees from Takeda Oncology, AstraZeneca Pharmaceuticals, and Boehringer Ingelheim. Dr. Di Carli has received investigator-initiated institutional research grant
Funding
Dr. Divakaran and Dr. Zhou were supported by a T32 postdoctoral training grant from the National Heart, Lung, and Blood Institute (T32 HL094301). Dr. Divakaran was also supported by a joint KL2/Catalyst Medical Research Investigator Training (CMeRIT) award from Harvard Catalyst and the Boston Claude D. Pepper Older Americans Independence Center (5P30AG031679-10). Mr. Caron was supported in part by the Goodman Master Clinician Scholar Award (awarded to Dr. Groarke) and the Gelb Master Clinician
References (40)
- et al.
Coronary microvascular disease pathogenic mechanisms and therapeutic options: JACC state-of-the-art review
J Am Coll Cardiol
(2018) - et al.
International standardization of diagnostic criteria for microvascular angina
Int J Cardiol
(2018) - et al.
Prevalence of coronary microvascular dysfunction among patients with chest pain and nonobstructive coronary artery disease
JACC Cardiovasc Interv
(2015) - et al.
Coronary functional abnormalities in patients with angina and nonobstructive coronary artery disease
J Am Coll Cardiol
(2019) - et al.
Coronary microvascular dysfunction and cardiovascular risk in obese patients
J Am Coll Cardiol
(2018) - et al.
Coronary microvascular dysfunction identifies patients at high risk of adverse events across cardiometabolic diseases
J Am Coll Cardiol
(2017) - et al.
Cardiovascular health of patients with cancer and cancer survivors: A roadmap to the next level
J Am Coll Cardiol
(2015) - et al.
Risk of heart disease in relation to radiotherapy and chemotherapy with anthracyclines among 19,464 breast cancer patients in Denmark, 1977–2005
Radiother Oncol
(2017) - et al.
Agreement of visual estimation of coronary artery calcium from low-dose CT attenuation correction scans in hybrid PET/CT and SPECT/CT with standard Agatston score
J Am Coll Cardiol
(2010) - et al.
Development and validation of a clinical score to estimate the probability of coronary artery disease in men and women presenting with suspected coronary disease
Am J Med
(1997)
Radiation-related heart disease: Current knowledge and future prospects
Int J Radiat Oncol Biol Phys
2016 SCCT/STR guidelines for coronary artery calcium scoring of noncontrast noncardiac chest CT scans: A report of the Society of Cardiovascular Computed Tomography and Society of Thoracic Radiology
J Cardiovasc Comput Tomogr
Effects of sex on coronary microvascular dysfunction and cardiac outcomes
Circulation
A randomized, placebo-controlled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): impact on angina and myocardial perfusion reserve
Eur Heart J
Coronary microvascular function and cardiovascular risk factors in women with angina pectoris and no obstructive coronary artery disease: The iPOWER study
J Am Heart Assoc
Ranolazine in symptomatic diabetic patients without obstructive coronary artery disease: Impact on microvascular and diastolic function
J Am Heart Assoc
Coronary microvascular dysfunction and future risk of heart failure with preserved ejection fraction
Eur Heart J
Coronary microvascular dysfunction, left ventricular remodeling, and clinical outcomes in patients with chronic kidney impairment
Circulation
Association between coronary vascular dysfunction and cardiac mortality in patients with and without diabetes mellitus
Circulation
Interaction of impaired coronary flow reserve and cardiomyocyte injury on adverse cardiovascular outcomes in patients without overt coronary artery disease
Circulation
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All editorial decisions for this article, including selection of reviewers and the final decision, were made by guest editor Ahmed Tawakol, MD.