Elsevier

Journal of Nuclear Cardiology

Volume 29, Issue 6, December 2022, Pages 3072-3081
Journal of Nuclear Cardiology

Original Article
Coronary vasomotor dysfunction portends worse outcomes in patients with breast cancer

https://doi.org/10.1007/s12350-021-02825-1Get rights and content

Abstract

Background

Impaired MFR in the absence of flow-limiting CAD is associated with adverse events. Cardiovascular disease is an important cause of morbidity and mortality in patients with breast cancer. We sought to test the utility of MFR to predict outcomes in a cohort of patients with breast cancer.

Methods

We retrospectively studied consecutive patients with breast cancer or breast cancer survivors who underwent cardiac stress PET imaging from 2006 to 2017 at Brigham and Women’s Hospital. Patients with a history of clinically overt CAD, LVEF < 45%, or abnormal myocardial perfusion were excluded. Subjects were followed from time of PET to the occurrence of a first major adverse cardiovascular event (MACE) and all-cause death.

Results

The final cohort included 87 patients (median age 69.0 years, 98.9% female, mean MFR 2.05). Over a median follow-up of 7.6 years after PET, the lowest MFR tertile was associated with higher cumulative incidence of MACE (adjusted subdistribution hazard ratio 4.91; 95% CI 1.68-14.38; p = 0.004) when compared with the highest MFR tertile.

Conclusions

In patients with breast cancer, coronary vasomotor dysfunction was associated with incident cardiovascular events. MFR may have potential as a risk stratification biomarker among patients with/survivors of 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)

  • DarbySC et al.

    Radiation-related heart disease: Current knowledge and future prospects

    Int J Radiat Oncol Biol Phys

    (2010)
  • HechtHS et al.

    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

    (2017)
  • MurthyVL et al.

    Effects of sex on coronary microvascular dysfunction and cardiac outcomes

    Circulation

    (2014)
  • Bairey MerzCN et al.

    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

    (2016)
  • MygindND et al.

    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

    (2016)
  • ShahNR et al.

    Ranolazine in symptomatic diabetic patients without obstructive coronary artery disease: Impact on microvascular and diastolic function

    J Am Heart Assoc

    (2017)
  • TaquetiVR et al.

    Coronary microvascular dysfunction and future risk of heart failure with preserved ejection fraction

    Eur Heart J

    (2018)
  • BajajNS et al.

    Coronary microvascular dysfunction, left ventricular remodeling, and clinical outcomes in patients with chronic kidney impairment

    Circulation

    (2020)
  • MurthyVL et al.

    Association between coronary vascular dysfunction and cardiac mortality in patients with and without diabetes mellitus

    Circulation

    (2012)
  • TaquetiVR et al.

    Interaction of impaired coronary flow reserve and cardiomyocyte injury on adverse cardiovascular outcomes in patients without overt coronary artery disease

    Circulation

    (2015)
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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.

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