Abstract
Women who present with myocardial infarction (MI) are more likely to be diagnosed with non-obstructive coronary arteries (MINOCA), spontaneous coronary artery dissection (SCAD), and takotsubo syndrome (TS) than men. Malignancy may predispose to MI and TS through shared risk factors and inflammatory mediators. The aim of this study was to determine the prevalence of cancer in women presenting with clinical syndrome of MI, and the association between cancer and mechanism of MI presentation. Among 520 women who presented with MI and underwent coronary angiography at NYU Langone Health from 3/2016–3/2020 or 9/2020–9/2021, 122 (23%) had a prior diagnosis of cancer. Patients with cancer were older at MI presentation but had similar comorbidity to those without cancer history. The most common cancers were breast (39%), gynecologic (15%), and gastrointestinal (13%). Women with cancer history were more likely to have TS (17% vs 11% without cancer history p=0.049). Among women with a final diagnosis of MI, the type of MI (MINOCA, MI-CAD or SCAD), was not significantly different between groups (p=0.374). History of cancer was present in nearly a quarter of women presenting with MI and was associated with a greater likelihood of TS as compared to MI. MINOCA and SCAD were not more common among women with cancer history.
Keywords: cancer, takotsubo syndrome, myocardial infarction
Introduction
Women who present with myocardial infarction (MI) are more likely to be diagnosed with non-obstructive coronary arteries (MINOCA), spontaneous coronary artery dissection (SCAD), and takotsubo syndrome (TS) than men. Malignancy may predispose patients to develop MI and TS through shared risk factors, such as advanced age, smoking, and increased inflammation and oxidative stress.1, 2 There are several proposed pathophysiological mechanisms responsible for TS, including sympathetic nervous system activation and coronary vasospasm. The pathophysiology of TS in patients with cancer is not well defined. The literature suggests a ‘multi-hit hypothesis’ which includes the cancer itself, therapies including chemotherapy, radiotherapy, surgery, diagnostic procedures, emotional and psychosocial stress, acute illness like infection, pain, respiratory failure as contributory causes.3 Beyond the emotional stressor of a cancer diagnosis, cancer therapies, including surgery, radiation, and chemotherapy, may serve as physical triggers for TS or MI. Several case reports and registries have implicated systemic anticancer therapies with TS, including 5‐fluorouracil capecitabine, anthracyclines, trastuzumab, and immune checkpoint inhibitors, either alone or in combination with and without concurrent radiotherapy.3 Chemotherapeutic agents, most notably 5-fluorouracil, capecitabine and platinum agents, may cause MI due to coronary artery spasm.4–6 However, the likelihood of inducing coronary artery spasm was not higher among cancer patients than patients without cancer in a prior study, even when considering patients with active cancer.7 Radiation therapy for certain malignancies accelerates coronary artery disease, particularly ostial stenosis.8 Patients with cancer have a 3-fold greater risk of MI when compared to patients without cancer, with highest risk in lung, gastric, and pancreatic cancers, partially attributable to hypercoaguability and adverse effects from chemotherapeutic agents.9, 10 Although there is increasing recognition that cancer and cardiovascular disease coexist, there are limited data on mechanisms of MI sustained by cancer patients. It remains unclear what role cancer, whether inactive or active, may have on the development of MI, MINOCA, SCAD and TS. The aim of this study was to determine the prevalence of cancer in women with MI and the association between malignancy and mechanism of MI presentation.
Methods:
We analyzed the relationship between cancer history and final diagnosis of acute coronary syndrome in women age greater than18 years included in the NYU Registry of Women with MI. The registry included consecutive women with a clinical diagnosis of MI who underwent coronary angiography from March 2016 to March 2020 and then from September 2020 to September 2021 at NYU Langone Medical Center, excluding the intervening period during which screening was suspended due to the COVID-19 pandemic. The definition of MI required a rise and/or fall of cardiac troponin and ischemic symptoms and/or ECG changes, and/or evidence of new loss of viable myocardium or regional wall motion abnormality, consistent with the Universal Definition of MI.11 MINOCA was defined based on AHA criteria as MI presentation with less than 50% diameter stenosis in any major epicardial vessel by coronary angiography by visual estimation, and no alternative etiology of MI.12 Takotsubo syndrome was defined according to ESC criteria.13 Spontaneous coronary artery dissection (SCAD) was defined according to the Saw angiographic classification, with all coronary angiographic images retrospectively reviewed by an expert cardiologist (N.R.S. and/or H.R.R.) to confirm the diagnosis.14 MI-CAD was defined as MI with greater than or equal to 50% stenosis in a major epicardial vessel, not due to SCAD.
Medical records were retrospectively reviewed to identify malignancy diagnosed prior to or at the time of MI, excluding non-melanoma skin cancers. “Active cancer” was defined using the Haemostasis and Malignancy SSC definition: cancer diagnosed within the previous 6 months (180 days), recurrent, regionally advanced or metastatic cancer, cancer for which treatment had been administered within 6 months, or hematological cancer that is not in complete remission.15 “Inactive cancer” was defined as malignancy that was in remission and did not meet the active cancer definition. Chemotherapy and/or radiation was identified by searching the electronic medical record, reviewing hospital admission notes, oncology notes, primary care notes and the outpatient medication list. Documented emotional or physical triggers prior to the cardiac event were also recorded. A subset of medical records were reviewed by a second independent physician on the study team to ensure harmonization of data.
Descriptive analysis techniques were used to characterize study participants. We compared demographics, clinical history and final diagnosis (MI-CAD, MINOCA, or SCAD) between subgroups defined by: i) the presence or absence of cancer history and ii) inactive vs. active cancer among those with cancer history. Categorical data were analyzed using chi-square tests. Continuous data were analyzed using the Mann-Whitney U test and presented as medians and interquartile range (IQR). SPSS Statistics software 25.0 (IBM, Armonk, NY) was used for data analysis.
Results:
Among 520 women who underwent cardiac catheterization for a clinical diagnosis of MI, 122 (23%) had a prior diagnosis of cancer, with 37 active cancers and 85 inactive cancers. The most common cancers were breast cancer (39%), gynecologic malignancy (15%), gastrointestinal malignancy (13%), and respiratory malignancy (10%). The median interval between cancer diagnosis and the cardiac event was 5.1 years (IQR 2.1 – 14.2 years). The final cardiac diagnosis was MI in 457 patients (88%) and TS in 63 (12%). The MI subtype was MI-CAD in 347 patients (76% of MI), MINOCA in 97 (21% of MI), and SCAD in 13 (3% of MI).
Clinical characteristics of women with and without history of cancer
Women with any history of cancer were older (73 ± 10 vs 68 ± 14 years, p=0.001) and were more likely to be Caucasian (78% vs 56%, p=0.006) than women without a history of cancer. The frequency of hypertension, diabetes mellitus, hyperlipidemia, smoking, chronic obstructive lung disease, chronic kidney disease, stroke, and heart failure was not significantly different between groups (Table 1). Women with any history of cancer were less likely to present with chest pain (55% vs 67%, p= 0.013). Physical triggers were more commonly reported in patients with versus without any history of cancer (23% vs 13%, p=0.009). Even after restriction to patients who did not have TS, physical trigger was associated with cancer history (17.8% vs. 9.8%, p=0.026). No difference was observed in the proportion of ST-elevation MI (STEMI) (78% vs 76%, p=0.806), peak troponin concentrations (2.17 ng/mL, IQR 0.59–9.15 vs 1.78 ng/mL IQR 0.42–6.44, p=0.670) or median ejection fraction (50%, IQR 35–65, vs 55%, IQR 35–65, p=0.177) among women with and without a history of cancer (Table 1).
Table 1:
Baseline characteristics of women with cancer and without cancer presenting with a clinical syndrome of myocardial infarction, and undergoing angiography
| Women without cancer history (n=398) | Women with cancer history (n=122) | P value | |
|---|---|---|---|
| Demographics | |||
| Age, median (25th-75th percentile) | 69 (59–79) | 73 (67–80) | 0.001 |
| Race | |||
| White/Caucasian (%) | 234 (59%) | 93 (76%) | |
| Black/African American (%) | 51 (13%) | 11 (9%) | |
| Asian (%) | 32 (8%) | 2 (2%) | |
| Other | 60 (15%) | 13 (11%) | |
| Unknown | 21 (5%) | 3 (2%) | |
| Ethnicity | |||
| Hispanic/Latino | 49 (12%) | 10 (8%) | 0.103 |
| Not Hispanic/Latino | 288 (73% | 100 (82%) | |
| Unknown | 61 (15%) | 12 (10%) | |
| Medical History | |||
| Hypertension (%) | 290 (73%) | 87 (71%) | 0.729 |
| Diabetes Mellitus (%) | 149 (37%) | 34 (28%) | 0.065 |
| Hyperlipidemia (%) | 251 (63%) | 80 (66%) | 0.667 |
| Smoker (%) | 135 (34%) | 38 (31%) | 0.585 |
| COPD/Asthma (%) | 63 (16%) | 28 (23%) | 0.077 |
| CKD/ESRD (%) | 39 (10%) | 13 (11%) | 0.734 |
| Stroke (%) | 34 (9%) | 7 (6%) | 0.442 |
| Heart Failure | 50 (13%) | 17 (14%) | 0.757 |
| Symptoms on Presentation | |||
| Chest Pain | 268 (67%) | 67 (55%) | 0.013 |
| Dyspnea | 159 (40%) | 56 (46%) | 0.249 |
| Arm Pain | 74 (19%) | 11 (9%) | 0.012 |
| Jaw/neck pain | 27 (7%) | 10 (8%) | 0.553 |
| Nausea/Vomiting | 123 (31%) | 28 (23%) | 0.110 |
| Syncope/Pre-syncope | 33 (8%) | 3 (3%) | 0.025 |
| Other | 61 (15%) | 34 (28%) | <0.001 |
| Presence of Trigger | |||
| Emotional Trigger | 34 (9%) | 7 (6%) | 0.442 |
| Physical Trigger | 51 (13%) | 28 (23%) | 0.009 |
| Presentation Features | |||
| STEMI (%) | 294 (76%) | 94 (78%) | 0.806 |
| Peak Troponin ng/mL, median (25th-75th percentile) | 2.17 (0.59–9.15) | 1.78 (0.42–6.44) | 0.670 |
| LVEF (%), median (25th-75th percentile) | N=371 55 (35–65) |
N=112 50 (35–65) |
0.177 |
COPD: chronic obstructive pulmonday disease; CKD: chronic kidney disease; ESRD: end stage renal disease; STEMI: ST-elevation myocardial infarction; LVEF: left ventricular ejection fraction
Note that a physical trigger was associated with cancer history even after restriction to the subset of 457 patients who did not have TS (17.8% vs. 9.8%, p=0.027)
The subset of women with active cancer were more likely to be Caucasian than women without a cancer history (75% vs 59%, p=0.034); no other differences in baseline clinical characteristics were observed. Compared to women without any cancer history, women with an inactive prior cancer were less likely to report chest pain during MI (55% vs 67%, p=0.044) and more likely to report a physical trigger prceeding the event (24% vs 13%, p=0.017) (Table 2). The majority of physical triggers included 24 women with infection (11 had TS), 9 with acute respiratory failure (5 had TS), 4 with central nervous system events including stroke or seizure (1 of whom had TS), 2 with post surgical fracture (none of whom had TS), 40 with other events (12 had TS). Overall 37% of physical triggers occurred in women who had TS events.
Table 2:
Baseline characteristics of women with active cancer, inactive cancer, and without cancer presenting with a clinical syndrome of myocardial infarction, undergoing angiography
| Women without cancer history (n=398) | Women with active cancer (N= 37) | Women with inactive cancer (N=85) | P value | P value | ||
|---|---|---|---|---|---|---|
| Demographics | ||||||
| Age, median (25th-75th percentile) | 69 (59–79) | 72.5 (66.5–77.5) | 73 (68–81) | 0.324 | 0.001 | |
| Race | ||||||
| White/Caucasian (%) | 234 (59%) | 29 (78% | 64 (75%) | |||
| Black/African American (%) | 51 (13%) | 2 (5%) | 9 (11%) | |||
| Asian (%) | 32 (8%) | 1 (3%) | 1 (1%) | |||
| Other | 60 (15%) | 1 (3%) | 0 (0%) | |||
| Unknown | 21 (5%) | 4 (11%) | 11 (13%) | |||
| Ethnicity | ||||||
| Hispanic/Latino | 49 (13%) | 3 (8%) | 7 (8%) | 0.518 | 0.160 | |
| NonHispanic/Latino | 288 (74%) | 30 (81%) | 70 (82%) | |||
| Unknown | 61 (15%) | 4 (11%) | 8 (10%) | |||
| Medical History | ||||||
| Hypertension (%) | 290 (73%) | 24 (65%) | 63 (74%) | 0.338 | 0.893 | |
| Diabetes Mellitus (%) | 149 (37%) | 10 (27%) | 24 (28%) | 0.284 | 0.134 | |
| Hyperlipidemia (%) | 251 (63%) | 21 (57%) | 59 (69%) | 0.480 | 0.319 | |
| Smoker (%) | 135 (34%) | 11 (30%) | 27 (32%) | 0.717 | 0.800 | |
| COPD/Asthma (%) | 63 (16%) | 9 (24%) | 19 (22%) | 0.244 | 0.153 | |
| CKD/ESRD (%) | 39 (10%) | 4 (11%) | 9 (11%) | 0.775 | 0.842 | |
| Stroke (%) | 34 (9%) | 2 (5%) | 5 (6%) | 0.756 | 0.515 | |
| Heart Failure | 50 (13%) | 7 (19%) | 10 (12%) | 0.305 | >0.999 | |
| Symptoms on Presentation | ||||||
| Chest Pain | 268 (67%) | 20 (54%) | 47 (55%) | 0.106 | 0.044 | |
| Dyspnea | 159 (40%) | 16 (43%) | 40 (47%) | 0.728 | 0.228 | |
| Arm Pain | 74 (19%) | 3 (8.1) | 8 (9%) | 0.173 | 0.040 | |
| Jaw/neck pain | 27 (7%) | 0 | 10 (12%) | 0.152 | 0.120 | |
| Nausea/Vomiting | 123 (31%) | 6 (16%) | 22 (23%) | 0.063 | 0.434 | |
| Syncope/Pre-syncope | 33 (8%) | 0 | 3 (4%) | 0.097 | 0.172 | |
| Other | 61 (15%) | 7 (19%) | 27 (32%) | 0.635 | 0.001 | |
| Presence of Trigger | ||||||
| Emotional Trigger | 34 (9%) | 2 (5%) | 5 (6%) | 0.756 | 0.515 | |
| Physical Trigger | 51 (13%) | 8 (22%) | 20 (24%) | 0.136 | 0.017 | |
| Presentation Features | ||||||
| STEMI (%) | 91 (24%) | 13 (36%) | 14 (17%) | 0.107 | 0.195 | |
| Peak Troponin ng/mL, median (25th-75th percentile) | 2.17 (0.59–9.15) | 1.46 (0.48–9.46) | 1.90 (0.51–8.04) | 0.276 | 0.882 | |
| LVEF (%), median (25th-75th percentile) | N=367 55 (35–65) |
N=32 45 (35–65) |
N=78 50 (35–65) |
0.118 | 0.479 | |
Active cancer: cancer diagnosed within the previous 6 months (180 days), recurrent, regionally advanced or metastatic cancer, cancer for which treatment had been administered within 6 months, or hematological cancer that is not in complete remission; COPD: chronic obstructive pulmonday disease; CKD: chronic kidney disease; ESRD: end stage renal disease; STEMI: ST-elevation myocardial infarction; LVEF: left ventricular ejection fraction
History of cancer and final diagnosis of takotsubo syndrome or MI
Women with any history of cancer were more likely to receive a final diagnosis of TS than women without a history of cancer (17% vs 11%, p=0.049) (Table 3) (Figure a). Women with active cancer (22% vs 11%, p=0.043), but not those with inactive cancer (15% vs. 11%, p=0.212), were more likely to have a final diagnosis of TS as compared to women without history of cancer (Table 4).
Table 3:
Final Diagnosis by cancer history (values n (%))
| Women without cancer history (n=398) | Women with cancer history (n=122) | P value | |
|---|---|---|---|
| Final Diagnosis | |||
| MI (all) | 356 (89%) | 101 (83%) | 0.049 |
| TS | 42 (11%) | 21 (17%) | |
| MI Subtype (n=457) | |||
| MI-CAD | 271 (68%) | 76 (62%) | 0.374 |
| MINOCA | 73 (18%) | 24 (20%) | |
| SCAD | 12 (3%) | 1 (0.8%) | |
MI: myocardial infarction; TS: takotsubo syndrome; MI-CAD: myocardial infarction with coronary artery disease; MINOCA: myocardial infraction with nonobsructive coronary arteries; SCAD: spontaneous coronary artery dissection
Figure a:
MI subtypes based on cancer diagnosis. Women with any history of cancer were more likely to receive a final diagnosis of TS than women without a history of cancer (17% vs 11%, p=0.049)
Figure created with biorender.com. SCAD: spontaneous coronary artery dissection; MINOCA: myocardial infraction with nonobsructive coronary arteries; MI-CAD: myocardial infarction with coronary artery disease; TS: takotsubo syndrome
Table 4:
Final Diagnosis by active, inactive, and without cancer history (values n (%))
| Women without cancer history (n=398) | Women with active cancer (N= 37) | Women with inactive cancer (N=85) | P value* | P value** | |
|---|---|---|---|---|---|
| Final Diagnosis | |||||
| MI (all) | 356 (89%) | 29 (78%) | 72 (85%) | 0.043 | 0.212 |
| Takotsubo syndrome | 42 (11%) | 8 (22%) | 13 (15%) | ||
| MI Subtype (n=457) | |||||
| MI-CAD | 271 (68%) | 21 (57%) | 55 (65%) | 0.896 | 0.321 |
| MINOCA | 73 (18%) | 7 (19%) | 17 (20%) | ||
| SCAD | 12 (3%) | 1 (3%) | 0 | ||
comparing MI with active cancer history to MI without history of cancer;
comparing MI with inactive cancer to without cancer
Active cancer: cancer diagnosed within the previous 6 months (180 days), recurrent, regionally advanced or metastatic cancer, cancer for which treatment had been administered within 6 months, or hematological cancer that is not in complete remission; MI: myocardial infarction; TS: takotsubo syndrome; MI-CAD: myocardial infarction with coronary artery disease; MINOCA: myocardial infraction with nonobsructive coronary arteries; SCAD: spontaneous coronary artery dissection
History of cancer and type of MI
Among women with a final diagnosis of MI, no difference in the frequency of MI subtype was observed according to cancer status (p=0.374 for distribution; Table 3). When stratifying for history of active versus inactive cancers, there was also no association between cancer and MI subtype (Table 4). In the subgroup of patients with MI-CAD, no significant difference in the use of PCI between patients with and without cancer was observed (68% vs 73% p=0.425). There was no difference in prevalence of prior chemotherapy or radiation therapy amongst women with different MI subtypes.
Cancer therapy and final diagnosis of takotsubo syndrome or MI
Of the 122 women with history of cancer, 57 women (47%) had previously received or were currently receiving chemotherapy. Eighteen women (32%) were receiving chemotherapy at time of their cardiac event, most of whom were on maintenance chemotherapy. Women who received chemotherapy were more likely to have a final diagnosis of TS as compared to women without any cancer history (21% of women who received chemotherapy had final diagnosis of TS vs 11% without cancer history, p=0.008). However, there was no difference in the frequency of TS diagnosis between women with cancer with verus without chemotherapy (Table 5).
Table 5:
Final Diagnosis by history of chemotherapy
| Women without cancer history (n=398) | Women with cancer with chemotherapy (n=57) | Women with cancer without chemotherapy (n=65) | P value* | P value** | P value** | |
|---|---|---|---|---|---|---|
| Final Diagnosis | ||||||
| MI (all) | 356 (89%) | 44 (77%) | 57 (88%) | 0.008 | 0.673 | 0.125 |
| TS | 42 (11%) | 13 (23%) | 8 (12%) | |||
| MI Subtype (n=457) | ||||||
| MI-CAD | 271 (68%) | 31 (54%) | 45 (69%) | 0.208 | 0.783 | 0.346 |
| MINOCA | 73 (18%) | 13 (23%) | 11 (17%) | |||
| SCAD | 12 (3%) | 0 (0%) | 1 (2%) | |||
comparing women without cancer history to women with history of chemotherapy;
comparing women without cancer history to women with cancer but without chemotherapy
comparing women with chemotherapy to women with cancer without chemotherapy
MI: myocardial infarction; TS: takotsubo syndrome; MI-CAD: myocardial infarction with coronary artery disease; MINOCA: myocardial infraction with nonobsructive coronary arteries; SCAD: spontaneous coronary artery dissection
Among women with any history of cancer, fifty women (41%) previously underwent radiation therapy. None of the patients were undergoing radiation therapy at time of cardiac event. There was no difference in final diagnosis of TS amongst women who received radiation therapy compared to those without any cancer diagnosis (10% vs. 11%, p=0.755). However, women with cancer who did not receive radiation were more likely to have a diagnosis of TS than women without cancer history (21% vs. 11%, p=0.014) (Table 6).
Table 6:
Final Diagnosis by history of radiation therapy
| Women without cancer history (n=398) | Women with cancer with radiation (n=50) | Women with cancer without radiation (n=72) | P value* | P value** | P value*** | |
|---|---|---|---|---|---|---|
| Final Diagnosis | ||||||
| MI (all) | 356 (89%) | 44 (88%) | 57 (79%) | 0.755 | 0.014 | 0.204 |
| TS | 42 (11%) | 6 (12%) | 15 (21%) | |||
| MI Subtype (n=457) | ||||||
| MI-CAD | 271 (68%) | 31 (62%) | 45 (63%) | 0.561 | 0.372 | 0.405 |
| MINOCA | 73 (18%) | 12 (24%) | 12 (17%) | |||
| SCAD | 12 (3%) | 1 (2%) | 0 (0%) | |||
comparing women without cancer history to women with radiation history;
comparing women without cancer history to women with cancer but without radiation history;
comparing women with radiation to women with cancer without radiation history
MI: myocardial infarction; TS: takotsubo syndrome; MI-CAD: myocardial infarction with coronary artery disease; MINOCA: myocardial infarction with nonobsructive coronary arteries; SCAD: spontaneous coronary artery dissection
Discussion:
In this study of over 500 women presenting with a clinical syndrome consistent with MI who underwent angiography, 122 patients (23%) had a history of ongoing or prior cancer and 63 patients (12%) had TS. Women with history of cancer were more likely to have TS than women without history of cancer. Among women with history of cancer, those with a final diagnosis of TS were more likely to have received chemotherapy before or at the time of the cardiac event than those with a final diagnosis of MI. Among women with a final diagnosis of MI, there were no differences in the frequency of MI type (MI-CAD, MINOCA, or SCAD) between women with and without cancer history.
Although TS was more frequent among women with history of cancer, most women with a syndrome compatible with MI in our study did in fact have a final diagnosis of MI (88%) and not TS (12%). This is particularly important in light of reported better outcomes among active cancer patients treated invasively, rather than conservatively, for MI.16 There are implications for early antithrombotic therapy and potentially, selection for coronary angiography. With advancements in cancer treatments, cardiovascular disease has become the leading cause of death amongst cancer patients, with a higher incidence of MI in patients with active cancer and most prominent in the first six months after cancer diagnosis.17 Unfortunately, patients with cancer are less likely to receive guideline directed medical therapy, including percutaneous coronary intervention (PCI) and P2Y12 inhibitors.18, 19 Analysis of the United States National Inpatient Sample demonstrated that utilization of PCI in STEMI patients with cancer varied according to type of cancer, ranging from 17% in patients with colon cancer to 31% in patients with breast cancer.20 Patients treated with PCI were less likely to die than those who did not undergo coronary revascularization.19 Not only is cancer also associated with increased risk of TS but also with adverse events in TS, including increased need for respiratory support, longer hospitalization, and higher mortality.21–23 These findings highlight a potential gap in the care of cancer patients that is of particular importance as cancer detection and survivorship becomes increasingly common.
Despite the majority of patients having a final diagnosis of MI in our cohort, there has been steady nationwide increase in TS in the United States, with women comprising 83% of cases.24 Our study suggests that women with ongoing or prior history of cancer may represent a unique population at risk for TS. The prevalence of TS in our cohort was similar to an earlier study of 275 patients, which showed that greater than10% of cancer patients with acute coronary syndrome presentation were ultimately diagnosed with TS.25 Our findings that women with history of cancer were also more likely to have physical triggers including surgery, infection or radiation, than TS patients without cancer is consistent with results from the International Takotsubo Registry.23 Notably the higher prevalence of physical trigger among cancer patients was observed in patients with a final diagnosis of MI, rather than TS.
It is currently unclear to what extent this increased risk of TS amongst cancer patients is driven by cancer-related therapies, including chemotherapy, radiation, or surgery. Beyond a cancer diagnosis, there has been an increased nationwide incidence of TS in patients receiving chemotherapy. Chemotherapeutic agents including 5-fluorouracil, rituximab, vascular endothelial growth factor antagonists, and vascular disrupting agents have been implicated as triggers of TS and MI.26 A recent study reported that TS events during chemotherapy are associated with increased length of stay, increased in-hospital mortality, and increased healthcare charges.27 5-fluorouracil and capecitabine were the agents most commonly associated with TS. In such cases TS often occurs during the first cycle of chemotherapy.28 Some studies suggest that chemotherapy is a more significant risk factor for TS than the cancer itself.29 In our study, women diagnosed with TS were more likely to have received chemotherapy than women found to have MICAD, MINOCA or SCAD. Thirty seven percent of women in our cohort who underwent chemotherapy were on hormonal chemotherapy, primarily for breast cancer, but it remains unclear what effects hormonal chemotherapy may have on mechanism of MI or TS. In the International Takotsubo Registry, patient with TS and malignancy had higher long-term mortality but comparable short-term outcomes.23 Cancer patients undergoing chemotherapy should therefore be considered high risk for TS, prompting early recognition and initiation of therapy. Furthermore, we found that patients with cancer who presented with a clinical syndrome compatible with MI and had undergone radiation were less likely to have a final diagnosis of TS. Radiation therapy has the potential to accelerate coronary artery.8 Our finding deserves further investigation in a larger sample.
Women with cancer history were less likely to present with chest pain than women without cancer history. The frequency of presentation without chest pain in our study was similar to that reported for women in large studies of MI, 38–42%, but lower than a series of 201 cancer patients with NSTEMI (51%).16, 30, 31 We speculate that cancer treatments with effects of visceral nerves, such as radiation therapy, may contribute to the lower likelihood of chest pain during MI presentation among cancer pateints observed in our study.
Our study has several limitations. All patients in this study underwent coronary angiography which may have biased our study towards healthier cancer patients given our local clinical practice pattern during the study period dwhich included referral for angiography in most cases of type 1 MI unless there are major contraindications, or alternatively, toward sicker patients given that very low risk MI cases may have been treated without angiography. Interpretation of our results is limited by sample size. There were only 37 patients who had MI with active cancer, therefore any associations need to be interpreted with caution. Cancer is a heterogeneous entity, with prior studies demonstrating lung, gastric, or pancreatic cancers confer the highest risks of arterial thrombotic events, including MI.9 Our study only included women, because it was based on screening logs at one site for a study restricted to women.32 Therefore, results cannot be generalized to men. Furthermore, a majority of women in this study were Caucasians which limits generalizability of the study. Our registry did not include MI patients admitted during the peak of 2020 COVID-19 pandemic in New York City, but it does include consecutive women with MI who underwent angiography at our center during registry enrollment time periods. Other limitations of this study include those pertinent to all retrospective chart reviews that are dependent on the quality of clincal documentation. For example, we do not have access to reasons why revascularization was not performed.
In conclusion, a history of cancer was present in 23% of women with a clinical diagnosis of MI who were referred for coronary angiography. Cancer was associated a higher likelihood of a final diagnosis of TS, although most patients had a final diagnosis of MI regardless of cancer history. Active malignancy was associated with higher likelihood of TS as compared to MI but was not associated with differences in MI subtypes. These results suggest that cancer and its treatment may impact the development of TS. Further research is necessary to investigate the relationship of specific cancer therapies, such as chemotherapy, immunotherapy, and radiation treatment, with the incidence of MI and TS.
Funding:
American Heart Association grants 16SFRN28730004, 16SFRN2781006, and 812162
Footnotes
Disclosures: Dr. Reynolds reports in-kind donations from Abbott Vascular, Siemens, and Philips for related research. Dr. Smilowitz reports advisory board membership for Medyria. Dr. Hausvater is supported by NIH T32HL098129.
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