Introduction
Anthracyclines are the basic therapy for a wide range of solid tumors and hematologic cancers. Anthracyclines remain an important therapeutic option in breast cancer. However, their use is limited by the risk of therapy-related cardiovascular toxicity (CTR-CVT) [1–3]. One of the symptoms of cardiovascular complications from anthracycline use is left ventricular systolic dysfunction. A less known side effect of anti-cancer medications is coronary microcirculation damage [4]. Single reports from experimental studies indicate simultaneous irreversible coronary microcirculation dysfunction (CMD) following exposure to anthracyclines [1]. Many processes leading to the apoptosis of cardiomyocytes undoubtedly involve also vascular endothelial cells, causing their damage and CMD at the same time. Invasive assessment of microcirculation using the index of microcirculatory resistance (IMR) measurement is currently the gold standard in the diagnosis of CMD [4]. It has already been tested on many groups of patients, including stable angina pectoris, acute STEMI, and post-heart transplantation [5]. The advantage of IMR over coronary flow reserve (CFR) is that the IMR measurement is simple, microvascular-specific, quantitative, reproducible, and independent of hemodynamic changes. CMD-associated ischemia increases the risk of major adverse cardiovascular events (MACE) [6, 7]. In selected groups of patients, e.g. after heart transplantation, with hypertrophic cardiomyopathy or ST-segment elevation myocardial infarction, the severity of CMD is a significant independent risk factor for clinical deterioration and death [5, 8, 9].
This study aimed to assess the coronary microcirculation dysfunction in patients with ischemia with non-obstructed coronary artery disease (INOCA) treated with anthracyclines for malignancy.
Method
The study presents a retrospective analysis of five consecutive patients previously treated oncologically with typical angina pectoris symptoms, in whom coronary arteriography revealed no significant coronary artery stenosis (stenosis <40% of vessel diameter or 40%–60% of vessel diameter assessed as insignificant in functional testing such as fractional flow reserve [FFR> 0.80], Table 1). All patients were evaluated for CMD using the Coroventis CoroFlow Cardiovascular System (Abbott Vascular, Santa Clara, CA, US). CFR and IMR were assessed as part of the diagnosis of INOCA. CMD was diagnosed when IMR ≥25 and/or CFR <2.0.
|
Patient 1 |
Patient 2 |
Patient 3 |
Patient 4 |
Patient 5 |
|
|
Age, years |
57 |
59 |
61 |
59 |
54 |
|
Sex |
Female |
Female |
Female |
Female |
Female |
|
BMI, kg/m2 |
26 |
26 |
27 |
28 |
35.9 |
|
NYHA class |
II |
II |
II |
III |
II |
|
CCS class |
III |
III |
III |
III |
III |
|
HA |
Yes |
no |
Yes |
No |
Yes |
|
DM |
Yes |
no |
Yes |
No |
No |
|
Nicotinism |
No |
yes |
No |
No |
No |
|
Echocardiography |
|||||
|
EF, % |
55 |
25 |
35 |
43 |
60 |
|
GLS, % |
–14 |
–10 |
–11 |
–8 |
–18 |
|
EDD, mm |
48 |
69 |
54 |
56 |
47 |
|
LAVI, ml/m2 |
34 |
66 |
39 |
62 |
24 |
|
Location of the cancer |
Breast |
Ovarian |
Lymphoma |
Breast |
Breast |
|
Time since the end of chemotherapy, months |
13 |
11 |
13 |
6 |
15 |
|
Type of chemotherapy |
|||||
|
Doxorubicin |
Yes |
No |
Yes |
Yes |
Yes |
|
Dosage, mg/m2 |
240 |
0 |
420 |
240 |
240 |
|
Cyclophosphamide |
Yes |
No |
Yes |
Yes |
Yes |
|
Cisplatin |
No |
Yes |
No |
No |
No |
|
Docetaxel |
Yes |
No |
No |
Yes |
Yes |
|
Trastuzumab |
No |
No |
No |
Yes |
Yes |
|
Chest radiotherapy |
No |
No |
No |
No |
No |
|
Laboratory tests |
|||||
|
NT-proBNP, pg/ml |
450 |
11595 |
5300 |
1639 |
2060 |
|
Troponin, ng/ml |
0 |
0.03 |
0.03 |
0.7 |
0.012 |
|
LDL-C, mmol/l |
1.8 |
2.6 |
1.6 |
5.7 |
3.2 |
|
eGFR, ml/min/1.73 m3 |
78 |
26 |
61 |
56 |
90 |
|
Hb, mmol/dl |
7.2 |
6.6 |
6.4 |
7.1 |
7.5 |
|
Drugs used |
|||||
|
Beta-blocker |
Yes |
Yes |
Yes |
Yes |
No |
|
ACEI/ ARB |
Yes |
No |
Yes |
Yes |
Yes |
|
Ca-blocker |
No |
No |
No |
No |
Yes |
|
ARNI |
No |
Yes |
No |
No |
No |
|
SGLT-2 |
No |
Yes |
Yes |
No |
Yes |
|
Statin |
No |
Yes |
Yes |
Yes |
No |
|
Antidiabetic drugs |
No |
No |
Yes |
No |
No |
|
Insulin |
No |
No |
Yes |
No |
No |
|
Assessment of the coronary microcirculation: |
|||||
|
CFR |
1.9 |
3.2 |
2.4 |
1.9 |
1.6 |
|
IMR |
32 |
10 |
39 |
37 |
62 |
|
FFR |
0.91 |
0.9 |
0.86 |
0.94 |
0.93 |
Moreover, 12-lead ECG, transthoracic echocardiography, and laboratory tests, including myocardial dysfunction marker assays, were performed in all patients. Table 1 shows the clinical characteristics of patients along with detailed data on the chemotherapy used. Patients were assessed based on the following exclusion criteria: previous radiotherapy, the presence of an acute inflammatory condition (hs-CRP>10 mg/l), systemic connective tissue diseases, treatment with interferon, bleeding diathesis due to platelet or plasma disorders, acute renal failure or chronic kidney disease with GFR <30 ml/min/1.73 m2, allergy to iodinated contrast media, regadenoson, adenosine, uncontrolled asthma, 2nd and 3rd-degree atrioventricular block, or lack of informed consent.
RESULTS AND DISCUSSION
All five described patients had cancer. Three of them were diagnosed with breast cancer, one with lymphoma, and one with ovarian cancer. Four patients received chemotherapy with anthracyclines, while the ovarian cancer patient was administered cisplatin-based chemotherapy. On admission, all patients had symptoms of typical class III angina pectoris as defined by the Canadian Cardiovascular Society. None of the patients under analysis had been previously diagnosed with cardiovascular diseases. Left ventricular ejection fraction (LVEF) varied between 25% and 60%. The highest dose of anthracyclines was administered to the patient treated for lymphoma.
All patients underwent invasive coronary angiography, and then, due to no significant lesions in coronary arteries, a simultaneous assessment of coronary microcirculation was performed. CMD with a significantly increased IMR was revealed in all patients who were administered anthracyclines in the past. The patient who received non-anthracyclines chemotherapy presented normal coronary microcirculation function despite significantly impaired ejection fraction.
The presence of anthracyclines-related cardiotoxicity was proportional to the dose administered — the higher the dose, the higher the probability. With a dose of 400 mg/m2, the risk of symptomatic heart failure (HF) was 3%, with 550 mg/m2 — ٧٪ and with doses of ٧٠٠ mg/m2 — as many as 18% [2]. The risk of cardiotoxicity increased up to 35% if defined as an abnormal increase in cardiac biomarkers, such as troponin or NT-proBNP. It should be noted that no cardiac-safe dose of anthracyclines was determined. Persons with higher risk of cardiotoxicity include patients over 65 years, women, persons with low body weight, persons with a history of heart disease as well as patients who underwent chest radiotherapy [10].
The damage to coronary microcirculation due to anthracyclines administration is a new issue. In animal models, upon anthracyclines administration, permanent microcirculation damage was detected already at the subclinical stage [11]. Both a decrease in the density of the capillary network and dysfunction of other microcirculation vessels were demonstrated. Several mechanisms of anthracycline cardiotoxicity were proposed. Oxidative stress, initiated by doxorubicin, causes mitochondrial damage, which then leads to the apoptosis of both cardiomyocytes and endothelial cells. Moreover, through inhibition of topoisomerase IIb, therapeutic doses of doxorubicin can lead to direct DNA damage to endothelial cells and their further apoptosis in the non-oxidative mechanism [12]. Sodium-calcium and sodium-potassium pumps (Na+/K+-ATPase) also become damaged, which leads to the cells being overloaded with calcium ions and the death of the myocyte.
Our study has shown that CMD occurs both in patients with evident left ventricular systolic function damage and in patients with normal or slightly reduced ejection fraction. In line with the experimental studies, this may indicate that CMD clinically precedes evident cardiomyocyte dysfunction. Taking into account the irreversible cardiotoxicity mechanism of anthracyclines, by detecting this process at the stage of microcirculation and initiating cardio-protection, we can prevent patients from developing evident heart failure. The above hypothesis undoubtedly needs to be confirmed in subsequent prospective studies.
Article information
Conflict of interest: None declared.
Funding: None.
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