The predictive value of coronary artery calcium deposit for cardiovascular events in patients treated with immune checkpoint inhibitors

Abstract

Background

Immune checkpoint inhibitors (ICIs) have become the standard for treating various cancers. Nevertheless, their use may lead to significant cardiovascular immune-related adverse events (CV irAEs).

Objectives

We aimed to assess whether pre-treatment coronary artery calcium (CAC) deposition predicts CV irAEs in patients treated with ICIs.

Methods

A retrospective single-center cohort of patients treated with ICIs who performed pre-treatment chest computed tomography. A visual CAC assessment was categorized into Positive or Negative calcium deposits. Patients with pre-existing ischemic heart disease were excluded. The primary endpoint was the composite CV irAEs, including myocarditis, acute coronary syndrome, heart failure, and arrhythmias, and the secondary endpoint was all-cause mortality.

Results

The cohort included 240 patients with a median age of 67 (IQR 59–73) years and 47% female. The most prevalent type of cancer was lung cancer (36%), and the prominent ICIs was pembrolizumab (54%). Patients with Positive CAC (38%) were predominantly male, with higher rates of cardiovascular comorbidities. The primary outcome occurred in 36 cases (15%) at a median of 94 (IQR 48–338) days from the first ICIs dose. The Positive CAC group observed a non-significant trend toward a higher hazard for CV irAEs (HR 1.66, 95% CI 0.86–3.21, p = 0.13), with no significant difference in all-cause mortality (HR 1.15, 95% CI 0.88–1.51, p = 0.30).

Conclusion

Pre-treatment CAC deposition did not demonstrate an independent predictive role in assessing the risk of CV irAEs and all-cause mortality in patients treated with ICIs.

Supplementary Information

The online version contains supplementary material available at 10.1186/s40959-025-00389-4.

Introduction

Immune checkpoint inhibitors (ICIs) represent an innovative category of cancer therapy drugs designed to enhance the body’s natural immune response against cancer cells. However, their use may be hampered by immune-related adverse effects (irAEs) from the pro-inflammatory T cell overreaction [1]. Cardiovascular (CV) irAEs are relatively rare complications; however, they are potentially fatal. Although myocarditis is the most recognized CV irAEs, several other CV irAEs have been reported, including heart failure (HF), acute coronary syndromes (ACS), and arrhythmias [2]– [3]. A single-center study observed a 13% incidence of CV irAEs, including CV mortality, myocardial infarction, stroke, and HF hospitalization, in 252 lung cancer patients undergoing ICIs therapy [4]. Despite this, there are limited potential predictors for CV irAEs in patients treated with ICIs [5]. Therefore, the urgent need for practical CV risk stratification markers is becoming increasingly apparent.

Coronary artery calcium (CAC) scoring on computed tomography (CT) has emerged as a powerful predictor of CV events in the general population. Compared with patients with no coronary calcium, the adjusted risk of coronary events was increased by a factor of 7.73 to 9.12 [5]. However, the predictive utility of CAC as an early marker for CV irAEs following ICIs therapy has not been thoroughly examined. A small retrospective study showed that coronary and aortic calcification on baseline non-gated CT imaging was associated with CV events in patients treated with ICIs, while traditional CV risk factors were not [6].

Since chest CT is routinely performed in most cancer patients as a baseline evaluation, we believe it may play a role in CV risk stratification. Therefore, our study aimed to assess whether pre-treatment CAC deposit may predict the development of CV irAE and all-cause mortality in patients treated with ICIs therapy.

Methods

Study population

We conducted a retrospective, single-center, observational study at Tel-Aviv Sourasky Medical Center, a tertiary cancer center in Israel. Consecutive records of all patients treated with ICIs were reviewed between December 2015 and December 2021. The treating oncologist chose the specific therapy protocol according to current best practices. Our cohort included patients who performed pre-treatment chest CT before the initiation of ICIs therapy. Exclusion criteria included age under 18 years and a history of ischemic heart disease (IHD). The study was approved by the local Tel Aviv Sourasky Helsinki regulator ethics committee (Identifier: 0228-16-TLV).

Physicians from the research team retrieved baseline characteristics from electronic medical records. Baseline comorbidities included diabetes mellitus (DM), hypertension (HTN), hyperlipidemia, HF, atrial fibrillation (AF), and chronic kidney disease (CKD), and medical treatment (mainly cardio-protective medications, including renin-angiotensin receptor blocker (RAAS) inhibitors, beta blockers, mineralocorticoid receptor antagonist (MRA), and statins). Malignancy diagnosis, as well as the specific ICIs treatment, were also extracted. Baseline high-sensitivity Troponin I (hs-TnI) values and left ventricular ejection fraction (LVEF) were collected.

Computed tomography (CT)

Non-gated chest CT was performed as a routine assessment before the initiation of ICIs therapy. The initial intention was to use automated Agatston scoring, but the images were suboptimal or inadequate for scoring. Thus, visual coronary and aortic calcification were performed through visual analysis by cardiologists (M.S.), blinded to the clinical outcomes. The categorization of the CAC was classified as None (0), Mild (1) = < 1/3 the length of the entire artery, Moderate (2) = 1/3–2/3 the length of the entire artery, and Severe (3) = > 2/3 the length of the entire artery, based on similar scoring used in recent studies [6]. For the analyses, a CAC score of 0 or 1 was defined as a Negative CAC, and a score of 2 or 3 was defined as a Positive CAC.

Study endpoints

The primary endpoint was the composite CV irAEs, including myocarditis, a new HF diagnosis or an exacerbation, ACS, and arrhythmias (including atrial fibrillation/flutter and ventricular tachyarrhythmia), consistent with previously reported CV complications associated with ICIs [7]. All reported endpoints were defined and adjudicated according to the most recent ESC guidelines relevant to each condition, as current at the time of data collection (Supplementary 1). The secondary endpoint was all-cause mortality. Data on mortality were available through the Ministry of Health’s national database, which is updated monthly.

Statistical analysis

Categorical variables were expressed as frequencies and percentages. The distribution of continuous variables was assessed using histograms and Q–Q plots, with all continuous variables showing a non-normal distribution. Continuous variables were described using median and interquartile range (IQR). The association between baseline characteristics and outcomes was assessed using univariable and multivariable Cox proportional hazard models. Hazard ratios and 95% confidence intervals were reported. Kaplan-Meier curves were created to evaluate the association of coronary and aortic calcium with the primary and secondary outcomes. A two-tailed p-value of < 0.05 was considered significant for all analyses. All analyses were performed using IBM SPSS 27.0 software (SPSS Inc., Chicago, IL).

Results

Two hundred and forty patients were included in our cohort. The study baseline characteristics are shown in Table 1. The cohort’s median age was 67 years (interquartile range (IQR) 59–73), with 47% female. The most common malignancies were lung (36%) and gastrointestinal (13%), as shown in Fig. 1. Most patients were treated with pembrolizumab (54%) or nivolumab (30%) (Table 1).

Table 1.

Study characteristics and comparison based on coronary calcification

Variable	Negative n = 148	Positive n = 92	Total n = 240	p
Age, median (IQR)	63 (53–70)	73 (68–78)	67 (59–73)	< 0.001
Female sex, n (%)	78 (53)	35 (38)	113 (47)	0.027
Hyperlipidemia, n (%)	41 (28)	45 (49)	86 (36)	< 0.001
Hypertension, n (%)	45 (30)	50 (54)	95 (40)	< 0.001
Diabetes Mellitus, n (%)	25 (17)	30 (33)	55 (23)	0.005
Heart failure, n (%)	10 (7)	6 (7)	16 (7)	0.943
Atrial fibrillation, n (%)	9 (6)	14 (15)	23 (10)	0.019
CKD, n (%)	5 (3)	10 (11)	15 (6)	0.020
Statins	52 (35)	55 (60)	107 (45)	< 0.001
Angiotensin-Converting Enzyme Inhibitors	26 (18)	25 (27)	51 (21)	0.077
Angiotensin Receptor Blocker	12 (8)	19 (21)	31 (13)	0.005
Aldactone	6 (4)	1 (1)	7 (3)	0.184
Beta blockers	37 (25)	33 (36)	70 (29)	0.072
Fusid	16 (11)	13 (14)	29 (12)	0.443
Metformin	20 (14)	27 (29)	47 (20)	0.003
SGLT2 inhibitors	2 (1)	3 (3)	5 (2)	0.314
Cancer Type, n (%)				0.230
Lung	29 (32)	57 (38)	86 (36)
Gastrointestinal	11 (12)	20 (13)	31 (13)
Hematologic	13 (9)	11 (12)	24 (10)
Renal	10 (7)	13 (14)	23 (10)
TCC	2 (2)	12 (8)	14 (6)
Breast	7 (8)	5 (3)	12 (5)
Others	18 (20)	32 (22)	50 (21)
Immunotherapy				0.629
Pembrolizumab, n (%)	81 (55)	49 (53)	130 (54)
Nivolumab, n (%)	46 (31)	26 (28)	72 (30)
Atezolizumab, n (%)	11 (7)	12 (13)	23 (10)
Other, n (%)	10 (7)	5 (5)	15 (6)
Calcified Aorta, n (%)	93 (64)	85 (92)	178 (75)	< 0.001
High-sensitivity Troponin I, baseline, ng/L, median (IQR)	3 (0.01-10)	4 (0.03-11)	4 (0.015-10)	0.524
LVEF%, baseline, median (IQR)	60 (60–60)	60 (60–60)	60 (60–60)	0.283

n = number, IQR = interquartile range, CKD = chronic kidney disease, SGLT2 = sodium glucose cotransporter 2, TCC = transitional cell carcinoma, LVEF = left ventricle ejection fraction

Fig. 1.

Distribution of malignancies in the study cohort. GI = gastrointestinal; TCC = transitional cell carcinoma

Positive and negative CAC groups

Ninety-two (38%) patients were included in the Positive CAC group and 148 (62%) in the Negative CAC group. Patients in the Positive CAC group were older (73 vs. 63 years, p < 0.001), had a higher male representative (62% vs. 47%, p = 0.027), and had significantly higher rates of CV risk factors, including hyperlipidemia (49% vs. 28%, p < 0.001), HTN (54% vs. 30%, p < 0.001), DM (33% vs. 17%, p = 0.005), AF (15% vs. 6%, p = 0.019), and CKD (11% vs. 3%, p = 0.020) (Table 1). No differences were observed regarding cardio-protective therapy, including RAAS inhibitors (p = 0.711), beta blockers (p = 0.493), MRA (p = 0.708) and statins (p = 0.651). Almost all patients in the Positive CAC group presented with aortic calcification (92% vs. 64%, p < 0.001), while no differences were observed in hs-TnI and LVEF (Table 1).

Primary and secondary endpoints

The primary outcome occurred in 36 cases (15%) at a median of 94 (IQR 48–338) days from the first ICI’s dose. These cases included HF events (15 cases), new-onset arrhythmia (15 cases), ACS (4 cases), and myocarditis (2 cases). A trend towards a higher hazard of CV irAEs was observed in the Positive CAC group (HR 1.66, 95% CI 0.86–3.21, p = 0.13, Fig. 2); however, this did not reach statistical significance. Similarly, a comparable trend was noted between aortic calcifications and CV irAEs (HR 2.21, 95% CI 0.86–5.69, p = 0.10, Fig. 3). Univariate and multivariate Cox analyses for predictors of CV irAEs is shown in Table 2. Independent risk factors for the development of CV irAEs were older age (HR 1.03 for every additional year, 95% CI 1.002–1.07, p = 0.047) and lower baseline LVEF (HR 0.95 for every additional 5% LVEF, 95% CI 0.90–0.99, p = 0.010), while Positive CAC deposition was not (HR 1.66, 95% CI 0.86–3.21, p = 0.131). In univariate analysis, there was no association between the hazard of CV events and treatment with metformin (p = 0.164), ARB (p = 0.288), and MRA (p = 0.207). Higher risks of CV events were associated with treatments with statins (HR 2.14, p = 0.029), ACEi (HR 2.025, p = 0.042), and beta-blockers (HR 2.174, p = 0.023). However, when including each of these treatments in a multivariate cox regression model with CV comorbidities (age, HTN, DM, hyperlipidemia), they were no longer associated with CV events (p-values of 0.141, 0.126, 0.176, respectively).

Fig. 2.

Kaplan-Meier analysis of cardiovascular events stratified by patients with (green) and without (blue) coronary calcifications

Fig. 3.

Kaplan-Meier analysis of cardiovascular events stratified by patients with (green) and without (blue) aortic calcifications

Table 2.

Univariate and multivariate Cox analyses for predictors of CV events

Variable	Univariate		Multivariate
	HR (95% CI)	p	adjusted HR (95% CI)	p
Age	1.05 (1.01–1.08)	0.004	1.03 (1.00-1.07)	0.047
Female sex	0.75 (0.38–1.45)	0.382
Hyperlipidemia	1.76 (0.91–3.38)	0.091
Hypertension	1.59 (0.83–3.08)	0.158
Diabetes Mellitus	1.35 (0.65–2.79)	0.434
Calcified coronary	1.66 (0.86–3.21)	0.131
Calcified Aorta	2.21 (0.86–5.69)	0.100	1.70 (0.58–5.02)	0.343
High-sensitivity Troponin I, baseline	0.99 (0.98–1.01)	0.422
LVEF%, baseline	0.94 (0.89–0.98)	0.008	0.95 (0.90–0.99)	0.010

LVEF = left ventricle ejection fraction

Median (IQR) survival was 10 months (6.6–13.4 months), with only 19 patients (8%) surviving at 5 years. Positive CAC (HR 1.15, 95% CI 0.88–1.51, p = 0.30, Fig. 4) or aortic calcifications (HR 1.09, 95% CI 0.80–1.49, p = 0.57) did not appear to predict all-cause mortality. These findings were consistent in the analysis of 1-year mortality (n = 112), both for Positive CAC (HR 1.96, 95% CI 0.79–4.84, p = 0.15) and aortic calcifications (HR 1.99, 95% CI 0.58–6.84, p = 0.28). There were no differences between the groups in terms of medications used (supplementary data Table 1).

Fig. 4.

Kaplan-Meier analysis of mortality stratified by patients with (green) and without (blue) coronary calcifications

Discussion

We assessed the predictive role of baseline CAC deposit, evaluated by non-gated CT imaging, for the development of CV irAEs and all-cause mortality in patients treated with ICIs therapy. While a Positive CAC deposit was frequent, it was not found to be an independent predictor for clinical outcomes.

The incidence and spectrum of ICIs-induced cardiotoxicity are increasing, significantly impacting the management of ICIs therapy and patient prognosis [8, 9]. Still, no strategy has been proven to identify patients at higher risk for CV irAEs and guide and implement cardio-protective treatments. While the HFA-ICOS [10] implanted a risk stratification for cardiotoxic cancer therapies, it is not available specifically for ICIs, and evidence in this group is limited. Therefore, the urge for a simple, accessible, routine assessment for risk stratification for CV irAEs is increasing. Chest CT imaging is used routinely among cancer patients as a baseline evaluation. CAC has been reported as a highly specific imaging biomarker for CV risk in the general population [5]; however, data regarding its role in cancer patients is limited [6].

Schiffer et al. [6] showed a significant association between worse coronary calcification and CV events. While we observed a higher trend of CV events in the Positive CAC group in our cohort, it did not reach statistical significance and was probably driven by the higher comorbidities in this group, as noted in the multivariate analysis. This lack of association suggests that while CAC deposits are a recognized marker of subclinical atherosclerosis in the general population [5], their predictive value may be limited in the specific context of CV irAEs. Mortality was also not associated with evidence of CAC. Although the etiologies for mortality were unavailable, given the high mortality rate compared to the rate of CV irAEs, this was likely driven by the malignancy itself.

Previous studies have highlighted the potential for ICIs to exacerbate CV risks through mechanisms involving immune-mediated inflammation and accelerated atherosclerosis [11]. Our data did not support a direct link between baseline positive CAC deposits and an increased risk of CV irAEs or all-cause mortality. The absence of a significant association in our study could be attributed to several factors. Firstly, the CT scans were not done according to the protocol of the CAC regimen. Secondly, the high baseline prevalence of traditional cardiac risk factors within our cohort could have overshadowed the incremental risk posed by CAC deposits. Finally, although representative of real-world clinical practice, the heterogeneity of cancer types and treatment regimens may have introduced variability that affected the outcomes.

Study limitations

Our study has several limitations. First, it is a single-center study, and thus, the generalization of our results is limited. However, since Tel Aviv Sourasky is a tertiary referral cancer center in Israel, the study population includes a variety of ethnic origins from all over the country and, therefore, represents a wide range of populations in Israel. Second, this is a retrospective study, and thus, our results are subject to the effects of potential confounders inherent to the nature of such studies and may be biased by their design. Third, the CT scans were not performed according to the CAC protocol, and in some studies, they included intravenous contrast, which may have affected the reading and results.

Conclusions

Baseline-positive CAC deposits did not predict CV irAEs or all-cause mortality in patients treated with ICIs therapy. These findings underscore the complexity of managing CV risks in cancer patients treated with ICIs. While CAC scoring remains a valuable tool for assessing atherosclerotic burden in the general population, its utility in predicting ICIs-related CV events warrants further investigation. Future prospective studies with larger and more contemporary cohorts of patients, including those treated with novel and combination therapies, are needed to elucidate the interplay between ICIs, CAC deposits, and CV events. This is particularly relevant given the increasing use of ICIs, advancements in CT technology, and the growing utilization of Cardiac CT.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Author contributions

M.S, M.L.P AND J.C wrote the main manuscript; O.F, S.K AND Z.R performed the statistics; G.L, H.S AND M.S performed and supervised the calcium deposit scoring; M.P.G, L.Z, D.V AND A.R.H collected the electronic data; O.H, Y.T, S.B AND J.C supervised the study and manuscript.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.

Disclosures

All authors have nothing to disclose.

The study was approved by the Tel Aviv Sourasky Medical Center Helsinki committee (#TLV-0228-16).