High neutrophil-to-lymphocyte ratio is associated with cancer therapy-related cardiovascular toxicity in high-risk cancer patients under immune checkpoint inhibitor therapy

Haj-Yehia, Elias; Mincu, Raluca I.; Korste, Sebastian; Lampe, Lena; Margraf, Simone M.; Michel, Lars; Mahabadi, Amir A.; Ferdinandy, Péter; Rassaf, Tienush; Totzeck, Matthias

doi:10.1007/s00392-023-02327-9

Cited by 5 publications

(2 citation statements)

References 64 publications

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“…showed a correlation with NLR and the length of hospital stay in myocarditis patients. Previous studies have shown that NLR increased in patients with ICI‐induced myocarditis and that elevated NLR is associated with major adverse cardiovascular events related to ICI therapy 20–22 . Our results further confirm the association between NLR and cardiovascular events as reported in previous studies.…”

Section: Discussionsupporting

confidence: 92%

“…Previous studies have shown that NLR increased in patients with ICI‐induced myocarditis and that elevated NLR is associated with major adverse cardiovascular events related to ICI therapy. 20 , 21 , 22 Our results further confirm the association between NLR and cardiovascular events as reported in previous studies. NLR reflects inflammatory activity, which may be as a possible mediator for severe myocarditis in cancer patients receiving ICIs.…”

Section: Discussionsupporting

confidence: 91%

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Cardiovascular adverse events associated with immune checkpoint inhibitors: A retrospective multicenter cohort study

Zheng,

Chen,

Song

et al. 2024

Cancer Medicine

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BackgroundOver the past decade, immune checkpoint inhibitors (ICIs) have significantly transformed cancer treatment. However, ICIs inevitably may cause a spectrum of immune‐related adverse events, among which cardiovascular toxicity, particularly myocarditis, while infrequent, has garnered increasing attention due to its high fatality rate.MethodsWe conducted a multicenter retrospective study to characterize ICI‐associated cardiovascular adverse events. Logistic regression was performed to explore the risk factors for the development of myocarditis and severe myocarditis. Receiver operating characteristic curves were conducted to assess the diagnostic abilities of cardiac biomarkers to distinguish different cardiovascular toxicities, and the performance and calibration were evaluated using Hosmer–Lemeshow test.ResultsForty‐four patients were identified, including thirty‐five myocarditis, five heart failure, three arrhythmias, and one myocardial infarction. Compared with other patients, myocarditis patients had higher cardiac troponin‐I (cTnI) levels (p < 0.001), higher creatine kinase levels (p = 0.003), higher creatine kinase isoenzyme‐MB (CK‐MB) levels (p = 0.013), and shorter time to the incidence of adverse cardiovascular events (p = 0.022) after ICI treatment. Twenty‐one patients (60%) were classified as severe myocarditis, and they presented higher cardiac troponin I (cTnI) levels (p = 0.013), higher N‐terminal pro‐B‐type natriuretic peptide levels (p = 0.031), higher creatine kinase levels (p = 0.018), higher CK‐MB levels (p = 0.026), and higher neutrophil to lymphocyte ratio (NLR) levels (p = 0.016) compared to non‐severe myocarditis patients after ICI treatment. Multivariate logistic regression showed that CK‐MB (adjusted odds ratio [OR]: 1.775, 95% confidence interval [CI]: 1.055–2.984, p = 0.031) was the independent risk factor of the development of ICI‐associated myocarditis, and cTnI (adjusted OR: 1.021, 95% CI: 1.002–1.039, p = 0.03) and NLR (adjusted OR: 1.890, 95% CI: 1.026–3.483, p = 0.041) were the independent risk factors of ICI‐associated severe myocarditis. The receiver operating characteristic curve showed an area under curve of 0.785 (95% CI: 0.642 to 0.928, p = 0.013) for CK‐MB, 0.765 (95% CI: 0.601 to 0.929, p = 0.013) for cTnI, and 0.773 for NLR (95% CI: 0.597 to 0.948, p = 0.016).ConclusionsElevated CK‐MB after ICI treatment is the independent risk factor for the incidence of ICI‐associated myocarditis, and elevated cTnI and NLR after ICI treatment are the independent risk factors for the development of ICI‐associated severe myocarditis. CK‐MB, cTnI, and NLR demonstrated a promising predictive utility for the identification of ICI‐associated myocarditis and severe myocarditis.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 91%

Cardiovascular adverse events associated with immune checkpoint inhibitors: A retrospective multicenter cohort study

Zheng,

Chen,

Song

et al. 2024

Cancer Medicine

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Aortic regurgitation is associated with African American and Asian race, smoking, renal disease, and numerous autoimmune diseases in addition to traditional cardiovascular risk factors but has lower risk with alcohol intake

Timmerman,

Hashemzadeh,

Movahed

2024

Clin Res Cardiol

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Effects of sex and obesity on immune checkpoint inhibition-related cardiac systolic dysfunction in aged mice

Sayour,

Kucsera,

Alhaddad

et al. 2024

Basic Res Cardiol

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Despite accumulating data on underlying mechanisms, the influence of sex and prevalent cardio-metabolic co-morbidities on the manifestation and severity of immune checkpoint inhibitor (ICI)-induced cardiotoxicity has not been well defined. To elucidate whether sex and prevalent cardio-metabolic co-morbidities affect ICI-induced cardiotoxicity, we randomized 17-month-old male and female mice to receive control diet (CON) or high-fat diet (HFD) + L-NAME—a well-established mouse model of cardio-metabolic co-morbidities—for 17 weeks (n = 5–7), and evaluated markers of T-cell function in the spleen. As expected, HFD + L-NAME significantly increased body- and heart weight, and serum cholesterol levels, and caused no systolic dysfunction, however, led to diastolic dysfunction, cardiomyocyte hypertrophy, and increased fibrosis only in males compared to corresponding CON. Western blot analyses of splenic immune checkpoint protein levels showed differential expression depending on sex and prevalent cardio-metabolic co-morbidities, suggesting T-cell exhaustion in both sexes on HFD + L-NAME, but more pronounced in males. In a sub-study with a similar setup, we tested cardiotoxic manifestations of ICI by treating mice with anti-PD-1 monoclonal antibody (ICI) for the last 2 weeks of diet administration (n = 5–7). After 2 weeks of ICI treatment, cardiac systolic functions significantly decreased in CON, but not in HFD + L-NAME groups of both sexes compared to baseline (before ICI administration). In conclusion, in this exploratory study using aged mice, we describe for the first time that ICI-related systolic dysfunction is diminished in both sexes when obesity and hypercholesterolemia are present, possibly due to obesity-related T-cell exhaustion.

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High neutrophil-to-lymphocyte ratio is associated with cancer therapy-related cardiovascular toxicity in high-risk cancer patients under immune checkpoint inhibitor therapy

Cited by 5 publications

References 64 publications

Cardiovascular adverse events associated with immune checkpoint inhibitors: A retrospective multicenter cohort study

Cardiovascular adverse events associated with immune checkpoint inhibitors: A retrospective multicenter cohort study

Aortic regurgitation is associated with African American and Asian race, smoking, renal disease, and numerous autoimmune diseases in addition to traditional cardiovascular risk factors but has lower risk with alcohol intake

Effects of sex and obesity on immune checkpoint inhibition-related cardiac systolic dysfunction in aged mice

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