Myocardial Work Brings New Insights into Left Ventricular Remodelling in Cardio-Oncology Patients

Ferreira, V; Mano, T; Cardoso, I; Cruz, Madalena Coutinho; Branco, Luísa Moura; Almeida-Morais, Luís; Timóteo, Ana Teresa; Galrinho, A; Castelo, A; Bras, P Garcia; Simão, Diana; Sardinha, M.; Gonçalves, António Valentim; Ferreira, Rui Cruz

doi:10.3390/ijerph19052826

Cited by 12 publications

(13 citation statements)

References 57 publications

(84 reference statements)

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“…Notably, ICIs can induce a pro-inflammatory phenotype in cardiac and vascular tissues therefore the identification of new players of cardiotoxicity mediated by short-term ICIs therapy still need further attention. Recent consensus statements highlights on the importance of new predictive biomarkers of ICIs-mediated cardiotoxicity (12,13). Indeed, echocardiographic biomarkers such as changes in global longitudinal strain (GLS) (12), or myocardial work (MW) (13) or increases in plasma levels of galectin-3 and cytokines (14) are of great interest in clinical cardioncology.…”

Section: Introductionmentioning

confidence: 99%

“…Recent consensus statements highlights on the importance of new predictive biomarkers of ICIs-mediated cardiotoxicity (12,13). Indeed, echocardiographic biomarkers such as changes in global longitudinal strain (GLS) (12), or myocardial work (MW) (13) or increases in plasma levels of galectin-3 and cytokines (14) are of great interest in clinical cardioncology. Considering that Pembrolizumab and Ipilimumab recognize both human and mice PD-1 and CTLA-4 epitopes (15, 16), we have highlighted on the vascular and myocardial inflammation in female mice through immunohistochemistry and ELISA methods shedding light on potential pathways involved in ICIs cardiotoxicity, including NLRP3, MyD88 and DAMPs.…”

Section: Introductionmentioning

confidence: 99%

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Immune checkpoint inhibitor therapy increases systemic SDF-1, cardiac DAMPs Fibronectin-EDA, S100/Calgranulin, galectine-3, and NLRP3-MyD88-chemokine pathways

Quagliariello

Passariello

Mauro

et al. 2022

Front. Cardiovasc. Med.

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BackgroundImmune checkpoint inhibitors (ICIs) have significantly changed the oncology clinic in recent years, improving survival expectations in cancer patients. ICI therapy have a broad spectrum of side effects from endocrinopathies to cardiovascular diseases. In this study, pro-inflammatory and pro-fibrotic effects of short-term ICIs therapy in preclinical models were analyzed.MethodsFirstly, in a human in vitro model, human cardiomyocytes co-cultured with hPBMC were exposed to ICIs (with CTLA-4 or PD-1 blocking agents, at 200 nM) for 72 h. After treatment, production of DAMPs and 12 cytokines were analyzed in the supernatant through colorimetric and enzymatic assays. C57/Bl6 mice were treated with CTLA-4 or PD-1 blocking agents (15 mg/kg) for 10 days. Before (T0), after three days (T3) and after treatments (T10), ejection fraction, fractional shortening, radial and longitudinal strain were calculated by using bidimensional echocardiography (Vevo 2100, Fujfilm). Fibrosis, necrosis, hypertrophy and vascular NF-kB expression were analyzed through Immunohistochemistry. Myocardial expression of DAMPs (S100- Calgranulin, Fibronectin and Galectine-3), MyD88, NLRP3 and twelve cytokines have been analyzed. Systemic levels of SDF-1, IL-1β, and IL-6 were analyzed before, during and after ICIs therapy.ResultsRadial and longitudinal strain were decreased after 10 days of ICIs therapy. Histological analysis of NF-kB expression shows that short-term anti-CTLA-4 or anti-PD-1 treatment increased vascular and myocardial inflammation. No myocardial hypertrophy was seen with the exception of the pembrolizumab group. Myocardial fibrosis and expression of galectin-3, pro-collagen 1-α and MMP-9 were increased after treatment with all ICIs. Both anti-CTLA-4 or anti-PD-1 treatments increased the expression of DAMPs, NLRP3 inflammasome and MyD88 and induced both in vitro and in vivo the secretion of IL-1β, TNF-α and IL-6. Systemic levels of SDF-1, IL-1β and IL-6 were increased during and after treatment with ICIs.ConclusionsShort therapy with PD-1 and CTLA-4 blocking agents increases vascular expression of NF-kB, systemic SDF-1, IL-1β, IL-6 levels and myocardial NLRP3, MyD88 and DAMPs expression in preclinical models. A pro-inflammatory cytokine storm was induced in myocardial tissues and in cultured cardiac cells after ICIs therapy. The overall picture of the study suggests new putative biomarkers of ICIs-mediated systemic and myocardial damages potentially useful in clinical cardioncology.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immune checkpoint inhibitor therapy increases systemic SDF-1, cardiac DAMPs Fibronectin-EDA, S100/Calgranulin, galectine-3, and NLRP3-MyD88-chemokine pathways

Quagliariello

Passariello

Mauro

et al. 2022

Front. Cardiovasc. Med.

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“…More specifically global work index and global work efficiency had a more pronounced variation in patients with treatment-induced cardiac dysfunction. 32 , 33 …”

Section: Discussionmentioning

confidence: 99%

Cardiac function in women receiving dual anti-Her2 antibodies (trastuzumab and pertuzumab) combined with chemotherapy for breast cancer

Zekri

Rasool

Rizvi

et al. 2023

Womens Health (Lond Engl)

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Background: Chemotherapy regimens containing a combination of anti-Her2 antibodies are effective but can be associated with cardiac toxicity. Objectives: We evaluate the outcome with a particular focus on the cardiac function of patients with Her2 over-expressed breast cancer receiving Chemotherapy regimens combined with Trastuzumab and Pertuzumab in routine clinical practice settings. Design and methods: The initial cohort of patients who started Chemotherapy regimens in combination with Trastuzumab and Pertuzumab before September 2019 in four cancer units were reviewed retrospectively. All patients had regular measurements of left ventricular ejection fraction by Doppler ultrasound. Results: Sixty-seven patients were identified. Chemotherapy regimens in combination with Trastuzumab and Pertuzumab treatment were administered in the neoadjuvant and palliative settings in 28 (41.8%) and 39 (58.2%) patients, respectively. All patients underwent left ventricular ejection fraction assessment prior to starting Chemotherapy regimens in combination with Trastuzumab and Pertuzumab treatment and at 3 and 6 months later. Subsequently, left ventricular ejection fraction was measured at 9, 12, 15, 18, 21, and 24 months as long as patients are still receiving any of the treatment components. Compared to baseline, the mean left ventricular ejection fraction was not significantly different at any of the subsequent time points (range; decrease by 0.936% to increase by 1.087%: T-test P value not statistically significant for all comparisons). Trastuzumab and Pertuzumab administration was withheld temporarily for two patients due to clinically suspected cardiac toxicity which was excluded upon further investigations. In the neoadjuvant cohort, 82.3% of patients were relapse free at 3 years. The median progression-free survival was 20 months, and the median overall survival was 41 months in the palliative cohort. Conclusion: In this cohort describing our limited initial experience, dual anti-Her2 antibodies (Trastuzumab and Pertuzumab) combined with chemotherapy is effective and not associated with significant cardiac toxicity when the left ventricular ejection fraction is measured every 3 months. This may suggest that previous concerns about cardiotoxicity may have been overemphasized. Further studies investigating less frequent left ventricular ejection fraction monitoring may be warranted.

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“…Of note, both longitudinal strain and mechanical dispersion are not specific parameters to detect myocardial fibrosis, because they reflect the comprehensive changes of pathophysiological status in the myocardium (e.g., fibrosis, hypertrophy, microvascular ischemia) ( 68 , 69 ). Myocardial work is another novel parameter of transthoracic echocardiography, reflecting the stroke work through pressure-strain loop by incorporating deformation and afterload information of the left ventricle ( 70 ). Recent studies indicated that parameters of myocardial work were associated with CMR findings of fibrosis and global constructive work (GCW) showed a better ability to predict myocardial fibrosis compared with GLS ( 71 , 72 ).…”

Section: Detection: Laboratory Biomarkers and Imaging Techniquesmentioning

confidence: 99%

Detection of myocardial fibrosis: Where we stand

Zhu

Zhao

Lü

2022

Front. Cardiovasc. Med.

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Myocardial fibrosis, resulting from the disturbance of extracellular matrix homeostasis in response to different insults, is a common and important pathological remodeling process that is associated with adverse clinical outcomes, including arrhythmia, heart failure, or even sudden cardiac death. Over the past decades, multiple non-invasive detection methods have been developed. Laboratory biomarkers can aid in both detection and risk stratification by reflecting cellular and even molecular changes in fibrotic processes, yet more evidence that validates their detection accuracy is still warranted. Different non-invasive imaging techniques have been demonstrated to not only detect myocardial fibrosis but also provide information on prognosis and management. Cardiovascular magnetic resonance (CMR) is considered as the gold standard imaging technique to non-invasively identify and quantify myocardial fibrosis with its natural ability for tissue characterization. This review summarizes the current understanding of the non-invasive detection methods of myocardial fibrosis, with the focus on different techniques and clinical applications of CMR.

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Myocardial Work Brings New Insights into Left Ventricular Remodelling in Cardio-Oncology Patients

Cited by 12 publications

References 57 publications

Immune checkpoint inhibitor therapy increases systemic SDF-1, cardiac DAMPs Fibronectin-EDA, S100/Calgranulin, galectine-3, and NLRP3-MyD88-chemokine pathways

Immune checkpoint inhibitor therapy increases systemic SDF-1, cardiac DAMPs Fibronectin-EDA, S100/Calgranulin, galectine-3, and NLRP3-MyD88-chemokine pathways

Cardiac function in women receiving dual anti-Her2 antibodies (trastuzumab and pertuzumab) combined with chemotherapy for breast cancer

Detection of myocardial fibrosis: Where we stand

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