Cardiovascular toxicity of checkpoint inhibitors: review of associated toxicity and design of the Spanish Immunotherapy Registry of Cardiovascular Toxicity

Immune checkpoint inhibitors (ICI) have changed the prognosis of many tumors. However, concerning associated cardiotoxicity has been reported. Little is known about the real-life incidence-specific surveillance protocols or the translational correlation between the underlying mechanisms and the clinical presentation of ICI-induced cardiotoxicity. The lack of data from prospective studies led us to review the current knowledge and to present the creation of the Spanish Immunotherapy Registry of Cardiovascular Toxicity (SIR-CVT), a prospective registry of patients receiving ICI that aims to examine the role of hsa-miR-Chr8:96, (a specific serum biomarker of myocarditis) in the early diagnosis of ICI-induced myocarditis. An exhaustive prospective cardiac imaging study will be performed before and during the first 12 months of treatment. The correlation between clinical, imaging, and immunologic parameters may improve our understanding of ICI-induced cardiotoxicity and enable simpler surveillance protocols. We assess ICI-induced cardiovascular toxicity and describe the rationale of the SIR-CVT (AU)

Microplastic in industrial aquaculture: Occurrence in the aquatic environment, feed and organisms (Dicentrarchus labrax).

The increasing use of plastics and the growing concern about their impact on the environment and living beings makes it necessary to study how microplastics (MP) affect aquaculture systems. In order to gain an in-depth understanding of these systems, this study covers the water intake, the purification treatment at the inlet, the water in the culture tanks, as well as the feed used in the feeding and the organism itself. For this purpose, five samples were taken, both in the water line, feed and sea bass during the weeks of the experiment. It is shown that the available purification systems reduce the amount of MP entering from the receiving environment. However, new MP are observed in the sea bass tank, which may be due mainly to those added through the feed and found in the feed, as well as in the piping and other materials used in current aquaculture systems (PTFE, PA, among others). If focusing on the feed that can reach the consumer, in the case of this study, carried out with sea bass, some types of MP (PE, PTFE, PS and PA) were found in 4 head samples and 4 skin/muscle samples. Although inlet water purification systems manage to reduce a high percentage of MPs in the system, it is observed that there are other access routes that should be considered and reduced in aquaculture facilities to prevent them from reaching the human consumer.

Cardiotoxicity Secondary to Immune Checkpoint Inhibitors in the Elderly: Safety in Real-World Data.

INTRODUCTION: Immunotherapy represents a key pillar of cancer treatments, with high response rates and long survival. Its use is increasing, mainly at the expense of the geriatric population due to the ageing of this population. However, despite its benefit, its safety in certain areas such as cardiotoxicity is largely unknown. The aim of this study is to assess the safety of immunotherapy in elderly patients using real-world data. METHODS: This is an ambispective study of patients ≥ 70 years old with solid tumours who were treated with immunotherapy at the University Hospital of Salamanca. Cardiotoxicity was assessed using the CTCAEv5.0 criteria. RESULTS: In total, 195 patients were included (76.9% male and 23.1% female), with a mean age of 75 years [70-93]. The percentage of patients with cardiotoxicity was 1.54%; 1.35% of patients with previous heart disease were diagnosed with cardiotoxicity, and 1.65% of those without previous heart disease were diagnosed with cardiotoxicity. The median time from the initiation of treatment until the cardiac event was 45 days [14-96]. The most frequent toxicity was myocarditis in 66.7% of patients, followed by arrhythmias in 33.3% of patients. CONCLUSIONS: Immunotherapy is shown to be a safe treatment in elderly cancer patients in terms of cardiotoxicity. The event rate shows no difference between patients with or without cardiac comorbidity.

Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.

Influence of tourism on microplastic contamination at wastewater treatment plants in the coastal municipality of Chiclana de la Frontera.

The tourism is one of the most important sources of the economy in the Bay of Cadiz. Specifically, the municipality of Chiclana de la Frontera, with a population lower than 90,000 citizens, located in the southeast of Spain. During the summer season the population duplicates leading to an increment in flow at wastewater treatment plants (WWTPs). These facilities have been reported as a source of microplastics (MPs) into marine ecosystems, therefore the aim of the present study is to investigate if the tourism affects the presence, discharge and in the receiving environment. Samples were taken at the influent and effluent of the municipal WWTPs (one located at the urban area and other located at resort area) during 2021 (including low and high season). MPs were collected and extracted from wastewater matrixes following the method recommended by the National Oceanic and Atmospheric Administration and UTS treatment to reduce organic matter and cellulose, respectively. The analysis of the samples was performed according to their abundance, shape, size, and type of polymer, along with the removal rates of MPs at WWTPs. The results showed heterogeneous MPs abundance ranging from 1246.4 to 345.7 MPs/L and 72.9 to 4.2, in the influent and effluent, respectively, increasing the presence of MPs at resort WWTP during high season. Fibers were the predominant shape within all the samples. A total of 17 polymers were identified, by ATR-FTIR, where Acrylates, PE and PA were the largest polymers found. Despite the high MPs retention performance of the WWTPs analyzed (84.1-99.3 %), a combined contribution of approximately 1.4 × 107-5.9 × 108 MPs/d to the aquatic environment was estimated. Finally, these results indicate that the increase of MPs in the wastewater at WWTP-B was related with the population increase as a consequence of summer tourism.

Cardiovascular toxicity of checkpoint inhibitors: review of associated toxicity and design of the Spanish Immunotherapy Registry of Cardiovascular Toxicity.

Immune checkpoint inhibitors (ICI) have changed the prognosis of many tumors. However, concerning associated cardiotoxicity has been reported. Little is known about the real-life incidence-specific surveillance protocols or the translational correlation between the underlying mechanisms and the clinical presentation of ICI-induced cardiotoxicity. The lack of data from prospective studies led us to review the current knowledge and to present the creation of the Spanish Immunotherapy Registry of Cardiovascular Toxicity (SIR-CVT), a prospective registry of patients receiving ICI that aims to examine the role of hsa-miR-Chr8:96, (a specific serum biomarker of myocarditis) in the early diagnosis of ICI-induced myocarditis. An exhaustive prospective cardiac imaging study will be performed before and during the first 12 months of treatment. The correlation between clinical, imaging, and immunologic parameters may improve our understanding of ICI-induced cardiotoxicity and enable simpler surveillance protocols. We assess ICI-induced cardiovascular toxicity and describe the rationale of the SIR-CVT.

Intermediate molecular phenotypes to identify genetic markers of anthracycline-induced cardiotoxicity risk.

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex disease whose polygenic component is mainly unidentified. We propose that levels of intermediate molecular phenotypes in the myocardium associated with histopathological damage could explain CDA susceptibility; so that variants of genes encoding these intermediate molecular phenotypes could identify patients susceptible to this complication. A genetically heterogeneous cohort of mice generated by backcrossing (N = 165) was treated with doxorubicin and docetaxel. Cardiac histopathological damage was measured by fibrosis and cardiomyocyte size by an Ariol slide scanner. We determine intramyocardial levels of intermediate molecular phenotypes of CDA associated with histopathological damage and quantitative trait loci (ipQTLs) linked to them. These ipQTLs seem to contribute to the missing heritability of CDA because they improve the heritability explained by QTL directly linked to CDA (cda-QTLs) through genetic models. Genes encoding these molecular subphenotypes were evaluated as genetic markers of CDA in three cancer patient cohorts (N = 517) whose cardiac damage was quantified by echocardiography or Cardiac Magnetic Resonance. Many SNPs associated with CDA were found using genetic models. LASSO multivariate regression identified two risk score models, one for pediatric cancer patients and the other for women with breast cancer. Molecular intermediate phenotypes associated with heart damage can identify genetic markers of CDA risk, thereby allowing a more personalized patient management. A similar strategy could be applied to identify genetic markers of other complex trait diseases.

Mean Velocity of the Pulmonary Artery as a Clinically Relevant Prognostic Indicator in Patients with Heart Failure with Preserved Ejection Fraction.

BACKGROUND: Right ventricular (RV) to pulmonary circulation (PC) coupling can stratify prognosis in heart failure (HF). In this study, we assessed the prognostic role of the mean velocity of the pulmonary artery (mvPA) determined by cardiac magnetic resonance (CMR) in HF with preserved ejection fraction (HFpEF). METHODS: Inclusion of 58 HFpEF outpatients that underwent CMR with measurement of RV-PC coupling parameters including mvPA between 2016 and 2019. The primary combined endpoint was a composite of HF readmissions and all-cause mortality. RESULTS: Optimal cut-off value of mvPA calculated by receiver operating curve for the prediction of the primary endpoint was 9 cm/s. Over a median follow-up of 23 months (interquartile range: 24), 21 patients met the primary endpoint. The primary endpoint was more frequent in patients with mvPA ≤ 9 cm/s, as indicated by Kaplan-Meier survival curves; Log-Rank: 9.193, p = 0.02, regardless of RV dysfunction. On Cox multivariate analysis, mvPA ≤ 9 cm/s emerged as an independent prognostic predictor of the primary endpoint (HR: 4.11, 95% CI: 1.28-13.19, p = 0.017), together with left atrial area by CMR (HR: 1.08, 95% CI: 1.01-1.24, p = 0.034). CONCLUSIONS: In our HFpEF cohort, mvPA was associated with a higher rate of the primary endpoint, regardless of RV function, thus enabling identification of patients at higher risk of cardiovascular events before structural damage onset.

[Pericardial and myocardial involvement after SARS-CoV-2 infection: a cross-sectional descriptive study in healthcare workers]. / Afección pericárdica y miocárdica tras infección por SARS-CoV-2: estudio descriptivo transversal en trabajadores sanitarios.

Introduction and objectives: The cardiac sequelae of SARS-CoV-2 infection are still poorly documented. We conducted a cross-sectional study in healthcare workers to report evidence of pericardial and myocardial involvement after SARS-CoV-2 infection. Methods: We studied 139 healthcare workers with confirmed past SARS-CoV-2 infection. Participants underwent clinical assessment, electrocardiography, and laboratory tests, including immune cell profiling and cardiac magnetic resonance (CMR). Clinically suspected pericarditis was diagnosed when classic criteria were present and clinically suspected myocarditis was based on the combination of at least 2 CMR criteria. Results: Median age was 52 (41-57) years, 71.9% were women, and 16.5% were previously hospitalized for COVID-19 pneumonia. On examination (10.4 [9.3-11.0] weeks after infection-like symptoms), participants showed hemodynamic stability. Chest pain, dyspnea or palpitations were present in 41.7% participants, electrocardiographic abnormalities in 49.6%, NT-proBNP elevation in 7.9%, troponin in 0.7%, and CMR abnormalities in 60.4%. A total of 30.9% participants met criteria for either pericarditis and/or myocarditis: isolated pericarditis was diagnosed in 5.8%, myopericarditis in 7.9%, and isolated myocarditis in 17.3%. Most participants (73.2%) showed altered immune cell counts in blood, particularly decreased eosinophil (27.3%; P < .001) and increased cytotoxic T cell numbers (17.3%; P < .001). Clinically suspected pericarditis was associated (P < .005) with particularly elevated cytotoxic T cells and decreased eosinophil counts, while participants diagnosed with clinically suspected myopericarditis or myocarditis had lower (P < .05) neutrophil counts, natural killer-cells, and plasma cells. Conclusions: Pericardial and myocardial involvement with clinical stability are frequent after SARS-CoV-2 infection and are associated with specific immune cell profiles.Full English text available from:www.revespcardiol.org/en.

Pericardial and myocardial involvement after SARS-CoV-2 infection: a cross-sectional descriptive study in healthcare workers.

INTRODUCTION AND OBJECTIVES: The cardiac sequelae of SARS-CoV-2 infection are still poorly documented. We conducted a cross-sectional study in healthcare workers to report evidence of pericardial and myocardial involvement after SARS-CoV-2 infection. METHODS: We studied 139 healthcare workers with confirmed past SARS-CoV-2 infection. Participants underwent clinical assessment, electrocardiography, and laboratory tests, including immune cell profiling and cardiac magnetic resonance (CMR). Clinically suspected pericarditis was diagnosed when classic criteria were present and clinically suspected myocarditis was based on the combination of at least 2 CMR criteria. RESULTS: Median age was 52 (41-57) years, 71.9% were women, and 16.5% were previously hospitalized for COVID-19 pneumonia. On examination (10.4 [9.3-11.0] weeks after infection-like symptoms), participants showed hemodynamic stability. Chest pain, dyspnea or palpitations were present in 41.7% participants, electrocardiographic abnormalities in 49.6%, NT-proBNP elevation in 7.9%, troponin in 0.7%, and CMR abnormalities in 60.4%. A total of 30.9% participants met criteria for either pericarditis and/or myocarditis: isolated pericarditis was diagnosed in 5.8%, myopericarditis in 7.9%, and isolated myocarditis in 17.3%. Most participants (73.2%) showed altered immune cell counts in blood, particularly decreased eosinophil (27.3%; P<.001) and increased cytotoxic T cell numbers (17.3%; P <.001). Clinically suspected pericarditis was associated (P <.005) with particularly elevated cytotoxic T cells and decreased eosinophil counts, while participants diagnosed with clinically suspected myopericarditis or myocarditis had lower (P <.05) neutrophil counts, natural killer-cells, and plasma cells. CONCLUSIONS: Pericardial and myocardial involvement with clinical stability are frequent after SARS-CoV-2 infection and are associated with specific immune cell profiles.

Predictors of cardiovascular events and all-cause of death in patients with transfusion-dependent myelodysplastic syndrome.

Cardiovascular disease (CVD) involves the second cause of death in low-risk myelodysplastic syndrome (MDS) population. Prospective study to characterise the CVD and to identify predictors for the combined event (CE) cardiovascular event and/or all-cause mortality in transfusion dependent low-risk MDS patients. Thirty-one patients underwent a cardiac assessment including biomarkers and cardiac magnetic resonance (cMR) with parametric sequences (T1, T2 and T2* mapping) and myocardial deformation by feature tracking (FT) and were analysed for clonal hematopoiesis of indeterminate potential mutations. Cardiac assessment revealed high prevalence of unknown structural heart disease (51% cMR pathological findings). After 2·2 [0·44] years follow-up, 35·5% of patients suffered the CE: 16% death, 29% cardiovascular event. At multivariate analysis elevated NT-proBNP ≥ 486pg/ml (HR 96·7; 95%-CI 1·135-8243; P = 0·044), reduced native T1 time < 983ms (HR 44·8; 95%-CI 1·235-1623; P = 0·038) and higher left ventricular global longitudinal strain (LV-GLS) (HR 0·4; 95%-CI 0·196-0·973; P = 0·043) showed an independent prognostic value. These variables, together with the myocardial T2* time < 20ms, showed an additive prognostic value (Log Rank: 12·4; P = 0·001). In conclusion, low-risk MDS patients frequently suffer CVD. NT-proBNP value, native T1 relaxation time and longitudinal strain by FT are independent predictors of poor cardiovascular prognosis, thus, their determination would identify high-risk patients who could benefit from a cardiac treatment and follow-up.

Magnetic Resonance Myocardial Feature Tracking in Transfusion-Dependent Myelodysplastic Syndrome.

BACKGROUND: Myocardial deformation with echocardiography allows early detection of systolic dysfunction and is related to myocardial iron overload (MIO) determined by T2* in hereditary anemias under transfusion support. Our aim was to analyze the diagnostic and prognostic usefulness of magnetic resonance feature tracking (MR-FT) myocardial strain in low-risk myelodysplastic syndromes (LR-MDS) patients. METHODS: Prospective study in transfusion-dependent LR-MDS patients and healthy controls who underwent a cardiac MR-FT. We analyzed the relationships between strain MR-FT and iron overload parameters and its prognostic impact in cardiovascular events and/or death. RESULTS: Thirty-one patients and thirteen controls were included. MIO (T2* < 20 ms) was detected in 9.7% of patients. Left ventricular global longitudinal strain (LV-GLS) by MR-FT was pathological (> -19.3%) in 32.3% of patients. Less negative strain values correlated with lower T2* (R = -0.37, p = 0.033) and native myocardial T1 (R = -0.39, p = 0.031) times. LV-GLS by MR-FT was significantly associated with higher incidence of the combined cardiovascular events and/or all-cause death (p = 0.047), with a cut-off value of -17.7% for predicting them (63% sensitivity and 81% specificity, area under the curve = 0.69). After adjusting analysis including demographic, biomarkers and imaging variables, a higher LV-GLS value by MR-FT remained as predictor of combined event in transfusion-dependent LR-MDS patients (hazard ratio, 0.4; confidence interval, 0.15-0.98; p = 0.045). CONCLUSIONS: Longitudinal myocardial strain by MR-FT in LR-MDS patients is associated to MIO and correlates with adverse events in the follow-up, what could serve as a prognostic tool.

Estratificación, monitorización y control del riesgo cardiovascular en pacientes con cáncer. Documento de consenso de SEC, FEC, SEOM, SEOR, SEHH, SEMG, AEEMT, AEEC y AECC / Stratification and management of cardiovascular risk in cancer patients. A consensus document of the SEC, FEC, SEOM, SEOR, SEHH, SEMG, AEEMT, AEEC, and AECC

El incremento de la supervivencia del enfermo con cáncer, junto con el desarrollo de nuevas terapias antitumorales, han puesto de relieve el impacto negativo que las complicaciones vasculares asociadas con el tratamiento oncohematológico tienen en la salud cardiovascular del paciente con cáncer. El objetivo de este documento de consenso, promovido por el Grupo de Trabajo de Cardio-oncología de la Sociedad Española de Cardiología (SEC) y elaborado conjuntamente con diferentes áreas de conocimiento de la SEC junto con la Sociedad Española de Hematología y Hemoterapia (SEHH), la Sociedad Española de Oncología Médica (SEOM), la Sociedad Española de Oncología Radioterápica (SEOR), la Sociedad Española de Médicos Generales y de Familia (SEMG), la Asociación Española de Especialistas en Medicina del Trabajo (AEEMT), la Asociación Española de Enfermería Cardiovascular (AEEC), la Fundación Española del Corazón (FEC) y la Asociación Española contra el Cáncer (AECC), es proporcionar un enfoque coordinado, multidisciplinar y práctico para la estratificación, la monitorización y el tratamiento del riesgo cardiovascular de los pacientes con cáncer. (AU)

Both cancer treatment and survival have significantly improved, but these advances have highlighted the deleterious effects of vascular complications associated with anticancer therapy. This consensus document aims to provide a coordinated, multidisciplinary and practical approach to the stratification, monitoring and treatment of cardiovascular risk in cancer patients. The document is promoted by the Working Group on Cardio Oncology of the Spanish Society of Cardiology (SEC) and was drafted in collaboration with experts from distinct areas of expertise of the SEC and the Spanish Society of Hematology and Hemotherapy (SEHH), the Spanish Society of Medical Oncology (SEOM), the Spanish Society of Radiation Oncology (SEOR), the Spanish Society of General and Family Physicians (SEMG), the Spanish Association of Specialists in Occupational Medicine (AEEMT), the Spanish Association of Cardiovascular Nursing (AEEC), the Spanish Heart Foundation (FEC), and the Spanish Cancer Association (AECC). (AU)

Stratification and management of cardiovascular risk in cancer patients. A consensus document of the SEC, FEC, SEOM, SEOR, SEHH, SEMG, AEEMT, AEEC, and AECC.

Both cancer treatment and survival have significantly improved, but these advances have highlighted the deleterious effects of vascular complications associated with anticancer therapy. This consensus document aims to provide a coordinated, multidisciplinary and practical approach to the stratification, monitoring and treatment of cardiovascular risk in cancer patients. The document is promoted by the Working Group on Cardio Oncology of the Spanish Society of Cardiology (SEC) and was drafted in collaboration with experts from distinct areas of expertise of the SEC and the Spanish Society of Hematology and Hemotherapy (SEHH), the Spanish Society of Medical Oncology (SEOM), the Spanish Society of Radiation Oncology (SEOR), the Spanish Society of General and Family Physicians (SEMG), the Spanish Association of Specialists in Occupational Medicine (AEEMT), the Spanish Association of Cardiovascular Nursing (AEEC), the Spanish Heart Foundation (FEC), and the Spanish Cancer Association (AECC).