Computational approaches identify a transcriptomic fingerprint of drug-induced structural cardiotoxicity.

Structural cardiotoxicity (SCT) presents a high-impact risk that is poorly tolerated in drug discovery unless significant benefit is anticipated. Therefore, we aimed to improve the mechanistic understanding of SCT. First, we combined machine learning methods with a modified calcium transient assay in human-induced pluripotent stem cell-derived cardiomyocytes to identify nine parameters that could predict SCT. Next, we applied transcriptomic profiling to human cardiac microtissues exposed to structural and non-structural cardiotoxins. Fifty-two genes expressed across the three main cell types in the heart (cardiomyocytes, endothelial cells, and fibroblasts) were prioritised in differential expression and network clustering analyses and could be linked to known mechanisms of SCT. This transcriptomic fingerprint may prove useful for generating strategies to mitigate SCT risk in early drug discovery.

The Clot Thickens: Differential Coagulotoxic and Cardiotoxic Activities of Anguimorpha Lizard Venoms.

Despite their evolutionary novelty, lizard venoms are much less studied in comparison to the intense research on snake venoms. While the venoms of helodermatid lizards have long been assumed to be for defensive purposes, there is increasing evidence of toxic activities more useful for predation than defence (such as paralytic neurotoxicity). This study aimed to ascertain the effects of Heloderma, Lanthanotus, and Varanus lizard venoms on the coagulation and cardiovascular systems. Anticoagulant toxicity was demonstrated for the Varanus species studied, with the venoms prolonging clotting times in human and bird plasma due to the destructive cleavage of fibrinogen. In contrast, thromboelastographic analyses on human and bird plasmas in this study demonstrated a procoagulant bioactivity for Heloderma venoms. A previous study on Heloderma venom using factor-depleted plasmas as a proxy model suggested a procoagulant factor was present that activated either Factor XI or Factor XII, but could not ascertain the precise target. Our activation studies using purified zymogens confirmed FXII activation. Comparisons of neonate and adult H. exasperatum, revealed the neonates to be more potent in the ability to activate FXII, being more similar to the venom of the smaller species H. suspectum than the adult H. exasperatum. This suggests potent FXII activation a basal trait in the genus, present in the small bodied last common ancestor. This also indicates an ontogenetic difference in prey preferences in the larger Heloderma species paralleing the change in venom biochemistry. In addition, as birds lack Factor XII, the ability to clot avian plasma suggested an additional procoagulant site of action, which was revealed to be the activation of Factor VII, with H. horridum being the most potent. This study also examined the effects upon the cardiovascular system, including the liberation of kinins from kininogen, which contributes to hypotension induction. This form of toxicity was previously described for Heloderma venoms, and was revealed in this study was to also be a pathophysiological effect of Lanthanotus and Varanus venoms. This suggests that this toxic activity was present in the venom of the last common ancestor of the anguimorph lizards, which is consistent with kallikrein enzymes being a shared toxin trait. This study therefore uncovered novel actions of anguimorph lizard venoms, not only contributing to the evolutionary biology body of knowledge but also revealing novel activities to mine for drug design lead compounds.

Changes in protein fluxes in skeletal muscle during sequential stages of muscle regeneration after acute injury in male mice.

Changes in protein turnover play an important role in dynamic physiological processes, including skeletal muscle regeneration, which occurs as an essential part of tissue repair after injury. The inability of muscle tissue to recapitulate this regenerative process can lead to the manifestation of clinical symptoms in various musculoskeletal diseases, including muscular dystrophies and pathological atrophy. Here, we employed a workflow that couples deuterated water (2H2O) administration with mass spectrometry (MS) to systematically measure in-vivo protein turnover rates across the muscle proteome in 8-week-old male C57BL6/J mice. We compared the turnover kinetics of over 100 proteins in response to cardiotoxin (CTX) induced muscle damage and regeneration at unique sequential stages along the regeneration timeline. This analysis is compared to gene expression data from mRNA-sequencing (mRNA-seq) from the same tissue. The data reveals quantitative protein flux signatures in response to necrotic damage, in addition to sequential differences in cell proliferation, energy metabolism, and contractile gene expression. Interestingly, the mRNA changes correlated poorly with changes in protein synthesis rates, consistent with post-transcriptional control mechanisms. In summary, the experiments described here reveal the signatures and timing of protein flux changes during skeletal muscle regeneration, as well as the inability of mRNA expression measurements to reveal changes in directly measured protein turnover rates. The results of this work described here provide a better understanding of the muscle regeneration process and could help to identify potential biomarkers or therapeutic targets.

CardioDPi: An explainable deep-learning model for identifying cardiotoxic chemicals targeting hERG, Cav1.2, and Nav1.5 channels.

The cardiotoxic effects of various pollutants have been a growing concern in environmental and material science. These effects encompass arrhythmias, myocardial injury, cardiac insufficiency, and pericardial inflammation. Compounds such as organic solvents and air pollutants disrupt the potassium, sodium, and calcium ion channels cardiac cell membranes, leading to the dysregulation of cardiac function. However, current cardiotoxicity models have disadvantages of incomplete data, ion channels, interpretability issues, and inability of toxic structure visualization. Herein, an interpretable deep-learning model known as CardioDPi was developed, which is capable of discriminating cardiotoxicity induced by the human Ether-à-go-go-related gene (hERG) channel, sodium channel (Na_v1.5), and calcium channel (Ca_v1.5) blockade. External validation yielded promising area under the ROC curve (AUC) values of 0.89, 0.89, and 0.94 for the hERG, Na_v1.5, and Ca_v1.5 channels, respectively. The CardioDPi can be freely accessed on the web server CardioDPipredictor (http://cardiodpi.sapredictor.cn/). Furthermore, the structural characteristics of cardiotoxic compounds were analyzed and structural alerts (SAs) can be extracted using the user-friendly CardioDPi-SAdetector web service (http://cardiosa.sapredictor.cn/). CardioDPi is a valuable tool for identifying cardiotoxic chemicals that are environmental and health risks. Moreover, the SA system provides essential insights for mode-of-action studies concerning cardiotoxic compounds.

Prescripción de fármacos cardiotóxicos en pacientes con enfermedades cardiovasculares / Prescription of cardiotoxic drugs in patients with cardiovascular diseases

Introducción: El uso de fármacos con potencial cardiotóxico para tratar enfermedades no cardiovasculares coexistentes resulta un agravante evitable. Objetivo: Evaluar la prescripción de 5 fármacos cardiotóxicos en pacientes con enfermedades cardiovasculares. Métodos: Se realizó un estudio descriptivo transversal (enmarcado en los estudios de utilización de medicamentos) de marzo a diciembre de 2020 en el Policlínico Santa Cruz (Artemisa, Cuba), en una población de 234 sujetos con enfermedades cardiovasculares que habían sido tratados con domperidona, azitromicina, ciprofloxacina, ibuprofeno y diclofenaco. Las variables estudiadas fueron: sexo, edad, consumo de fármacos cardiotóxicos, motivo de indicación, enfermedades cardiovasculares, forma farmacéutica, dosis diaria, intervalo de las dosis y duración del tratamiento. Se realizó un análisis estadístico descriptivo. Resultados: Los fármacos más prescritos fueron la azitromicina (n= 63), el ibuprofeno (n= 59) y la ciprofloxacina (n= 57). Sus principales motivos de indicación fueron, respectivamente, la neumonía adquirida en la comunidad (38,1 por ciento), las infecciones de piel y tejidos blandos (28,8 por ciento), y las infecciones del tracto urinario (43,8 por ciento). La principal enfermedad cardiovascular fue la hipertensión arterial. Para los 5 fármacos seleccionados se reportó su esquema terapéutico (forma farmacéutica, dosis diaria, intervalo de dosis y duración del tratamiento). Conclusiones: Aunque en todos los casos el motivo de indicación es el adecuado, los fármacos pueden sustituirse por otros de menor riesgo cardiovascular. En su mayoría, los esquemas terapéuticos son correctos, salvo en los casos de la domperidona (duración prolongada) y el diclofenaco (altas dosis)(AU)

Introduction: The use of drugs with cardiotoxic potential to treat coexisting noncardiovascular diseases results in avoidable aggravation. Objective: To assess the prescription of 5 cardiotoxic drugs in patients with cardiovascular disease. Methods: A cross-sectional descriptive study (framed in the studies of drug utilization) was carried out from March to December 2020 in the Policlínico Santa Cruz (Artemisa, Cuba), in a population of 234 subjects with cardiovascular diseases who had been treated with domperidone, azithromycin, ciprofloxacin, ibuprofen and diclofenac. The variables studied were: sex, age, consumption of cardiotoxic drugs, reason for indication, cardiovascular disease, pharmaceutical form, daily dose, dose interval, and duration of treatment. Descriptive statistical analysis was performed. Results: The most prescribed drugs were azithromycin (n= 63), ibuprofen (n= 59) and ciprofloxacin (n= 57). Their main reasons for indication were, respectively, community-acquired pneumonia (38.1 percent), skin and soft tissue infections (28.8 percent), and urinary tract infections (43.8 percent). The main cardiovascular disease was arterial hypertension. For the 5 selected drugs, their therapeutic scheme (pharmaceutical form, daily dose, dose interval and duration of treatment) was reported. Conclusions: Although in all cases the reason for indication was adequate, the drugs can be substituted by others of lower cardiovascular risk. For the most part, the therapeutic regimens are correct, except in the cases of domperidone (prolonged duration) and diclofenac (high doses)(AU)

Is paclitaxel less cardiotoxic in the treatment of breast cancer before or after doxorubicin? / Qual estratégia terapêutica é menos cardiotóxica no tratamento do câncer de mama: uso de paclitaxel antes ou depois da doxorrubicina?

Background: The combination of doxorubicin (DOX) with paclitaxel (PTX) effectively treats breast cancer (BC). However, DOX-associated cardiotoxicity (CTX) is aggravated by the use of PTX. Consensus is lacking about which drug sequence involves the most CTX. Objectives: To evaluate whether DOX followed by PXT or the reverse sequence has the greatest cardiotoxic potential in the treatment of BC. Methods: Prospective study of women with primary BC who received four cycles of DOX and 12 infusions of PTX. Participants were divided into Group 1 (G1; PXT before DOX) and Group 2 (G2; DOX before PXT) at the discretion of the oncologist. CTX was defined as an absolute reduction in left ventricular ejection fraction (LVEF) > 10% to a value <53%. Patients underwentclinical evaluations and echocardiography before treatment (Phase 1) and one year after treatment (Phase 2). Results: Sixty-nine women were evaluated: 19 in G1 and 50 in G2. The groups had similar clinical characteristics. The doses of radiation, DOX, and PTX used were similar. Eight (11.6%) patients developed CTX: two (10.5%) in G1 and six (12.0%) in G2 (p=0.62). The mean LVEF was similar between groups in Phase 1 (G1=65.1±3.5%; G2=65.2±3.9%; p=0.96), with a significant reduction noted after one year in both groups: G1=61.4±8.1% (p=0.021) and G2=60.8±7.6% (p<0,001). Although lower, mean LVEF remained similar between groups after Phase 2 (p=0.79). Conclusions: In women with BC who underwent chemotherapy, the incidence of CTX at the end of the first year of treatment was similar regardless of whether DOX was used before or after PTX. (AU)

Propuesta de protocolo de biopsia cardíaca. Servicio de Anatomía Patológica y Departamento de Cardiología / Proposal of cardiac biopsy protocol. Service of Pathology and Department of Cardiology / Proposta de protocolo de biópsia cardíaca. Serviços de anatomia patológica e departamento de cardiologia

Introducción: Las biopsias endomiocárdicas se utilizan habitualmente para el diagnóstico de muchas patologías que han sido agrupadas por Billigham y Tazelaar en inflamatorias, metabólicas, endocrinas, neuromusculares, tóxicas, procesos linfoproliferativos y el diagnóstico de rechazo a trasplante cardíaco para evaluar la cardiotoxicidad por drogas (antraciclinas, dexoxirubina, cocaína, alcohol, entre otras); también como análisis de miocardio isquémico y su zona limítrofe. Objetivo: Trataremos de evaluar desde un punto de vista cuantitativo, la amplitud de observaciones que se han hecho de la biopsia cardíaca, en un innumerable listado de patologías, desde la MO a la ME (Microscopía óptica a microscopía electrónica). Se intentará graduar los hallazgos morfológicos de la misma, enlazándolos con la topografía y función, teniendo en cuenta, además, los factores bioquímicos y genéticos, organismos vivos, drogas, agentes físicos y procedimientos diagnósticos. Material y Métodos: Para el presente estudio se realizó una recopilación bibliográfica teniendo en cuenta los siguientes criterios: 1) cambios morfológicos sub-celulares-matriz tisular; 2) score de necrosis; 3) score inflamatorio, 4) score de fibrosis; 5) depósitos intracelulares y de pigmentos. Procesamiento de las muestran fijadas en formol buffer (tiempo 2-12 hs.) con coloración de rutina: H/E, Pas, Masson, Zihel Neelsen prolongada, Perls, Azul de Toluidina, Rojo Congo, Orceina. Panel con técnicas de I.H.Q.(BIO SB®).Conclusión: Creemos importante establecer un método que permita hacer una adecuada correlación clínico patológica aplicable a mejorar la interpretación de la injuria tisular, celular y facilitar de este modo, una correcta elección terapéutica.

Introdução: As biópsias endomiocárdicas são utilizadas habitualmente para o diagnóstico de muitas patologias, que foram agrupadas por Billigham e Tazelaar em inflamatórias, metabólicas, endócrinas, neuromusculares, tóxicas, processos linfoproliferativos e o diagnóstico de rejeição a trasplante cardíaco, para avaliar a cardiotoxicidade por drogas (antraciclinas, doxorrubicina, cocaína, álcool, entre outras). Também como análise de miocárdio isquêmico e sua zona limítrofe. Objetivo: Trataremos de avaliar sob o ponto de vista quantitativo, a amplidão de observações feitas da biópsia cardíaca, em uma inumerável lista de patologias, de MO a ME.Tentaremos graduar os descobrimentos morfológicos da mesma, enlaçando-os com a topografia e função, levando em consideração também os fatores bioquímicos e genéticos, organismos vivos, drogas, agentes físicos, procedimentos e diagnósticos.Material e Métodos: para o presente estudo realizou-se uma recopilação bibliográfica considerando os seguintes critérios, 1) alterações morfológicas subcelulares-matriz tissular; 2) escore de necrose; 3) escore inflamatório, 4) escore de fibrose; 5) depósitos intracelulares e de pigmentos. Processamento das amostras fixadas em formol buffer (tempo 2 -12 h.) com coloração de rotina: H/E, Pas, Masson, Zihel Neelsen prolongada, Perls, Azul de Toluidina, Vermelho Congo, Orceína. Painel com técnicas de I.H.Q. (BIO SB®). Conclusão: Achamos importante estabelecer um método que permita fazer uma adequada correlação clínico patológica aplicável a melhorar a interpretação da injúria tisular celular e, deste modo, facilitar uma correta decisão terapêutica.

Introduction: The endomiocárdica biopsies is habitually used for the diagnosis of many pathologies, grouped by Billigham and Tazelaar in inflammatory, metabolic, endocrine, neuromuscular, toxic, processes linfoproliferative and in diagnosis of rejection to heart transplant or to evaluate the cardiotoxicity for drugs (antracicline, dexoxirubine, cocaine, alcohol among other). Also as analysis of cardiac ischemia and their bordering area. Objective: We will try to evaluate from a quantitative point of view, the width of observations that you/they have been made of the heart biopsy in a countless listing of pathologies, from the MO to ME. We will try to graduate the morphologic discoveries of the same one, connecting them with the topography and function, also keeping in mind the biochemical and genetic factors, alive organisms, you drug, physical agents, procedures diagnoses. (Sherman Bloom, pag 329, I Diagnose of Cardiovasc. Pathology).Material and Methods: for the present study was carried out a bibliographical summary keeping in mind the following approaches, 1) changes morphologic subcellular-main tissue; 2) necrosis score; 3) inflammatory score 4) fibrosis score; 5) deposits intracellular and of pigments. Prosecution of they show them fixed in formol buffer (time 2 -12 hs.) with routine coloration: H/E, Pas, Masson, Zihel lingering Neelsen, Perls, Blue of Toluidine, Red Congo, Orceine. Panel with technical of I.H.Q. (BIO SB®). Conclusion: We believe as very important to establish a methodology eich allow an applicable pathological clinical appropriate correlation to improve the interpretation of the tissue insult and to facilitate in this way a correct therapeutic election.

Dosagem de marcadores cardíacos CK-MB e TnIc e eletrólitos no envenenamento experimental por veneno de sapo em cães / Determination of cardiac markers and CK-MB TnIc and electrolyte in experimental poisoning by poison frog in dogs

Dentre os sinais sistêmicos causados pelo envenenamento por veneno de sapo (bufotoxina) em cães, os efeitos cardiotóxicos são um dos mais importantes. O objetivo deste estudo foi avaliar as potenciais alterações no músculo cardíaco de cães envenenados experimentalmente por veneno de sapo e observar as alterações eletrolíticas que podem ocorrer nesse tipo de envenenamento. Utilizaram-se 20 cães divididos em grupo controle (n=5) e grupo envenenado (n=15). O veneno de sapo foi extraído por meio de compressão manual das glândulas paratóides. Após anestesia geral, os cães do grupo controle receberam placebo (solução fisiológica) e os do grupo envenenado uma alíquota do veneno por sonda orogástrica. As colheitas de sangue para dosagem dos marcadores cardíacos foram realizadas seis e 24 horas após o envenenamento. As colheitas de sangue para dosagem dos eletrólitos foram realizadas antes e duas, quatro, seis e 12 horas após o envenenamento. A análise estatística empregada foi o teste não-paramétrico de Mann-Withney (P<0,05). Os cães envenenados por veneno de sapo apresentaram elevação dos níveis dos marcadores cardíacos CK-MB e TnIc, confirmando a cardiotoxicidade do veneno. Hipocalemia e hipocalcemia foram também observadas nos cães envenenados.

Among the systemic signs of toad venom (bufotoxin) poisoning in dogs, the cardiotoxic effects are one of the most important. Thus, the objective of this experiment was to evaluate potential changes in the cardiac muscle in dogs poisoned experimentally by toad venom and to observe the eletrolyte alterations which may occur in this condition. Twenty dogs divided into control group (n=5) and poisoned group (n=15) were utilized. The toad venom was extracted by manual compression of the paratoidic glands. After general anesthesia, dogs in the control group received placebo and dogs in the poisoned group received the venom by orogastric catheter. Samples for dosage were collected 6 hours and 24 hours after poisoning and 0, 2, 4, 6 and 12 hours after poisoning for electrolytes dosage. The Man-Withney test was used for statistical analysis (P<0.05). The poisoned dogs showed (saline) elevated levels of cardiac markers CK-MB and TnIc, confirming the cardiotoxic effect of the bufotoxin. Hypokalemia and hypocalcemia were also observed.

Cardiotoxicidade e quimioterapia / Cardiotoxicity and chemotherapy

JUSTIFICATIVA E OBJETIVOS: Muitos esquemas de quimioterapia são relacionados a efeitos cardiotóxicos, particularmente no seguimento em longo prazo. A avaliação cardiológica é necessária, mas o treinamento específico neste campo em particular é escasso. O objetivo deste estudo foi apresentar os mecanismos de ação e efeitos adversos, principalmente cardíacos, de diferentes fármacos usados frequentemente em oncologia. CONTEÚDO: Recomendações gerais para prevenção, diagnóstico precoce e estratégias terapêuticas serão discutidas. CONCLUSÃO: Pesquisas adicionais são necessárias para desenvolver novas estratégias de prevenção e tratamento das principais complicações.