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ABSTRACT: Unhealthy lifestyles have placed a significant burden on individuals' cardiovascular health. Anthocyanins are water-soluble flavonoid pigments found in a wide array of common foods and fruits. Anthocyanins have the potential to contribute to the prevention and treatment of cardiovascular disease by improving lipid profiles and vascular function, reducing blood glucose levels and blood pressure, and inhibiting inflammation. These actions have been demonstrated in numerous clinical and preclinical studies. At the cellular and molecular level, anthocyanins and their metabolites could protect endothelial cells from senescence, apoptosis, and inflammation by activating the phosphoinositide 3-kinase/protein kinase B/endothelial nitric oxide synthases, silent information regulator 1 (SIRT1), or nuclear factor erythroid2-related factor 2 pathways and inhibiting the nuclear factor kappa B, Bax, or P38 mitogen-activated protein kinase pathways. Furthermore, anthocyanins prevent vascular smooth muscle cell from platelet-derived growth factor -induced or tumor necrosis factor-α-induced proliferation and migration by inhibiting the focal adhesion kinase and extracellular regulated protein kinases signaling pathways. Anthocyanins could also attenuate vascular inflammation by reducing the formation of oxidized lipids, preventing leukocyte adhesion and infiltration of the vessel wall, and macrophage phagocytosis of deposited lipids through reducing the expression of cluster of differentiation 36 and increasing the expression of ATP-binding cassette subfamily A member 1 and ATP-binding cassette subfamily G member 1. At the same time, anthocyanins could lower the risk of thrombosis by inhibiting platelet activation and aggregation through down-regulating P-selectin, transforming growth factor-1, and CD40L. Thus, the development of anthocyanin-based supplements or derivative drugs could provide new therapeutic approaches to the prevention and treatment of vascular diseases.
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Antocianinas , Antiinflamatorios , Enfermedades Cardiovasculares , Transducción de Señal , Humanos , Antocianinas/farmacología , Antocianinas/uso terapéutico , Animales , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Fármacos Cardiovasculares/uso terapéutico , Fármacos Cardiovasculares/farmacologíaRESUMEN
Global health concerns persist due to the multifaceted nature of heart diseases, which include lifestyle choices, genetic predispositions, and emerging post-COVID complications like myocarditis and pericarditis. This broadens the spectrum of cardiovascular ailments to encompass conditions such as coronary artery disease, heart failure, arrhythmias, and valvular disorders. Timely interventions, including lifestyle modifications and regular medications such as antiplatelets, beta-blockers, angiotensin-converting enzyme inhibitors, antiarrhythmics, and vasodilators, are pivotal in managing these conditions. In drug development, topological indices play a critical role, offering cost-effective computational and predictive tools. This study explores modified reverse degree topological indices, highlighting their adjustable parameters that actively shape the degree sequences of molecular drugs. This feature makes the approach suitable for datasets with unique physicochemical properties, distinguishing it from traditional methods that rely on fixed degree approaches. In our investigation, we examine a dataset of 30 drug compounds, including sotagliflozin, dapagliflozin, dobutamine, etc., which are used in the treatment of cardiovascular diseases. Through the structural analysis, we utilize modified reverse degree indices to develop quantitative structure-property relationship (QSPR) models, aiming to unveil essential understandings of their characteristics for drug development. Furthermore, we compare our QSPR models against the degree-based models, clearly demonstrating the superior effectiveness inherent in our proposed method.
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Fármacos Cardiovasculares , Relación Estructura-Actividad Cuantitativa , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/farmacología , Fenómenos Químicos , HumanosRESUMEN
Recent breakthroughs in human genetics and in information technologies have markedly expanded our understanding at the molecular level of the response to drugs, i.e., pharmacogenetics (PGx), across therapy areas. This review is restricted to PGx for cardiovascular (CV) drugs. First, we examined the PGx information in the labels approved by regulatory agencies in Europe, Japan, and North America and related recommendations from expert panels. Out of 221 marketed CV drugs, 36 had PGx information in their labels approved by one or more agencies. The level of annotations and recommendations varied markedly between agencies and expert panels. Clopidogrel is the only CV drug with consistent PGx recommendation (i.e., "actionable"). This situation prompted us to dissect the steps from discovery of a PGx association to clinical translation. We found 101 genome-wide association studies that investigated the response to CV drugs or drug classes. These studies reported significant associations for 48 PGx traits mapping to 306 genes. Six of these 306 genes are mentioned in the corresponding PGx labels or recommendations for CV drugs. Genomic analyses also highlighted the wide between-population differences in risk allele frequencies and the individual load of actionable PGx variants. Given the high attrition rate and the long road to clinical translation, additional work is warranted to identify and validate PGx variants for more CV drugs across diverse populations and to demonstrate the utility of PGx testing. To that end, pre-emptive PGx combining genomic profiling with electronic medical records opens unprecedented opportunities to improve healthcare, for CV diseases and beyond. SIGNIFICANCE STATEMENT: Despite spectacular breakthroughs in human molecular genetics and information technologies, consistent evidence supporting PGx testing in the cardiovascular area is limited to a few drugs. Additional work is warranted to discover and validate new PGx markers and demonstrate their utility. Pre-emptive PGx combining genomic profiling with electronic medical records opens unprecedented opportunities to improve healthcare, for CV diseases and beyond.
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Fármacos Cardiovasculares , Enfermedades Cardiovasculares , Estudio de Asociación del Genoma Completo , Farmacogenética , Humanos , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/genética , Farmacogenética/métodos , Fármacos Cardiovasculares/uso terapéutico , Fármacos Cardiovasculares/farmacología , Estudio de Asociación del Genoma Completo/métodosRESUMEN
Cardiovascular disease (CVD) is one of the leading causes of death worldwide, and its internal medicine treatments are mostly single/few-target chemical drugs. Long-term use of cardiovascular drugs for complex chronic diseases may lead to serious adverse drug reactions. Traditional Chinese medicine (TCM) has been used to treat heart diseases for thousands of years, helping to ease symptoms and prolong patients' lifespan in ancient China. TCM has the pharmacological characteristics of being multi-component, multi-target and multi-pathway, and the combined application of TCM and western medicine can be an alternative treatment for chronic and intractable diseases with high safety levels. This article reviewed the interactions and synergistic effect of TCM and cardiovascular drugs. In the treatment of arrhythmia, TCM combined with western medicine can more effectively regulate patients' cardiac electrophysiological characteristics, reduce the onsets of premature beat and heart rate variability, lower the levels of QT interval dispersion and serum inflammatory factors, alleviate clinical symptoms and TCM syndromes, and improve cardiac function with good safety levels. In the treatment of hypertension, integrative medicine can more steadily reduce blood pressure and levels of serum inflammatory factors and improve hemodynamic indexes and exercise tolerance, and it has high safety levels, especially for pregnant women. As for coronary heart disease, the combination of TCM and antiplatelet drugs may promote the absorption of each other. However, the interaction risk of pharmacokinetic mechanism between them is low at the dose of efficacy. Integrative medicine can reduce the level of N-terminal pro-brain natriuretic peptide, delay cardiac remodeling and improve heart function and quality of life for patients with heart failure with high safety levels.
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Fármacos Cardiovasculares , Enfermedades Cardiovasculares , Medicamentos Herbarios Chinos , Medicina Tradicional China , Humanos , Medicina Tradicional China/métodos , Fármacos Cardiovasculares/farmacocinética , Fármacos Cardiovasculares/efectos adversos , Fármacos Cardiovasculares/farmacología , Medicamentos Herbarios Chinos/efectos adversos , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/farmacocinética , Enfermedades Cardiovasculares/tratamiento farmacológico , Interacciones de Hierba-Droga , Animales , Interacciones FarmacológicasRESUMEN
Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have emerged as a promising tool for studying cardiac physiology and drug responses. However, their use is largely limited by an immature phenotype and lack of high-throughput analytical methodology. In this study, we developed a high-throughput testing platform utilizing hPSC-CMs to assess the cardiotoxicity and effectiveness of drugs. Following an optimized differentiation and maturation protocol, hPSC-CMs exhibited mature CM morphology, phenotype, and functionality, making them suitable for drug testing applications. We monitored intracellular calcium dynamics using calcium imaging techniques to measure spontaneous calcium oscillations in hPSC-CMs in the presence or absence of test compounds. For the cardiotoxicity test, hPSC-CMs were treated with various compounds, and calcium flux was measured to evaluate their effects on calcium dynamics. We found that cardiotoxic drugs withdrawn due to adverse drug reactions, including encainide, mibefradil, and cetirizine, exhibited toxicity in hPSC-CMs but not in HEK293-hERG cells. Additionally, in the effectiveness test, hPSC-CMs were exposed to ATX-II, a sodium current inducer for mimicking long QT syndrome type 3, followed by exposure to test compounds. The observed changes in calcium dynamics following drug exposure demonstrated the utility of hPSC-CMs as a versatile model system for assessing both cardiotoxicity and drug efficacy. Overall, our findings highlight the potential of hPSC-CMs in advancing drug discovery and development, which offer a physiologically relevant platform for the preclinical screening of novel therapeutics.
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Diferenciación Celular , Evaluación Preclínica de Medicamentos , Miocitos Cardíacos , Células Madre Pluripotentes , Humanos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/citología , Evaluación Preclínica de Medicamentos/métodos , Diferenciación Celular/efectos de los fármacos , Células Madre Pluripotentes/efectos de los fármacos , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/metabolismo , Fármacos Cardiovasculares/farmacología , Calcio/metabolismo , Cardiotoxicidad , Ensayos Analíticos de Alto Rendimiento/métodos , Células HEK293 , Señalización del Calcio/efectos de los fármacosRESUMEN
Quadruple therapy is effective for patients with heart failure with reduced ejection fraction, providing significant clinical benefits, including reduced mortality. Clinicians are now in an era focused on how to initiate and titrate quadrable therapy in the early phase of the disease trajectory, including during heart failure hospitalization. However, patients with heart failure with reduced ejection fraction still face a significant "residual risk" of mortality and heart failure hospitalization. Despite the effective implementation of quadruple therapy, high mortality and rehospitalization rates persist in heart failure with reduced ejection fraction, and many patients cannot maximize therapy due to side effects such as hypotension and renal dysfunction. In this context, ivabradine, vericiguat, and omecamtiv mecarbil may have adjunct roles in addition to quadruple therapy (note that omecamtiv mecarbil is not currently approved for clinical use). However, the contemporary use of ivabradine and vericiguat is relatively low globally, likely due in part to the under-recognition of the role of these therapies as well as costs. This review offers clinicians a straightforward guide for bedside evaluation of potential candidates for these medications. Quadruple therapy, with strong evidence to reduce mortality, should always be prioritized for implementation. As second-line therapies, ivabradine could be considered for patients who cannot achieve optimal heart rate control (≥ 70 bpm at rest) despite maximally tolerated beta-blocker dosing. Vericiguat could be considered for high-risk patients who have recently experienced worsening heart failure events despite being on quadrable therapy, but they should not have N-terminal pro-B-type natriuretic peptide levels exceeding 8000 pg/mL. In the future, omecamtiv mecarbil may be considered for severe heart failure (New York Heart Association class III to IV, ejection fraction ≤ 30%, and heart failure hospitalization within 6 months) when current quadrable therapy is limited, although this is still hypothesis-generating and requires further investigation before its approval.
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Quimioterapia Combinada , Insuficiencia Cardíaca , Ivabradina , Volumen Sistólico , Humanos , Ivabradina/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Volumen Sistólico/efectos de los fármacos , Volumen Sistólico/fisiología , Fármacos Cardiovasculares/uso terapéutico , Fármacos Cardiovasculares/farmacología , Pirimidinas/uso terapéutico , Urea/análogos & derivados , Urea/uso terapéutico , Benzazepinas/uso terapéutico , Benzazepinas/farmacología , Compuestos Heterocíclicos con 2 AnillosRESUMEN
Chronic wound treatments pose a challenge for healthcare worldwide, particularly for the people in developed countries. Chronic wounds significantly impair quality of life, especially among the elderly. Current research is devoted to novel approaches to wound care by repositioning cardiovascular agents for topical wound treatment. The emerging field of medicinal products' repurposing, which involves redirecting existing pharmaceuticals to new therapeutic uses, is a promising strategy. Recent studies suggest that medicinal products such as sartans, beta-blockers, and statins have unexplored potential, exhibiting multifaceted pharmacological properties that extend beyond their primary indications. The purpose of this review is to analyze the current state of knowledge on the repositioning of cardiovascular agents' use and their molecular mechanisms in the context of wound healing.
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Fármacos Cardiovasculares , Reposicionamiento de Medicamentos , Cicatrización de Heridas , Humanos , Cicatrización de Heridas/efectos de los fármacos , Fármacos Cardiovasculares/farmacología , Fármacos Cardiovasculares/uso terapéutico , AnimalesRESUMEN
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. A total of 28 new molecular entities (NMEs) were approved by the U.S. Food and Drug Administration (FDA) for the treatment of cardiovascular diseases from 2011 to 2023. Approximately 25 % of the medications were sanctioned for the management of diverse vascular disorders. The other major therapeutic areas of focus included antilipemic agents (15 %), blood pressure disease (11 %), heart failure, hyperkalemia, and cardiomyopathy (7-8% each). Among all the approved drugs, there are a total of 22 new chemical entities (NCEs), including inhibitors, agonists, polymers, and inorganic compounds. In addition to NCEs, 6 biological agents (BLAs), including monoclonal antibodies, small interfering RNAs (siRNAs), and antisense oligonucleotides, have also obtained approval for the treatment of cardiovascular diseases. From this perspective, approved NCEs are itemized and discussed based on their disease, targets, chemical classes, major drug metabolites, and biochemical and pharmacological properties. Systematic analysis has been conducted to examine the binding modes of these approved drugs with their targets using cocrystal structure information or docking studies to provide valuable insights for designing next-generation agents. Furthermore, the synthetic approaches employed in the creation of these drug molecules have been emphasized, aiming to inspire the development of novel, efficient, and applicable synthetic methodologies. Generally, the primary objective of this review is to provide a comprehensive examination of the clinical applications, pharmacology, binding modes, and synthetic methodologies employed in small-molecule drugs approved for treating CVD. This will facilitate the development of more potent and innovative therapeutics for effectively managing cardiovascular diseases.
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Fármacos Cardiovasculares , Enfermedades Cardiovasculares , Química Farmacéutica , Aprobación de Drogas , United States Food and Drug Administration , Humanos , Estados Unidos , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/farmacología , Fármacos Cardiovasculares/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológicoRESUMEN
OBJECTIVE: Aim: To investigate the effect of ivabradine on the hemodynamics and contractility of the myocardium and the features of NT-pro-BNP production in patients with stable ischemic heart disease after endovascular revascularization of the myocardium depending on the number of affected coronary arteries during 12 months of therapy. PATIENTS AND METHODS: Materials and Methods: The object of the study was 120 patients with stable coronary artery disease: angina pectoris of functional class III with heart failure IIA FC III with preserved and moderately reduced ejection fraction of the left ventricle, who underwent coronary artery stenting. The examined patients were randomized according to the number of affected coronary vessels and the method of treatment. RESULTS: Results: Ivabradine in patients with stable ischemic heart disease after 12 months of therapy had a significant beneficial effect on the structural and functional parameters of the myocardium (contributed to the reverse remodeling of the left ventricle), which did not depend on the number of stented coronary arteries (p<0.05). In patients with stented one coronary artery, all structural and functional indicators of the heart after 12 months of treatment reached the values of practically healthy individuals from the control group. The use of ivabradine in patients with stable ischemic heart disease with heart failure with preserved and intermediate ejection fraction of the left ventricle after coronary stenting made it possible to ensure the correction of a number of clinical and pathogenetic links of the disease, which generally contributed to the improvement of metric and volumetric parameters of the heart. CONCLUSION: Conclusions: Ivabradine made it possible to significantly increase the effectiveness of standard therapy, which was manifested by a faster recovery of the geometry and contractility of the left ventricle. Therefore, the use of ivabradine along with standard therapy was appropriate for such a contingent of patients. The management of patients with stable coronary heart disease should combine adequate (surgical and pharmacological) treatment of the underlying disease, further individual medication correction of symptoms and circulatory disorders inherent in coronary heart disease and heart failure.
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Ivabradina , Péptido Natriurético Encefálico , Fragmentos de Péptidos , Humanos , Ivabradina/uso terapéutico , Ivabradina/farmacología , Masculino , Péptido Natriurético Encefálico/sangre , Péptido Natriurético Encefálico/metabolismo , Femenino , Persona de Mediana Edad , Miocardio/metabolismo , Stents , Anciano , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Resultado del Tratamiento , Benzazepinas/uso terapéutico , Benzazepinas/farmacología , Fármacos Cardiovasculares/uso terapéutico , Fármacos Cardiovasculares/farmacologíaRESUMEN
Cardiovascular diseases (CVDs) have a complex pathogenesis and pose a major threat to human health. Cardiomyocytes have a low regenerative capacity, and their death is a key factor in the morbidity and mortality of many CVDs. Cardiomyocyte death can be regulated by specific signaling pathways known as programmed cell death (PCD), including apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis, etc. Abnormalities in PCD can lead to the development of a variety of cardiovascular diseases, and there are also molecular-level interconnections between different PCD pathways under the same cardiovascular disease model. Currently, the link between programmed cell death in cardiomyocytes and cardiovascular disease is not fully understood. This review describes the molecular mechanisms of programmed death and the impact of cardiomyocyte death on cardiovascular disease development. Emphasis is placed on a summary of drugs and potential therapeutic approaches that can be used to treat cardiovascular disease by targeting and blocking programmed cell death in cardiomyocytes.
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Enfermedades Cardiovasculares , Miocitos Cardíacos , Humanos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Miocitos Cardíacos/efectos de los fármacos , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/patología , Animales , Apoptosis/efectos de los fármacos , Transducción de Señal , Fármacos Cardiovasculares/uso terapéutico , Fármacos Cardiovasculares/farmacologíaRESUMEN
The global incidence of cardiac diseases is increasing, imposing a substantial socioeconomic burden on healthcare systems. The pathogenesis of cardiovascular disease is complex and not fully understood, and the physiological function of the heart is inextricably linked to well-regulated cardiac muscle movement. Myosin light chain kinase (MLCK) is essential for myocardial contraction and diastole, cardiac electrophysiological homeostasis, vasoconstriction of vascular nerves and blood pressure regulation. In this sense, MLCK appears to be an attractive therapeutic target for cardiac diseases. MLCK participates in myocardial cell movement and migration through diverse pathways, including regulation of calcium homeostasis, activation of myosin light chain phosphorylation, and stimulation of vascular smooth muscle cell contraction or relaxation. Recently, phosphorylation of myosin light chains has been shown to be closely associated with the activation of myocardial exercise signaling, and MLCK mediates systolic and diastolic functions of the heart through the interaction of myosin thick filaments and actin thin filaments. It works by upholding the integrity of the cytoskeleton, modifying the conformation of the myosin head, and modulating innervation. MLCK governs vasoconstriction and diastolic function and is associated with the activation of adrenergic and sympathetic nervous systems, extracellular transport, endothelial permeability, and the regulation of nitric oxide and angiotensin II. Additionally, MLCK plays a crucial role in the process of cardiac aging. Multiple natural products/phytochemicals and chemical compounds, such as quercetin, cyclosporin, and ML-7 hydrochloride, have been shown to regulate cardiomyocyte MLCK. The MLCK-modifying capacity of these compounds should be considered in designing novel therapeutic agents. This review summarizes the mechanism of action of MLCK in the cardiovascular system and the therapeutic potential of reported chemical compounds in cardiac diseases by modifying MLCK processes.
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Quinasa de Cadena Ligera de Miosina , Transducción de Señal , Humanos , Quinasa de Cadena Ligera de Miosina/metabolismo , Animales , Transducción de Señal/efectos de los fármacos , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/enzimología , Fármacos Cardiovasculares/uso terapéutico , Fármacos Cardiovasculares/farmacologíaRESUMEN
BACKGROUND: Sex differences (SDs) in pharmacology of cardiovascular (CV) drugs have been described previously; however, paradoxically, there are scarce recommendations in therapy based on these differences. It is of utmost importance to identify whether these SDs determine a modified clinical response and the potential practical implications for this, to provide a base for personalized medicine. AREA OF UNCERTAINTY: The aim of this article was to outline the most important pharmacological drivers of cardiovascular drugs that differ between women and men, along with their implications and challenges in clinical practice. DATA SOURCES: A detailed assessment of English-written resources reflecting SDs impact in CV drug pharmacology was performed using PubMed and Embase databases. RESULTS: Despite large variations in CV drug pharmacokinetics and pharmacodynamics in individuals, correcting for height, weight, surface area, and body composition compensate for most "sex-dependent" differences. In addition, individual, cultural, and social factors significantly impact disease management in women versus men. Gender-biased prescribing patterns and gender-dependent adherence to therapy also influence outcomes. The development of sex-specific guidelines requires that they should reflect the SDs implications for the management of a disease and that the evidence should be carefully evaluated as to whether there is an adequate representation of both sexes and whether sex-disaggregated data are reported. CONCLUSIONS: Pharmacological drivers are under the influence of an impressive number of differences between women and men. However, to establish their significance in clinical practice, an adequate representation of women in studies and the reporting of distinct results is mandatory.
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Fármacos Cardiovasculares , Enfermedades Cardiovasculares , Humanos , Femenino , Masculino , Enfermedades Cardiovasculares/tratamiento farmacológico , Factores Sexuales , Fármacos Cardiovasculares/uso terapéutico , Fármacos Cardiovasculares/farmacología , Caracteres Sexuales , Pautas de la Práctica en Medicina/estadística & datos numéricos , Pautas de la Práctica en Medicina/normasRESUMEN
BACKGROUND: Acute decompensated heart failure (ADHF) presents a significant global health challenge, with high morbidity, mortality, and healthcare costs. The current therapeutic options for ADHF are limited. Ivabradine, a selective inhibitor of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, has emerged as a potential therapy for ADHF by reducing the heart rate (HR) without negatively affecting myocardial contractility. However, the evidence regarding the efficacy and safety of ivabradine in patients with ADHF is limited and inconsistent. This meta-analysis aimed to evaluate the efficacy and safety of ivabradine for ADHF based on observational studies. METHODS: A systematic literature search was conducted following PRISMA guidelines to identify relevant observational studies comparing ivabradine with placebo in adult patients with ADHF. Data were pooled using a random-effects model, and heterogeneity was assessed. The risk of bias was evaluated using the Newcastle-Ottawa Scale. RESULTS: Four observational studies comprising a total of 12034 patients. Meta-analysis revealed that ivabradine significantly reduced all-cause mortality (RR: 0.66, 95 % CI: 0.49-0.89, p < 0.01) and resting HR (MD: -12.54, 95 % CI: -21.66-3.42, p < 0.01) compared to placebo. However, no significant differences were observed in cardiovascular mortality, hospital readmission for all causes, changes in LVEF, or changes in LVEDD. Sensitivity and publication bias assessments were conducted for each outcome. CONCLUSION: Ivabradine may be beneficial for reducing mortality and HR in patients with ADHF. However, its impact on other clinical outcomes such as cardiovascular mortality, hospital readmission, and cardiac function remains inconclusive. Further research, particularly well-designed RCTs with larger sample sizes and longer follow-up durations, are warranted.
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Fármacos Cardiovasculares , Insuficiencia Cardíaca , Frecuencia Cardíaca , Ivabradina , Humanos , Enfermedad Aguda , Fármacos Cardiovasculares/uso terapéutico , Fármacos Cardiovasculares/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/mortalidad , Frecuencia Cardíaca/efectos de los fármacos , Ivabradina/uso terapéutico , Resultado del TratamientoAsunto(s)
Angiografía Coronaria , Enfermedad Hepática en Estado Terminal , Frecuencia Cardíaca , Ivabradina , Ivabradina/uso terapéutico , Ivabradina/farmacología , Humanos , Frecuencia Cardíaca/efectos de los fármacos , Enfermedad Hepática en Estado Terminal/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Angiografía por Tomografía Computarizada , Femenino , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Fármacos Cardiovasculares/uso terapéutico , Fármacos Cardiovasculares/farmacología , Benzazepinas/uso terapéutico , Benzazepinas/farmacología , AncianoRESUMEN
OBJECTIVES: Flavonoids are polyphenolic compounds found in a wide range of foods, including fruits, vegetables, tea plants, and other natural products. They have been mainly classified as flavanols, flavonols, flavones, isoflavones, flavanones, and flavanonols. In this comprehensive review, we will discuss preclinical pieces of evidence on the potential of flavonoids for the prevention/treatment of myocardial ischemia-reperfusion (IR) injury. KEY FINDINGS: In-vitro and in-vivo studies have shown that flavonoids play an important role in preventing ischemic heart disease (IHD). They possess strong anti-oxidant, anti-inflammatory, anti-bacterial, anti-thrombotic, anti-apoptotic, and anti-carcinogenic activities. In addition, at a molecular level, flavonoids also modulate various pathways like MAPK, NFκB etc. to confer beneficial effects. SUMMARY: The current review of flavonoids in myocardial ischemia-reperfusion injury furnishes updated information that could drive future research. The in-vitro and in-vivo experiments have demonstrated various favourable pharmacological properties of flavonoids. This review provides valuable information to conduct clinical studies, validating the safety aspects of flavonoids in the clinical domain.
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Flavonoides , Daño por Reperfusión Miocárdica , Humanos , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/fisiopatología , Flavonoides/farmacología , Animales , Transducción de Señal/efectos de los fármacos , Antioxidantes/farmacología , Antiinflamatorios/farmacología , Miocardio/metabolismo , Miocardio/patología , Apoptosis/efectos de los fármacos , Fármacos Cardiovasculares/farmacología , Fármacos Cardiovasculares/uso terapéuticoRESUMEN
BACKGROUND: One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility. METHODS: In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results. The primary end point was the change from baseline to week 24 in the peak oxygen uptake as assessed by cardiopulmonary exercise testing. The 10 prespecified secondary end points (tested hierarchically) were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), improvement in the New York Heart Association (NYHA) functional class, change in the pressure gradient after the Valsalva maneuver, occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver, and duration of eligibility for septal reduction therapy (all assessed at week 24); change in the KCCQ-CSS, improvement in the NYHA functional class, change in the pressure gradient after the Valsalva maneuver, and occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver (all assessed at week 12); and change in the total workload as assessed by cardiopulmonary exercise testing at week 24. RESULTS: A total of 282 patients underwent randomization: 142 to the aficamten group and 140 to the placebo group. The mean age was 59.1 years, 59.2% were men, the baseline mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8%. At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P<0.001). The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo. The incidence of adverse events appeared to be similar in the two groups. CONCLUSIONS: Among patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo. (Funded by Cytokinetics; SEQUOIA-HCM ClinicalTrials.gov number, NCT05186818.).
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Cardiomiopatía Hipertrófica , Fármacos Cardiovasculares , Prueba de Esfuerzo , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Bencilaminas , Miosinas Cardíacas/antagonistas & inhibidores , Cardiomiopatía Hipertrófica/tratamiento farmacológico , Cardiomiopatía Hipertrófica/fisiopatología , Método Doble Ciego , Tolerancia al Ejercicio/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Uracilo/análogos & derivados , Maniobra de Valsalva , Obstrucción del Flujo Ventricular Externo/tratamiento farmacológico , Obstrucción del Flujo Ventricular Externo/fisiopatología , Obstrucción del Flujo Ventricular Externo/etiología , Fármacos Cardiovasculares/farmacología , Fármacos Cardiovasculares/uso terapéutico , Contracción Miocárdica/efectos de los fármacos , Contracción Miocárdica/fisiología , Administración OralRESUMEN
Mast cells are tissue-resident immune cells strategically located in different compartments of the normal human heart (the myocardium, pericardium, aortic valve, and close to nerves) as well as in atherosclerotic plaques. Cardiac mast cells produce a broad spectrum of vasoactive and proinflammatory mediators, which have potential roles in inflammation, angiogenesis, lymphangiogenesis, tissue remodelling, and fibrosis. Mast cells release preformed mediators (e.g. histamine, tryptase, and chymase) and de novo synthesized mediators (e.g. cysteinyl leukotriene C4 and prostaglandin D2), as well as cytokines and chemokines, which can activate different resident immune cells (e.g. macrophages) and structural cells (e.g. fibroblasts and endothelial cells) in the human heart and aorta. The transcriptional profiles of various mast cell populations highlight their potential heterogeneity and distinct gene and proteome expression. Mast cell plasticity and heterogeneity enable these cells the potential for performing different, even opposite, functions in response to changing tissue contexts. Human cardiac mast cells display significant differences compared with mast cells isolated from other organs. These characteristics make cardiac mast cells intriguing, given their dichotomous potential roles of inducing or protecting against cardiovascular diseases. Identification of cardiac mast cell subpopulations represents a prerequisite for understanding their potential multifaceted roles in health and disease. Several new drugs specifically targeting human mast cell activation are under development or in clinical trials. Mast cells and/or their subpopulations can potentially represent novel therapeutic targets for cardiovascular disorders.
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Enfermedades Cardiovasculares , Mastocitos , Humanos , Mastocitos/metabolismo , Mastocitos/inmunología , Mastocitos/efectos de los fármacos , Mastocitos/patología , Animales , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/patología , Enfermedades Cardiovasculares/inmunología , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/genética , Transducción de Señal , Fenotipo , Miocardio/patología , Miocardio/metabolismo , Miocardio/inmunología , Fármacos Cardiovasculares/uso terapéutico , Fármacos Cardiovasculares/farmacología , Plasticidad de la Célula/efectos de los fármacos , Mediadores de Inflamación/metabolismoRESUMEN
Cardiovascular drugs (CVDs) are agents working on the heart and the vascular system to treat many cardiovascular disorders. Such disorders represent the leading cause for morbidity and mortality worldwide. The treatment regimen includes different administered drugs on chronic basis. The cumulative drugs in human body coincides with exposure to electromagnetic radiations from different sources leading to drug-radiation interaction that may lead to drug photosensitization. Such photosensitization may lead to mutagenesis, cancer, and cell death due to molecular damage to DNA. This work involves the application of two bioluminescent genosensors; Terbium chloride and EvaGreen are utilized to investigate potential DNA damage caused by frequently used CVDs following UVA irradiation. A variety of CVDs are investigated. Ten drugs; Amiloride, Atorvastatin, Captopril, Enalapril, Felodipine, Hydrochlorothiazide, Indapamide, Losartan, Triamterene and Valsartan are studied. The study's findings showed that such drugs induced DNA damage following UVA irradiation. The induced DNA damage altered the fluorescence of terbium chloride and EvaGreen genosensors, proportionally. The results are confirmed by viscosity measurements reflecting the possible intercalation of CVDs with DNA. Also, the work is applied on calf thymus DNA to mimic the actual biological variability. The demonstrated bioluminescent genosensors provide automatic, simple and low-cost methods for assessing DNA-drug interactions.
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Fármacos Cardiovasculares , Daño del ADN , ADN , Daño del ADN/efectos de los fármacos , Fármacos Cardiovasculares/farmacología , ADN/efectos de los fármacos , Rayos Ultravioleta , Animales , Colorantes Fluorescentes/química , Humanos , Técnicas Biosensibles/métodos , Viscosidad , Bovinos , Terbio/químicaRESUMEN
The development of new molecules for the treatment of calmodulin related cardiovascular or neurodegenerative diseases is an interesting goal. In this work, we introduce a novel strategy with four main steps: (1) chemical synthesis of target molecules, (2) Förster Resonance Energy Transfer (FRET) biosensor development and in vitro biological assay of new derivatives, (3) Cheminformatics models development and in vivo activity prediction, and (4) Docking studies. This strategy is illustrated with a case study. Firstly, a series of 4-substituted Riluzole derivatives 1-3 were synthetized through a strategy that involves the construction of the 4-bromoriluzole framework and its further functionalization via palladium catalysis or organolithium chemistry. Next, a FRET biosensor for monitoring Ca2+-dependent CaM-ligands interactions has been developed and used for the in vitro assay of Riluzole derivatives. In particular, the best inhibition (80%) was observed for 4-methoxyphenylriluzole 2b. Besides, we trained and validated a new Networks Invariant, Information Fusion, Perturbation Theory, and Machine Learning (NIFPTML) model for predicting probability profiles of in vivo biological activity parameters in different regions of the brain. Next, we used this model to predict the in vivo activity of the compounds experimentally studied in vitro. Last, docking study conducted on Riluzole and its derivatives has provided valuable insights into their binding conformations with the target protein, involving calmodulin and the SK4 channel. This new combined strategy may be useful to reduce assay costs (animals, materials, time, and human resources) in the drug discovery process of calmodulin inhibitors.
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Calmodulina , Fármacos Cardiovasculares , Simulación del Acoplamiento Molecular , Fármacos Neuroprotectores , Riluzol , Riluzol/análogos & derivados , Riluzol/síntesis química , Riluzol/química , Riluzol/farmacología , Calmodulina/antagonistas & inhibidores , Calmodulina/química , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Fármacos Cardiovasculares/síntesis química , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/farmacología , Desarrollo de Medicamentos , Simulación del Acoplamiento Molecular/métodos , Técnicas Biosensibles , Aprendizaje Automático , Humanos , Animales , Línea Celular , Transferencia Resonante de Energía de Fluorescencia/métodos , Encéfalo/efectos de los fármacos , Ligandos , Conformación ProteicaRESUMEN
ABSTRACT: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally. CVD and kidney disease are closely related, with kidney injury increasing CVD mortality. The pathogenesis of cardiovascular and renal diseases involves complex and diverse interactions between multiple extracellular and intracellular signaling molecules, among which transient receptor potential vanilloid 1 (TRPV1)/transient receptor potential ankyrin 1 (TRPA1) channels have received increasing attention. TRPV1 belongs to the vanilloid receptor subtype family of transient receptor potential ion channels, and TRPA1 belongs to the transient receptor potential channel superfamily. TRPV1/TRPA1 are jointly involved in the management of cardiovascular and renal diseases and play important roles in regulating vascular tension, promoting angiogenesis, antifibrosis, anti-inflammation, and antioxidation. The mechanism of TRPV1/TRPA1 is mainly related to regulation of intracellular calcium influx and release of nitric oxide and calcitonin gene-related peptide. Therefore, this study takes the TRPV1/TRPA1 channel as the research object, analyzes and summarizes the process and mechanism of TRPV1/TRPA1 affecting cardiovascular and renal diseases, and lays a foundation for the treatment of cardiorenal diseases.