RESUMEN
We studied changes of pulmonary microhemodynamics when modeling pulmonary artery thromboembolism on perfused isolated rabbit lungs after pretreatment with ranolazine and ivabradine. The increase in pulmonary artery pressure, pulmonary vascular resistance, and pre- and postcapillary resistance was less pronounced than in control animals, but was close to that in case of pulmonary thromboembolism after pretreatment with voltage-gated Na+ channel blockers lidocaine and ropivacaine. The increase of capillary filtration coefficient inversely correlated with values of capillary hydrostatic pressure. Thus, ranolazine and ivabradine exhibit the properties of voltage-gated Na+ channel blockers mainly in smooth muscles of pulmonary arterial vessels and promote the decrease in endothelial permeability.
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Ivabradina , Arteria Pulmonar , Embolia Pulmonar , Ranolazina , Resistencia Vascular , Animales , Conejos , Ivabradina/farmacología , Ivabradina/uso terapéutico , Embolia Pulmonar/tratamiento farmacológico , Embolia Pulmonar/fisiopatología , Ranolazina/farmacología , Resistencia Vascular/efectos de los fármacos , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/fisiopatología , Pulmón/efectos de los fármacos , Pulmón/irrigación sanguínea , Modelos Animales de Enfermedad , Masculino , Lidocaína/farmacología , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacologíaRESUMEN
ABSTRACT: Heart rate (HR) stands as a prognostic indicator of cardiovascular disease and a modifiable risk factor in heart failure (HF). Medication intolerance can curtail the application of conventional HR-lowering ß-blockers to the optimum target dose. Ivabradine (IVA), a specific negative-chronotropic agent, selectively inhibits I f current in pacemaker cells of the sinoatrial node without depressing myocardial contractility or comprising hemodynamics. This review summarized ivabradine's clinical labeled and off-label uses and mechanism of action focusing on the clinical outcomes. PubMed was searched up to January 2024 using the main keywords of IVA, coronary artery disease (CAD), HF, postural tachycardia syndrome (POTS), and tachyarrhythmia. To comprehensively review IVA's clinical indications, mechanisms, and therapeutic effects, all studies investigating treatment with IVA in humans were included, comprising different types of studies such as randomized controlled trials and longitudinal prospective observational studies. After screening, 141 studies were included in our review. A large number of reviewed articles were allocated to heart failure with reduced ejection fraction and CAD, suggesting IVA as an alternative to ß-blockers in case of contraindications or intolerance. The beneficial effects of IVA as premedication for coronary computed tomography angiography, HR lowering in POTS, and inappropriate sinus tachycardia constituted most studies among off-label uses. The promising results have been reported on the efficacy of IVA in controlling HR, especially in patients with inappropriate sinus tachycardia or POTS. Owing to the unique mechanism of action, IVA has the potential to be used more frequently in future clinical practice.
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Fármacos Cardiovasculares , Frecuencia Cardíaca , Ivabradina , Ivabradina/uso terapéutico , Ivabradina/efectos adversos , Humanos , Frecuencia Cardíaca/efectos de los fármacos , Fármacos Cardiovasculares/uso terapéutico , Fármacos Cardiovasculares/efectos adversos , Resultado del Tratamiento , Uso Fuera de lo Indicado , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Animales , Potenciales de Acción/efectos de los fármacosAsunto(s)
Antipsicóticos , Clozapina , Delirio , Ivabradina , Esquizofrenia , Humanos , Clozapina/efectos adversos , Clozapina/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Antipsicóticos/efectos adversos , Antipsicóticos/uso terapéutico , Delirio/inducido químicamente , Ivabradina/uso terapéutico , Ivabradina/efectos adversos , Masculino , Adulto , Benzazepinas/efectos adversos , Benzazepinas/uso terapéuticoRESUMEN
Ivabradine, as a specific If current inhibitor, has been widely used in the treatment of chronic heart failure in adults due to its ability to reduce heart rate without affecting myocardial contractility and blood pressure. It has also shown good effects in various types of tachyarrhythmias. However, the application of ivabradine in pediatric cardiovascular diseases still faces many limitations. This article reviews the current research progress on the use of ivabradine in treating pediatric cardiovascular diseases both domestically and internationally, aiming to provide guidance for pediatric cardiologists. Citation:Chinese Journal of Contemporary Pediatrics, 2024, 26(7): 782-788.
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Benzazepinas , Enfermedades Cardiovasculares , Ivabradina , Ivabradina/uso terapéutico , Ivabradina/farmacología , Humanos , Niño , Enfermedades Cardiovasculares/tratamiento farmacológico , Benzazepinas/uso terapéutico , Benzazepinas/farmacologíaRESUMEN
Over the last decade, randomized clinical trials of several pharmacologic agents have demonstrated a reduction in cardiovascular mortality and other important secondary outcomes. Angiotensin-Neprilysin Inhibitors and Sodium-Glucose Co-transporter 2 inhibitors have now become pillars in the treatment of heart failure. Ivabradine is a negative chronotropic agent used as an adjunctive therapy in patients with heart failure. Two new hypertension therapies, zilebresiran and aprocitentan, are currently in investigational stages. Finally, mavacamten has emerged as a pharmacologic treatment for hypertrophic obstructive cardiomyopathy. Practitioners must be familiar with the indications and side effects of newer therapies as they are now frequently prescribed.
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Enfermedades Cardiovasculares , Humanos , Enfermedades Cardiovasculares/tratamiento farmacológico , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Fármacos Cardiovasculares/uso terapéutico , Hipertensión/tratamiento farmacológico , Antihipertensivos/uso terapéutico , Ivabradina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Aminobutiratos/uso terapéutico , Antagonistas de Receptores de Angiotensina/uso terapéutico , Valsartán , Ácidos Dicarboxílicos , Ácidos Grasos , ARN Interferente PequeñoRESUMEN
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
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
HCN1-4 channels are the molecular determinants of the If/Ih current that crucially regulates cardiac and neuronal cell excitability. HCN dysfunctions lead to sinoatrial block (HCN4), epilepsy (HCN1), and chronic pain (HCN2), widespread medical conditions awaiting subtype-specific treatments. Here, we address the problem by solving the cryo-EM structure of HCN4 in complex with ivabradine, to date the only HCN-specific drug on the market. Our data show ivabradine bound inside the open pore at 3 Å resolution. The structure unambiguously proves that Y507 and I511 on S6 are the molecular determinants of ivabradine binding to the inner cavity, while F510, pointing outside the pore, indirectly contributes to the block by controlling Y507. Cysteine 479, unique to the HCN selectivity filter (SF), accelerates the kinetics of block. Molecular dynamics simulations further reveal that ivabradine blocks the permeating ion inside the SF by electrostatic repulsion, a mechanism previously proposed for quaternary ammonium ions.
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Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización , Ivabradina , Simulación de Dinámica Molecular , Ivabradina/química , Ivabradina/farmacología , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/química , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/metabolismo , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/antagonistas & inhibidores , Humanos , Microscopía por Crioelectrón , Animales , Canales de Potasio/química , Canales de Potasio/metabolismo , Proteínas Musculares/química , Proteínas Musculares/metabolismoRESUMEN
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
BACKGROUND: Ivabradine, a pure bradycardic agent, can be given to heart failure reduced ejection fraction (HFrEF) patients with a sinus rhythm of ≥70 bpm on a maximum beta blocker dose, or when beta blockers are contraindicated. This study aimed to see how ivabradine affects the clinical and haemodynamic outcomes of HFrEF patients. METHODS: This systematic review and meta-analysis searched ClinicalTrials.gov, OpenMD, ProQuest, PubMed, and ScienceDirect for potential articles. All relevant data were extracted. For all pooled effects, the random effect model was applied. RESULTS: A total of 18,972 heart failure (HF) patients from nine randomised clinical trials (RCTs) were involved in this study. Ivabradine decreased the risk of HF mortality (RR 0.79; 95% CI 0.64-0.98; p=0.03) and HF hospitalisation (RR 0.80; 95% CI 0.65-0.97; p=0.03). Ivabradine was related to a greater reduction in heart rate (MD -12.21; 95% CI -15.47 - -8.96; p<0.01) and left ventricular ejection fraction (LVEF) improvement (MD 3.24; 95% CI 2.17-4.31; p <0.01) compared with placebo. Asymptomatic bradycardia (RR 4.25; 95% CI 3.36-5.39; p<0.01) and symptomatic bradycardia (RR 3.99; 95% CI 3.17-5.03; p<0.01) were higher in the ivabradine group. CONCLUSION: Ivabradine can reduce the risk of HF mortality and HF hospitalisation in HFrEF patients. Ivabradine also effectively reduces resting heart rate and improves LVEF. However, ivabradine is associated with a greater risk of symptomatic and asymptomatic bradycardia.
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Insuficiencia Cardíaca , Ivabradina , Ensayos Clínicos Controlados Aleatorios como Asunto , Volumen Sistólico , Ivabradina/uso terapéutico , Humanos , Volumen Sistólico/fisiología , Volumen Sistólico/efectos de los fármacos , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Hemodinámica/efectos de los fármacos , Hemodinámica/fisiología , Fármacos Cardiovasculares/uso terapéutico , Función Ventricular Izquierda/fisiología , Función Ventricular Izquierda/efectos de los fármacosAsunto(s)
Benzazepinas , Ivabradina , Ivabradina/uso terapéutico , Ivabradina/farmacología , Humanos , Benzazepinas/uso terapéutico , Benzazepinas/farmacología , Arritmias Cardíacas/tratamiento farmacológico , Antiarrítmicos/uso terapéutico , Antiarrítmicos/farmacología , Taquicardia Ventricular/tratamiento farmacológicoRESUMEN
Malnutrition results in autonomic imbalance and heart hypertrophy. Overexpression of hyperpolarization-activated cyclic nucleotide-gated channels (HCN) in the left ventricles (LV) is linked to hypertrophied hearts and abnormal myocardium automaticity. Given that ivabradine (IVA) has emerging pleiotropic effects, in addition to the widely known bradycardic response, this study evaluated if IVA treatment could repair the autonomic control and cardiac damages in malnourished rats. AIM: Assess the impact of IVA on tonic cardiovascular autonomic control and its relationship with hemodynamics regulation, LV inflammation, and HCN gene expression in post-weaning protein malnutrition condition. MAIN METHODS: After weaning, male rats were divided into control (CG; 22 % protein) and malnourished (MG; 6 % protein) groups. At 35 days, groups were subdivided into CG-PBS, CG-IVA, MG-PBS and MG-IVA (PBS 1 ml/kg or IVA 1 mg/kg) received during 8 days. We performed jugular vein cannulation and electrode implant for drug delivery and ECG registration to assess tonic cardiovascular autonomic control; femoral cannulation for blood pressure (BP) and heart rate (HR) assessment; and LV collection to evaluate ventricular remodeling and HCN gene expression investigation. KEY FINDINGS: Malnutrition induced BP and HR increases, sympathetic system dominance, and LV remodeling without affecting HCN gene expression. IVA reversed the cardiovascular autonomic imbalance; prevented hypertension and tachycardia; and inhibited the LV inflammatory process and fiber thickening caused by malnutrition. SIGNIFICANCE: Our findings suggest that ivabradine protects against malnutrition-mediated cardiovascular damage. Moreover, our results propose these effects were not attributed to HCN expression changes, but rather to IVA pleiotropic effects on autonomic control and inflammation.
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Sistema Nervioso Autónomo , Frecuencia Cardíaca , Hipertensión , Ivabradina , Ratas Wistar , Taquicardia , Animales , Ivabradina/farmacología , Masculino , Ratas , Taquicardia/tratamiento farmacológico , Taquicardia/fisiopatología , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Sistema Nervioso Autónomo/efectos de los fármacos , Sistema Nervioso Autónomo/fisiopatología , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Destete , Presión Sanguínea/efectos de los fármacos , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/metabolismo , Desnutrición/tratamiento farmacológico , Desnutrición Proteico-Calórica/tratamiento farmacológico , Desnutrición Proteico-Calórica/fisiopatología , Desnutrición Proteico-Calórica/complicaciones , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/fisiopatología , Remodelación Ventricular/efectos de los fármacosAsunto(s)
Síndrome Post Agudo de COVID-19 , Síndrome de Taquicardia Postural Ortostática , Humanos , Antiinfecciosos/uso terapéutico , Fármacos Cardiovasculares/uso terapéutico , Ensayos Clínicos como Asunto , COVID-19/complicaciones , COVID-19/terapia , Tratamiento Farmacológico de COVID-19 , Inmunoglobulinas Intravenosas/uso terapéutico , Ivabradina/uso terapéutico , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/terapia , Síndrome Post Agudo de COVID-19/etiología , Síndrome Post Agudo de COVID-19/terapia , Síndrome de Taquicardia Postural Ortostática/etiología , Síndrome de Taquicardia Postural Ortostática/terapiaRESUMEN
Duchenne muscular dystrophy (DMD) is an intractable X-linked myopathy caused by dystrophin gene mutations. Patients with DMD suffer from progressive muscle weakness, inevitable cardiomyopathy, increased heart rate (HR), and decreased blood pressure (BP). The aim of this study was to clarify the efficacy and tolerability of ivabradine treatment for DMD cardiomyopathy.A retrospective analysis was performed in 11 patients with DMD, who received ivabradine treatment for more than 1 year. Clinical results were analyzed before (baseline), 6 months after, and 12 months after the ivabradine administration.The initial ivabradine dose was 2.0 ± 1.2 mg/day and the final dose was 5.6 ± 4.0 mg/day. The baseline BP was 95/64 mmHg. A non-significant BP decrease to 90/57 mmHg was observed at 1 month but it recovered to 97/62 mmHg at 12 months after ivabradine administration. The baseline HR was 93 ± 6 bpm and it decreased to 74 ± 12 bpm at 6 months (P = 0.011), and to 77 ± 10 bpm at 12 months (P = 0.008). A linear correlation (y = 2.2x + 5.1) was also observed between the ivabradine dose (x mg/day) and HR decrease (y bpm). The baseline LVEF was 38 ± 12% and it significantly increased to 42 ± 9% at 6 months (P = 0.011) and to 41 ± 11% at 12 months (P = 0.038). Only 1 patient with the lowest BMI of 11.0 kg/m2 and BP of 79/58 mmHg discontinued ivabradine treatment at 6 months, while 1-year administration was well-tolerated in the other 10 patients.Ivabradine decreased HR and increased LVEF without lowering BP, suggesting it can be a treatment option for DMD cardiomyopathy.
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Cardiomiopatías , Distrofia Muscular de Duchenne , Humanos , Ivabradina/uso terapéutico , Distrofia Muscular de Duchenne/complicaciones , Distrofia Muscular de Duchenne/tratamiento farmacológico , Distrofia Muscular de Duchenne/genética , Estudios Retrospectivos , Cardiomiopatías/complicaciones , Cardiomiopatías/tratamiento farmacológico , Distrofina/genéticaRESUMEN
Ivabradine, a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel inhibitor, has been reported to induce photosensitivity-related visual disturbances such as phosphene in humans. Ivabradine-induced visual disturbances are caused by inhibition of HCN channels in the retina, and the mechanisms have been verified using HCN channel knockout mice and electroretinography (ERG). However, in rats, classical ERG using single flash light stimulus with standard analyses of waveform amplitude and latency has not revealed abnormal retinal function after administration of ivabradine. To verify whether retinal dysfunction after ivabradine administration was detectable in rats, we performed ERG using multistep flash light stimulation at the time when plasma concentration of ivabradine was high. Furthermore, the mechanism of the change in the waveform that appeared after the b-wave was investigated. Ivabradine and cilobradine, a selective HCN channel inhibitor, were administered subcutaneously to rats at 4-40 mg/kg as a single dose, and flash or long-duration ERG recordings at each light stimulus luminance were conducted 1.5 h after administration. Plasma and retinal concentrations of both compounds were measured immediately after the ERG recordings. In the flash ERG, prolongation of a- and/or b-wave latencies were detected at each light stimulus, and dose-dependent waveform changes after the b-wave were recorded at the specific light stimulus luminance for both compounds. These ERG changes increased in response to increasing plasma and retinal concentrations for both ivabradine and cilobradine. In the long-duration light stimulus ERG, a change in the waveform of the b-wave trough and attenuation of the c-wave were recorded, suggesting that the feedback control in the photoreceptor cells may be inhibited. This study revealed that the retinal dysfunction by HCN channel inhibitors in rats can be detected by multistep light stimulus ERG. Additionally, we identified that the inhibition of feedback current and the sustained responses in the photoreceptor cells cause the retinal dysfunction of HCN channel inhibitors in rats.
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Electrorretinografía , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización , Ratones , Humanos , Ratas , Animales , Ivabradina , Retina , Visión Ocular , Trastornos de la Visión , Ratones Noqueados , Estimulación LuminosaRESUMEN
Ivabradine is a recently introduced inhibitor of the If ion channel, which exhibits the capacity to reduce heart rate while preserving hemodynamic stability. At present, ivabradine finds its clinical indication in patients suffering from heart failure with reduced ejection fraction and maintaining a relative sinus rhythm refractory to beta-blockers. To optimize heart rate control, it is recommended to pursue an aggressive up-titration of ivabradine. This approach may ameliorate tachycardia-induced hypotension by incrementally enhancing cardiac output and allow further up-titration of agents aimed at ameliorating heart failure, such as beta-blockers. Both the modulation of heart rate itself and the up-titration of agents targeting heart failure lead to cardiac reverse remodeling, consequently culminating in a subsequent reduction in mortality and morbidity. A novel overlap theory that our team proposed recently has emerged in recent times. Under trans-mitral Doppler echocardiography, the E-wave and A-wave closely juxtapose one another without any overlapping at the optimal heart rate. Employing echocardiography-guided ivabradine for heart-rate modulation to minimize the overlap between the E-wave and A-wave appears to confer substantial benefits to patients with heart failure. This approach facilitates superior cardiac reverse remodeling and yields more favorable clinical outcomes when compared to those patients who do not receive echocardiography-guided care. The next pertinent issue revolves around the potential expansion of ivabradine's clinical indications to encompass a broader spectrum of diseases. It is imperative to acknowledge that ivabradine may not yield clinically significant benefits in patients afflicted by heart failure with preserved ejection fraction, acute heart failure, sepsis, or stable angina. An important fact yet to be explored is the clinical applicability of ivabradine in patients with atrial fibrillation, a concern that beckons future investigation. In this review, the concept of overlap theory it introduced, along with its application to expand the indication of ivabradine and the overlap theory-guided optimal ivabradine therapy.