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Background: The major membrane currents responsible for sinoatrial (SA) rhythm generation are generally studied in isolated cardiac cells using electrophysiological tools. Such studies are resource and labor-intensive. Materials and Methods: Here, we have studied four major currents in isolated rat heart preparations, perfused in Langendorff mode, and demonstrate that this is a good preparation for such studies. Heart rates of isolated perfused rat hearts were recorded using surface electrocardiogram before and after perfusion with drugs and solutions that affect the four major currents responsible for SA rhythm generation. Results: The rates of whole isolated hearts beating with SA rhythm decreased with cesium and decreased by about half with ivabradine, both blockers of the funny current (If). Importantly, the rhythm was not abolished even with a high dose of ivabradine at which total blockade of If is expected. The rate was not affected by nickel, a blocker of T-type calcium current. The SA rhythm was abolished by the reduction or removal of sodium from the perfusate (interventions that inhibit the calcium-extrusive mode of the sodium-calcium exchanger) or by nifedipine, the L-type calcium channel blocker. Discussion: The inferences made based on these observations are (a) If contributes significantly to pacemaking, (b) ICaT does not play a role and (c) INCX and ICaL are obligatory rhythm-generating currents in the SA node. Cyclical calcium release from SR during diastole (the calcium clock), responsible for driving INCX in its forward mode is probably a phenomenon independent of membrane events, as total If blockade did not abolish rhythm generation. These results corroborate with published literature where most studies were done on single cells.

Abstract Aims A therapeutic strategy for chronic heart failure (HF) is to lower resting heart rate (HR). Ivabradine is a well‐known HR‐lowering agent, but limited prospective data exist regarding its use in Chinese patients. This study aimed to evaluate the effectiveness and safety of ivabradine in Chinese patients with chronic HF. Methods and results This multicentre, single‐arm, prospective, observational study enrolled Chinese patients with chronic HF. The primary outcome was change from baseline in HR at 1 and 6 months, measured by pulse counting. Effectiveness was also evaluated using laboratory tests, the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score (CSS) and overall summary score (OSS), and New York Heart Association (NYHA) class. Treatment‐emergent adverse events (TEAEs) were assessed. A post hoc analysis examined the effectiveness and safety of ivabradine combined with an angiotensin receptor–neprilysin inhibitor (ARNI) or beta‐blocker. A total of 1003 patients were enrolled [mean age 54.4 ± 15.0 years, 773 male (77.1%), mean baseline HR 88.5 ± 11.3 b.p.m., mean blood pressure 115.7/74.4 ± 17.2/12.3 mmHg, mean left ventricular ejection fraction 30.9 ± 7.6%, NYHA Classes III and IV in 48.8% and 22.0% of patients, respectively]. HR decreased by a mean of 12.9 and 16.1 b.p.m. after 1 and 6 months, respectively (both P

Introduction: Ivabradine reduces heart rate (HR), episodes of angina, and nitrate consumption, and increases exercise capacity in patients with chronic angina (CA). In this exploratory study, myocardial perfusion scintigraphy (MPS) was used to evaluate changes in the percentage of myocardial ischemia after ivabradine therapy in patients with CA. Methods: This prospective, open-label, single-arm study included patients with CA receiving maximum tolerated doses of beta blockers, who had a resting HR ≥ 70 bpm and had experienced ischemia according to MPS during an exercise test at baseline. Participants received ivabradine 5 mg twice daily (titrated according to HR) concomitant with beta blockers. A second MPS was performed after 3 months, without interruption of treatment with beta blockers or ivabradine. The primary outcome was change in the percentage of myocardial ischemia from baseline to 3 months. Time to ischemia during the exercise test, the proportion of patients presenting angina during the exercise test, and health status, assessed using the seven-item Seattle Angina Questionnaire-7 (SAQ-7), were also evaluated. Results: Twenty patients (3 females) with a mean (± standard deviation [SD]) age of 62.2 ± 6.5 years were included in the study, of whom 55% had diabetes, 70% had previous myocardial revascularization, and 45% had previous myocardial infarction. The percentage of patients with myocardial ischemia significantly decreased from baseline to 3 months after initiation of treatment with ivabradine (− 2.9%; 95% confidence interval [CI] − 0.3 to − 5.5; p = 0.031). Mean time to appearance of ischemia increased from 403 ± 176 s at baseline to 466 ± 136 s at 3 months after initiation of ivabradine (Δ62 s; 95% CI 18–106 s; p = 0.008), and the proportion of patients experiencing angina during the exercise test decreased from 40% at baseline to 5% also at 3 months (p = 0.016). Mean resting HR decreased from 76 ± 7 bpm at baseline to 55 ± 8 bpm at 3 months (p < 0.001). The mean SAQ-7 summary score improved from 69 ± 21 at baseline to 83 ± 12 at 3 months (p = 0.001). No serious adverse effects were reported. Conclusion: Ivabradine added to beta blockers was associated with a reduction in detectable myocardial ischemia by MPS in patients with CA. Infographic available for this article. Trial Registration: The trial has been retrospectively registered with the Brazilian Registry of Clinical Trials (REBEC) under the following number RBR-5fysqrh (date of registration: 30 November 2023). [ABSTRACT FROM AUTHOR]

Although morphine has been used for treatment-resistant dyspnea in end-stage heart failure patients, information on its cardiovascular safety profile remains limited. Morphine was intravenously administered to halothane-anesthetized dogs (n=4) in doses of 0.1, 1 and 10 mg/kg/10 min with 20 min of observation period. The low and middle doses attained therapeutic (0.13 µg/mL) and supratherapeutic (0.97 µg/mL) plasma concentrations, respectively. The low dose hardly altered any of the cardiovascular variables except that the QT interval was prolonged for 10-15 min after its start of infusion. The middle dose reduced the preload and afterload to the left ventricle for 5-15 min, then decreased the left ventricular contractility and mean blood pressure for 10-30 min, and finally suppressed the heart rate for 15-30 min. Moreover, the middle dose gradually but progressively prolonged the atrioventricular conduction time, QT interval/QTcV, ventricular late repolarization period and ventricular effective refractory period without altering the intraventricular conduction time, ventricular early repolarization period or terminal repolarization period. A reverse-frequency-dependent delay of ventricular repolarization was confirmed. The high dose induced cardiohemodynamic collapse mainly due to vasodilation in the initial 2 animals by 1.9 and 3.3 min after its start of infusion, respectively, which needed circulatory support to treat. The high dose was not tested further in the remaining 2 animals. Thus, intravenously administered morphine exerts a rapidly appearing vasodilator action followed by slowly developing cardiosuppressive effects. Morphine can delay the ventricular repolarization possibly through IKr inhibition in vivo, but its potential to develop torsade de pointes will be small. [ABSTRACT FROM AUTHOR]

Background: A large proportion of nursing home (NH) residents suffer from dementia and effects of conventional anti-dementia drugs on their health is poorly known. We aimed to investigate the associations between exposure to anti-dementia drugs and mortality among NH residents. Methods: This retrospective longitudinal observational study involved 329 French NH and the residents admitted in these facilities since 2014 and having major neurocognitive disorder. From their electronic health records, we obtained their age, sex, level of dependency, Charlson comorbidity index, and Mini mental examination score at admission. Exposure to anti-dementia drugs was determined using their prescription into 4 categories: none, exposure to acetylcholinesterase inhibitors (AChEI) alone, exposure to memantine alone, exposure to AChEI and memantine. Survival until the end of 2019 was studied in the entire cohort by Cox proportional hazards. To alleviate bias related to prescription of anti-dementia drugs, we formed propensity-score matched cohorts for each type of anti-dementia drug exposure, and studied survival by the same method. Results: We studied 25,358 NH residents with major neurocognitive disorder. Their age at admission was 87.1 + 7.1 years and 69.8% of them were women. Exposure to anti-dementia drugs occurred in 2,550 (10.1%) for AChEI alone, in 2,055 (8.1%) for memantine alone, in 460 (0.2%) for AChEI plus memantine, whereas 20,293 (80.0%) had no exposure to anti-dementia drugs. Adjusted hazard ratios for mortality were significantly reduced for these three groups exposed to anti-dementia drugs, as compared to reference group: HR: 0.826, 95%CI 0.769 to 0.888 for AChEI; 0.857, 95%CI 0.795 to 0.923 for memantine; 0.742, 95%CI 0.640 to 0.861 for AChEI plus memantine. Results were consistent in propensity-score matched cohorts. Conclusion: The use of conventional anti-dementia drugs is associated with a lower mortality in nursing home residents with dementia and should be widely used in this population. [ABSTRACT FROM AUTHOR]

Background: The risk of contrast-associated acute kidney injury is relatively higher in patients with diabetes mellitus compared to non-diabetics. Recent trials have revealed the renoprotective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors. We aimed to investigate the possible preventive effect of SGLT2 inhibitors against contrastassociated acute kidney injury in the diabetic population who underwent coronary angiography with a diagnosis of stable angina or acute coronary syndrome. Methods: This was a cross-sectional and single-center study. We enrolled 345 patients with type II diabetes mellitus who were divided into 2 groups: using an SGLT2 inhibitor (group 1; n = 133) in addition to other antidiabetic medication and not using an SGLT2 inhibitor (group 2; n = 212). Both groups were compared in terms of contrast-associated acute kidney injury incidence. We also compared groups for the duration of hospitalization. Results: Baseline characteristics (age, sex, risk factors and medications) and laboratory findings were similar between the 2 groups. The means of administered contrast volume were also similar (160.42 (± 70.31) mL vs. 158.72 (± 81.24) mL, P = 0.83) between groups 1 and 2, respectively. We found that contrast-associated acute kidney injury incidence was significantly higher in group 2 compared to group 1 (n = 56 (26.4%) vs. n = 12 (9.0%), P < 0.001). The duration of hospitalization was significantly longer in group 2 (3.25 (± 2.03) days) than in group 1 (2.54 (± 1.39) days) (P = 0.001). Conclusion: We found that contrast-associated acute kidney injury was significantly lower, and the duration of hospitalization was significantly shorter in diabetic patients using SGLT2 inhibitors compared to non-users. [ABSTRACT FROM AUTHOR]

In patients with septic shock, compensatory tachycardia initially serves to maintain adequate cardiac output and tissue oxygenation but may persist despite appropriate fluid and vasopressor resuscitation. This sustained elevation in heart rate and altered heart rate variability, indicative of autonomic dysfunction, is a well-established independent predictor of adverse outcomes in critical illness. Elevated heart rate exacerbates myocardial oxygen demand, reduces ventricular filling time, compromises coronary perfusion during diastole, and impairs the isovolumetric relaxation phase of the cardiac cycle, contributing to ventricular-arterial decoupling. This also leads to increased ventricular and atrial filling pressures, with a heightened risk of arrhythmias. Ivabradine, a highly selective inhibitor of the sinoatrial node's pacemaker current (If or "funny" current), mitigates heart rate by modulating diastolic depolarization slope without affecting contractility. By exerting a selective chronotropic effect devoid of negative inotropic properties, ivabradine shows potential for improving hemodynamics in septic shock patients with cardiac dysfunction. This review evaluates the plausible mechanisms and existing evidence regarding the utility of ivabradine in managing patients with septic shock. [ABSTRACT FROM AUTHOR]

The objective of the present study was to evaluate clinical, cardiorespiratory, and Doppler echocardiographic changes in rabbits sedated with midazolam and morphine combined with or without dexmedetomidine. This study was a blinded, randomized, controlled experiment that included 16 adult male New Zealand rabbits weighing 3.1 ± 0.3 kg. The animals were sedated using one of the following protocols: 1 mg/kg midazolam and 2 mg/kg morphine (MIDA, n = 8), or 25 mg/kg dexmedetomidine, 2 mg/kg morphine and 1 mg/kg midazolam (DEX, n = 8). Sedation latency, duration of the sedation and recovery period, sedation scores, heart rate (HR), respiratory rate (f), peripheral oxygen saturation (SpO2), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), mean arterial pressure (MAP), and recta temperature were recorded, and Doppler echocardiography was performed. Latency periods were 7.3±1.6 min in the DEX group and 10.9 ± 5.0 min in the MIDA group (P = 0.112). Sedation duration was 122.4±14 min in the DEX group and 71.2 ± 32 min in the MIDA group (P = 0.005), whereas recovery time was 35.7±17.7 min in the DEX group and 32.5 ± 25.3 min in the MIDA group (P = 0.743). The sedation scores for the DEX group were significantly higher than those for the MIDA group throughout the monitoring period. Reductions in HR, SAP, MAP, and DAP values were observed in both groups relative to baseline values, and were significantly lower in the DEX group compared to the MIDA group. Minimal Doppler echocardiographic changes were observed. Dexmedetomidine used in combination with midazolam and morphine incremented the quality and duration of sedation in rabbits. Both protocols elicited cardiorespiratory changes that were welltolerated, with minimal changes in myocardial function. [ABSTRACT FROM AUTHOR]

Aims: A therapeutic strategy for chronic heart failure (HF) is to lower resting heart rate (HR). Ivabradine is a well‐known HR‐lowering agent, but limited prospective data exist regarding its use in Chinese patients. This study aimed to evaluate the effectiveness and safety of ivabradine in Chinese patients with chronic HF. Methods and results: This multicentre, single‐arm, prospective, observational study enrolled Chinese patients with chronic HF. The primary outcome was change from baseline in HR at 1 and 6 months, measured by pulse counting. Effectiveness was also evaluated using laboratory tests, the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score (CSS) and overall summary score (OSS), and New York Heart Association (NYHA) class. Treatment‐emergent adverse events (TEAEs) were assessed. A post hoc analysis examined the effectiveness and safety of ivabradine combined with an angiotensin receptor–neprilysin inhibitor (ARNI) or beta‐blocker. A total of 1003 patients were enrolled [mean age 54.4 ± 15.0 years, 773 male (77.1%), mean baseline HR 88.5 ± 11.3 b.p.m., mean blood pressure 115.7/74.4 ± 17.2/12.3 mmHg, mean left ventricular ejection fraction 30.9 ± 7.6%, NYHA Classes III and IV in 48.8% and 22.0% of patients, respectively]. HR decreased by a mean of 12.9 and 16.1 b.p.m. after 1 and 6 months, respectively (both P < 0.001). At Month 6, improvements in the KCCQ CSS and OSS of ≥5 points were observed in 72.1% and 74.1% of patients, respectively (both P < 0.001). Left ventricular ejection fraction increased by 12.1 ± 11.6 (P < 0.001), and 66.7% of patients showed improvement in NYHA class (P < 0.001). At Month 6, the overall proportion of patients in NYHA Classes III and IV was reduced to 13.5% and 2.1%, respectively. Serum brain natriuretic peptide (BNP) and N‐terminal pro‐BNP changed by −331.9 ng/L (−1238.6, −134.0) and −1113.8 ng/L (−2202.0, −297.2), respectively (P < 0.001). HR reductions and improvements in NYHA and KCCQ scores with ivabradine were similar with and without use of ARNIs or beta‐blockers. Of 498 TEAEs in 296 patients (29.5%), 73 TEAEs in 55 patients (5.5%) were considered related to ivabradine [most frequent sinus bradycardia (n = 7) and photopsia (n = 7)]. TEAEs were reported in a similar number of patients in ARNI and beta‐blocker subgroups (21.9–35.6%). Conclusions: Ivabradine treatment reduced HR and improved cardiac function and health‐related quality of life in Chinese patients with chronic HF. Benefits were seen irrespective of whether or not patients were also taking ARNIs or beta‐blockers. Treatment was well tolerated with a similar profile to previous ivabradine studies. [ABSTRACT FROM AUTHOR]

Abstract Introduction Ivabradine reduces heart rate (HR), episodes of angina, and nitrate consumption, and increases exercise capacity in patients with chronic angina (CA). In this exploratory study, myocardial perfusion scintigraphy (MPS) was used to evaluate changes in the percentage of myocardial ischemia after ivabradine therapy in patients with CA. Methods This prospective, open-label, single-arm study included patients with CA receiving maximum tolerated doses of beta blockers, who had a resting HR ≥ 70 bpm and had experienced ischemia according to MPS during an exercise test at baseline. Participants received ivabradine 5 mg twice daily (titrated according to HR) concomitant with beta blockers. A second MPS was performed after 3 months, without interruption of treatment with beta blockers or ivabradine. The primary outcome was change in the percentage of myocardial ischemia from baseline to 3 months. Time to ischemia during the exercise test, the proportion of patients presenting angina during the exercise test, and health status, assessed using the seven-item Seattle Angina Questionnaire-7 (SAQ-7), were also evaluated. Results Twenty patients (3 females) with a mean (± standard deviation [SD]) age of 62.2 ± 6.5 years were included in the study, of whom 55% had diabetes, 70% had previous myocardial revascularization, and 45% had previous myocardial infarction. The percentage of patients with myocardial ischemia significantly decreased from baseline to 3 months after initiation of treatment with ivabradine (− 2.9%; 95% confidence interval [CI] − 0.3 to − 5.5; p = 0.031). Mean time to appearance of ischemia increased from 403 ± 176 s at baseline to 466 ± 136 s at 3 months after initiation of ivabradine (Δ62 s; 95% CI 18–106 s; p = 0.008), and the proportion of patients experiencing angina during the exercise test decreased from 40% at baseline to 5% also at 3 months (p = 0.016). Mean resting HR decreased from 76 ± 7 bpm at baseline to 55 ± 8 bpm at 3 months (p

Abstract Background Ivabradine, a medical treatment for heart failure (HF), reduces heart rate (HR) and prolongs diastolic perfusion time. It is frequently prescribed to patients with HF who have a suboptimal response or intolerance to beta‐blockers. Degenerative mitral regurgitation (MR) is a valvular heart disease often associated with the development of HF and atrial fibrillation (AF). However, studies comparing the effects of ivabradine and beta‐blockers on MR are lacking. Therefore, this study aimed to explore the potential therapeutic effects of ivabradine and carvedilol on MR using a rat model. Methods and results Using a novel echo‐guided mini‐invasive surgery, MR was created in 12‐weeks‐old Sprague–Dawley rats. After 2 weeks, the rats were randomized to receive either ivabradine or carvedilol for 4 weeks. Echocardiography was performed at baseline and at two‐week intervals. Following haemodynamic studies, postmortem tissues were analysed. Notably, the MR‐induced myocardial dysfunction did not improve considerably after treatment with ivabradine or carvedilol. However, in haemodynamic studies, pharmacological therapies, particularly carvedilol, mitigated MR‐induced chamber dilatation (end‐systolic volume and end‐diastolic volume; MR vs. MR + Carvedilol; P

Abstract Background Carivalan® dosage form containing carvedilol and ivabradine is widely indicated for patients with stable angina. Three precise, eco-friendly and reproducible spectrophotometric techniques were created for resolving the researched drugs in their mixtures using zero and/or ratio spectra. Technique I is a factorized dual wavelength coupled with spectrum subtraction (FDW-SS), technique II is a ratio difference, and technique III is a constant center coupled with spectrum subtraction (CC-SS). Moreover, CAR and IVA were simultaneously determined in the existence of their oxidative degradation products exploiting the newly developed induced tripartite amplitude difference coupled with ratio subtraction (ITAD-RS) technique. Results The calibration curves for CAR and IVA showed linearity within 3.0–30.0 µg/ml, each. Techniques' precision, accuracy, and linearity ranges were resolved and validated in harmony with ICH guidelines. Additionally, the specificity was examined by examining created combinations of the proposed drugs with LOD of 0.258 and 0.290 for CAR, while for IVA 0.272 and 0.204. Conclusion These techniques were used to determine the presence of the provided drugs in Carivalan® tablets. There is statistical comparison between the found results of the offered spectrophotometric techniques and the previously reported ones with no discernible variance in the acquired results.

The Japanese national guidelines recommend significantly lower doses of carvedilol for heart failure with reduced ejection fraction (HFrEF) management than the US guidelines. Using real-world data, we determined whether initial and target doses of carvedilol in Japanese patients (JPNs) differ from those in US patients (USPs), especially in Asian Americans (ASA) and Caucasians (CA), and investigated differences in outcomes. We collected data from the electronic medical records, including demographics, carvedilol dosing, tolerability, cardiac functional indicators like EF, cardiovascular events including all-cause deaths, and laboratory values from the University of California, San Diego Health and Osaka University. JPNs had significantly lower doses (mg/day) of carvedilol initiation (66 USPs composed of 38 CAs and 28 ASAs, 17.1±16.2; 93 JPNs, 4.3±4.2, p<0.001) and one year after initiation (33.0±21.8; 11.2±6.5, p<0.001), and a significantly lower relative rate (RR) of dose discontinuation and reduction than USPs (RR: 0.406, 95% confidence interval (CI): 0.181–0.911, p<0.05). CAs showed the highest reduction rate (0.184), and ASAs had the highest discontinuation rate (0.107). A slight mean difference with narrow 95% CI ranges straddling zero was observed between the two regions in the change from the baseline of each cardiac functional indicator (LVEF, -0.68 [−5.49–4.12]; LVDd, −0.55 [−3.24–2.15]; LVDd index, −0.25 [−1.92–1.43]; LVDs, −0.03 [−3.84–3.90]; LVDs index, −0.04 [−2.38–2.30]; heart rate, 1.62 [−3.07–6.32]). The event-free survival showed no difference (p = 0.172) among the races. Conclusively, despite JPNs exhibiting markedly lower carvedilol doses, their dose effectiveness has the potential to be non-inferior to that in USPs. Dose de-escalation, not discontinuation, could be an option in some Asian and ASA HFrEF patients intolerable to high doses of carvedilol. [ABSTRACT FROM AUTHOR]

Introduction: Since the 1970s, fetal scalp blood sampling (FSBS) has been used as a second‐line test of the acid–base status of the fetus to evaluate fetal well‐being during labor. The commonly employed thresholds that delineate normal pH (>7.25), subnormal (7.20–7.25), and pathological pH (<7.20) guide clinical decisions. However, these experienced‐based thresholds, based on observations and common sense, have yet to be confirmed. The aim of the study was to investigate if pH drop rate accelerates at the common thresholds (7.25 and 7.20) and to explore the possibility of identifying more accurate thresholds. Material and methods: A retrospective study was conducted at a tertiary maternity hospital between June 2017 and July 2021. Patients with at least one FSBS during labor for category II fetal heart rate and delivery of a singleton cephalic infant were included. The rate of change in pH value between consecutive samples for each patient was calculated and plotted as a function of pH value. Linear regression models were used to model the evolution of the pH drop rate estimating slope and standard errors across predefined pH intervals. Exploration of alternative pH action thresholds was conducted. To explore the independence of the association between pH value and pH drop rate, multiple linear regression adjusted on age, body mass index, parity, oxytocin stimulation and suspected small for gestational age was performed. Results: We included 2047 patients with at least one FSBS (total FSBS 3467); with 2047 umbilical cord blood pH, and a total of 5514 pH samples. Median pH values were 7.29 1 h before delivery, 7.26 30 min before delivery. The pH drop was slow between 7.40 and 7.30, then became more pronounced, with median rates of 0.0005 units/min at 7.25 and 0.0013 units/min at 7.20. Out of the alternative pH thresholds, 7.26 and 7.20 demonstrated the best alignment with our dataset. Multiple linear regression revealed that only pH value was significantly associated to the rate of pH change. Conclusions: Our study confirms the validity and reliability of current guideline thresholds for fetal scalp pH in category II fetal heart rate. [ABSTRACT FROM AUTHOR]

Regardless of the currently proposed best medical treatment for heart failure patients, the morbidity and mortality rates remain high. This is due to several reasons, including the interaction between oral cardiac drug administration and gut microbiota. The relation between drugs (especially antibiotics) and gut microbiota is well established, but it is also known that more than 24% of non-antibiotic drugs affect gut microbiota, altering the microbe's environment and its metabolic products. Heart failure treatment lies mainly in the blockage of neuro-humoral hyper-activation. There is debate as to whether the administration of heart-failure-specific drugs can totally block this hyper-activation, or whether the so-called intestinal dysbiosis that is commonly observed in this group of patients can affect their action. Although there are several reports indicating a strong relation between drug–gut microbiota interplay, little is known about this relation to oral cardiac drugs in chronic heart failure. In this review, we review the contemporary data on a topic that is in its infancy. We aim to produce scientific thoughts and questions and provide reasoning for further clinical investigation. [ABSTRACT FROM AUTHOR]

OBJECTIVE To determine the time of onset and duration of action of distal paravertebral blocks (DPB) in dairy cattle using lidocaine and lidocaine plus xylazine (LX). ANIMALS 10 healthy adult Holstein cows. METHODS Unilateral DPB were performed in 6 cows at L1, L2, and L4. They received 2 treatments (lidocaine and LX) in a blinded random crossover design. Due to treatment failure, 4 additional cows were enrolled. The lidocaine treatment received 1,800 mg (90 mL) of lidocaine, and treatment LX received 1,784 mg (89.2 mL) of lidocaine and 16 mg (0.8 mL) of xylazine. Anesthesia was assessed by response (rapid movements of the tail, directed movements of the feet, or turning of the head towards the site of the needle pricks) to 6 approximately 1-cm deep needle pricks to the paralumbar fossa with a 22-gauge hypodermic needle. The time of onset, duration of action, maximum sedation score, and average heart rate (HR) were compared between treatments. RESULTS Duration of anesthesia was significantly prolonged after DPB in cows treated with LX (251.6 ± 96.94 minutes) compared to lidocaine (105.8 ± 35.9 minutes; P = .01). Treatment with LX was associated with significantly lower average heart rate (56 ± 3 beats/min) compared to cows treated with lidocaine (59 ± 3 beats/min; P = .045). The LX treatment was associated with mild sedation but was not significant (P = .063). CLINICAL RELEVANCE The addition of xylazine to a lidocaine DPB provides a longer duration of anesthesia, is inexpensive and practical, and can be implemented with ease. [ABSTRACT FROM AUTHOR]

Background: Ivabradine, a medical treatment for heart failure (HF), reduces heart rate (HR) and prolongs diastolic perfusion time. It is frequently prescribed to patients with HF who have a suboptimal response or intolerance to beta‐blockers. Degenerative mitral regurgitation (MR) is a valvular heart disease often associated with the development of HF and atrial fibrillation (AF). However, studies comparing the effects of ivabradine and beta‐blockers on MR are lacking. Therefore, this study aimed to explore the potential therapeutic effects of ivabradine and carvedilol on MR using a rat model. Methods and results: Using a novel echo‐guided mini‐invasive surgery, MR was created in 12‐weeks‐old Sprague–Dawley rats. After 2 weeks, the rats were randomized to receive either ivabradine or carvedilol for 4 weeks. Echocardiography was performed at baseline and at two‐week intervals. Following haemodynamic studies, postmortem tissues were analysed. Notably, the MR‐induced myocardial dysfunction did not improve considerably after treatment with ivabradine or carvedilol. However, in haemodynamic studies, pharmacological therapies, particularly carvedilol, mitigated MR‐induced chamber dilatation (end‐systolic volume and end‐diastolic volume; MR vs. MR + Carvedilol; P < 0.05) and decreased compliance (end‐systolic pressure–volume relationship; MR vs. MR + Carvedilol; P < 0.05). Compared with ivabradine, a shorter duration (MR vs. MR + Carvedilol; P < 0.05) and reduced inducibility (MR vs. MR + Carvedilol and MR vs. MR + Ivabradine; P < 0.05) of AF were observed in MR rats treated with carvedilol. Similarly, reduced cardiac fibrosis and apoptosis were observed in the MR rat model in the treatment groups, especially in those treated with carvedilol (MR vs. MR + Carvedilol; P < 0.01). Conclusions: Although both ivabradine and carvedilol, at least in part, mitigated MR‐induced chamber dilatation and decreased compliance, carvedilol had a better effect on reversing MR‐induced cardiac fibrosis, apoptosis, and arrhythmogenesis than ivabradine. When compared with Ivabradine, MR rats treated with carvedilol exhibited a shorter duration and reduced inducibility of AF, thus providing more effective suppression of HCN4. Further investigations are required to validate our findings. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Eukaryotic cells engage in autophagy, an internal process of self-degradation through lysosomes. Autophagy can be classified as selective or non-selective depending on the way it chooses to degrade substrates. During the process of selective autophagy, damaged and/or redundant organelles like mitochondria, peroxisomes, ribosomes, endoplasmic reticulum (ER), lysosomes, nuclei, proteasomes, and lipid droplets are selectively recycled. Specific cargo is delivered to autophagosomes by specific receptors, isolated and engulfed. Selective autophagy dysfunction is closely linked with cancers, neurodegenerative diseases, metabolic disorders, heart failure, etc. Through reviewing latest research, this review summarized molecular markers and important signaling pathways for selective autophagy, and its significant role in cancers. Moreover, we conducted a comprehensive analysis of small-molecule compounds targeting selective autophagy for their potential application in anti-tumor therapy, elucidating the underlying mechanisms involved. This review aims to supply important scientific references and development directions for the biological mechanisms and drug discovery of anti-tumor targeting selective autophagy in the future. [ABSTRACT FROM AUTHOR]

Background: Carivalan® dosage form containing carvedilol and ivabradine is widely indicated for patients with stable angina. Three precise, eco-friendly and reproducible spectrophotometric techniques were created for resolving the researched drugs in their mixtures using zero and/or ratio spectra. Technique I is a factorized dual wavelength coupled with spectrum subtraction (FDW-SS), technique II is a ratio difference, and technique III is a constant center coupled with spectrum subtraction (CC-SS). Moreover, CAR and IVA were simultaneously determined in the existence of their oxidative degradation products exploiting the newly developed induced tripartite amplitude difference coupled with ratio subtraction (ITAD-RS) technique. Results: The calibration curves for CAR and IVA showed linearity within 3.0–30.0 µg/ml, each. Techniques' precision, accuracy, and linearity ranges were resolved and validated in harmony with ICH guidelines. Additionally, the specificity was examined by examining created combinations of the proposed drugs with LOD of 0.258 and 0.290 for CAR, while for IVA 0.272 and 0.204. Conclusion: These techniques were used to determine the presence of the provided drugs in Carivalan® tablets. There is statistical comparison between the found results of the offered spectrophotometric techniques and the previously reported ones with no discernible variance in the acquired results. [ABSTRACT FROM AUTHOR]

Background: Ivabradine reduces heart rate by inhibiting the "funny current" expressed on the sinoatrial node and improves mortality and morbidity in patients with systolic heart failure and sinus tachycardia. The funny current is known to be expressed also on the atrioventricular node according to experimental studies. However, the impact of ivabradine on PR interval remained unknown. Methods: Patients with a left ventricular ejection fraction of less than 50% who received 1 month of ivabradine were screened. Electrocardiographic and echocardiographic data, particularly concerning heart rate, the PR interval, and trans-mitral flow pattern, were collected at baseline and 1-month follow-up. The primary endpoint was defined as the composite of cardiovascular death and hospital readmission for worsening heart failure following ivabradine administration. Results: In the cohort of 29 enrolled patients (median age: 66 years, 62% male), the median baseline heart rate was 86 beats per minute and the median PR interval was 168 milliseconds. Following ivabradine administration, a significant decrease of 20 beats per minute in the heart rate and a significant increase of 24 milliseconds in the PR interval were observed. The truncated interval of the A-wave, detected in the trans-mitral flow, consistently demonstrated a negative correlation with the PR interval both before and after the administration of ivabradine. During a median of 1.8 years of follow-up, six patients reached the primary endpoint. A combination of heart rate reduction and PR prolongation following ivabradine administration, both of which were independent factors associated with the primary endpoint (p < 0.05 for both), was associated with greater freedom from the primary endpoint compared with either/neither of them (p = 0.002). Conclusions: Ivabradine seems to prolong PR interval, which is a novel surrogate marker of favorable clinical outcomes in patients with systolic heart failure. This effect may be associated with the dynamics of the trans-mitral flow pattern, in conjunction with heart rate and the PR interval. Clinical implications of PR interval-guided ivabradine therapy remains the future concern. [ABSTRACT FROM AUTHOR]

Objective: Polypharmacy prevalence is increasing worldwide, and it is becoming more popular among the elderly. This study aimed to compare the prevalence of potentially inappropriate medications (PIMs) using the Beers criteria (2019 edition), criteria for potentially inappropriate medications for older adults in China (Chinese criteria), Screening Tool of Older Persons’ Prescriptions (STOPP), and Screening Tool to Alert to Right Treatment (START) criteria and to identify risk factors associated with PIM use. Methods: This was a cross-sectional study with a sample of 276 inpatients aged ≥65 years old from January 2020 to June 2020. A cross-sectional study was conducted to analyze PIMs based on the Beers (2019 edition), Chinese, STOPP, and START criteria. PIMs use was analysed based on four different criteria and logistic regression analysis was used to investigate independent factors associated with PIM use. Results: The mean number of medications used by the elderly population was nine (range, 0–28). A total of 252 patients (accounting for 91.30%) took five or more medications and 120 patients (accounting for 43.48%) took 10 or more medications. The prevalence rates of PIMs were 66.30% (183/276), 55.07% (152/ 276), 26.45% (73/276), and 64.13% (177/276) determined by the Beers, Chinese, STOPP, and START criteria, respectively. The top PIMs screened using the Beers, Chinese, and STOPP criteria were proton pump inhibitors, clopidogrel, and benzodiazepines, respectively. Missed use of ACEI in patients with systolic heart failure and/or coronary artery disease was found to be the most common potential prescription omission (PPOs) analyzed using the START criteria. Logistic regression analysis showed that the strongest predictor of PIMs, as determined by all four criteria, was an increased number of medications (p < 0.001). Age was another risk factor for PIMs based on the STOPP criteria in our study (p < 0.05). Conclusion: Polypharmacy and PIMs were common in our study, and the risk of PIMs correlated with polypharmacy. Application of the Beers, Chinese, STOPP, and START criteria is a useful tool for detecting PIM use. [ABSTRACT FROM AUTHOR]

Objective(s): To investigate the effects and mechanisms of ivabradine (IVA) on isoprenaline-induced cardiac injury. Materials and Methods: Forty male C57BL/6 mice were randomly divided into control group, model group, high-dose IVA group, and low-dose IVA group. The control group was given saline, other groups were given subcutaneous injections of isoproterenol (ISO) 5 mg/kg/d to make the myocardial remodeling model. A corresponding dose of IVA (high dose 50 mg/kg/d, low dose 10 mg/kg/d) was given by gavage (30 days). A transthoracic echocardiogram was obtained to detect the structure and function of the heart. An electron microscope was used to explore the cardiomyocytes' apoptosis and autophagy. HE staining and Masson's trichrome staining were performed to explore myocardial hypertrophy and fibrosis. Western blot was used to detect Bax, Bcl-2, cleaved caspase-3, Becline-1, LC3, phosphorylated p38 mitogen-activated protein kinase (p-p38MAPK), phosphorylated extracellular regulated protein kinases1/2 (p-ERK1/2), phosphorylated c-Jun N-terminal kinase (p-JNK), and a-smooth muscle actin (a-SMA) in the myocardium. Results: Heart rate in the IVA groups was reduced, and the trend of heart rate reduction was more obvious in the high-dose group. Echocardiography showed that IVA improved the cardiac structure and function compared to the model group. IVA attenuated cardiac fibrosis, decreased cardiomyocyte apoptosis, and increased autophagy. The phosphorylated MAPK in the ISO-induced groups was increased. IVA treatment decreased the p-p38MAPK level. There were no differences in p-ERK and p-JNK levels. Conclusion: The beneficial effects of IVA on myocardial injury are related to blocking the p38MAPK signal pathway, decreasing cardiomyocyte apoptosis, and increasing cardiomyocyte autophagy. [ABSTRACT FROM AUTHOR]

Introduction: Peri-anaesthetic haemodynamic alterations, such as hypertension and tachycardia, can cause increased bleeding during Functional Endoscopic Sinus Surgery (FESS), impairing the visibility of the surgical field and resulting in scarring, adhesions, and prolonged surgery time. Various strategies involving pharmacological techniques have been used to mitigate these unfavourable reflexes. Alpha-2 agonists, such as Clonidine, are currently being employed to attenuate sympathoadrenal stimulation caused by tracheal intubation and surgery. Ivabradine is a new drug that selectively lowers Heart Rate (HR) by inhibiting cardiac funny current channels. Aim: To compare the effects of premedication with oral Clonidine versus oral Ivabradine on attenuating haemodynamic stress response and improving the quality of the surgical field in FESS. Materials and Methods: The present randomised, placebocontrolled, double-blind study was conducted in the Department of Anaesthesiology and Intensive care at Rajendra Hospital, Government Medical College, Patiala, Punjab, India from April 2021 to December 2022 on 90 American Soceity of Anaesthelogists (ASA) Physical status I and II adult patients (aged 18-60 years) undergoing FESS. Group A (n=30) received oral Ivabradine 5 mg, Group B (n=30) received oral Clonidine 0.2 mg, and Group C (n=30) received oral placebo tablets 2 hours before surgery. Haemodynamic parameters, including HR and Mean Arterial Pressure (MAP), quality of the intraoperative surgical field, postoperative sedation score, Visual Analogue Scale (VAS) score, time to analgesia request, blood loss, and adverse effects, were recorded. Descriptive statistics were used to calculate mean±Standard Deviation (SD) and percentage. Analysis of Variance (ANOVA), Tukey post-hoc test, Kruskal-wallis H test, and Pearson's Chi-square were applied as appropriate. Results: The mean ages were 33.87±12.84, 35.03±12.93, and 40.9±14.46 years for Groups A, B, and C, respectively. The mean weights were 60.5±8.91, 57.83±5.66, and 57.9±5.42 kg, and the mean duration of surgery was 88.67±4.29, 88.8±4.29, and 88.03±3.93 minutes for Groups A, B, and C, respectively. There were no significant differences in terms of gender, ASA score, and type of surgery between the groups. Baseline HR and MAP were comparable among the groups. HR was significantly lower in both Groups A and B compared to Group C at all time intervals (p-value <0.001). Both drugs significantly attenuated tachycardia and hypertension in response to cardiovascular stress induced by laryngoscopy, endotracheal intubation, and extubation. However, Group B showed significantly better control of MAP throughout the intraoperative period and at extubation. The average category scale score, estimated blood loss, and postoperative VAS Score were all significantly lower in Group B than in Group A. Postoperative sedation scores were significantly higher in Group B, and the time to first rescue analgesic was longest in Group B (p<0.05). No significant side effects were observed. Conclusion: Both Clonidine and Ivabradine effectively attenuated the haemodynamic stress response. Clonidine provided better control of MAP, resulting in reduced bleeding, improved operative field visibility, and lower postoperative analgesic requirements compared to Ivabradine. [ABSTRACT FROM AUTHOR]

Background Pulsus alternans has been considered a sign of poor prognosis in patients undergoing treatments for heart failure. However, it may be overlooked in patients with intra-aortic balloon pumps (IABPs). The use of IABP and ivabradine for a β-blocker introduction in a patient with dilated cardiomyopathy (DCM) and pulsus alternans and its consequence have never been reported. Case summary In a 16-year-old high school boy with idiopathic DCM [left ventricular end-diastolic diameter (LVDd), 72 mm; left ventricular ejection fraction (LVEF), 18%], the introduction of carvedilol therapy failed, causing cardiogenic shock under inotropes. Therefore, an IABP support was provided, and he was transferred to our hospital. The arterial pressure waveform under IABP demonstrated pulsus alternans with sinus tachycardia at 135/min. Ivabradine reduced the heart rate to ∼100/min and eliminated the pulsus alternans neither decreasing the cardiac index nor increasing the pulmonary artery wedge pressure. Subsequently, carvedilol was reintroduced, and IABP and inotropes were discontinued. Then, 112 days after his transfer to our hospital, left ventricular reverse remodelling was confirmed (LVDd, 54 mm; LVEF, 44%), and he returned to school. The carvedilol dose reached 20 mg/day in 4 months after discharge, and further improvement was observed a year after discharge (LVDd, 54 mm; LVEF, 52%). Discussion Pulsus alternans is considered a predictor of poor prognosis. However, IABP and ivabradine may stabilize the haemodynamics in pulsus alternans, leading to a successful β-blocker introduction. [ABSTRACT FROM AUTHOR]

Background: While ivabradine has demonstrated benefits in heart rate control and prognosis for chronic heart failure patients, its application in acute decompensated heart failure remains underexplored. Hypothesis: For patients with acute decompensated heart failure with reduced ejection fraction (HFrEF) who are intolerant to β‐blockers or unable to further titrate their dosage, the use of ivabradine is hypothesized to be effective and safe is improving outcomes. Methods: This retrospective, multicenter database analysis included patients with hospitalized decompensated heart failure with a left ventricular ejection fraction of ≤40% from June 1, 2015 to December 31, 2020. The exclusion criteria were a baseline heart rate of <70 bpm, previous use of ivabradine, mortality during admission, existing atrial fibrillation, or atrial flutter. The primary outcome was the composite of cardiovascular death and hospitalization for heart failure. Results: Of the 4163 HFrEF patients analyzed, 684 (16.4%) were administered ivabradine during their index admission. After matching, there were 617 patients in either group. The results indicated that ivabradine use was not significantly associated with the risk of the primary composite outcome (hazard ratio: 1.10; 95% confidence interval: 0.94−1.29). Similarly, the risk of secondary outcomes and adverse renal events did not significantly differ between the ivabradine and non‐ivabradine cohorts (all p >.05). Conclusion: For hospitalized acute decompensated heart failure patients who are intolerant to β‐blockers or cannot further titrate them, ivabradine offers a consistent therapeutic effect. No significant disparities were noted between the ivabradine and non‐ivabradine groups in heart failure hospitalization and cardiovascular death. [ABSTRACT FROM AUTHOR]

The article discusses the results of a randomized trial called the NICE study, which aimed to assess the role of measuring natriuretic peptides (NPs) in the management of patients with heart failure (HF) and preserved ejection fraction (HFpEF). The trial found that serial post-discharge measurement of N-terminal pro-B-type natriuretic peptide (NT-proBNP) did not significantly reduce HF rehospitalizations at 6 months compared to usual care. However, there was a lower risk of all-cause death in the NT-proBNP group. The article highlights the limitations of the study and discusses the conflicting results of other trials on NP monitoring in HF. It suggests that NP measurements should be used as part of a comprehensive monitoring approach for HF treatment optimization. [Extracted from the article]

Abstract Aims Early start and patient profile‐oriented heart failure (HF) management has been recommended. In this post hoc analysis from the SHIFT trial, we analysed the treatment effects of ivabradine in HF patients with systolic blood pressure (SBP) 25% (HR 0.85, 95% CI 0.72–1.01 vs. HR 0.80, 95% CI 0.71–0.90, P interaction = 0.53), and NYHA III–IV and II (HR 0.83, 95% CI 0.74–0.94 vs. HR 0.81, 95% CI 0.69–0.94, P interaction = 0.79). The effect was more pronounced in patients with RHR ≥ 75 compared with

Background: An important biomarker for chronic heart failure is raised plasma myeloperoxidase (MPO) concentrations, which indicate increased oxidative stress and leukocyte activation. When managing this intricate cardiovascular condition, monitoring MPO levels provides information for prognosis and customized therapies. Aims and Objective: To study Plasma myeloperoxidase levels in chronic heart failure and its prognostic significance and Echocardiographic factors. Methodology: The ADEPT study's neurohormonal sub-study, which focuses on 140 ambulatory patients with stable, chronic systolic heart failure, is described in depth in the research methodology. The study uses SAS and JMP statistical software versions 5.1 and 9.1 for statistical analyses, and it covers participant demographics, data collection techniques, laboratory protocols, and statistical analysis. When a p-value was 0.05 or less, it was considered significant. Result: "Elevated plasma myeloperoxidase (MPO) in chronic heart failure (CHF) is linked to right ventricular dysfunction and influences the efficacy of cardiac resynchronization therapy. Higher MPO levels correlate with increased risk of adverse events, and integrating MPO with B-type natriuretic peptide enhances the accuracy of predicting future clinical outcomes, offering a valuable tool for personalized CHF management. Conclusion: "Elevated myeloperoxidase (MPO) levels in chronic heart failure (CHF) correlate with worsened right ventricular function, especially in patients with LVEF below 35%. High MPO levels predict adverse outcomes; enhancing BNP, testing is accuracy, and serve as a potential prognostic indicator for CRT response. MPO also reflects CHF severity in echocardiographic parameters, underlining its significance in predicting adverse clinical events. [ABSTRACT FROM AUTHOR]

Introduction: Scombroid poisoning is a condition that occurs after ingestion of seafood and can cause cardiac and respiratory effects, shock, and life-threatening conditions, as well as gastrointestinal findings caused by increased histamine levels. Case Report: The detailed history of the 80-year-old male patient who presented to the emergency department with chest pain, nausea and vomiting revealed that he had consumed an excessive amount of anchovies 10 hours prior to admission. On follow-up, the patient's blood pressure was 142/66 mmHg and heart rate was 48/min. Bradycardia, PR interval prolongation and ST depressions were observed on the initial ECG. No troponin elevation was observed during the patient's follow-up in the emergency department, and the patient was treated with antihistamines, steroids, and fluid resuscitation, and his condition was assessed as scombroid toxicity. The follow-up ECG of the patient whose symptoms resolved after treatment showed that the bradycardia had resolved, the heart rhythm was 65 bpm, the PR interval prolongation had returned to normal, and the signs of first-degree AV block had resolved. Conclusion: While tachycardia and bronchospasm have been observed in scambroid poisoning in the literature, in our case bradycardia was observed to develop as a result of vagal stimulation due to increased histamine. Increased histamine levels can cause lifethreatening situations by producing bradycardia, which can develop into asystole with vagal nerve impulses. The use of antihistamines in the treatment of bradycardia, which is one of the effects of histamine, shows a good prognosis, as in our case. [ABSTRACT FROM AUTHOR]

Background: Heart failure is a chronic disease linked with significant morbidity and mortality, and uncontrolled resting heart rate is a risk factor for adverse outcomes. This systematic literature review aimed to assess the efficacy, safety, and patient-reported outcomes (PROs) of ivabradine in patients with heart failure (HF) with reduced ejection fraction (HFrEF) in randomized controlled trials (RCTs) and observational studies. Methods: We searched electronic databases from their inception to July 2021 to include studies that reported on efficacy, safety, or PROs of ivabradine in patients with HFrEF. Results: Of 1947 records screened, 51 RCTs and 6 observational studies were identified. Ivabradine on top of background therapy demonstrated a significant reduction in composite outcomes including hospitalization for HF or cardiovascular death. In addition, observational studies suggested that ivabradine was associated with a significant reduction in mortality. Across all studies, ivabradine use on top of background therapy was associated with greater reductions in heart rate, improved EF, and improved health-related quality of life (QoL) and comparable risk of total adverse events compared to those treated with background therapy alone. Conclusions: Ivabradine on top of background therapy is beneficial for heart rate, hospitalization risk for HF, mortality, EF, and patients' QoL. Moreover, these benefits were achieved with no significant increase in the overall risk of total adverse events. [ABSTRACT FROM AUTHOR]

Background and Objectives: Cancer therapy containing anthracyclines is associated with cancer-treatment-related cardiac dysfunction and heart failure (HF). Conventional cardioprotective medications can be frequently complicated by their blood-pressure-lowering effect. Recently, elevated resting heart rate was shown to independently predict mortality in patients with cancer. As a heart rate-lowering drug without affecting blood pressure, ivabradine could present an alternative management of anthracyclines-induced cardiotoxicity. Materials and Methods: This study aimed to investigate the probable protective effects of ivabradine in cancer patients with elevated heart rate (>75 beats per minute) undergoing anthracycline chemotherapy. Patients referred by oncologists for baseline cardiovascular risk stratification before anthracycline chemotherapy who met the inclusion criteria and had no exclusion criteria were randomly assigned to one of two strategies: ivabradine 5 mg twice a day (intervention group) or controls. Electrocardiogram, transthoracic echocardiogram with global longitudinal strain (GLS), troponin I (Tn I), and N-terminal natriuretic pro-peptide (NT-proBNP) were performed at baseline, after two and four cycles of chemotherapy and at six months of follow-up. The primary endpoint was the prevention of a >15% reduction in GLS. Secondary endpoints were effects of ivabradine on Tn I, NT-proBNP, left ventricular (LV) systolic and diastolic dysfunction, right ventricle dysfunction, and myocardial work indices. Results: A total of 48 patients were enrolled in the study; 21 were randomly assigned to the ivabradine group and 27 to the control group. Reduced GLS was detected 2.9 times less often in patients receiving ivabradine than in the control group, but this change was non-significant (OR [95% CI] = 2.9 [0.544, 16.274], p = 0.208). The incidence of troponin I elevation was four times higher in the control group (OR [95% CI] = 4.0 [1.136, 14.085], p = 0.031). There was no significant change in NT-proBNP between groups, but the increase in NT-proBNP was almost 12% higher in the control group (OR [95% CI] = 1.117 [0.347, 3.594], p = 0.853). LV diastolic dysfunction was found 2.7 times more frequently in the controls (OR [95% CI] = 2.71 [0.49, 15.10], p = 0.254). Patients in the ivabradine group were less likely to be diagnosed with mild asymptomatic CTRCD during the study (p = 0.045). No differences in right ventricle function were noted. A significant difference was found between the groups in global constructive work and global work index at six months in favour of the ivabradine group (p = 0.014 and p = 0.025). Ivabradine had no adverse effects on intracardiac conduction, ventricular repolarization, or blood pressure. However, visual side effects (phosphenes) were reported in 14.3% of patients. Conclusions: Ivabradine is a safe, well-tolerated drug that has shown possible cardioprotective properties reducing the incidence of mild asymptomatic cancer-therapy-induced cardiac dysfunction, characterised by a new rise in troponin concentrations and diminished myocardial performance in anthracycline-treated women with breast cancer and increased heart rate. However, more extensive multicentre trials are needed to provide more robust evidence. [ABSTRACT FROM AUTHOR]

New, simple, accurate, sensitive and validated high performance thin layer chromatographic (HPTLC) method coupled with UV absorbance mode and fluorescence (FL) detectors which were used for simultaneous determination of ivabradine (IVA) and metoprolol (MET) in their bulk and pharmaceutical dosage form using TLC silica 60 F254 plates and non-fluorescent TLC silica gel 60 plates. The developing system was chloroform: methanol: formic acid: ammonia (8.5:1.5:0.2:0.1, v/v). Desnitometric analysis in UV absorbance mode was set at λ = 275 nm. While, fluorescence mode was performed with excitation at 260 nm for quantitative simultaneous determination of IVA and MET using optical filter K320. The retention factors values were 0.45 ± 0.05 and 0.89 ± 0.01 of IVA and MET, respectively. UV absorbance mode, linearity was 50.0–600.0 ng/band for IVA and 50.0–900.0 ng/band for MET. For fluorescence mode, the linearity ranges were 18.0–400.0 ng/band and 50.0–550.0 ng/band for IVA and MET; respectively. ICH guidelines were followed in respect to linearity and range, accuracy, precision and selectivity, limit of detection (LOD), limit of quantitation (LOQ) and robustness. The analytical eco-scale, green analytical procedure index (GAPI) and analytical greenness metric tools were used to assess the suggested method. The quantitative proposed method results showed there was no statistically significant difference at 95% confidence when compared to the reported method of high performance liquid chromatography (HPLC). [ABSTRACT FROM AUTHOR]

Aim. Pharmacologic reduction in heart rate with beta-blockers (BB) or ivabradine is associated with improved survival in heart failure (HF) with sinus rhythm. We analyzed the association of different heart rate-reducing drug treatments on outcomes in HF outpatients. Methods. Consecutive patients with HF in sinus rhythm referred to a specialized tertiary service were prospectively enrolled from August 2015 until March 2018. Clinical characteristics were assessed at baseline. We performed Cox regression analyses to examine the effect of the resting heart rate and different heart rate-reducing drug regimens on all-cause mortality and a composite endpoint of "all-cause mortality or heart transplantation" over a mean follow-up of 3.1 years. Results. Of the 278 patients included, 213 (76.6%) were male, the median age was 57.0 years (IQR 49.0–66.1), and 185 (73.7%) had an ejection fraction <40%. Most patients received BB in submaximal [n = 118] or maximum dose [n = 136]. Patients on BB in maximum dose plus ivabradine [n = 24] were younger (53.0 vs. 58.0 years) and had a lower EF (25 vs. 31%). Higher resting heart rate was associated with an increased risk of death or transplantation (HR 1.03 [1.01, 1.06], p = 0.0072), even after adjusting for age and sex. There were no differences between the groups concerning all-cause mortality or the composite endpoint. Conclusion. Our prospective study confirms the association between low heart rate and survival in HF patients receiving various heart rate-reducing medications. We could not identify a specific effect of either regimen. [ABSTRACT FROM AUTHOR]

An increase in blood pressure and increased heart rate is commonly associated with laryngoscopy and intubation if done before attaining an adequate depth of anaesthesia. However failure to counteract the catecholamine response to intubation may have disastrous consequences. In patients with hypertension, increased intracranial pressure, aneurysmal vascular disease, and diseased cerebral vasculature or ischemic heart disease, additional care has to be taken while intubating. Hence, we performed a study to optimize the hemodynamics prior to laryngoscopy and intubation. METHODS AND MATERIALS- This is a prospective randomized controlled trial that included 60 patients divided into two groups- I and II. The study included of patients aged 18-60 years, both males and females, weighing between 50-70 kgs, belonging to ASA class I/II. The study excluded those patients with Hypersensitivity to ivabradine, Resting heart rate below or equal to 60 beats per minute, SA and AV block patients, Patient on antihypertensive medications, Patient with severe hepatic insufficiency and Pregnant females and lactating mothers. Drug--Ivabradine in 2.5mg and 5 mg doses Each patient underwent a thorough preanaesthetic examination and all routine laboratory test including hemogram, coagulogram, biochemical indices, X-Ray chest and ECG and other special investigations if necessary. RESULTS- There was a statistically significant difference in the SBP, MBP and DBP at 30 and 45 minute duration post administration of IVABRADINE 5 mg when compared to 2.5 mg. However, there was no significant alteration in SpO2 and EtCO2. CONCLUSION- IVABRADINE is a safe drug administered prior to the laryngoscopy and intubation as it ensures optimal hemodynamics throughout the procedure. [ABSTRACT FROM AUTHOR]

Background: Ginsenoside Rb2 is beneficial in cardiovascular disease treatment, yet its role in heart failure (HF) is obscure. This study aimed to investigate the effect and mechanism of ginsenoside Rb2 on HF. Methods: The left anterior descending branch-ligated HF rat model and oxygen-glucose deprivation/reoxygenation (OGD/R) H9c2 cell model were constructed. Ginsenoside Rb2 were applied for intervention. Heart function indexes, miR-216a-5p expression, autophagy, oxidative stress, apoptosis, cell morphology, and proliferation were detected to explore the effect of ginsenoside Rb2 on HF. Overexpression of miR-216a-5p was employed to explore the specific mechanism of ginsenoside Rb2 on HF. Results: Ginsenoside Rb2 improved the heart function of HF rats, including the reduction of heart rate, LVEDP, and heart weight/ body weight ratio, and the increase of LVSP, +dP/dtmax, -dP/dtmax, LVEF, and LVFS. It also down-regulated miR-216a-5p expression and enhanced OGD/R-induced cardiomyocyte viability. Ginsenoside Rb2 up-regulated Bcl2, LC3B II/I, and Beclinl, and down-regulated Bax, Caspase-3, and p62 in the myocardium of HF rats and OGD/R-induced H9c2 cells. Moreover, ginsenoside Rb2 increased the levels of SOD and CAT, but decreased the levels of MDA and ROS in the myocardium of HF rats and OGD/R-induced H9c2 cells. However, overexpression of miR-216a-5p promoted the apoptosis and oxidative stress of cardiomyocytes and inhibited autophagy, thus reversing the therapeutic effect of ginsenoside Rb2 on HF in vivo and in vitro. Conclusion: Ginsenoside Rb2 demonstrated potential as a therapeutic intervention for HF by enhancing autophagy and reducing apoptosis and oxidative stress through miR-216a-5p downregulation. Further research could explore its application in clinical trials and investigate the complex mechanism networks underlying its effects. [ABSTRACT FROM AUTHOR]

Aims: Early start and patient profile‐oriented heart failure (HF) management has been recommended. In this post hoc analysis from the SHIFT trial, we analysed the treatment effects of ivabradine in HF patients with systolic blood pressure (SBP) < 110 mmHg, resting heart rate (RHR) ≥ 75 b.p.m., left ventricular ejection fraction (LVEF) ≤ 25%, New York Heart Association (NYHA) Class III/IV, and their combination. Methods and results: The SHIFT trial enrolled 6505 patients (LVEF ≤ 35% and RHR ≥ 70 b.p.m.), randomized to ivabradine or placebo on the background of guideline‐defined standard care. Compared with placebo, ivabradine was associated with a similar relative risk reduction of the primary endpoint (cardiovascular death or HF hospitalization) in patients with SBP < 110 and ≥110 mmHg [hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.74–1.08 vs. HR 0.80, 95% CI 0.72–0.89, P interaction = 0.34], LVEF ≤ 25% and >25% (HR 0.85, 95% CI 0.72–1.01 vs. HR 0.80, 95% CI 0.71–0.90, P interaction = 0.53), and NYHA III–IV and II (HR 0.83, 95% CI 0.74–0.94 vs. HR 0.81, 95% CI 0.69–0.94, P interaction = 0.79). The effect was more pronounced in patients with RHR ≥ 75 compared with <75 (HR 0.76, 95% CI 0.68–0.85 vs. HR 0.97, 95% CI 0.81–0.1.16, P interaction = 0.02). When combining these profiling parameters, treatment with ivabradine was also associated with risk reductions comparable with patients with low‐risk profiles for the primary endpoint (relative risk reduction 29%), cardiovascular death (11%), HF death (49%), and HF hospitalization (38%; all P values for interaction: 0.40). No safety concerns were observed between study groups. Conclusions: Our analysis shows that RHR reduction with ivabradine is effective and improves clinical outcomes in HF patients across various risk indicators such as low SBP, high RHR, low LVEF, and high NYHA class to a similar extent and without safety concern. [ABSTRACT FROM AUTHOR]

We aimed to investigate the potential benefits of two doses of ivabradine (IVA)-an If sodium channel blocker against isoproterenol (ISO)-induced myocardial damage in rats.The rats were randomly divided into 4 groups: Control group (n=8); Saline was administered, ISO group (n=12); 150 mg/kg ISO was administered for 2 days, ISO+IVA (1 mg/kg) group (n=12); 1 mg/kg IVA was administered for 4 days in addition to ISO. ISO+IVA (10 mg/kg) group (n=12): 10 mg/kg IVA was administered for 4 days in addition to ISO. Thereafter, hemodynamic, histopathological, and biochemical studies were performed. In the ISO+IVA (1 mg/kg) and ISO+IVA (10 mg/kg) groups, ISO-induced myocardial changes including an increase in density of granulation tissue and degenerated cardiomyocyte were equally decreased. HR was mildly reduced, and arterial blood pressures were slightly increased in the IVA-treated groups versus the ISO group. In the hearts of IVA-treated groups, malondialdehyde (MDA) levels were significantly reduced and glutathione (GSH) level and catalase (CAT) activity were mildly increased compared to the ISO group. Elevation of GSH and CAT activity were more pronounced in the ISO+IVA (10 mg/kg) group. Our results indicate that both 1 mg/kg and 10 mg/kg doses of IVA are effective against heart damage induced by ISO via its negative chronotropic, anti-oxidant (dose-dependent), anti-inflammatory and anti-degenerative properties. [Med-Science 2023; 12(3.000): 667-73]

Objectives: Ivabradine may have a role in rate control of atrial fibrillation (AF) due to effects on HCN channels in AV node. We studied role of Ivabradine in rate control of rheumatic AF. Methods: 80 patients, rheumatic AF, HR > 100 bpm (age 47 ± 11 yrs, AF duration 6.8 ± 2.9 years, rate 131 ± 16 bpm) on maximally tolerated ββ or CCB's, randomized to Ivabradine or escalated ββ/CCB. Ivabradine started @ 2.5 mg BD; increased to 5 mg BD if inadequate response at 1 week (failure to decrease HR 1 EHRA class; baseline 60% vs 17%3Better LA Strain (22.8 ± 2.8% vs 20.6 ± 2.5%)Ivabradine was well tolerated and there was no drug withdrawal. Conclusion: Our data suggest that Ivabradine can be an option for rate control in rheumatic AF.

Abstract New, simple, accurate, sensitive and validated high performance thin layer chromatographic (HPTLC) method coupled with UV absorbance mode and fluorescence (FL) detectors which were used for simultaneous determination of ivabradine (IVA) and metoprolol (MET) in their bulk and pharmaceutical dosage form using TLC silica 60 F254 plates and non-fluorescent TLC silica gel 60 plates. The developing system was chloroform: methanol: formic acid: ammonia (8.5:1.5:0.2:0.1, v/v). Desnitometric analysis in UV absorbance mode was set at λ = 275 nm. While, fluorescence mode was performed with excitation at 260 nm for quantitative simultaneous determination of IVA and MET using optical filter K320. The retention factors values were 0.45 ± 0.05 and 0.89 ± 0.01 of IVA and MET, respectively. UV absorbance mode, linearity was 50.0–600.0 ng/band for IVA and 50.0–900.0 ng/band for MET. For fluorescence mode, the linearity ranges were 18.0–400.0 ng/band and 50.0–550.0 ng/band for IVA and MET; respectively. ICH guidelines were followed in respect to linearity and range, accuracy, precision and selectivity, limit of detection (LOD), limit of quantitation (LOQ) and robustness. The analytical eco-scale, green analytical procedure index (GAPI) and analytical greenness metric tools were used to assess the suggested method. The quantitative proposed method results showed there was no statistically significant difference at 95% confidence when compared to the reported method of high performance liquid chromatography (HPLC).

In patients with septic shock, compensatory tachycardia initially serves to maintain adequate cardiac output and tissue oxygenation but may persist despite appropriate fluid and vasopressor resuscitation. This sustained elevation in heart rate and altered heart rate variability, indicative of autonomic dysfunction, is a well-established independent predictor of adverse outcomes in critical illness. Elevated heart rate exacerbates myocardial oxygen demand, reduces ventricular filling time, compromises coronary perfusion during diastole, and impairs the isovolumetric relaxation phase of the cardiac cycle, contributing to ventricular-arterial decoupling. This also leads to increased ventricular and atrial filling pressures, with a heightened risk of arrhythmias. Ivabradine, a highly selective inhibitor of the sinoatrial node’s pacemaker current (If or “funny” current), mitigates heart rate by modulating diastolic depolarization slope without affecting contractility. By exerting a selective chronotropic effect devoid of negative inotropic properties, ivabradine shows potential for improving hemodynamics in septic shock patients with cardiac dysfunction. This review evaluates the plausible mechanisms and existing evidence regarding the utility of ivabradine in managing patients with septic shock.

Sinoatrial node myocytes (SAMs) act as cardiac pacemaker cells by firing spontaneous action potentials (APs) that initiate each heartbeat. The funny current (If) is critical for the generation of these spontaneous APs; however, its precise role during the pacemaking cycle remains unresolved. Here, we used the AP-clamp technique to quantify If during the cardiac cycle in mouse SAMs. We found that If is persistently active throughout the sinoatrial AP, with surprisingly little voltage-dependent gating. As a consequence, it carries both inward and outward current around its reversal potential of -30 mV. Despite operating at only 2 to 5% of its maximal conductance, If carries a substantial fraction of both depolarizing and repolarizing net charge movement during the firing cycle. We also show that β-adrenergic receptor stimulation increases the percentage of net depolarizing charge moved by If, consistent with a contribution of If to the fight-or-flight increase in heart rate. These properties were confirmed by heterologously expressed HCN4 channels and by mathematical models of If Modeling further suggested that the slow rates of activation and deactivation of the HCN4 isoform underlie the persistent activity of If during the sinoatrial AP. These results establish a new conceptual framework for the role of If in pacemaking, in which it operates at a very small fraction of maximal activation but nevertheless drives membrane potential oscillations in SAMs by providing substantial driving force in both inward and outward directions.

Abstract Background Elevated resting heart rate (HR) predicts poor outcomes in patients with coronary artery disease. Ivabradine has been recommended as a second-line anti-anginal agent in chronic coronary syndrome, while there are no clear indications for acute ST-elevation myocardial infarction (STEMI). Results We systematically searched PubMed, Medline, EMBASE, Clinical Trials.gov, and the Cochrane Central Register of Controlled Trials with search terms Ivabradine and Acute myocardial infarction. There are two study outcomes from this study: therapeutic and safety effects. Therapeutic effects include the efficacy of Ivabradine on HR, all-cause mortality, heart failure incidence, left ventricular function and remodeling. Safety effects include troponin levels and ischemic events (recurrent angina pectoris). A total of 6 RCTs was included and showed that Ivabradine was associated with greater resting HR reduction [MD − 5.40; 95%CI − 8.60, − 2.20], improvement of left ventricular ejection fraction [MD 2.98; 95%CI 0.44, 5.51], and left ventricular end systolic volume [MD − 3.81; 95%CI − 6.88, − 0.75]. However, Ivabradine had no impact on all-cause mortality [OR 0.76; 95%CI 0.35, 1.67], heart failure incidence [OR 0.61; 95%CI 0.21, 1.80], and recurrent angina pectoris [OR 0.71; 95%CI 0.50, 1.00]. Conclusions Ivabradine is safe and effective for resting HR reduction in patients with STEMI; however, it has no significant influence on mortality. These results suggest that an elevated HR is only a marker of risk but not a modifiable determinant of outcomes in patients who have suffered an acute myocardial infarction.

ABSTRACTBackground: Heart failure is a chronic disease linked with significant morbidity and mortality, and uncontrolled resting heart rate is a risk factor for adverse outcomes. This systematic literature review aimed to assess the efficacy, safety, and patient-reported outcomes (PROs) of ivabradine in patients with heart failure (HF) with reduced ejection fraction (HFrEF) in randomized controlled trials (RCTs) and observational studies.Methods: We searched electronic databases from their inception to July 2021 to include studies that reported on efficacy, safety, or PROs of ivabradine in patients with HFrEF.Results: Of 1947 records screened, 51 RCTs and 6 observational studies were identified. Ivabradine on top of background therapy demonstrated a significant reduction in composite outcomes including hospitalization for HF or cardiovascular death. In addition, observational studies suggested that ivabradine was associated with a significant reduction in mortality. Across all studies, ivabradine use on top of background therapy was associated with greater reductions in heart rate, improved EF, and improved health-related quality of life (QoL) and comparable risk of total adverse events compared to those treated with background therapy alone.Conclusions: Ivabradine on top of background therapy is beneficial for heart rate, hospitalization risk for HF, mortality, EF, and patients’ QoL. Moreover, these benefits were achieved with no significant increase in the overall risk of total adverse events.

Background Perioperative myocardial injury is common after major noncardiac surgery and is associated with adverse outcomes. This study investigated the use of ivabradine in patients undergoing urgent surgery for fracture. Methods and Results This was a prospective, double‐blind, placebo‐controlled, randomized clinical trial. Participants were enrolled 1:1 into ivabradine or placebo arm, and study drug was commenced before operation and continued for 7 days or until discharge. High‐sensitivity troponin I was measured daily using Abbott Alinity analyzer and assay, and heart rate data were obtained using continuous Holter monitoring. A total of 199 patients underwent acute orthopedic surgery, 98 in the ivabradine group and 101 in the placebo group. The mean age was 78.7 years (range, 77.5–79.9 years), with 68% women. The average heart rate was 5 to 11 beats per minute lower in the ivabradine group compared with the placebo group at all time points (P