Cardiac Late Sodium Research Articles

The efficacy of ranolazine in improving glycemic parameters in patients with type 2 diabetes mellitus: a meta-analysis

Ranolazine is an anti-anginal drug that mediates its effects by inhibition of cardiac late sodium current. Although it is not indicated for the treatment of type 2 diabetes mellitus (T2DM), several clinical trials have shown that ranolazine was associated with a reduction in HbA1c. The objective of this meta-analysis is to determine the efficacy and safety of ranolazine in improving glycemic control in patients with T2DM. A total of five randomized controlled trials involving 2,680 patients were included in the analysis. The pooled analysis showed that ranolazine may improve glycemic control with a modest decrease in HbA1c and FBS. The difference in HbA1c was -0.38% (95% CI -0.59 to -0.17), favoring ranolazine. Sensitivity analysis showed a difference of HbA1c of -0.49% (CI -0.67, -0.31), still favoring the ranolazine group. There was also a statistically significant difference in fasting glucagon, favoring the ranolazine group (-2.70 pg/ml: 95% CI -5.24 to -0.16). The risk of hypoglycemia with ranolazine was comparable with placebo (RR 1.27 95% CI 0.84 to 1.91). Overall, ranolazine appears to be a safe and effective option for improving glycemic control in patients with T2DM, with a modest decrease in HbA1c and FBS, and a lower risk of hypoglycemia compared to placebo. However, further studies are needed to confirm these findings and to investigate the long-term safety and efficacy of ranolazine in this patient population.

Correction to: Empagliflozin Inhibits Cardiac Late Sodium Current by Ca/Calmodulin-Dependent Kinase II.

Correction to: Empagliflozin Inhibits Cardiac Late Sodium Current by Ca/Calmodulin-Dependent Kinase II.

Abstract 11556: Sodium/Glucose Co-Transporter 2 Inhibition and Attenuation of the Action Potential Duration in Patient-Specific Re-Engineered Heart Cells With Congenital Long QT Syndrome

Background: Long QT syndrome (LQTS) stems from cardiac action potential duration (APD) prolonging pathogenic variants in KCNQ1 (LQT1), KCNH2 (LQT2), or SCN5A (LQT3). Sodium/glucose co-transporter 2 inhibitor (SGLT2i), a class of drugs used to treat type II diabetes and all forms of heart failure, reduces cardiac late sodium channel current. Objective: To test the ability of three commercially available SGLT2i to reduce APD in patient-specific induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) models of LQT1, LQT2, and LQT3. Method: Patient-specific iPSC-CMs and a CRISPR/Cas9 gene-edited variant corrected, isogenic control (IC) iPSC-CMs were generated. The variant-corrected IC was used to determine the curative APD in order to establish the degree of APD attenuation. The SCN5A-P1332L (LQT3) and IC iPSC-CMs were tested with 10 μM of either canagliflozin (CANA), dapagliflozin (DAPA), or empagliflozin (EMPA). An ATXII (5μM)-induced APD prolongation iPSC-CM model, mimicking drug-induced LQT3, was also treated. The APD was measured 30 minutes, 1 hour, and 2 hours after treatment using local extracellular action potential recordings on multielectrode array. The efficacy of these SGLT2i were also tested in KCNQ1-V254M (LQT1) and KCNH2-G604S (LQT2) iPSC-CMs. Results: The APD90 was prolonged in SCN5A-P1332L iPSC-CMs compared to its IC (469 ± 4 ms vs 305 ± 2 ms, p<0.0001). While 10 μM of SGLT2i had no APD shortening effect on the KCNQ1-V254M or KCNH2-G604S iPSC-CMs, all three SGLT2i compounds shortened the APD90 of the SCN5A-P1332L iPSC-CMs after 1 hour of treatment from 463±5 ms to 432±6 ms (EMPA, 18.8% attenuation, p=0.0002), 459±8 ms to 430±5 ms (CANA, 17.5%, p=0.004), and 453±6 ms to 434±4 ms (DAPA, 11.4%, p=0.01). Additionally, IC iPSC-CMs treated with 5 μM of ATXII induced significant APD prolongation from 318±9 ms to 379±12 ms (p=0.0003) after 30 min incubation. However, co-incubation of ATXII and SGLT2i abolished the APD prolonging effect of ATXII. Conclusions: Therapeutically inhibiting SGLT2 effectively shortens the cardiomyocyte APD in human heart cell models of the LQT3, but not LQT1 or LQT2. This pre-clinical data compels further assessment of SGLT2i as a novel therapy for patients with congenital LQT3.

Fibroblast growth factor homologous factors serve as a molecular rheostat in tuning arrhythmogenic cardiac late sodium current.

Voltage-gated sodium (Nav1.5) channels support the genesis and brisk spatial propagation of action potentials in the heart. Disruption of NaV1.5 inactivation results in a small persistent Na influx known as late Na current (I Na,L), which has emerged as a common pathogenic mechanism in both congenital and acquired cardiac arrhythmogenic syndromes. Here, using low-noise multi-channel recordings in heterologous systems, LQTS3 patient-derived iPSCs cardiomyocytes, and mouse ventricular myocytes, we demonstrate that the intracellular fibroblast growth factor homologous factors (FHF1-4) tune pathogenic I Na,L in an isoform-specific manner. This scheme suggests a complex orchestration of I Na,L in cardiomyocytes that may contribute to variable disease expressivity of NaV1.5 channelopathies. We further leverage these observations to engineer a peptide-inhibitor of I Na,L with a higher efficacy as compared to a well-established small-molecule inhibitor. Overall, these findings lend insights into molecular mechanisms underlying FHF regulation of I Na,L in pathophysiology and outline potential therapeutic avenues.

Late Sodium Current of the Heart: Where Do We Stand and Where Are We Going?

Late sodium current has long been linked to dysrhythmia and contractile malfunction in the heart. Despite the increasing body of accumulating information on the subject, our understanding of its role in normal or pathologic states is not complete. Even though the role of late sodium current in shaping action potential under physiologic circumstances is debated, it’s unquestioned role in arrhythmogenesis keeps it in the focus of research. Transgenic mouse models and isoform-specific pharmacological tools have proved useful in understanding the mechanism of late sodium current in health and disease. This review will outline the mechanism and function of cardiac late sodium current with special focus on the recent advances of the area.

Diabetes and SGLT2-iss inhibitors in patients with heart failure with preserved or mid-range left ventricular ejection fractions.

Diabetic patients frequently develop heart failure with preserved (HFpEF) or mid-range (HFmEF) cardiac ejection fractions. This condition may be secondary to diabetic cardiomyopathy or one of several relevant comorbidities, mainly hypertension. Several mechanisms link diabetes to HFpEF or HFmEF. Among these, non-enzymatic glycation of interstitial proteins, lipotoxicity, and endothelial dysfunction may promote structural damage and ultimate lead to heart failure. Findings from several large-scale trials indicated that treatment with sodium/glucose cotransporter 2 inhibitors (SGLT2-iss) resulted in significant improvements in cardiovascular outcomes in diabetic patients with high cardiovascular risk. However, there is currently some evidence that suggests a clinical advantage of using SGLT2-iss specifically in cases of HFpEF or HFmEF. Preclinical and clinical studies revealed that SGLT2-iss treatment results in a reduction in left ventricular mass and improved diastolic function. While some of the beneficial effects of SGLT2-iss have already been characterized (e.g., increased natriuresis and diuresis as well as reduced blood pressure, plasma volume, and arterial stiffness, and nephron-protective activities), there is increasing evidence suggesting that SGLT2-iss may have direct actions on the heart. These findings include SGLT2-iss-mediated reductions in the expression of hypertrophic foetal genes and diastolic myofilaments stiffness, increases in global phosphorylation of myofilament regulatory proteins (in HFpEF), inhibition of cardiac late sodium channel current and Na+/H+ exchanger activity, metabolic shifts, and effects on calcium cycling. Preliminary data from previously published studies suggest that SGLT2-iss could be useful for the treatment of HFpEF and HFmEF. Several large ongoing trials, including DELIVER AND EMPEROR -preserved have been designed to evalute the efficacy of SGLT2-iss in improving clinical outcomes in patients diagnosed with HFpEF. The goal of this manuscript is to review the use of SGLT2-iss inhibitors for HFpEF or HFmEF associated with diabetes.

Mechanical effects of ranolazine on normal and diabetic-isolated rat heart

Background and purpose:Diabetic cardiomyopathy is a complication of diabetes defined as cardiac dysfunction without the involvement of pericardial vessels, hypertension, or cardiac valve disorders. Ranolazine, an antianginal drug, acts through blocking of cardiac late sodium channels and/or inhibiting beta-oxidation of fatty acids. With regard to its mechanism of action, the present work has been carried out to investigate the potential useful effects of ranolazine on the systolic and diastolic dysfunctions in an experimental rat model of diabetic cardiomyopathy. Lidocaine, as a sodium channel blocker, was used to have a clearer image of the involved mechanisms.Experimental approach:Diabetes was induced by streptozocin. After 8 weeks, the effects of cumulative concentrations of ranolazine and lidocaine were evaluated on diabetic and normal hearts by the Langendorff method. Finally, the hearts were isolated from the Langendorff system and adenosine three phosphates (ATP) and adenosine diphosphate (ADP) concentrations were measured to assay the metabolic effect of ranolazine.Findings/Results:Ranolazine significantly decreased the velocity of systolic contraction (+dP/dt) and the velocity of diastolic relaxation (-dP/dt) and developed pressure in normal and diabetic rat hearts. However, this negative effect was greater in normal hearts compared to diabetics. Ranolazine (100 μM) decreased the ATP level only in normal hearts and the ATP/ADP ratio decreased significantly (P < 0.05) in both groups. This reduction was more prominent in normal hearts.Conclusion and implications:It is concluded that in the isolated rat heart preparation, ranolazine has no benefit on diabetic cardiomyopathy and may even worsen it. It seems that these effects are related to the metabolic effects of ranolazine.

Phospho-ablation of cardiac sodium channel Nav1.5 mitigates susceptibility to atrial fibrillation and improves glucose homeostasis under conditions of diet-induced obesity

BackgroundAtrial fibrillation (AF) is the most common sustained arrhythmia, with growing evidence identifying obesity as an important risk factor for the development of AF. Although defective atrial myocyte excitability due to stress-induced remodeling of ion channels is commonly observed in the setting of AF, little is known about the mechanistic link between obesity and AF. Recent studies have identified increased cardiac late sodium current (INa,L) downstream of calmodulin-dependent kinase II (CaMKII) activation as an important driver of AF susceptibility.MethodsHere, we investigated a possible role for CaMKII-dependent INa,L in obesity-induced AF using wild-type (WT) and whole-body knock-in mice that ablates phosphorylation of the Nav1.5 sodium channel and prevents augmentation of the late sodium current (S571A; SA mice).ResultsA high-fat diet (HFD) increased susceptibility to arrhythmias in WT mice, while SA mice were protected from this effect. Unexpectedly, SA mice had improved glucose homeostasis and decreased body weight compared to WT mice. However, SA mice also had reduced food consumption compared to WT mice. Controlling for food consumption through pair feeding of WT and SA mice abrogated differences in weight gain and AF inducibility, but not atrial fibrosis, premature atrial contractions or metabolic capacity.ConclusionsThese data demonstrate a novel role for CaMKII-dependent regulation of Nav1.5 in mediating susceptibility to arrhythmias and whole-body metabolism under conditions of diet-induced obesity.

The selective late sodium current inhibitor eleclazine reduces atrial fibrillation dominant frequency and facilitates the suppression of arrhythmia in HL-1 cells

Abstract Background The cardiac late sodium current (INaL) has been increasingly implicated in the initiation of atrial fibrillation (AF). In fact, it has been reported that the augmentation of INaL in pathophysiological conditions prolongs repolarization and facilitates the appearance of afterdepolarizations, which can act as triggers of arrhythmic activity. Eleclazine is a novel selective inhibitor of INaL and is undergoing clinical testing for the treatment of cardiac arrhythmias. Purpose The aim of this study was to investigate the effects of eleclazine on spectral characteristics of atrial fibrillation in cultured atrial myocyte monolayer in order to assess whether this inhibitor could protect against cardiac arrhythmias. Methods Confluent HL-1 murine atrial myocyte monolayer with spontaneous fibrillatory activity was cultured in 1.5 cm diameter petri dishes (n=10). A high-resolution optical mapping system was used to record fibrillatory activity under basal conditions (without drug), and under eleclazine at increasing concentrations (1, 3 and 5 μM). Power spectra of optical signals were estimated by using Welch periodogram and dominant frequency (frequency with the largest peak in the spectrum between 0.05 and 30 Hz) was determined. The incidence of spontaneous defibrillation was analyzed under control and drug conditions. An ANOVA and a chi-squared test were used. Significance was reached when p&amp;lt;0.05. Results Eleclazine at 1, 3 and 5 μM significantly decreased dominant frequency with respect to basal conditions (basal: 4.74±1.31 Hz; 1μM: 3.59±1.17 Hz, p&amp;lt;0.001; 3μM: 3.19±0.64 Hz, p&amp;lt;0.01; 5μM: 2.58±0.40 Hz, p&amp;lt;0.01). The magnitude of drug-induced decrease in AF activation frequency was enhanced by increasing concentrations (1μM: 27%, 3μM: 42%; 5μM: 46%; p&amp;lt;0.05). After the analysis of optical signals, we observed that the incidence of spontaneous defibrillation in atrial monolayers was significantly greater under eleclazine 5μM action than under control conditions (chi-square=5.00, p=0.025). In fact, under the action of eleclazine 5μM, fibrillatory activity was suppressed in 4 of the 10 monolayers, phenomenon that did not occur in any case of control situation. Conclusions Selective late INa inhibition with eleclazine reduced dominant frequency of atrial fibrillation and facilitates the termination of arrhythmia in cultured atrial myocyte monolayer. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos III, Ministerio de Innovaciόn y Ciencia, Spain; Generalitat Valenciana, Spain

Multiple mechanisms underlie increased cardiac late sodium current

We recently reported a quantitative relationship between the degree of functional perturbation reported in the literature for 356 variants in the cardiac sodium channel gene SCN5A and the penetrance of resulting arrhythmia phenotypes. In the course of that work, we identified multiple SCN5A variants, including R1193Q, that are common in populations but are reported in human embryonic kidney (HEK) cells to generate large late sodium current (INa-L). The purpose of this study was to compare the functional properties of R1193Q with those of the well-studied type 3 long QT syndrome mutation ΔKPQ. We compared functional properties of SCN5A R1193Q with those of ΔKPQ in Chinese hamster ovary (CHO) cells at baseline and after exposure to intracellular phosphatidylinositol (3,4,5)-trisphosphate (PIP3), which inhibits INa-L generated by decreased Phosphoinositide 3-kinase (PI3K) activity. We also used CRISPR/Cas9 editing to generate R1193Q in human-induced pluripotent stem cells differentiated to cardiomyocytes (hiPSC-CMs). Both R1193Q and ΔKPQ generated robust INa-L in CHO cells. PIP3 abrogated the late current phenotype in R1193Q cells but had no effect on ΔKPQ. Homozygous R1193Q hiPSC-CMs displayed increased INa-L and long action potentials with frequent triggered beats, which were reversed with the addition of PIP3. The consistency between the late current produced in HEK cells, CHO cells, and hiPSC-CMs suggests that the late current is a feature of the SCN5A R1193Q variant in human cardiomyocytes but that the mechanism by which the late current is produced is distinct and indirect, as compared with the more highly penetrant ΔKPQ. These data suggest that observing a late current in an invitro setting does not necessarily translate to highly pathogenic type 3 long QT syndrome phenotype but depends on the underlying mechanism.

Inhibition of the α-Subunit of Phosphoinositide 3-Kinase in Heart Increases Late Sodium Current and Is Arrhythmogenic.

Although inhibition of phosphoinositide 3-kinase (PI3K) is an emerging strategy in cancer therapy, we and others have reported that this action can also contribute to drug-induced QT prolongation and arrhythmias by increasing cardiac late sodium current (INaL). Previous studies in mice implicate the PI3K-α isoform in arrhythmia susceptibility. Here, we have determined the effects of new anticancer drugs targeting specific PI3K isoforms on INaL and action potentials (APs) in mouse cardiomyocytes and Chinese hamster ovary cells (CHO). Chronic exposure (10-100 nM; 5-48 hours) to PI3K-α-specific subunit inhibitors BYL710 (alpelisib) and A66 and a pan-PI3K inhibitor (BKM120) increased INaL in SCN5A-transfected CHO cells and mouse cardiomyocytes. The specific inhibitors (10-100 nM for 5 hours) markedly prolonged APs and generated triggered activity in mouse cardiomyocytes (9/12) but not in controls (0/6), and BKM120 caused similar effects (3/6). The inclusion of water-soluble PIP3, a downstream effector of the PI3K signaling pathway, in the pipette solution reversed these arrhythmogenic effects. By contrast, inhibition of PI3K-β, -γ, and -δ isoforms did not alter INaL or APs. We conclude that inhibition of cardiac PI3K-α is arrhythmogenic by increasing INaL and this effect is not seen with inhibition of other PI3K isoforms. These results highlight a mechanism underlying potential cardiotoxicity of PI3K-α inhibitors.

Anti-arrhythmic potential of the late sodium current inhibitor GS-458967 in murine Scn5a-1798insD+/- and human SCN5A-1795insD+/- iPSC-derived cardiomyocytes.

Selective inhibition of cardiac late sodium current (INaL) is an emerging target in the treatment of ventricular arrhythmias. We investigated the electrophysiological effects of GS-458967 (GS967), a potent, selective inhibitor of INaL, in an overlap syndrome model of both gain and loss of sodium channel function, comprising cardiomyocytes derived from both human SCN5A-1795insD+/- induced pluripotent stem cells (hiPSC-CMs) and mice carrying the homologous mutation Scn5a-1798insD+/-. On patch-clamp analysis, GS967 (300 nmol/l) reduced INaL and action potential (AP) duration in isolated ventricular myocytes from wild type and Scn5a-1798insD+/- mice, as well as in SCN5A-1795insD+/- hiPSC-CMs. GS967 did not affect the amplitude of peak INa, but slowed its recovery, and caused a negative shift in voltage-dependence of INa inactivation. GS967 reduced AP upstroke velocity in Scn5a-1798insD+/- myocytes and SCN5A-1795insD+/- hiPSC-CMs. However, the same concentration of GS967 did not affect conduction velocity in Scn5a-1798insD+/- mouse isolated hearts, as assessed by epicardial mapping. GS967 decreased the amplitude of delayed after depolarizations and prevented triggered activity in mouse Scn5a-1798insD+/- cardiomyocytes. The INaL inhibitor GS967 decreases repolarization abnormalities and has anti-arrhythmic effects in the absence of deleterious effects on cardiac conduction. Thus, selective inhibition of INaL constitutes a promising pharmacological treatment of cardiac channelopathies associated with enhanced INaL. Our findings furthermore implement hiPSC-CMs as a valuable tool for assessment of novel pharmacological approaches in inherited sodium channelopathies.

Eleclazine, an inhibitor of the cardiac late sodium current, is superior to flecainide in suppressing catecholamine-induced ventricular tachycardia and T-wave alternans in an intact porcine model

The capacity of catecholamines to induce ventricular tachycardia (VT) is well documented. The effectiveness of the novel cardiac late sodium inhibitor eleclazine in suppressing catecholamine-induced VT in a large animal model was compared with that of flecainide. In 13 closed-chest anesthetized Yorkshire pigs, spontaneous VT and surges in T-wave alternans (TWA) level measured using the Modified Moving Average method were induced by epinephrine (2.0 µg/kg, i.v., bolus over 1 minute). Effects of eleclazine (0.3 mg/kg, i.v., infused over 15 minutes; n = 6) or flecainide (1 mg/kg, i.v., bolus over 2 minutes followed by 1 mg/kg/hr, i.v., for 1 hour; n = 7) on VT incidence and TWA level were measured from right intraventricular electrogram recordings. Epinephrine reproducibly elicited hemodynamically significant spontaneous VT in all 13 pigs and increased TWA level by 33-fold compared to baseline (P < .001). Eleclazine reduced the incidence of epinephrine-induced ventricular premature beats and couplets by 51% (from 31.3 ± 1.91 to 15.2 ± 5.08 episodes; P = .038) and the incidence of 3- to 7-beat VT by 56% (from 10.8 ± 3.45 to 4.7 ± 3.12 episodes; P = .004). Concurrently, the drug reduced the peak epinephrine-induced TWA level by 64% (from 217 ± 22.2 to 78 ± 15.3 µV; P < .001). Flecainide also reduced the incidence of epinephrine-induced ventricular premature beats and couplets by 53% (from 40.4 ± 6.37 to 19.0 ± 2.73 episodes; P = .024) but did not affect the incidence of VT (from 15.0 ± 3.08 to 11.6 ± 2.93 episodes; P = .29) or the peak TWA level (from 207 ± 30.6 to 172 ± 26.2 µV; P = .34). Selective inhibition of cardiac late sodium current with eleclazine is more effective than flecainide in reducing catecholamine-induced VT and TWA in an intact porcine model.

Inhibition of the cardiac late sodium current with eleclazine protects against ischemia-induced vulnerability to atrial fibrillation and reduces atrial and ventricular repolarization abnormalities in the absence and presence of concurrent adrenergic stimulation

Myocardial ischemia carries dual risk for initiating atrial and ventricular arrhythmias that can be exacerbated by adrenergic stimulation. The purpose of this study was to investigate whether selective inhibition of the cardiac late sodium current (INa) with eleclazine decreases susceptibility to ischemia-induced atrial fibrillation (AF) and atrial and ventricular repolarization abnormalities before and after epinephrine infusion. In chloralose-anesthetized, open-chest, male Yorkshire pigs (n = 12), atrial and ventricular ischemia was induced by partial occlusion of the left circumflex coronary artery proximal segment to reduce flow by 75%. Epinephrine (0.5 µg/kg IV bolus over 1 minute; n = 6) was infused before and at 2 hours after eleclazine (0.9 mg/kg IV bolus over 15 minutes). Left circumflex coronary artery occlusion significantly increased ventricular dispersion of repolarization (T-wave alternans [TWA] by 861%, T-wave heterogeneity by 286%, Tpeak-Tend interval by 74%) and atrial repolarization alternans (TWAa) by 2850% and lowered AF threshold by 65%. Eleclazine reduced the ischemia-induced surge in TWA by 81% (P = .007), T-wave heterogeneity by 23% (P = .035), and Tpeak-Tend by 28% (P = .014), suppressed the ischemia-induced surge in atrial TWAa by 64% (P = .002), and reduced the ischemia-induced fall in AF threshold to 20%. It shortened baseline QT interval by 6% (P <.001), JT interval by 8% (P <.001), and atrial action potential duration (PTa) by 8% (P = .002). Similar beneficial effects of eleclazine were observed after epinephrine infusion without reducing contractility (P = .054). Selective inhibition of cardiac late INa with eleclazine confers dual protection against vulnerability to ischemia-induced AF and reduces atrial and ventricular repolarization abnormalities before and during adrenergic stimulation without negative inotropic effects.

Eleclazine, a new selective cardiac late sodium current inhibitor, confers concurrent protection against autonomically induced atrial premature beats, repolarization alternans and heterogeneity, and atrial fibrillation in an intact porcine model

The cardiac late sodium current (INa) has been increasingly implicated in the initiation of atrial fibrillation (AF). Eleclazine (formerly known as GS-6615) is a new selective late INa inhibitor and is undergoing clinical testing for the treatment of cardiac arrhythmias. We tested whether late INa inhibition by eleclazine confers protection against atrial premature beats (APBs) and AF. In closed-chest anesthetized Yorkshire pigs, epinephrine (2.0 µg/kg, intravenous, bolus over 1 minute) was administered alone to induce APBs (n = 6) or in combination with intrapericardial acetylcholine (0.5-4 mL of 12.5 mM solution) to induce spontaneous AF (n = 11). Effects of eleclazine (0.3 and 0.9 mg/kg, intravenous, over 15 minutes) on APBs and AF were determined. Epinephrine-induced APBs were reduced >3-fold (P < .04) after eleclazine (0.9 mg/kg) infusion. The combined administration of epinephrine and acetylcholine resulted in AF in all animals tested, which was invariably preceded by APBs. Eleclazine pretreatment suppressed AF in all 7 animals in at least 1 test episode during the 60- to 150-minute observation period (P = .04). The plasma eleclazine level at 120 minutes was 828 ± 45.8 nM, within exposure range evaluated clinically. Eleclazine shortened ventricular QT and atrial PTa intervals by 7% (P < .001 for both) and reduced atrial repolarization alternans (P = .003) and heterogeneity (P = .021) without attenuation of the inotropic response to catecholamine (P = .56). The drug inhibited the enhanced late INa of single atrial myocytes with a potency of 736 ± 67 nM. Selective cardiac late INa inhibition with eleclazine suppresses autonomically mediated atrial repolarization alternans and heterogeneity, APBs, and AF in an intact porcine model.

The Antianginal Agent Ranolazine Inhibits Mitochondrial β-Oxidation Pathway

Abstract Backgrounds: Ranolazine had two main functions: blocking cardiac late sodium channels and / or inhibition of 3- ketoacyl coenzyme A thiolase, an important enzyme in s-oxidation of fatty acids. Diabetic cardiomyopathy is a complication, defined as cardiac dysfunction without the involvement of epicardial vessels. In this study, the effect of ranolazine on fatty acid oxidation was investigated in diabetic rats induced by streptozotocin. Methods: After 8 weeks of diabetic induction, the effect of ranolazine on fatty acid oxidation rate was studied. Statistical data were analyzed using Mann-Whitney test. Results: The activity of s-oxidation enzymes were inhibited by ranolazine in the normal rat hearts significantly, while no significant inhibition was seen in diabetic ones. Conclusion: Our data suggest that the clinical efficacy of ranolazine in diabetic patients is associated with a mechanism other than inhibition of the s-oxidation pathway activity, although various hypotheses exist in the literature.

The Selective Cardiac Late Sodium Current Inhibitor GS-458967 Suppresses Autonomically Triggered Atrial Fibrillation in an Intact Porcine Model.

The anti-atrial fibrillation (AF) effects of GS-458967 (GS-967), a selective, potent inhibitor of cardiac late Na(+) current (I(Na)), were evaluated in a novel model of AF induction that does not require electrical stimuli. In 6 closed-chest anesthetized pigs, AF was induced by intrapericardial acetylcholine (1 mL of 100 mM solution) followed within 1 minute by epinephrine (20 μg/kg, i.v., bolus over 1 min). Effects of GS-967 (0.4 mg/kg, i.v., infused over 30 min) on inducibility and duration of AF were analyzed. Administration of acetylcholine followed by epinephrine elicited spontaneous AF that persisted for 12.03 ± 1.22 minutes (mean ± SEM) in all 6 pigs. Following GS-967, AF did not occur in 5 of 6 pigs when plasma concentration was 383 ± 150 nM. In the single animal in which AF could still be induced, the arrhythmia lasted 6.3 minutes. Partial return of AF inducibility occurred in 2 of 6 animals at 90 minutes, when plasma concentration of GS-967 was 228 ± 35 nM. GS-967 reduced the QT interval (P = 0.004), consistent with cardiac late I(Na) inhibition, but did not affect heart rate, mean arterial pressure, QRS duration, or PR interval. Epinephrine infusion alone, tested in a separate group (N = 6), did not provoke AF. Selective cardiac late I(Na) inhibition with GS-967 suppresses spontaneous induction of AF in a novel model that does not require provocative electrical stimuli. Because this mode of action has only a mild on effect on contractility, it offers an advantage over contemporary anti-AF agents, which can have negative inotropic actions.

Ранолазин – ингибитор позднего натриевого тока. Возможности использования при аритмиях. Результаты клинических исследований

Ранолазин – ингибитор позднего натриевого тока. Возможности использования при аритмиях. Результаты клинических исследований

Selective late INa inhibition by GS-458967 exerts parallel suppression of catecholamine-induced hemodynamically significant ventricular tachycardia and T-wave alternans in an intact porcine model

Catecholamines can elicit early and delayed afterdepolarizations (EADs and DADs), resulting in ventricular tachyarrhythmias. As inhibition of the cardiac late sodium current (I(Na)) suppresses EADs and DADs, we examined whether GS-458967 (GS-967), a potent inhibitor of this current that is devoid of beta-adrenergic blocking action, can prevent epinephrine-induced ventricular tachycardia (VT) induction in an intact porcine model. In 12 closed-chest anesthetized pigs, spontaneous VT was induced by epinephrine administration (2.0 µg/kg, intravenous, bolus over 1 minute). Effects of GS-967 (0.4 mg/kg, intravenous, infused over 30 minutes) on VT incidence, T-wave alternans (TWA) level, and hemodynamic and electrophysiologic parameters before and after epinephrine were analyzed (N = 6). Effects of vehicle control were investigated in 6 animals. TWA was measured using the Modified Moving Average method. Epinephrine elicited spontaneous hemodynamically significant nonsustained VT in all 6 pigs and increased TWA by 28-fold compared to baseline (P < .001). GS-967 reduced mean 3- to 7-beat VT incidence by 55% (from 9.5 ± 2.72 to 4.3 ± 0.76 beats/min, P = .020) and ≥8-beat VT incidence by 56% (from 1.6 ± 0.47 to 0.7 ± 0.42 beats/2 min, P = .033) and eliminated the VT-associated hypotension, with no changes in chronotropic and minimal attenuation of the inotropic responses to epinephrine. Concurrently, GS-967 at 30, 60, and 90 minutes reduced the magnitude of the epinephrine-induced surge in TWA by 56% (from 140 ± 13.2 to 62 ± 12.1 µV, P < .01), 62% (to 53 ± 8.3 µV, P < .01), and 51% (to 69 ± 14.0 µV, P < .01) (means ± SEM), respectively. Selective cardiac late INa inhibition with GS-967 confers significant protection against catecholamine-induced VT and TWA.

Effect of Ranolazine Monotherapy on Glycemic Control in Subjects With Type 2 Diabetes.

OBJECTIVERanolazine is an antianginal drug that mediates its effects by inhibition of cardiac late sodium current. Although ranolazine is not approved for the treatment of type 2 diabetes, in post hoc analyses of pivotal angina trials, ranolazine was associated with reductions in percent glycosylated hemoglobin (HbA1c) in subjects with type 2 diabetes. The study prospectively assessed the safety and efficacy of ranolazine in subjects with type 2 diabetes with inadequate glycemic control managed by lifestyle alone.RESEARCH DESIGN AND METHODSThe study was conducted worldwide in 465 subjects, with baseline HbA1c of 7–10% (53–86 mmol/mol) and fasting serum glucose of 130–240 mg/dL, randomized to placebo versus ranolazine.RESULTSCompared with placebo, there was a greater decline in HbA1c at week 24 from baseline (primary end point) in subjects taking ranolazine (mean difference −0.56% [−6.1 mmol/mol]; P < 0.0001). Moreover, the proportion of subjects achieving an HbA1c <7.0% was greater with ranolazine (25.6% vs. 41.2%; P = 0.0004). Ranolazine was associated with reductions in fasting (mean difference −8 mg/dL; P = 0.0266) and 2-h postprandial glucose (mean difference −19 mg/dL; P = 0.0008 vs. placebo). Subjects taking ranolazine trended toward a greater decrease from baseline in fasting insulin (P = 0.0507), a greater decrease in fasting glucagon (P = 0.0003), and a lower postprandial 3-h glucagon area under the curve (P = 0.0031 vs. placebo). Ranolazine was safe and well tolerated.CONCLUSIONSCompared with placebo, use of ranolazine monotherapy over 24 weeks, in subjects with type 2 diabetes and inadequate glycemic control on diet and exercise alone, significantly reduced HbA1c and other measures of glycemic control.