Optimal Medical Therapy for Stable Ischemic Heart Disease: Focus on Anti-anginal Therapy.

Chronic coronary disease (CCD) is a major cause of morbidity and mortality worldwide. The most common symptom of CCD is exertional angina pectoris, a discomfort in the chest that commonly occurs during activities of daily life. Patients are dismayed by recurring episodes of angina and seek medical help in preventing or minimizing episodes. Angina occurs when the coronary arteries are unable to supply sufficient blood flow to the cardiac muscle to meet the metabolic needs of the left ventricular myocardium. While lifestyle changes and aggressive risk factor modification play a critical role in the management of CCD, management of angina usually requires pharmacologic therapy. Medications such as beta-blockers, calcium channel blockers, nitrates, ranolazine, and others ultimately work to improve the mismatch between myocardial blood flow and metabolic demand. This manuscript briefly describes the pathophysiologic basis for symptoms of angina, and how currently available anti-anginal therapies contribute to preventing or minimize the occurrence of angina.

Efficacy of nicorandil and ranolazine in prevention of contrast-induced nephropathy in patients with mild-to-moderate renal dysfunction: a randomized controlled trial.

INTRODUCTION: Contrast-induced nephropathy (CIN) is a common complication after percutaneous coronary intervention (PCI). There is conflicting evidence regarding efficacy of nicorandil in CIN prevention. With respect to ranolazine, there is physiological possibility as well as data in animal study regarding its protective effect against CIN; there is, however, no human data till date. AIM AND OBJECTIVES: To assess the efficacy of nicorandil and ranolazine in preventing CIN. The secondary endpoint was to measure difference in postprocedure acute kidney injury (AKI) incidence across groups. Also, patients were followed up till 6 months for major adverse events. MATERIAL AND METHODS: This single-center randomized controlled study included 315 patients of coronary artery disease with mild-to-moderate renal dysfunction undergoing elective PCI. Eligible patients were assigned to either nicorandil (n = 105), ranolazine (n = 105) or control group (n = 105) in 1 : 1 : 1 ratio by block randomization. All enrolled patients were given intravenous sodium chloride at rate of 1.0 mL/kg/h (0.5 mL/kg/h for patients with left ventricular ejection fraction <45%) from 6 h before procedure till 12 h after procedure. Iso-osmolar contrast agent (iodixanol) was used for all patients. In addition to hydration, patients in nicorandil group received oral nicorandil (10 mg, 3 times/d) and those in ranolazine group received oral ranolazine (1000 mg, 2 times/d) 1 day before procedure and for 2 days after PCI. Patients in control group received only hydration. RESULTS: Total number of CIN was 34 (10.7%), which included 19 (18.1%) in control, 8 (7.6%) in nicorandil and 7 (6.6%) in ranolazine group. There was significant association of CIN reduction across groups ( P  = 0.012). On pairwise comparison also, there was significant benefit across control and ranolazine as well as control and nicorandil ( P  < 0.025). There was numerically higher incidence of AKI in controls; the difference, however, did not reach statistical significance after applying Bonferroni correction ( P  = 0.044). Over 6-month follow-up, adverse events were similar across groups. CONCLUSION: While this study adds to existing literature that supports role for nicorandil in CIN prevention, the efficacy of ranolazine in protecting against CIN has been demonstrated in humans for the first time.

Association between Ranolazine, Ischemic Preconditioning, and Cardioprotection in Patients Undergoing Scheduled Percutaneous Coronary Intervention.

Background and Objectives: Remote ischemic preconditioning (RIPC) has demonstrated efficacy in protecting against myocardial ischemia-reperfusion injury when applied before percutaneous coronary revascularization. Ranolazine, an anti-ischemic drug, has been utilized to minimize ischemic events in chronic angina patients. However, there is a lack of trials exploring the combined effects of ranolazine pretreatment and RIPC in patients undergoing percutaneous coronary interventions (PCIs). Materials and Methods: The present study is a prospective study which enrolled 150 patients scheduled for nonemergent percutaneous coronary revascularization. Three groups were formed: a control group undergoing only PCIs, an RIPC group with RIPC applied to either upper limb before the PCI (preconditioning group), and a group with RIPC before the PCI along with prior ranolazine treatment for stable angina (ranolazine group). Statistical analyses, including ANOVAs and Kruskal-Wallis tests, were conducted, with the Bonferroni correction for type I errors. A repeated-measures ANOVA assessed the changes in serum enzyme levels (SGOT, LDH, CRP, CPK, CK-MB, troponin I) over the follow-up. Statistical significance was set at p < 0.05. Results: The ranolazine group showed (A) significantly lower troponin I level increases compared to the control group for up to 24 h, (B) significantly lower CPK levels after 4, 10, and 24 h compared to the preconditioning group (p = 0.020, p = 0.020, and p = 0.019, respectively) and significantly lower CPK levels compared to the control group after 10 h (p = 0.050), and (C) significantly lower CK-MB levels after 10 h compared to the control group (p = 0.050). Conclusions: This study suggests that combining RIPC before scheduled coronary procedures with ranolazine pretreatment may be linked to reduced ischemia induction, as evidenced by lower myocardial enzyme levels.

ChaMP-CMD: A Phenotype-Blinded, Randomized Controlled, Cross-Over Trial.

BACKGROUND: Angina with nonobstructive coronary arteries is a common condition for which no effective treatment has been established. We hypothesized that the measurement of coronary flow reserve (CFR) allows identification of patients with angina with nonobstructive coronary arteries who would benefit from anti-ischemic therapy. METHODS: Patients with angina with nonobstructive coronary arteries underwent blinded invasive CFR measurement and were randomly assigned to receive 4 weeks of amlodipine or ranolazine. After a 1-week washout, they crossed over to the other drug for 4 weeks; final assessment was after the cessation of study medication for another 4 weeks. The primary outcome was change in treadmill exercise time, and the secondary outcome was change in Seattle Angina Questionnaire summary score in response to anti-ischemic therapy. Analysis was on a per protocol basis according to the following classification: coronary microvascular disease (CMD group) if CFR<2.5 and reference group if CFR≥2.5. The study protocol was registered before the first patient was enrolled (International Standard Randomised Controlled Trial Number: ISRCTN94728379). RESULTS: Eighty-seven patients (61±8 years of age; 62% women) underwent random assignment (57 CMD group and 30 reference group). Baseline exercise time and Seattle Angina Questionnaire summary scores were similar between groups. The CMD group had a greater increment (delta) in exercise time than the reference group in response to both amlodipine (difference in delta, 82 s [95% CI, 37-126 s]; P<0.001) and ranolazine (difference in delta, 68 s [95% CI, 21-115 s]; P=0.005). The CMD group reported a greater increment (delta) in Seattle Angina Questionnaire summary score than the reference group in response to ranolazine (difference in delta, 7 points [95% CI, 0-15]; P=0.048), but not to amlodipine (difference in delta, 2 points [95% CI, -5 to 8]; P=0.549). CONCLUSIONS: Among phenotypically similar patients with angina with nonobstructive coronary arteries, only those with an impaired CFR derive benefit from anti-ischemic therapy. These findings support measurement of CFR to diagnose and guide management of this otherwise heterogeneous patient group.

Anti-ischemic and pleiotropic effects of ranolazine in chronic coronary syndromes.

The vast majority of antianginal drugs decrease heart rate and or blood pressure levels or the inotropic status of the left ventricle to decrease myocardial oxygen consumption (MVO2) and thus anginal symptoms. Ranolazine presents a completely different mechanism of action, which reduces the sodium-dependent calcium overload inhibiting the late sodium current. Current European Society of Cardiology (ESC) guidelines for the management of angina in patients with chronic coronary symptoms recommend the use of several drugs such as ranolazine, b-blockers, calcium channel blockers, long-acting nitrates, ivabradine, nicorandil and trimetazidine for angina relief. However, ranolazine, in addition to symptom relief properties, is an antianginal drug showing favorable effects in decreasing the arrhythmic burden and in ameliorating the glycemic profile of these patients. In this review, we summarize the available data regarding the antianginal and pleiotropic effects of this drug.

Anti-inflammatory reprogramming of microglia cells by metabolic modulators to counteract neurodegeneration; a new role for Ranolazine.

Microglia chronic activation is a hallmark of several neurodegenerative diseases, including the retinal ones, possibly contributing to their etiopathogenesis. However, some microglia sub-populations have anti-inflammatory and neuroprotective functions, thus making arduous deciphering the role of these cells in neurodegeneration. Since it has been proposed that functionally different microglia subsets also rely on different metabolic routes, we hypothesized that modulating microglia metabolism might be a tool to enhance their anti-inflammatory features. This would have a preventive and therapeutic potential in counteracting neurodegenerative diseases. For this purpose, we tested various molecules known to act on cell metabolism, and we revealed the anti-inflammatory effect of the FDA-approved piperazine derivative Ranolazine on microglia cells, while confirming the one of the flavonoids Quercetin and Naringenin, both in vitro and in vivo. We also demonstrated the synergistic anti-inflammatory effect of Quercetin and Idebenone, and the ability of Ranolazine, Quercetin and Naringenin to counteract the neurotoxic effect of LPS-activated microglia on 661W neuronal cells. Overall, these data suggest that using the selected molecules -also in combination therapies- might represent a valuable approach to reduce inflammation and neurodegeneration while avoiding long term side effects of corticosteroids.

The Role of Ranolazine in Heart Failure-Current Concepts.

Heart failure is a complex clinical syndrome with a detrimental impact on mortality and morbidity. Energy substrate utilization and myocardial ion channel regulation have gained research interest especially after the introduction of sodium-glucose co-transporter 2 inhibitors in the treatment of heart failure. Ranolazine or N-(2,6-dimethylphenyl)-2-(4-[2-hydroxy-3-(2-methoxyphenoxy) propyl] piperazin-1-yl) acetamide hydrochloride is an active piperazine derivative which inhibits late sodium current thus minimizing calcium overload in the ischemic cardiomyocytes. Ranolazine also prevents fatty acid oxidation and favors glycose utilization ameliorating the "energy starvation" of the failing heart. Heart failure with preserved ejection fraction is characterized by diastolic impairment; according to the literature ranolazine could be beneficial in the management of increased left ventricular end-diastolic pressure, right ventricular systolic dysfunction and wall shear stress which is reflected by the high natriuretic peptides. Fewer data is evident regarding the effects of ranolazine in heart failure with reduced ejection fraction and mainly support the control of the sodium-calcium exchanger and function of sarcoendoplasmic reticulum calcium adenosine triphosphatase. Ranolazine's therapeutic mechanisms in myocardial ion channels and energy utilization are documented in patients with chronic coronary syndromes. Nevertheless, ranolazine might have a broader effect in the therapy of heart failure and further mechanistic research is required.

Metabolic rewiring induced by ranolazine improves melanoma responses to targeted therapy and immunotherapy.

Resistance of melanoma to targeted therapy and immunotherapy is linked to metabolic rewiring. Here, we show that increased fatty acid oxidation (FAO) during prolonged BRAF inhibitor (BRAFi) treatment contributes to acquired therapy resistance in mice. Targeting FAO using the US Food and Drug Administration-approved and European Medicines Agency-approved anti-anginal drug ranolazine (RANO) delays tumour recurrence with acquired BRAFi resistance. Single-cell RNA-sequencing analysis reveals that RANO diminishes the abundance of the therapy-resistant NGFRhi neural crest stem cell subpopulation. Moreover, by rewiring the methionine salvage pathway, RANO enhances melanoma immunogenicity through increased antigen presentation and interferon signalling. Combination of RANO with anti-PD-L1 antibodies strongly improves survival by increasing antitumour immune responses. Altogether, we show that RANO increases the efficacy of targeted melanoma therapy through its effects on FAO and the methionine salvage pathway. Importantly, our study suggests that RANO could sensitize BRAFi-resistant tumours to immunotherapy. Since RANO has very mild side-effects, it might constitute a therapeutic option to improve the two main strategies currently used to treat metastatic melanoma.

Bayesian Network Meta-analysis of Randomized Controlled Trials on the Efficacy of Antiarrhythmics in the Pharmacological Cardioversion of Paroxysmal Atrial Fibrillation.

PURPOSE: Since atrial fibrillation (AF) is one of the major arrhythmias managed in hospitals worldwide, it has a major impact on public health. The guidelines agree on the desirability of cardioverting paroxysmal AF episodes. This meta-analysis aims to answer the question of which antiarrhythmic agent is most effective in cardioverting a paroxysmal AF. MATERIALS AND METHODS: A systematic review and Bayesian network meta-analysis, searching MEDLINE, Embase, and CINAHL, were performed, including randomized controlled trials (RCTs) enrolling a population of unselected adult patients with a paroxysmal AF that compared at least two pharmacological regimes to restore the sinus rhythm or a cardioversion agent against a placebo. The main outcome was efficacy in restoring sinus rhythm. RESULTS: Sixty-one RCTs (7988 patients) were included in the quantitative analysis [deviance information criterion (DIC) 272.57; I2 = 3%]. Compared with the placebo, the association verapamil-quinidine shows the highest SUCRA rank score (87%), followed by antazoline (86%), vernakalant (85%), tedisamil at high dose (i.e., 0.6 mg/kg; 80%), amiodarone-ranolazine (80%), lidocaine (78%), dofetilide (77%), and intravenous flecainide (71%). Taking into account the degree of evidence of each individual comparison between pharmacological agents, we have drawn up a ranking of pharmacological agents from the most effective to the least effective. CONCLUSIONS: In comparing the antiarrhythmic agents used to restore sinus rhythm in the case of paroxysmal AF, vernakalant, amiodarone-ranolazine, flecainide, and ibutilide are the most effective medications. The verapamil-quinidine combination seems promising, though few RCTs have studied it. The incidence of side effects must be taken into account in the choice of antiarrhythmic in clinical practice. CLINICAL TRIAL REGISTRATION: PROSPERO: International prospective register of systematic reviews, 2022, CRD42022369433 (Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022369433 ).

Cost-utility of Ranolazine for Chronic Stable Angina Pectoris: Systematic Review and Meta-analysis.

PURPOSE: Ranolazine is used to treat stable angina pectoris, the most common symptom of ischemic heart disease. Appropriate management of chronic stable angina pectoris is essential from both a clinical and an economic view point. METHODS: This systematic review and meta-analysis adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included cost-utility analyses, which compared ranolazine with other standard treatments for treating stable angina pectoris. The search was conducted in PubMed, EMBASE, and Scopus databases. A random-effects model based on the DerSimonian and Laird method was used to pool the incremental net benefit reported in purchasing power parity adjusted US dollars. The modified economic evaluation checklist was used to assess the risk of bias. FINDINGS: The pooled results from 7 selected studies with a time horizon of 1 year show that add-on ranolazine was significantly cost-effective compared with standard treatment, with a pooled incremental net benefit of US$1335 (95% CI, 500 to 2169) but with substantial heterogeneity (I2 = 79.46%). On subgroup analysis, ranolazine was cost-effective from the payers' perspective (US$1975; 95% CI, 1042 to 2908; I2 = 69.23) but not from a societal perspective (US$297; 95% CI, -241 to 715; I2 = 0%)]. There was limited evidence from lower economies. IMPLICATIONS: Pooled evidence suggests that add-on ranolazine therapy is cost-effective for chronic stable angina pectoris up to a 1-year time horizon. There is a lacuna of evidence from low- and middle-income countries and on long-term cost-effectiveness. The current evidence synthesis may provide a macroeconomic point of view for policy makers regarding the direction of ranolazine's cost-effectiveness for evidence-informed policy-making. PROSPERO identifier: CRD42022332454.

Modulation of post-pacing action potential duration and contractile responses on ventricular arrhythmogenesis in chloroquine-induced long QT syndrome.

BACKGROUND: Excitation-contraction (E-C) coupling, the interaction of action potential duration (APD) and contractility, plays an essential role in arrhythmogenesis. We aimed to investigate the arrhythmogenic role of E-C coupling in the right ventricular outflow tract (RVOT) in the chloroquine-induced long QT syndrome. METHODS: Conventional microelectrodes were used to record electrical and mechanical activity simultaneously under electrical pacing (cycle lengths from 1000-100 ms) in rabbit RVOT tissue preparations before and after chloroquine with and without azithromycin. KB-R7943 (a Na+-Ca2+ exchanger [NCX] inhibitor), ranolazine (a late sodium current inhibitor), or MgSO4 were used to assess their pharmacological responses in the chloroquine-induced long QT syndrome. RESULTS: Sequential infusion of chloroquine and chloroquine plus azithromycin triggered ventricular tachycardia (VT) (33.7%) after rapid pacing compared to baseline (6.7%, p = 0.004). There were greater post-pacing increases of the first occurrence of contractility (ΔContractility) in the VT group (VT vs. non-VT: 521.2 ± 50.5% vs. 306.5 ± 26.8%, p < 0.001). There was no difference in the first occurrence of action potential at 90% repolarization (ΔAPD90) (VT vs. non-VT: 49.7 ± 7.4 ms vs. 51.8 ± 13.1 ms, p = 0.914). Pacing-induced VT could be suppressed to baseline levels by KB-R7943 or MgSO4. Ranolazine did not suppress pacing-induced VT in chloroquine-treated RVOT. ΔContractility was reduced by KB-R7943 and MgSO4, but not by ranolazine. CONCLUSION: ΔContractility (but not ΔAPD) played a crucial role in the genesis of pacing-induced VT in the long QT tissue model, which can be modulated by NCX (but not late sodium current) inhibition or MgSO4.

Safety and efficacy of ranolazine in hypertrophic cardiomyopathy: Real-world experience in a National Referral Center.

OBJECTIVES: We assessed the efficacy and safety of ranolazine in real-world patients with hypertrophic cardiomyopathy (HCM). BACKGROUND: Ranolazine is an anti-anginal drug that inhibits the late phase of the inward sodium current. In a small prospective trial, ranolazine reduced the arrhythmic burden and improved biomarker profile in HCM patients. However, systematic reports reflecting real-world use in this setting are lacking. METHODS: Changes in clinical and instrumental features, symptoms and arrhythmic burden were evaluated in 119 patients with HCM before and during treatment with ranolazine at a national referral centre for HCM. RESULTS: Patients were treated with ranolazine for 2 [1-4] years; 83 (70%) achieved a dosage ≥1000 mg per day. Treatment interruption was necessary in 24 patients (20%) due to side effects (n = 10, 8%) or disopyramide initiation (n = 8, 7%). Seventy patients (59%) were treated with ranolazine for relief of angina. Among them, 51 (73%) had total symptomatic relief and 47 patients (67%) showed ≥2 Canadian Cardiovascular society (CCS) angina grade improvement. Sixteen patients (13%) were treated for recurrent ventricular arrhythmias, including 4 with a clear ischemic trigger, who experienced no further arrhythmic episodes while on ranolazine. Finally, 33 patients (28%) were treated for heart failure associated with severe diastolic dysfunction: no symptomatic benefit could be observed in this group. CONCLUSION: Ranolazine was safe and well tolerated in patients with HCM. The use of ranolazine may be considered in patients with HCM and microvascular angina.

Effects of ranolazine on various outcomes in patients with stable angina: an updated meta-analysis.

OBJECTIVE: We determined the effect of ranolazine vs. placebo in angina patients on 1) selective measures of the ischemic burden, 2) cardiovascular outcomes, including atrial fibrillation incidence, 3) the in-treatment glycohemoglobin levels and the permanent discontinuations because of side effects, and 4) the achieved between-arms blood pressure and heart rate difference. METHODS: PubMed and Cochrane Collaboration Library databases were searched for eligible trials until end of September 2020. Trial quality was assessed by the Rob2 tool. Risk ratios or achieved mean differences during follow-up and 95% confidence interval (CI) of categorical or continuous outcomes, respectively, were calculated (random-effects model). The relationship between discontinuation rates and ranolazine's mean dose was investigated by meta-regression analysis. RESULTS: We selected 18 trials (n = 12,995 patients in patients with macro or microvascular coronary heart disease. Achieved blood pressure and heart rate at rest were not different between randomized arms. Ranolazine administration compared to placebo was associated with an increase of 1) total exercise duration by 30 seconds (95% CI, 18-42), 2) time to 1 mm ST-segment depression by 44 seconds (95% CI, 30-54), and 3) time to angina onset by 40 seconds (95% CI, 30-54). On average, the incidence of atrial fibrillation was reduced by 25% following ranolazine treatment compared to placebo, while glycohemoglobin showed a mean decrease of 0.4% (95% CI, 0.3-0.5%). DISCUSSION: Ranolazine remains an effective anti-ischemic drug, increases the angina-free exercise duration, delays the onset of ST-segment depression. The beneficial effects of ranolazine are extended to atrial fibrillation reduction rates and better glycemic control.

Ranolazine Attenuates Brain Inflammation in a Rat Model of Type 2 Diabetes.

Recent studies suggest a pathogenetic association between metabolic disturbances, including type 2 diabetes (T2DM), and cognitive decline and indicate that T2DM may represent a risk factor for Alzheimer's disease (AD). There are a number of experimental studies presenting evidence that ranolazine, an antianginal drug, acts as a neuroprotective drug. The aim of the present study was to evaluate the effects of ranolazine on hippocampal neurodegeneration and astrocytes activation in a T2DM rat model. Diabetes was induced by a high fat diet (HFD) and streptozotocin (STZ) injection. Animals were divided into the following groups: HFD/STZ + Ranolazine, HFD/STZ + Metformin, HFD/STZ + Vehicle, NCD + Vehicle, NCD + Ranolazine and NCD + Metformin. The presence of neurodegeneration was evaluated in the hippocampal cornus ammonis 1 (CA1) region by cresyl violet staining histological methods, while astrocyte activation was assessed by western blot analysis. Staining with cresyl violet highlighted a decrease in neuronal density and cell volume in the hippocampal CA1 area in diabetic HFD/STZ + Vehicle rats, while ranolazine and metformin both improved T2DM-induced neuronal loss and neuronal damage. Moreover, there was an increased expression of GFAP in the HFD/STZ + Vehicle group compared to the treated diabetic groups. In conclusion, in the present study, we obtained additional evidence supporting the potential use of ranolazine to counteract T2DM-associated cognitive decline.

Ranolazine Interacts Antagonistically with Some Classical Antiepileptic Drugs-An Isobolographic Analysis.

Ranolazine, an antianginal and antiarrhythmic drug blocking slow inactivating persistent sodium currents, is described as a compound with anticonvulsant potential. Since arrhythmia often accompanies seizures, patients suffering from epilepsy are frequently co-treated with antiepileptic and antiarrhythmic drugs. The aim of this study was to evaluate the effect of ranolazine on maximal-electroshock (MES)-induced seizures in mice as well as interactions between ranolazine and classical antiepileptic drugs in this model of epilepsy. Types of pharmacodynamic interactions were established by isobolographic analysis of obtained data. The main findings of the study were that ranolazine behaves like an antiseizure drug in the MES test. Moreover, ranolazine interacted antagonistically with carbamazepine, phenytoin, and phenobarbital in the proportions of 1:3 and 1:1. These interactions occurred pharmacodynamic, since ranolazine did not change the brain levels of antiepileptic drugs measured in the fluorescence polarization immunoassay. Ranolazine and its combinations with carbamazepine, phenytoin, and phenobarbital did not impair motor coordination evaluated in the chimney test. Unfortunately, an attempt to conduct a passive avoidance task (evaluating long-term memory) resulted in ranolazine-induced delayed lethality. In conclusion, ranolazine exhibits clear-cut anticonvulsant properties in the MES test but interacts antagonistically with some antiepileptic drugs. The obtained results need confirmation in clinical studies. The mechanisms of ranolazine-induced toxicity require specific explanation.

Nicorandil and ranolazine overdose management.

A man in his 60s was admitted to the emergency department with chest pain following an intentional overdose of nicorandil and ranolazine. He was known to have an extensive cardiac history and had taken his prescribed medication with suicidal ideation. On presentation, he was hypotensive with a blood pressure of 70/50 mm Hg despite fluid resuscitation. He was commenced on vasopressor support and transferred to the intensive care unit. Despite an adequate blood pressure on vasopressors, he suffered a ventricular fibrillation cardiac arrest. Return of spontaneous circulation with a Glasgow Coma Score of 15 was achieved following cardiopulmonary resuscitation and three direct current shocks. Following subsequent continuous overnight significant vasopressor dependence, a dose of glucagon was given, and within 2 hours, his vasopressor requirement ceased, maintaining an unsupported normal blood pressure. He remained stable and was subsequently discharged to the coronary care unit for monitoring.

[Impact of late sodium current inhibition on cardiac electrophysiology parameters and ventricular arrhythmias in isolated Langendorff perfused rabbit hearts with short QT interval].

Objective: To determine the electrophysiological effects and related mechanisms of late sodium current inhibitors on hearts with short QT intervals. Methods: The electrophysiological study was performed on isolated Langendorff perfused rabbit hearts. A total of 80 New Zealand White rabbits were used and 34 hearts without drug treatment were defined as control group A, these hearts were then treated with IKATP opener pinacidil, defined as pinacidil group A. Then, 27 hearts from pinacidil group A were selected to receive combined perfusion with sodium channel inhibitors or quinidine, a traditional drug used to treat short QT syndrome, including ranolazine combined group (n=9), mexiletine combined group (n=9), and quinidine combined group (n=9). Nineteen out of the remaining 46 New Zealand rabbits were selected as control group B (no drug treatments, n=19), and then treated with pinacidil, defined as pinacidil group B (n=19). The remaining 27 rabbits were treated with sodium inhibitors or quinidine alone, including ranolazine alone group (n=9), mexiletine alone group (n=9), and quinidine alone group (n=9). Electrocardiogram (ECG) physiological parameters of control group A and pinacidil group A were collected. In control group B and pinacidil group B, programmed electrical stimulation was used to induce ventricular arrhythmias and ECG was collected. ECG physiological parameters and ventricular arrhythmia status of various groups were analyzed. The concentrations of pinacidil, ranolazine, mexiletine and quinidine used in this study were 30, 10, 30 and 1 µmol/L, respectively. Results: Compared with control group A, the QT interval, 90% of the repolarization in epicardial and endocardial monophasic action potential duration (MAPD90-Epi, MAPD90-Endo) was shortened, the transmural dispersion of repolarization (TDR) was increased, and the effective refractor period (ERP) and post-repolarization refractoriness (PRR) were reduced in pinacidil group A (all P<0.05). Compared with the pinacidil group A, MAPD90-Epi, MAPD90-Endo, QT interval changes were reversed in quinidine combined group and mexiletine combined group (all P<0.05), but not in ranolazine combined group. All these three drugs reversed the pinacidil-induced increases of TDR and the decreases of ERP and PRR. The induced ventricular arrhythmia rate was 0 in control group B, and increased to 10/19 (χ2=13.6, P<0.05) in pinacidil group B during programmed electrical stimulation. Compared with the pinacidil group B, incidences of ventricular arrhythmia decreased to 11% (1/9), 11% (1/9) and 0 (0/9) (χ2=4.5, 4.5, 7.4, P<0.05) respectively in ranolazine group, mexiletine group and quinidine group. Conclusions: Inhibition of late sodium current does not increase but even decreases the risk of malignant arrhythmia in hearts with a shortened QT interval. The antiarrhythmic mechanism might be associated with the reversal of the increase of TDR and the decrease of refractoriness (including both ERP and PRR) of hearts with shortened QT interval.

Pharmacologic modulation of intracellular Na+ concentration with ranolazine impacts inflammatory response in humans and mice.

Changes in Ca2+ influx during proinflammatory stimulation modulates cellular responses, including the subsequent activation of inflammation. Whereas the involvement of Ca2+ has been widely acknowledged, little is known about the role of Na+. Ranolazine, a piperazine derivative and established antianginal drug, is known to reduce intracellular Na+ as well as Ca2+ levels. In stable coronary artery disease patients (n = 51) we observed reduced levels of high-sensitive C-reactive protein (CRP) 3 mo after the start of ranolazine treatment (n = 25) as compared to the control group. Furthermore, we found that in 3,808 acute coronary syndrome patients of the MERLIN-TIMI 36 trial, individuals treated with ranolazine (1,934 patients) showed reduced CRP values compared to placebo-treated patients. The antiinflammatory effects of sodium modulation were further confirmed in an atherosclerotic mouse model. LDL-/- mice on a high-fat diet were treated with ranolazine, resulting in a reduced atherosclerotic plaque burden, increased plaque stability, and reduced activation of the immune system. Pharmacological Na+ inhibition by ranolazine led to reduced express of adhesion molecules and proinflammatory cytokines and reduced adhesion of leukocytes to activated endothelium both in vitro and in vivo. We demonstrate that functional Na+ shuttling is required for a full cellular response to inflammation and that inhibition of Na+ influx results in an attenuated inflammatory reaction. In conclusion, we demonstrate that inhibition of Na+-Ca2+ exchange during inflammation reduces the inflammatory response in human endothelial cells in vitro, in a mouse atherosclerotic disease model, and in human patients.