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Ranolazine is an anti-anginal medication given to patients with chronic angina and persistent symptoms despite medical therapy. We examined 11 491 chronic total occlusion (CTO) percutaneous coronary interventions (PCI) that were performed at 41 US and non-US centers between 2012 and 2023 in the PROGRESS-CTO Registry. Patients on ranolazine at baseline had more comorbidities, more complex lesions, lower procedural and technical success (based on univariable but not multivariable analysis), and higher incidence of major adverse cardiac events (MACE) (on both univariable and multivariable analysis).

Approximately 90% of diabetic males have varying degrees of testicular dysfunction. The current study investigates the possible beneficial consequences of ranolazine against T1DM-induced testicular dysfunction in rats. Thirty-two male Sprague Dawley rats were assorted into 4 groups; normal, diabetic (single 50 mg/kg STZ, I.P.) and ranolazine (40 and 80 mg/kg, orally). The present investigation revealed that the hypoglycemic impact of ranolazine significantly improved the testicular weight and body weight of the final rats, as well as the concentration of blood testosterone, sperm count, and viability, all of which were associated with STZ-induced testicular dysfunction. Furthermore, as demonstrated by elevated reduced glutathione (GSH) activity and lowered malondialdehyde (MDA) levels, diabetic rats administered ranolazine showed a noteworthy improvement in the oxidant/antioxidant ratio. Furthermore, a substantial rise in beclin-1 concentration was seen in conjunction with a significant decrease in thioredoxin-interacting protein (TXNIP) and interleukin-18 (IL-18) concentrations when ranolazine was administered. Although ranolazine exhibited a reduction in inflammation as seen by lower expression of nuclear factor-κB (NF-κB) and cluster of differentiation (CD68) in the testicles, these biochemical findings were validated by improvements in the morphological and histopathological outcomes of both the pancreatic and testicular tissues. In conclusion, daily oral administration of ranolazine (40 and 80 mg/kg) for 8 weeks could be a promising therapy for T1DM-induced testicular dysfunction through its dose-dependent anti-oxidant and anti-inflammatory effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Multi-faceted evidence from a range of cancers suggests strongly that de novo expression of voltage-gated sodium channels (VGSCs) plays a significant role in driving cancer cell invasiveness. Under hypoxic conditions, common to growing tumours, VGSCs develop a persistent current (I NaP ) which can be blocked selectively by ranolazine., Methods: Several different carcinomas were examined. We used data from a range of experimental approaches relating to cellular invasiveness and metastasis. These were supplemented by survival data mined from cancer patients., Results: In vitro, ranolazine inhibited invasiveness of cancer cells especially under hypoxia. In vivo, ranolazine suppressed the metastatic abilities of breast and prostate cancers and melanoma. These data were supported by a major retrospective epidemiological study on breast, colon and prostate cancer patients. This showed that risk of dying from cancer was reduced by ca.60% among those taking ranolazine, even if this started 4 years after the diagnosis. Ranolazine was also shown to reduce the adverse effects of chemotherapy on heart and brain. Furthermore, its anti-cancer effectiveness could be boosted by co-administration with other drugs., Conclusions: Ranolazine, alone or in combination with appropriate therapies, could be reformulated as a safe anti-metastatic drug offering many potential advantages over current systemic treatment modalities., (© 2024. The Author(s).)

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., Competing Interests: Disclosures All authors have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

A recent study investigated the correlation between telmisartan (TEL) exposure and Alzheimer's disease (AD) risk among African Americans (AAs) and European Americans. Their findings indicated that moderate-to-high TEL exposure was linked to a decreased incidence of AD among AAs. These results suggest a potential association between TEL and a reduced risk of AD specifically within the AA population. Here, we investigated the effects of TEL, either alone or in combination with ranolazine (Ran) or dapagliflozin (Dapa), on voltage-gated Na + currents ( INa ) in Neuro-2a cells. TEL, primarily used for treating hypertension and cardiovascular disorders, showed a stimulatory effect on INa , while Ran and Dapa reversed this stimulation. In Neuro-2a cells, we demonstrated that with exposure to TEL, the transient ( INa(T) ) and late ( INa(L) ) components of INa were differentially stimulated with effective EC 50 's of 16.9 and 3.1 μM, respectively. The research implies that TEL's impact on INa might be associated with enhanced neuronal excitability. This study highlights the complex interplay between TEL, Ran, and Dapa on INa and their potential implications for AD, emphasizing the need for further investigation to understand the mechanisms involved., (Copyright © 2024 Copyright: © 2024 Journal of Physiological Investigation.)

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., Competing Interests: Declaration of Competing Interest None, (Copyright © 2023 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

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.

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., Competing Interests: Disclosures None.

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., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., (© 2023. The Author(s).)

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 NGFR hi 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., (© 2023. The Author(s).)

Competing Interests: Disclosures None.

Competing Interests: Competing interests The authors declare no competing interests.

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., (Copyright © 2022 Hellenic Society of Cardiology. Published by Elsevier B.V. All rights reserved.)

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 (I 2  = 79.46%). On subgroup analysis, ranolazine was cost-effective from the payers' perspective (US$1975; 95% CI, 1042 to 2908; I 2  = 69.23) but not from a societal perspective (US$297; 95% CI, -241 to 715; I 2  = 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., Competing Interests: Declaration of Interest None declared., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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 + -Ca 2+ exchanger [NCX] inhibitor), ranolazine (a late sodium current inhibitor), or MgSO 4 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 (ΔAPD 90 ) (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 MgSO 4 . Ranolazine did not suppress pacing-induced VT in chloroquine-treated RVOT. ΔContractility was reduced by KB-R7943 and MgSO 4 , 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 MgSO 4 ., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest Prof. Olivotto is in the advisory board and had research grant from BMS-Myokardia, Cytokinetics, Boston Scientific, Sanofi Genzyme, Shire Takeda, Amicus, Menarini International, Bayer, Tenaya., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

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, 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., Competing Interests: The authors declare no conflicts of interest.

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 I KATP 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 (MAPD 90 -Epi, MAPD 90 -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, MAPD 90 -Epi, MAPD 90 -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 (χ 2 =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) (χ 2 =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.

Changes in Ca2 + influx during proinflammatory stimulation modulates cellular responses, including the subsequent activation of inflammation. Whereas the involvement of Ca 2+ 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 + -Ca 2+ exchange during inflammation reduces the inflammatory response in human endothelial cells in vitro, in a mouse atherosclerotic disease model, and in human patients.

Introduction/aims: Neuronal hyperexcitability (manifested by cramps) plays a pathological role in amyotrophic lateral sclerosis (ALS), and drugs affecting it may help symptomatic management and slow disease progression. We aimed to determine safety and tolerability of two doses of ranolazine in patients with ALS and evaluate for preliminary evidence of drug-target engagement by assessing muscle cramp characteristics., Methods: We performed an open-label dose-ascending study of ranolazine in 14 individuals with ALS in two sequential cohorts: 500 mg (cohort 1) and 1000 mg (cohort 2) orally twice daily. Each had a 2-week run-in period, 4-week drug administration, and 6-week safety follow-up. Primary outcome was safety and tolerability. Exploratory measures included cramp frequency and severity, fasciculation frequency, cramp potential duration, ALS Functional Rating Scale---Revised score, and forced vital capacity., Results: Six and eight participants were enrolled in cohorts 1 and 2, respectively. There were no serious adverse events. Two subjects in cohort 2 discontinued the drug due to constipation. The most frequent drug-related adverse event was gastrointestinal (40%). Cramp frequency decreased by 54.8% (95% confidence interval [CI], 39%-70.8%) and severity decreased by 46.3% (95% CI, 29.5-63.3%), which appeared to be dose-dependent, with decreased awakening due to cramps. Other outcomes showed no change., Discussion: Ranolazine was well tolerated in ALS up to 2000 mg/day, with gastrointestinal side effects being the most frequent. Ranolazine reduced cramp frequency and severity, supporting its investigation for muscle cramps in a future placebo-controlled trial., (© 2022 Wiley Periodicals LLC.)

Background: The RAID (Ranolazine Implantable Cardioverter-Defibrillator) randomized placebo-controlled trial showed that ranolazine treatment was associated with reduction in recurrent ventricular tachycardia (VT) requiring appropriate implantable cardioverter-defibrillator (ICD) therapy., Objectives: This study aimed to identify groups of patients in whom ranolazine treatment would result in the highest reduction of ventricular tachyarrhythmia (VTA) burden., Methods: Andersen-Gill analyses were performed to identify variables associated with risk for VTA burden among 1,012 patients enrolled in RAID. The primary endpoint was VTA burden defined as VTA episodes requiring appropriate treatment., Results: Multivariate analysis identified 7 factors associated with increased VTA burden: history of VTA, age ≥65 years, New York Heart Association functional class ≥III, QRS complex (≥130 ms), low ejection fraction (<30%), atrial fibrillation (AF), and concomitant antiarrhythmic drug (AAD) therapy. The effect of ranolazine on VTA burden was seen among patients without concomitant AAD therapy (HR [HR]: 0.68; 95% CI: 0.55-0.84; P < 0.001), whereas no effect was seen among those who are concomitantly treated with other AADs (HR: 1.33; 95% CI: 0.90-1.96; P = 0.16); P = 0.003 for interaction. In patients with cardiac resynchronization therapy (CRT) ICDs, ranolazine treatment was associated with a 36% risk reduction for VTA recurrence (HR: 0.64; 95% CI: 0.47-0.86; P < 0.001), whereas among patients with ICDs without CRT no significant effect was noted (HR: 0.94; 95% CI: 0.74-1.18; P = 0.57); P = 0.047 for interaction., Conclusions: In patients with high risk for VTA, ranolazine is effective in reducing VTA burden, with significantly greater effect in CRT-treated patients, those without AF, and those not treated with concomitant AADs. In patients already on AADs or those with AF, the addition of ranolazine did not affect VTA burden. (Ranolazine Implantable Cardioverter-Defibrillator Trial [RAID]; NCT01215253)., Competing Interests: Funding Support and Author Disclosures This study was supported by grants from the National Heart, Lung, and Blood Institute: Clinical Coordination Center (UO1 HL096607) and Data Coordination Center (UO1 HL096610. Study drug and additional financial support for drug distribution was provided by Gilead Sciences grant number IN-US-259-0125. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of excess fat in the liver in the absence of alcohol and increases one's risk for both diabetes and cardiovascular disease (e.g., angina). We have shown that the second-line anti-anginal therapy, ranolazine, mitigates obesity-induced NAFLD, and our aim was to determine whether these actions of ranolazine also extend to NAFLD associated with type 2 diabetes (T2D). Eight-week-old male C57BL/6J mice were fed either a low-fat diet or a high-fat diet for 15 weeks, with a single dose of streptozotocin (STZ; 75 mg/kg) administered in the high-fat diet-fed mice at 4 weeks to induce experimental T2D. Mice were treated with either vehicle control or ranolazine during the final 7 weeks (50 mg/kg once daily). We assessed glycemia via monitoring glucose tolerance, insulin tolerance, and pyruvate tolerance, whereas hepatic steatosis was assessed via quantifying triacylglycerol content. We observed that ranolazine did not improve glycemia in mice with experimental T2D, while also having no impact on hepatic triacylglycerol content. Therefore, the salutary actions of ranolazine against NAFLD may be limited to obese individuals but not those who are obese with T2D.

Background: The clinical picture of coronary artery disease has changed considerably in past years. As a consequence, the medical condition was re-defined in 2019 as "chronic coronary syndrome" (CCS). In view of these developments, the primary aim of the ALTHEA study was to gain current insights into the management of patients with CCS and stable angina in German primary care settings., Method: ALTHEA is a national, cross-sectional study that used a structured 10-item-questionaire containing single-choice and multiple-choice questions on diagnosis, symptomatic therapy and quality of life of patients with suspected or confirmed CCS and stable angina. Interviewees were primary care practitioners (PCPs) from Germany., Results: Interviews were conducted between April and September 2021. In total 1,050 PCPs were asked country-wide, aimed at achieving a representative sample. Of the 1,050 PCPs 1,021 replied. The majority of respondents indicated that they would carry out instrument-based diagnostic tests on their own, including a stress electrocardiogram, if CCS was suspected. Regarding treatment goals, the majority of the interviewees gave more relevance to an enhanced quality of life compared to prognostic improvements. In addition, most participants stated that they independently initiate and control symptomatic therapy in patients with suspected CCS and stable angina. Amongst the available antianginal medications, the interviewees showed preferences in terms of efficacy (betablockers), tolerability (ranolazine) and effect on quality of life (ranolazine)., Conclusions: The cross-sectional study shows that PCPs currently serve as relevant guides to cardiologists in the care of patients with suspected CCS and stable angina. PCPs provide support in several areas such as diagnosis and symptomatic therapy, in part intersecting with cardiologists' tasks. Hence the study reveals a close link between primary care and cardiology in the management of patients with CCS., (© 2022. Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Ranolazine was approved by the US Food and Drug Administration as an antianginal drug in 2006, and has been used since in certain groups of patients with stable angina. The therapeutic action of ranolazine was initially attributed to inhibitory effects on fatty acids metabolism. As investigations went on, however, it developed that the main beneficial effects of ranolazine arise from its action on the late sodium current in the heart. Since late sodium currents were discovered to be involved in various heart pathologies such as ischemia, arrhythmias, systolic and diastolic dysfunctions, and all these conditions are associated with heart failure, ranolazine has in some way been tested either directly or indirectly on heart failure in numerous experimental and clinical studies. As the heart continuously remodels following any sort of severe injury, the inhibition by ranolazine of the underlying mechanisms of cardiac remodeling including ion disturbances, oxidative stress, inflammation, apoptosis, fibrosis, metabolic dysregulation, and neurohormonal impairment are discussed, along with unresolved issues. A projection of pathologies targeted by ranolazine from cellular level to clinical is provided in this review., (Copyright © 2022. Published by Elsevier B.V.)

Chronic stable angina pectoris, the most prevalent symptomatic manifestation of coronary artery disease, greatly impairs quality of life and is associated with an increased risk for adverse cardiovascular outcomes. Better understanding of the pathophysiologic mechanisms of myocardial ischemia permitted new therapeutic strategies to optimize the management of angina patients. Ideally, antianginal drug treatment should be tailored to individual patient's profile and chosen according to the pathophysiology, hemodynamic profile, adverse effects, potential drug interactions and comorbidities. In this respect, and because of its peculiar mechanism of action, ranolazine represents an alternative therapeutic approach in patients with chronic stable angina and may be considered the first choice in presence of comorbidities that difficult the use of traditional therapies.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver pathology in the developed world. Nonalcoholic fatty liver disease is associated with a higher risk of cardiovascular disease. We investigated the impact of ranolazine on liver tests in patients with NAFLD and coronary artery disease (CAD). Patients who had established CAD and NAFLD (as assessed by raised serum transaminase activity, sonographic criteria, and the absence of any other obvious liver disease) were allocated to "on ranolazine" (n = 40) or "not on ranolazine" (n = 35) groups. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured in all patients at baseline and at the end of the study. After 6 months of ranolazine treatment, both ALT and AST activities were significantly lower in patients in the "on ranolazine" group compared with "not on ranolazine" patients (change from baseline: ALT, -11.0 ± 1.7 IU/L, P < .001; AST, -5.2 ± 1.9 IU/L, P =.009). In conclusion, the present study showed that treatment with ranolazine for 6 months led to a significant reduction in the activities of both serum aminotransferases in patients with stable CAD and NAFLD.

Background: Ranolazine is a second-line drug for the management of chronic coronary syndromes (CCS). Glucose-lowering and endothelial effects have also been reported with this agent. However, whether ranolazine may improve short-term glycemic variability (GV), strictly related to the prognosis of patients with type 2 diabetes (T2D), is unknown. Thus, we aimed to explore the effects of adding ranolazine to standard anti-ischemic and glucose-lowering therapy on long- and short-term GV as well as on endothelial function and oxidative stress in patients with T2D and CCS., Methods: Patients starting ranolazine ( n = 16) were evaluated for short-term GV, haemoglobin 1Ac (Hb1Ac) levels, endothelial-dependent flow-mediated vasodilation (FMD), and oxidative stress levels at enrolment and after 3-month follow-up. The same measurements were collected from 16 patients with CCS and T2D that did not receive ranolazine, matched for age, gender, and body mass index., Results: A significant decline in Hb1Ac levels was reported after 3-month ranolazine treatment (mean change -0.60%; 2-way ANOVA p = 0.025). Moreover, among patients receiving ranolazine, short-term GV indexes were significantly improved over time compared with baseline ( p = 0.001 for time in range; 2-way ANOVA p = 0.010). Conversely, no significant changes were reported in patients without ranolazine. Finally, greater FMD and lower oxidative stress levels were observed in patients on ranolazine at 3 months., Conclusions: Ranolazine added to standard anti-ischemic and glucose-lowering therapy demonstrated benefit in improving the glycemic status of patients with T2D and CCS. How this improvement contributes to the overall myocardial benefit of ranolazine requires further studies., Competing Interests: The authors declare that they have no conflict of interest related to the content of the manuscript., (Copyright © 2021 Annunziata Nusca et al.)

Background: β-Blockers are first-line therapy in patients with long QT syndrome (LQTS). However, β-blockers had genotype dependent efficacy (LQT1>LQT2>LQT3). Sodium channel blockers have been recommended as add-on therapy for LQT3 patients. However, the pooled effect of sodium channel blockers in all LQTS patients remains unknown., Methods: We conducted a systematic electronic search of PubMed, Embase, and the Cochrane Library. Fixed effects model was used to assess the effect of sodium channel blockers on QTc, cardiac events (CEs), and the proportion of QTc ≥ 500 ms and QTc ≤ 460 ms in LQTS patients., Results: Pooled analysis of 14 studies with 213 LQTS (9 LQT1 + 63 LQT2 + 135 LQT3 + 6 others) patients showed that sodium channel blockers significantly shortened QTc by nearly 50 ms (mean difference [MD], -49.43; 95% confidence interval [CI], -57.80 to -41.05, p < .001), reduced the incidence of CEs (risk ratio [RR], 0.23; 95% CI, 0.11-0.47; p < .001) and the proportion of QTc ≥ 500 ms (RR, 0.33; 95% CI, 0.24-0.47; p < .001), and increased the proportion of QTc ≤ 460 ms (RR, 10.33; 95% CI, 4.62-23.09; p < .001). Sodium channel blockers significantly shortened QTc both in LQT3 and LQT2 patients, while the QTc shortening effect in LQT3 was superior to that in LQT2 (57.39 vs. 36.61 ms). Mexiletine, flecainide, and ranolazine all significantly shortened QTc, and the QTc shortening effect by mexiletine was the best (60.70 vs. 49.08 vs. 50.10 ms)., Conclusions: Sodium channel blockers can be useful both in LQT3 and LQT2 patients. Mexiletine, flecainide and ranolazine significantly shortened QTc in LQTS patients, and the QTc shortening effect by mexiletine was the best., (© 2021 Wiley Periodicals LLC.)

Ranolazine derives from piperazine and has been approved as a drug for the therapy of chronic stable angina. It acts by selectively inhibiting the late sodium inward current. Moreover, ranolazine has other metabolic features which makes it effective in other diseases as well as coronary artery ones. In this paper I make an updated review of all possible therapeutic roles of ranolazine: through cardiology and beyond.

Coronary microvascular dysfunction (CMD) is defined as a mismatch of myocardial blood supply and oxygen consumption due to a dysfunction of the coronary microvessels. Up to 20-30% of patients with CMD have progressive worsening of symptoms with significant impairment of quality of life. Large-scale randomized studies of the pharmacologic treatment of CMD are lacking. Classic anti-ischemic drugs are the initial form of treatment, but efficacy is often limited. Ranolazine has a unique mechanism of action that does not affect blood pressure or heart rate. When added to existing anti-anginal agents, ranolazine improved at least one domain in eight of ten studies in which a questionnaire was used to assess patient health status. Five studies evaluated coronary arterial flow reserve (CFR), reporting that patients with low values had significant improvement in CFR and suggesting that those with more severe CMD respond more favorably to ranolazine. In two studies, exercise duration and time to myocardial ischemia were significantly increased after treatment with ranolazine. Data are lacking for ranolazine use as the sole agent for CMD treatment. Some questions remain to be answered regarding ranolazine use for CMD. Larger studies of longer duration are needed to verify the effectiveness of ranolazine in the treatment of CMD., (© 2020. The Author(s), under exclusive licence to Springer Nature Switzerland AG part of Springer Nature.)

Background :Ranolazine and trimetazidine are piperazine derivatives used in antianginal therapy. There are data on the use of these drugs in the treatment of neuropathic pain. In this study, it was aimed to evaluate the antinociceptive effects of ranolazine and trimetazidine. Methods : Sixty patients who were started on trimetazidine or ranolazine treatment were included in the study. The patients were evaluated with Seattle Angina Questionnaire (SAQ), Visual Analog Scale (VAS) and State-Trait Anxiety Inventory (STAI) on the first day of treatment and at the first month follow-up. Results : The SAQ scores of the patients given ranolazine were statistically significantly higher than the patients given trimetazidine. The most significant increase was observed in terms of treatment satisfaction (53.03 ± 8.11 vs. 72.88 ± 5.29, p < 0.001) and quality of life (49.79 ± 8.62 vs. 68.01 ± 0.65, p = 0.016). The decrease in VAS ( p = 0.001) and the decrease in STAI scores ( p = 0.002) after treatment in the ranolazine group were significantly higher than in the trimetazidine group. Conclusions : Ranolazine and trimetazidine are two effective drugs in antianginal treatment. While both drugs are effective on general systemic musculoskeletal pain and anxiety, the efficacy of ranolazine is more pronounced.

The COVID-19 pandemic has become a burden to the global healthcare community. Despite the severity of the complications associated with COVID-19, no antiviral agent is yet available for the treatment of this disease. Several studies have reported arrhythmias as one of the numerous manifestations associated with COVID-19 infection. Clinicians use different therapeutic agents in the management of COVID-19 patients with arrhythmias, apart from ranolazine; however, some of these drugs are administered with caution because of their significant side effects. In this study, we reviewed the potential antiarrhythmic effects of ranolazine in the management of cardiac arrhythmias associated with COVID-19. Ranolazine is a second-line drug approved for the treatment of chronic stable angina pectoris. Previous studies have shown that ranolazine produces its beneficial cardiac effects without any significant impact on the body's hemodynamics; hence, blood pressure is not altered. Due to its reduced side effects, ranolazine may be more effective than other drugs in producing the desired relief from COVID-19 related arrhythmias, since it produces its antiarrhythmic effect by modulating sodium, potassium and calcium channels, and suppressing cytokine expression., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: A major outcome determinant in patients with precapillary pulmonary hypertension (PH) is right ventricular (RV) function. We studied the effect of ranolazine on RV function over 6 months using cardiovascular magnetic resonance (CMR) imaging in patients with precapillary PH (groups I, III, and IV)., Methods and Results: We enrolled patients with PH and RV dysfunction (CMR imaging ejection fraction [EF] of <45%) in a longitudinal, randomized, double-blinded, placebo controlled, multicenter study of ranolazine treatment. All enrolled patients were on stable PH-specific therapy. Enrolled patients were assessed using CMR imaging, New York Heart Association functional class, N-terminal pro brain natriuretic peptide, 6-minute walk test, and quality of life health outcomes at baseline and repeated at the end of treatment. The primary outcome was change in RVEF after 6 months of treatment. Analysis of covariance was used to analyze the longitudinal changes taking into account baseline values, age, and sex, based on per protocol population. Twenty-two patients were enrolled, and 9 patients completed follow-up CMR imaging after ranolazine treatment and 6 completed placebo treatment. There was significant increase in RVEF at end of treatment compared with baseline in the ranolazine group adjusted for baseline values, age, and sex. There were no statistically significant changes in secondary outcomes such as changes in New York Heart Association functional class, 6-minute walk distance, N-terminal pro brain natriuretic peptide, or quality of life measures. Ranolazine treated patients experienced a higher number of adverse events, but only one was discontinued owing to side effects., Conclusions: Ranolazine may improve RV function in patients with precapillary PH. Larger studies are needed to confirm the beneficial effects of ranolazine., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Microvascular dysfunction is known to play a key role in patients with angina and nonobstructive coronary artery disease. We investigated the impact of ranolazine among patients with angina and nonobstructive coronary artery disease., Methods: In this randomized, double-blinded, placebo-controlled pilot trial, 26 patients with angina once weekly or more, abnormal stress test, and nonobstructive coronary artery disease (<50% stenosis by angiography and fractional flow reserve >0.80) were randomized 1:1 to ranolazine or placebo for 12 weeks. Primary end point was ΔSeattle Angina Questionnaire (SAQ) angina frequency score. Baseline and 3 months follow-up SAQ, Duke Activity Status Index scores along with invasive fractional flow reserve, coronary flow reserve (CFR), hyperemic myocardial resistance, and cardiopulmonary exercise testing measurements were performed., Results: No significant differences in ΔSAQ angina frequency scores ( P =0.53) or Duke Activity Status Index ( P =0.76) were observed between ranolazine versus placebo, although patients on ranolazine had lesser improvement in SAQ physical limitation scores ( P =0.02) compared with placebo at 3 months. There were no significant differences in ΔCFR or Δhyperemic myocardial resistance between ranolazine and placebo groups. Patients treated with ranolazine, compared with placebo, had no significant improvement in maximum rate of oxygen consumption measured during incremental exercise (VO 2 max) and peak metabolic equivalents of task. Interestingly, in the ranolazine group, patients with baseline CFR<2.0 demonstrated greater gain in CFR compared with those with baseline CFR≥2.0 ( P =0.02)., Conclusions: Ranolazine did not demonstrate improvement in SAQ angina frequency score, invasive microvascular function, or peak metabolic equivalent compared with placebo at 3 months. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02147067.

The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation. In the absence of genetic confirmation, the diagnosis is supported by detailed electrophysiological testing, exclusion of other related disorders, and analysis of a variant of uncertain significance if present. Symptomatic treatment with a sodium channel blocker, such as mexiletine, is usually the first step in management, as well as educating patients about potential anesthetic complications., (© 2020 Wiley Periodicals, Inc.)

Ranolazine is approved for patients with chronic stable angina but has not been formally studied in patients with refractory angina pectoris (RAP). Patients with RAP have limited therapeutic options and significant limitations in their quality of life. The Ranolazine Refractory Angina Registry was designed to evaluate the safety, tolerability, and effectiveness of ranolazine in RAP patients in order to expand treatment options for this challenging patient population. Using an extensive prospective database, we enrolled 158 consecutive patients evaluated in a dedicated RAP clinic. Angina class, medications, major adverse cardiac events including death, myocardial infarction, and revascularization were obtained at 12, 24, and 36 months. At 3 years, 95 (60%) patients remained on ranolazine. A ≥2 class improvement in angina was seen in 48% (38 of 80 patients with known Canadian Cardiovascular Society class) of those who remained on ranolazine. Discontinuation due to side effects, ineffectiveness, cost, and progression of disease were the principle reasons for discontinuation, but primarily occurred within the first year. In conclusion, ranolazine is an effective antianginal therapy at 3-year follow-up in patients with RAP and may reduce cardiac readmission., (Copyright © 2020. Published by Elsevier Inc.)

We report the case of a 40-year-old man, transferred from another hospital to our ICU because of acute coronary syndrome. Coronarography did not show coronary stenosis. Twenty-four hours monitoring EKG allowed diagnosis of Prinzmetal angina and appropriate therapy was administered. Six months after discharge due recurrence of symptoms, ranolazine was added to therapy. After one year the patient is symptoms free.

Ranolazine is a drug used in refractory chronic stable angina. In this study, it was aimed to evaluate the protective effect of ranolazine in a testis torsion model in light of objective biochemical and pathological data. A total of 24 pre-pubertal male Wistar albino rats were separated into three groups of 8 as the sham group, control group and ranolazine group. Testis torsion was applied for 3 hr to all the rats in Group Control and Group Ranolazine. In Group Control, 0.9% NaCl was applied 1 hr after the torsion. In Group Ranolazine, ranolazine 30 mg/kg was dissolved in a 0.9% NaCl solution and was administered intraperitoneally 1 hr after torsion. Histopathological evaluation was made using the Cosentino score. As a result of the objective biochemical and pathological criteria used in this study, this protective effect of ranolazine was observed in testis torsion. The results obtained in this study may suggest that ranolazine is a drug that could be applied after detorsion to patients diagnosed with torsion., (© 2020 Blackwell Verlag GmbH.)

Background: More than 20% of patients presenting to the catheterization lab have no significant obstructive coronary artery disease (CAD) despite having angina. Several occult coronary abnormalities, including endothelial dysfunction, microvascular dysfunction (MVD), and/or a myocardial bridge (MB), may explain their symptoms. We studied the effect of ranolazine on symptoms and quality of life (QOL) in these patients., Methods: We retrospectively studied 53 patients prescribed with ranolazine, matched on sex and age, with 106 patients on standard of care who underwent comprehensive invasive testing. Endothelial dysfunction was defined as a decrease in luminal diameter of >20% after intracoronary acetylcholine, MVD as an index of microvascular resistance ≥25, and a MB as an echolucent half-moon sign and/or ≥10% systolic compression on intravascular ultrasound. A Seattle Angina Questionnaire (SAQ) and SF-12 questionnaire were completed at baseline and follow-up., Results: Median follow-up was 1.9 (1.7-2.2) years. Endothelial dysfunction was present in 109 (69%), MVD in 36 (23%), and an MB in 86 (54%). Both groups had significant improvement in all dimensions of the SF-12 and SAQ with the exception of treatment satisfaction. We found no significant difference in change in SAQ and SF-12 scores between the groups, although the ranolazine group had significantly lower baseline SAQ scores., Conclusion: In patients with angina and no obstructive CAD, ranolazine is no different than standard of care in symptomatic and QOL improvement. Further randomized trials are warrented to confirm our findings and identify novel medical therapies in this patient population., Competing Interests: Declaration of competing interest No conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Diabetic neuropathy (DN) is a common complication of diabetes mellitus (DM). Pathophysiology of DN includes inflammation and changes in expression and function of voltage-gated sodium channels (Nav) in peripheral nerves; and central reduction of Peroxisome Proliferator Activated Receptor-Gamma (PPAR-γ) expression., Aim: This study explored the effect of ranolazine (RN) versus pioglitazone (PIO) in DN induced in rats. The role of sciatic interleukin (IL)-1β, tumor necrosis factor-alpha (TNF)-α, Nav1.7, and spinal PPAR-γ expressions were determined., Materials and Methods: For induction of Type-2 DM, 40 high fat diet-fed rats were challenged by a single dose of intraperitoneal streptozotocin (30 mg/kg). One week later, oral PIO (10 mg/kg; once daily) or RN (20, 50 and 100 mg/kg; twice daily) were administered for six weeks. Weekly body weight and fasting blood sugar (FBS) were measured. Rats were tested for thermal hyperalgesia and mechanical allodynia. At the end of the experiment, sciatic nerves homogenates were examined for TNF-α and IL-1B levels, and Nav1.7 channel expression. Segments of spinal cords were investigated for the PPAR-γ gene expression. Evaluation of histopathology of sciatic nerves and spinal cords were done., Key Findings: In diabetic rats, PIO and RN individually improved evoked-pain behaviors, reduced sciatic TNF-α and 1L-1B levels; downregulated expressional levels of Nav1.7 channels; and increased the spinal PPAR-γ gene expression. RN in the dose of 100 mg/kg/day showed the most advantageous effects., Significance: RN has neuroprotective effects in Type-2 diabetes-induced DN. Further studies of combined RN-PIO treatment are recommended, especially in diabetic patients with cardiovascular co-morbidity., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)