Chronic stable angina (CSA) significantly impairs functional capacity and quality of life (QoL), with many patients remaining symptomatic despite standard treatment. Ranolazine, a late sodium current inhibitor, is utilized as an adjunctive antianginal therapy. This systematic review and meta-analysis evaluates its efficacy and safety in adult patients with CSA. We searched major databases through April 2025 for studies comparing ranolazine to placebo or standard therapy. Efficacy outcomes included angina burden, exercise parameters, QoL, and major adverse cardiovascular events (MACE), including myocardial infarction (MI) and revascularization. Safety was assessed via adverse event incidence. Data were synthesized using random-effects meta-analysis. Sixty-nine studies were included. Ranolazine significantly improved objective exercise measures, increasing exercise duration (mean difference {MD}, 33.1 seconds; 95% confidence interval {CI}, 27.3-38.9), time to angina onset (MD, 42.8 seconds; 95% CI, 34.2-51.5), and time to 1-mm ST depression (MD, 43.2 seconds; 95% CI, 33.8-52.6). Ranolazine was associated with a reduced risk of MI (risk ratio {RR}, 0.91; 95% CI, 0.84-0.98), coronary artery bypass grafting (CABG; RR, 0.55; 95% CI, 0.35-0.86), and any revascularization such as percutaneous coronary intervention (PCI) or CABG (RR, 0.77; 95% CI, 0.64-0.91). Adverse events were more frequent in the ranolazine group (RR, 1.45; 95% CI, 1.27-1.66) but were predominantly non-serious. Ranolazine provides robust symptomatic and functional benefits in patients with CSA. It is associated with modest reductions in MI and revascularization procedures, such as PCI or CABG. The data support ranolazine as an effective therapy for patients with CSA.

Cardiovascular medications used in coronary artery disease (CAD) can potentially modulate the risk of incident atrial fibrillation (AF). However, comprehensive data regarding medication-specific AF risk in the CAD population remain limited. This study aimed to identify prevalent medications prescribed to patients with CAD and evaluate their independent associations with AF risk. In this retrospective cohort study of 157,750 patients with CAD and related comorbidities, CAD-predominant medications were identified based on a frequency analysis of prescriptions in the overall cohort. Among 99,370 patients who received at least one such medication, associations with incident AF were evaluated using extended Cox proportional hazards models with time-varying covariates. Overall, 30 CAD-predominant medications were identified across nine pharmacological classes. In multivariable Cox proportional hazards models, six medications were significantly associated with AF risk, of which one was associated with a lower risk and five with a higher risk. Ezetimibe/rosuvastatin was associated with reduced AF risk, whereas diltiazem HCl, torasemide, heparin sodium, bisoprolol fumarate, and norepinephrine were associated with increased risk. Torasemide showed the strongest positive association. AF risk demonstrated heterogeneity across different CAD medications. Antilipidemic agents were associated with a lower AF risk, whereas certain diuretics, antianginal agents, antihypertensive, and vasoactive agents were associated with a higher risk. These results may have implications for individualized pharmacotherapy and AF prevention in patients with CAD.

Background: Chronic coronary syndrome (CCS) is a major source of morbidity and healthcare utilization, and a substantial proportion of patients continue to experience angina despite contemporary revascularization and guideline-directed medical therapy. Trimetazidine, a metabolic anti-ischemic agent that does not affect heart rate or blood pressure, has been used for decades as a non-hemodynamic add-on. Its position in international guidelines, however, has shifted. We aimed to synthesize current evidence on the clinical efficacy, safety, and guideline status of trimetazidine in CCS and coronary artery disease (CAD) and to delineate clinical circumstances in which a symptom-directed trial may be considered. Methods: We performed a structured narrative review of randomized controlled trials, network and conventional meta-analyses, and large observational studies indexed in PubMed/MEDLINE, Embase, and the Cochrane Library between January 1990 and March 2026. Reference lists of eligible articles, international clinical practice guidelines, and regulatory communications from European and national agencies were also examined. Results: Across pooled analyses, trimetazidine modestly but reproducibly improved exercise tolerance and reduced angina frequency and short-acting nitrate use, with efficacy comparable to other non-heart-rate-lowering antianginal agents. Improvements in left ventricular function were reported in small, single-center studies in ischemic cardiomyopathy and selected high-risk subgroups; however, these findings have not been validated in contemporary large-scale trials, and their clinical significance against modern guideline-directed therapy is unknown. The ATPCI trial confirmed safety but showed no reduction in major adverse cardiovascular events after percutaneous coronary intervention. Rare extrapyramidal effects prompted the 2012 European Medicines Agency referral and several prescribing restrictions. Conclusions: Trimetazidine remains a reasonable symptom-directed adjunct for residual angina in carefully selected CCS patients, particularly those in whom further hemodynamic up-titration is limited or poorly tolerated. The 2024 ESC class IIb recommendation may partly reflect a broader emphasis on prognostic benefit, although the neutral post-PCI outcome evidence and regulatory safety restrictions also support a more cautious position.

Lyme borreliosis is a multisystem infectious disease caused by Borrelia burgdorferi and transmitted to humans through the bite of infected Ixodes ticks that most commonly affects the skin, joints, nervous system, and, less frequently, the heart. Lyme carditis typically presents with atrioventricular conduction abnormalities, whereas coronary vascular involvement is rarely described. We report a case of a 74-year-old man with exertional chest discomfort, dyspnea, and palpitations several months after an untreated tick bite. Electrocardiography demonstrated ventricular bigeminy with repolarization abnormalities, and 24-hour Holter monitoring showed a high burden of polymorphic premature ventricular complexes, with one episode of non-sustained ventricular tachycardia. Echocardiography demonstrated preserved left ventricular systolic function. Serological testing showed positive anti-B. burgdorferi IgG antibodies and negative IgM antibodies, consistent with prior exposure. Invasive coronary angiography revealed no obstructive epicardial coronary artery disease but demonstrated marked ectasia of the left anterior descending and right coronary arteries, both measuring up to 6.5 mm, with prolonged mural contrast retention. In the setting of exertional angina, persistent contrast retention within ectatic coronary segments, frequent ventricular ectopy, baseline bradycardia, and QTc prolongation, ranolazine was initiated as an antianginal therapy with potential antiarrhythmic benefit. At one-month follow-up, the patient reported marked improvement in symptoms. Repeat Holter monitoring showed a reduction in premature ventricular complexes to less than 5%, with no further episodes of non-sustained ventricular tachycardia. This case suggests that, in patients with coronary ectasia and a history compatible with prior untreated B. burgdorferi infection, Lyme-associated coronary vascular injury may be considered as a possible underlying mechanism, although definitive causality remains difficult to establish. Coronary ectasia with prolonged contrast retention should be recognized as a potential substrate for myocardial ischemia and ventricular arrhythmogenesis in patients without obstructive coronary artery disease. In selected patients with anginal symptoms and frequent ventricular ectopy, particularly when beta-blockers or conventional antiarrhythmic drugs are limited by bradycardia, QTc prolongation, or concern for conduction disease, ranolazine may offer a useful therapeutic option with combined antianginal and potential antiarrhythmic benefit.

Voltage-gated sodium channels (VGSCs) have emerged as important promoters of the invasive phenotype in triple-negative breast cancer (TNBC), a clinically aggressive and therapeutically challenging subtype of breast cancer. Channel activity is enhanced by hypoxia, which promotes metastatic progression. Pharmacological inhibition of VGSCs by specific channel blockers, such as ranolazine (RAN), results in antimetastatic behavior. Independently, epidermal growth factor signaling has been shown (1) to enhance VGSC activity and (2) to also promote TNBC progression. Here, we aimed to test whether cotreatment of a model TNBC cell line, MDA-MB-231, with an epidermal growth factor receptor inhibitor (AG1478 [AG]) and RAN would produce a synergistic effect on invasiveness. Two different concentrations of AG (5 and 10 μM) were used, whereas RAN was used at a clinically relevant concentration (<5 μM) under hypoxia (1% O2). Excess 'over bliss score' was determined quantitatively to evaluate possible synergy. Indeed, both RAN and AG individually suppressed Matrigel invasion dose dependently without altering proliferative activity. Clear synergy was observed at low-concentration combinations. Specifically, combined with 5 μM AG, RAN was clearly synergistic at 1.25 μM (excess over bliss = +38.7%). In contrast, higher concentrations produced little or no synergy. We concluded that the inhibitory effect of RAN on TNBC invasiveness can be made more effective by combination with an inhibitor of epidermal growth factor receptor/tyrosine kinase inhibitor at low concentrations. Furthermore, because functional VGSCs occur in several carcinomas and receptor tyrosine kinases commonly promote their invasiveness, the results could have broader application, including via drug repurposing. SIGNIFICANCE STATEMENT: Triple-negative breast cancer is a highly aggressive malignancy with limited therapeutic options. Ranolazine, an antianginal drug and an inhibitor of the voltage-gated sodium channel persistent current, inhibited cells' invasiveness at clinically relevant concentrations. Efficacy was enhanced by combination with an epidermal growth factor receptor inhibitor (AG1478). Synergy occurred specifically at low concentrations. These findings raise the possibility of treating triple-negative breast cancer nontoxically while reducing the chance of developing drug resistance. The results are also potentially applicable to multiple carcinomas.

Cardiovascular drugs face many barriers to oral delivery, and self-nanoemulsifying drug delivery systems (SNEDDS) are becoming a promising nano-enabled drug delivery vehicle to address these challenges and aid precision cardiovascular delivery. The poor aqueous solubility and/or intestinal permeability, combined with high intestinal and hepatic clearance and, in some cases, intestinal P-glycoprotein (P-gp) efflux, leads to variable systemic exposure and inconsistent therapeutic activity of many antihypertensive drugs, antianginal drugs, and cardioprotective agents. Under gastrointestinal dilution conditions, SNEDDS spontaneously generate nanosized oil-in-water emulsions that keep drugs in a solubilized state, promote drug dissolution, enhance membrane interactions, increase intestinal permeability levels due to surfactant activity, reduce membrane fluidization by P-glycoprotein mediated efflux, increase lymphatic transport, decrease hepatic first pass metabolism, and decrease pharmacokinetic variability. This allows for more predictable pharmacokinetic performance, reduced interpatient variability, therapeutic optimization, and therefore an enabling concept of nano-enabled precision cardiology. This graphical abstract depicts the importance of self-nanoemulsifying drug delivery systems (SNEDDS) for enhancing drug absorption, providing enhanced bioavailability, increasing drug absorption and pharmacokinetic predictability, and facilitating precision cardiovascular therapy by overcoming the oral bioavailability barriers.

Coronary microvascular dysfunction (CMD), a common endotype of angina with non-obstructed coronary arteries (ANOCA), is linked to poor cardiovascular outcomes, and can significantly impact quality of life, mental health, and functional capacity. CMD management strategies focus on symptom control with antianginal therapies, with limited effect and prognostic benefit. While lifestyle changes and risk factor modification are advocated by international guidelines, evidence supporting cardiac rehabilitation for CMD is sparse. It is proposed that MICROFIT-a personalized lifestyle intervention programme, utilizing exercise training and dietary counselling, underpinned by behavioural change techniques, can improve symptoms of angina in patients with CMD. This study aims to examine the feasibility of undertaking a multicenter randomized controlled trial (RCT) of the MICROFIT programme vs. usual care in patients with CMD and explore its effects on symptoms of angina.

Cervicogenic angina is a frequently overlooked non-cardiac chest pain syndrome whose clinical manifestations closely resemble those of true cardiac angina, and conventional anti-anginal medications as well as coronary interventions often yield unsatisfactory results. This report describes a 61-year-old male patient who presented with recurrent precordial pain, chest tightness, dyspnea, and numbness of the neck, shoulders and upper extremities for one year. The patient was initially diagnosed with coronary artery disease and underwent coronary intervention, but symptoms recurred shortly after the procedure and sublingual nitroglycerin was ineffective. After cardiac causes were ruled out through specialized cardiac examinations, physical examination revealed positive paravertebral tenderness and signs of nerve root compression. Cervical magnetic resonance imaging demonstrated disc herniation at C5-C7 with nerve root compression, leading to a final diagnosis of cervicogenic angina. The patient underwent ultrasound-guided pulsed radiofrequency of the cervical nerve roots and cervical sympathetic nerve combined with low-temperature plasma ablation of the cervical facet joints, followed by postoperative adjunctive treatment with duloxetine. Neck-shoulder pain and precordial discomfort improved markedly, with the visual analog scale score decreasing from 7 preoperatively to 0 at the 3-month follow-up; Cervical range of motion markedly improved; precordial pain, chest tightness, and dyspnea resolved completely without recurrence, and sleep quality improved significantly. This case suggests that cervicogenic angina should be strongly suspected in patients with recurrent chest pain after a standard cardiac work-up has excluded a cardiac origin. Ultrasound-guided radiofrequency intervention is safe and effective, providing a reliable minimally invasive treatment strategy for this easily missed condition and deserves wider clinical application.

Ranolazine is a drug with a dual mode of action as a metabolic modulator and membrane stabilizer. It is better known for its anti-ischemic and antianginal properties rather than its antiarrhythmic effects. It also possesses favorable antioxidant capacity and effects on glycemic control. Ranolazine is listed in current guidelines as a second-line agent for chronic angina. As mentioned, myocardial cells have high inward late-phase sodium-channel activity under ischemic conditions, followed by an increase in intracellular sodium levels, thus enhancing active exchange with extracellular calcium. Ranolazine is the agent that disrupts this inward sodium-channel activity during ischemia and thus can effectively reduce myocardial demand. Ranolazine increases exercise duration on treadmill testing and time-to-ischemia in patients with stable angina. Most articles discussing the best medical treatment for stable ischemic heart disease include ranolazine as part of this optimal therapeutic scheme. As guidelines state, ranolazine is an appropriate alternative for symptom relief when beta-blockers are contraindicated or not tolerated, and it can also be employed in combination with beta-blockers if monotherapy fails to provide sufficient symptom relief. Also, when beta-blockers and/or calcium channel blockers fail to successfully control the symptoms, ranolazine pitches in as an important second-line agent. This is also true when these primary therapeutic agents produce hypotension or severe bradycardia, as ranolazine does not exert a vasoactive and hypotensive action, nor does it have a bradycardic effect, except for extremely rare instances.

Ranolazine is an established antianginal agent; however, its oral administration is associated with delayed onset of action and variable systemic exposure due to extensive hepatic first-pass metabolism. Intranasal drug delivery is a non-invasive alternative that enables rapid systemic absorption while bypassing hepatic metabolism, although rapid mucociliary clearance can limit drug residence and absorption. Chitosan, a natural mucoadhesive polymer, has been extensively investigated for intranasal delivery owing to its ability to prolong mucosal residence time and enhance epithelial permeability. The present study aimed to develop and evaluate mucoadhesive chitosan microspheres of ranolazine for intranasal administration to enhance systemic bioavailability and pharmacokinetic performance. Microspheres were prepared using an emulsification cross-linking technique and optimized using Design-Expert® software by systematically varying polymer concentration and stirring speed as independent variables, with particle size and mucoadhesive strength as dependent responses. The optimised formulation (FCH4) was comprehensively characterised for physicochemical properties, particle-size distribution, surface morphology, mucoadhesive strength, in vitro drug release, ex vivo nasal permeation, stability, histopathology, and in vivo pharmacokinetics. The formulations exhibited yields of 80-95% and encapsulation efficiencies of 45-70%. The optimized formulation (FCH4; drug-to-polymer ratio 1:4) demonstrated spherical morphology with a smooth surface, a mean particle size of 37.8 ± 0.3µm, high encapsulation efficiency, and strong mucoadhesive properties. The optimized chitosan microspheres provided sustained drug release over 24 h through diffusion- and polymer relaxation-mediated mechanisms. Ex vivo studies using goat nasal mucosa revealed significantly greater drug permeation (31.5± 2.1% at 240 min), corresponding to a 1.41-fold enhancement over the pure drug suspension, while preserving mucosal integrity. Pharmacokinetic evaluation in New Zealand White rabbits demonstrated significantly increased systemic exposure and prolonged plasma residence of ranolazine compared with the pure drug, confirming effective avoidance of hepatic first-pass metabolism. Collectively, these findings support mucoadhesive chitosan microspheres as a promising intranasal delivery platform for ranolazine and highlight the potential of formulation-driven intranasal strategies for drugs limited by unfavourable oral pharmacokinetics.