Management of chronic coronary syndromes has shifted from an obstructive coronary artery disease-focused model to a phenotype-guided approach that includes angina with nonobstructive coronary arteries/ ischemia with nonobstructive coronary arteries (INOCA), vasospastic angina (VSA), and coronary microvascular dysfunction (CMD). Background therapies such as statins, angiotensin-converting enzyme inhibitors, antiplatelets, and sodium-glucose cotransporter-2 inhibitor inhibitors improve vascular health, but the WARRIOR trial highlighted the limits of intensive therapy in unselected INOCA patients. Anti-ischemic treatment should be mechanism-based: calcium channel blockers for VSA, beta-blockers and ranolazine for CMD, while nitrates may worsen microvascular disease.

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.

Hypothyroidism is associated with cardiovascular complications, including supraventricular arrhythmias. Thus, this study investigated functional and morphological alterations in the atrial of hypothyroid rats and evaluated the effects of acute ranolazine treatment on arrhythmia susceptibility. Hypothyroidism was induced in Wistar rats with methimazole (0.02 % in drinking water) for 28 days. The experimental approach included in vivo electrocardiography (ECG), ex vivo assessment of atrial contractility and arrhythmia induction by burst pacing, histological analyses, PCR, and immunofluorescence. Hypothyroid rats exhibited reduced heart rate, prolonged P-wave duration, and increased PR interval, indicating impaired atrial function. Ex vivo atrial preparations also showed increased susceptibility to arrhythmias, characterized by a higher number and longer duration of arrhythmic episodes following burst pacing. Acute ex vivo administration of the antiarrhythmic drug ranolazine significantly reduced arrhythmias susceptibility. Histological analysis revealed myocardial disorganization, and increased vacuolization in hypothyroid rat atria. In addition, Cx43 expression was markedly reduced, potentially contributing to impaired intercellular electrical coupling and increased arrhythmogenic susceptibility. Overall, these findings demonstrate that hypothyroidism induces significant electrophysiological, structural and contractile atrial remodeling, resulting in increased susceptibility to atrial arrhythmia. These findings highlight the importance of thyroid hormone signaling in maintaining atrial electrical stability and suggest that targeting electrical instability with ranolazine may have therapeutic potential in hypothyroid cardiac remodeling.

Ovarian ischemia/reperfusion (I/R) injury is a major cause of tissue damage following the surgical detorsion of ovarian torsion and is characterized by excessive oxidative stress, inflammation, and progressive cellular injury. Although ranolazine has been reported to exert antioxidant and anti-inflammatory effects in various experimental models, its potential protective effects against ovarian I/R injury have not yet been investigated. This study aimed to evaluate whether pretreatment with ranolazine protects ovarian tissue against experimental I/R injury in rats. Twenty-four female Wistar albino rats were randomly assigned to four groups: a healthy group (HG), sham-operated group (SOG), ovarian ischemia/reperfusion (OIR) group, and ranolazine-treated ovarian ischemia/reperfusion (ROIR) group. Ovarian ischemia was induced by 1 h of torsion followed by 6 h of reperfusion. Ranolazine (50 mg/kg) was administered 1 h before the induction of ischemia as a preventive pretreatment. Oxidative stress markers (MDA, tGSH, SOD, and CAT), pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), histopathological alterations, and the expression of COX-1, COX-2, IL-1β, and IL-6 were evaluated by double immunofluorescence staining. Ovarian I/R significantly increased MDA and pro-inflammatory cytokine levels while markedly decreasing tGSH levels and SOD and CAT activities (p < 0.001). These biochemical alterations were accompanied by severe follicular degeneration, mononuclear cell infiltration, interstitial edema, decreased COX-1 immunoreactivity, and increased expression of COX-2, IL-1β, and IL-6. Ranolazine treatment significantly attenuated oxidative stress and inflammatory responses, preserved the antioxidant defense system, ameliorated histopathological damage, restored COX-1 immunoreactivity, and inhibited the expression of COX-2, IL-1β, and IL-6. This is the first experimental study evaluating ranolazine in ovarian I/R injury. These findings suggest that preventive pretreatment with ranolazine attenuates experimental ovarian I/R injury through antioxidant and anti-inflammatory mechanisms. Future studies are needed to determine whether similar protective effects can be achieved when ranolazine is administered after ovarian torsion or following surgical detorsion.

Structural coronary microvascular dysfunction (CMD) is a major pathophysiological mechanism underlying ischaemia with non-obstructive coronary arteries and is associated with persistent angina and impaired functional capacity. Although contemporary European guidelines recommend a structured, stepwise pharmacological approach, invasive confirmation of physiological improvement following this specific treatment protocol remains limited.

Heart failure is characterised by increased production of reactive oxygen species (ROS), which contribute to apoptotic signalling. Changes in excitation-contraction coupling in heart failure promote increased calcium extrusion and decreased calcium uptake by myocardial mitochondria. Mitochondrial calcium is required to increase the Krebs cycle flux to generate sufficient nicotinamide adenine dinucleotide (NADH) to match the increased energy demand seen in heart failure. Reduced NADH availability can decrease levels of reduced nicotinamide adenine dinucleotide phosphate (NADPH), leading to a loss of NADPH-mediated antioxidant capacity and thereby increasing ROS emission and oxidative damage. Accordingly, a group of therapies that increase mitochondrial calcium, such as sodium glucose-linked transporter 2 inhibitors and ranolazine, have been investigated as potential treatments in heart failure. Proposed mechanisms include reducing calcium extrusion from mitochondria via the Na+/Ca2+/Li+ exchanger. A second group of emerging therapies targets oxidative stress by directly scavenging ROS (MitoQ and SS-31) and has also been studied for use in heart failure. Contemporary research developments propose an alternative approach to targeting oxidative stress by enhancing endogenous antioxidant capacity through the administration of nicotinamide adenine dinucleotide (NAD) precursors, thereby increasing intracellular NAD availability.

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.