Ischemic Heart Disease (IHD) is a significant cause of mortality and morbidity. Incidence is expected to increase in the coming years, mainly due to an increase in the elderly population, which will have a negative impact on clinical outcomes and quality of life. A recent study estimated that globally, ischemic heart disease affects around 126 million individuals, with a crude prevalence rate of 1.655/100.000 people and expected to exceed 1.845 by 2030 (Khan et al., 2020).

Aging is a non-modifiable risk factor for cardiovascular disease and has been linked to increased inflammation, known as “inflammaging.” This condition is concomitant with a range of comorbidities, including heart failure, arterial hypertension, diabetes mellitus, chronic kidney disease, and sarcopenia that has been shown, especially in older people, to increase both the risk of IHD and cognitive impairment (CoI) (Liberale et al., 2020; Madhavan et al., 2018; Alonso Salinas et al., 2024).

Managing elderly patients with IHD could be challenging at the same time due to severe comorbidities, often limited treatment options, and atypical symptoms. The treatment for elderly patients with IHD is intended to improve quality of life, life expectancy, and the prevention of cardiovascular events. The initial therapeutic approach, suggested by guidelines, involves the administration of beta and calcium channel blockers as the preferred initial treatment option; Ranolazine should be considered as adjunctive therapy in cases of uncontrolled symptoms or as primary therapy for specific patients (Maron et al., 2020; Vrints et al., 2024; Santucci et al., 2020; Rousan and Thadani, 2019). In particular, Ranolazine, a late Na + current inhibitor, improves cardiac microcirculation and reduces tissue oxygen consumption with no significant effect on hemodynamic parameters and heart rate, reducing angina symptoms and improving exercise tolerance and quality of life (Tamargo and Lopez-Sendon, 2022; Manolis et al., 2024; Mehta et al., 2022; Timmis et al., 2006).

Particularly in the elderly, another intriguing aspect is the correlation between IHD and cognitive function. Indeed, several studies have demonstrated an association between IHD and an elevated risk of CoI secondary to vascular dementia (Liang et al., 2021). However, to date, we have no evidence on the possible neuroprotective role of antianginal therapy, particularly Ranolazine, on the onset of CoI. Some interesting data come from in vivo studies that indicate the neuroprotective effects of Ranolazine, probably due to anti-inflammatory and anti-apoptotic effects on brain tissue (Cassano et al., 2020; Samir et al., 2024).

Nevertheless, the available data on the real benefit of Ranolazine on cognitive function in elderly patients with IHD remain controversial. Considering the aforementioned factors, We hypothesize that Ranolazine use in elderly IHD patients with multiple comorbidities is associated with a slower rate of cognitive decline compared to standard therapy.

In this prospective observational study, 519 Caucasian patients were enrolled, between December 2017 and August 2023, at the Geriatric Department of “Renato Dulbecco” University-Hospital of Catanzaro. The study included patients suffering from IHD from the Catanzaro Metabolic Risk factors (CATAMERI), a longitudinal observational study assessing cardio-metabolic risk in individuals. The inclusion criteria were age>65 years; written informed consent; history of IHD. Exclusion criteria were: acute coronary syndrome in the previous 3 months, respiratory failure, severe renal dysfunction (estimated glomerular filtrate (eGFR) < 30 mL/min/1.73 m²); nephrotic syndrome, macroalbuminuria, severe hepatic impairment (Child–Pugh Class C); pregnancy or breastfeeding, prior diagnosis of dementia or severe psychiatric disorders. Follow-up visits were scheduled every 1 year, with a time window of 4 weeks (±4 weeks); and a pre-defined maximum follow-up of 4 years. A careful medical history was obtained in all subjects. A complete physical examination was performed, and both body weight and body mass index (BMI) were also measured. The study was approved by the local Institutional Ethics Committees, (code protocol number 2012.63). All patients signed informed consent, and the study procedures were carried out in accordance with the principles of the Declaration of Helsinki.

Blood samples were collected after at least 12 h of fasting on peripheral blood samples. Serum Albumin was measured with a colorimetric spectrophotometric method (Bromocresol green). Glycaemia was determined by the glucose oxidase method (glucose analyzer, BeckmanCoulter, Milan) and the homeostasis model assessment (HOMA) index was used for the determination of Insulin resistance (Matthews et al., 1985). Enzymatic methods (Roche Diagnostics GmbH, Mannheim, Germany) were used for determination of blood levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) by pyridoxal phosphate activated (liquid reagent), and gamma-glutamyltransferase (γ-GT) were evaluated by standardized method (COBAS Integra 800-Roche Diagnostics GmbH, Mannheim, Germany). Creatinine was measured using the Jaffé method. The CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation was used for the estimation of glomerular filtration rate (eGFR) (Levey et al., 2009). Serum uric acid (UA) levels were assessed using URICASE/POD method (Boehringer Mannheim, Mannheim, Germany). The immuno-turbidimetric method automated system (Cardio Phase hs-CRP, Milan, Italy) was used to assess the high-sensitivity C-reactive protein (hs-CRP).

The incidence of CoI during follow-up, defined as reduction ≥3 pt of Mini-Mental State Examination (MMSE) from baseline to follow-up (Dewan et al., 2024), was identified as a study endpoint. Data pertaining to CoI was collected during the follow-up period. In the event of an occurrence, a standardized form was completed by the examining physician. The details of each event were recorded, as well as death certificates, hospital discharge letters or copies of hospitalization medical records, and other clinical documentation obtained from patients or their relatives.

All patients underwent a CGA. Specifically, cognitive function was assessed using the Mini-Mental State Examination (MMSE) (Folstein et al., 1975), while the presence of depressive symptoms was estimated using the Geriatric Depression Scale (GDS) (Yesavage et al., 1982-1983). Functional status was assessed using activities of daily living (ADL) (Katz et al., 1963) and instrumental activities of daily living (IADL) (Lawton and Brody, 1969). The severity of the angina symptoms was appropriately assessed using the Canadian Angina Scale (CAS) (Campeau, 1976).

Data were expressed as mean ± standard deviation (SD), median and interquartile range (IQR), and number and percentage for categorical variables, when appropriate. Student’s t-test was performed for unpaired data for continuous variables, Mann–Whitney’s test for unpaired data for non-continuous variables and χ2 tests for categorical variables. According to Ranolazine therapy, the overall population was divided into two groups. The incidence of Cognitive events was evaluated as the number of events per 100 patient-year. A binary logistic regression analysis was performed on the incidence of CoI evaluated as reduction of MMSE ≥3 pt; subsequently, clinical significant variables and the variables that significantly associated with the occurrence of CoI were included in a multivariate stepwise logistic regression analysis to calculate the odds ratio (OR) for the independent variables associated with the incidence of CoI. Analysis was corrected for age, sex, comorbidities and pharmacological treatments. The differences were considered statistically significant for p value < 0.05. All analyses were performed using the SPSS 20.0 statistical program for Windows (SPSS Inc., Chicago, IL, United States).

From an initial population of 741 patients, 27 had acute coronary syndrome in the previous 3 months, 31 had chronic respiratory failure, 38 had severe renal dysfunction disease, and 25 had prior dementia; moreover, 37 confirmed deaths, 23 did not sign the consent form and 41 patients were lost during the follow up; these patients were excluded from analysis (Figure 1). Therefore, 519 patients with an average age of 74.2 ± 6.8 years were enrolled in the study for a follow-up of 4 years. Of these patients, 385 were male, 154 subjects were treated with Ranolazine, and 365 were not receiving this medication (control group). Table 1 shows the comorbidity and medical therapy of the entire study population. Table 2 shows the study population’s clinical, epidemiological, laboratory, and echocardiographic basal parameters, stratified by Ranolazine’s use. Statistically significant differences between the two groups were observed for number of patients with age≥75 years (p < 0.001) more represented in the no-Ranolazine group, prevalence of history of acute coronary syndrome (p < 0.046), sarcopenia (p < 0. 0001) and type 2 diabetes mellitus (T2DM) (p < 0.040) were more prevalent in Ranolazine group (Table 1). The Ranolazine group showed a higher CAS (p < 0.0001) that reflects more severe symptoms in this group compared to the non-Rolazine group.

During a follow-up of 4 years, we observed a total of 186 cases of CoI (8.9 events/100 patient-year) in the whole study population. The incidence of the primary outcome was significantly lower in the Ranolazine group versus the control group (p < 0.0001), also considering the incidence rate (35 cases, 5.7 events/100 patient-year vs. 151 cases, 10.3 events/100 patient-year) (p < 0.001) (Figure 2).

Binary logistic regression analysis revealed a statistically significant association between CoI occurrence and treatment with Ranolazine, GLP-1RAs, and SGLT2i, in addition to the reduction of MMSE, GDS, and Hb values, and the increase of ADL, IADL, and CAS values were significantly correlated (Supplementary Table S1). Consequently, the variables significantly correlated with the dependent variable were entered into a multivariate stepwise logistic regression model to determine the independent predictors of CoI (Table 3). Ranolazine (OR 0.39; CI 0.247–0.640) was particularly interesting, as it was associated with a 61% odds reduction of CoI occurrence. In addition, the following factors were found to be associated with an odds reduction of CoI: 60% for GLP1-RAs use (OR 0.40; CI 0.25–0.65), 57% for 1 point increase in ADL (OR 0.40; CI 0.39–0.73), 40% for SLGT2i utilization (OR 0.60; CI 0.38–0.952), 20% for an increase of 1 point in IADL (OR 0.80; CI 0.67–0.97), 15% for 1 point increase in Hb levels (OR 0.85; CI0.76–0.96) and 11% for 1 point reduction in GDS (OR 0.89; CI 0.83–0.96), respectively. Finally, a 1-point reduction in MMSE (OR 1.26; CI 1.12–1.42) and a 1-point increase in CAS (OR 1.25; CI 1.05–1.48) were associated with an increased risk of CoI for a 26% and 25%, respectively.

This is the first clinical evidence in humans; data concerning the neuroprotective effect of Ranolazine and the impact of the medication on CoI is primarily drawn from studies conducted in vitro or in murine models. The possible neuroprotective effects of Ranolazine in humans may be explained, as demonstrated in vitro, by its action on various isoforms of voltage-gated sodium channels, including neuronal isoforms (Theile and Cummins, 2011). Research on primary astrocyte cultures has shown that Ranolazine reduces TNF-α and IL-1β levels and increases PPAR-γ levels, promoting anti-inflammatory and neuroprotective effects by blocking sodium channels at therapeutic doses (Aldasoro et al., 2016). Pro-inflammatory cytokines released by astrocytes have been implicated in the pathogenesis of neurodegenerative diseases such as Alzheimer’s dementia (Fuller et al., 2010). Therefore, Ranolazine may have a neuroprotective role by acting on CoI and dementia. In addition, the transcription factor PPAR-γ, which regulates cellular energy metabolism and inflammation, has been shown to provide neuroprotection in neurodegenerative diseases such as stroke and Alzheimer’s disease (Chen et al., 2012). Even in animal models, Ranolazine has been shown to mitigate not only the cardiotoxicity but also the neurotoxicity induced by doxorubicin. In addition, the neuroprotective effect of Ranolazine has been demonstrated by the reduction of NFkB phosphorylation in the hippocampus, leading to a decrease in inflammation and the reduction of ROS levels with the improvement of mitochondrial dysfunction. In the same study, doxorubicin-induced hippocampal plasticity and cognitive dysfunction were evaluated, and the efficacy of Ranolazine in ameliorating these effects was demonstrated through its actions on dendritic fiber density and synaptophysin levels (Chunchai et al., 2022). Another interesting effect of Ranolazine has been observed on CoI in hyperglycemic rat models, which showed reduced hippocampal neuron degeneration after treatment (Cassano et al., 2022).

It is known that CoI in patients with T2DM has been associated with microvascular dysfunction that results in global atrophy and lacunar infarctions, particularly in cases of long-term diabetes. Notably, hyperglycemia damages the brain’s microvasculature, leading to neuron and myelin loss, reduced endothelial integrity, and astrocyte impairment, all contributing to CoI (Al Hamed and Elewa, 2020; Yan et al., 2020). Moreover, insulin resistance, associated with a chronic inflammatory state mediated by cytokines such as IL1-beta and IL6, is linked to Alzheimer’s dementia and CoI (Kamal et al., 2014).

The present study further underscores the association between the anti-diabetic medications GLP1-RAs and SGLT2-i and a reduced incidence of CoI. GLP-1 receptor agonists have been demonstrated to reduce the incidence of CoI by acting on the central resistance insulin mechanism. Moreover, these medications have been observed to cross the blood-brain barrier, acting directly on brain regions such as the hippocampus, frontal cortex, thalamus, and hypothalamus (Bassil et al., 2014). Furthermore, studies have shown that these medications can improve neuroinflammation, oxidative stress, and cellular survival (Cheng et al., 2022).

Regarding SGLT2i, they may exert their neuroprotective effects through multiple mechanisms, predominantly involving the cardiorenal axis and ati-inflammatory pathways in elderly patients (Shah et al., 2025). In addition, some authors have proposed a pleiotropic effect, suggesting benefits that extend to the neuroprotective role (Pawlos et al., 2021). In particular, the studies conducted on the MAGIC-HF (MAgna GraecIa Comorbidities in Heart Failure) registry have considered a population of elderly patients with T2DM and heart failure across the whole spectrum of ejection fraction with an IHD prevalence of approximately 60%. They have demonstrated that using SGLT2i improves the different items of CGA (Magurno et al., 2024; Mei et al., 2024). Moreover, evidence suggests that SGLT2i can improve cognitive function and reduce the incidence and progression of mild CoI and dementia in diabetic patients (Lard et al., 2024; Youssef et al., 2023). It has been hypothesized that SGLT2i exert a direct neuroprotective effect through the inhibition of acetylcholinesterase, the increase of brain-derived neurotrophic factor (BDNF) levels, the reduction of oxidative stress and the reduction of the accumulation of amyloid beta plaques, in addition, SGLT2i may improve cerebral insulin sensitivity similar to GLP1-Ras resulting in increased hippocampal synaptic plasticity (Mancinetti et al., 2023; Armentaro et al., 2024). However, further research is required to confirm these actions.

Concerning the impact of IHD symptoms, multivariate analysis indicates a correlation between elevated CAS scores and an augmented odds of CoI. As demonstrated by various studies, preserving optimal physical performance is associated with a reduced odds of CoI and the development of dementia, a crucial consideration for elderly patients (Boa Sorte Silva et al., 2024). The clinical efficacy of Ranolazine in reducing the severity and frequency of IHD symptoms has been demonstrated in several studies, including MERLIN TIMI-36, CARISA, OSCAR, ARETHA, and RANGER (Morrow et al., 2009; Sendón et al., 2012; Alexopoulos et al., 2016; Zweiker et al., 2019; Olympios et al., 2024). These findings align with the results of the present study, which also showed that worsening of angina symptoms, as indicated by a 1-point increase in the CAS score, increases the odds of developing CoI by 25%. In association with tailored exercise, this approach has been shown to enhance physical performance, with a significant reduction in frequency and burden of symptoms, thereby improving the quality of life of IHD patients (Willis et al., 2019). The present study also indicates that a one-point increase in IADL and ADL and a one-point decrease in GDS are associated with a reduced odds of CoI. This finding aligns with the results of the ACTIVE study, which emphasizes the role of self-reported impairments in IADL in predicting more severe CoI and the development of mild CoI and dementia (Tomaszewski et al., 2018).

These observations suggest that the alleviation of angina and IHD symptoms with drugs of proven effectiveness, such as Ranolazine, and the enhancement of physical performance may empower these patients to maintain their autonomy in daily life, thereby mitigating the risk of social isolation and depression, and consequently of CoI occurrence. Although it is important to acknowledge that the primary observations supporting the neuroprotective effect of ranolazine are mainly derived from murine and in vitro studies, our results derived from real-world practice with the aim of an integrated management of both cardiovascular and cognitive comorbidities. These representing a promising direction for future healthcare advancements, exploring the potential role of ranolazine and other antianginal drugs not only in reducing the burden of angina symptoms but also the incidence of CoI in elderly patients with IHD, condition which dramatically compromises the quality of life and prognosis of elderly patients.