Development trend analysis of ranolazine, based on bibliometrics

Abstract

Background:

Ranolazine is a highly effective inhibitor of the late sodium current and has been received approval from the FDA in 2006 for the treatment of chronic angina. To date, nearly 2000 papers have been published on it. It has demonstrated therapeutic potential in various fields, but uncertainties regarding its efficacy, safety risks, and limitations in expanding indications have hindered its clinical application. Therefore, we believe that the current period is the best time to conduct bibliometric analysis to overcome existing challenges and optimize interdisciplinary strategies.

Methods:

We searched and downloaded the papers in the Science Citation Index Expanded database of the Web of Science Core Collection on September 1, 2025. Microsoft Excel was applied to organize the data, WeiShengXin, CiteSpace and VOS viewer were used for data analysis and visualization.

Results:

A total of 1121 papers were included for follow-up research. The USA is the most productive country in this field and serves as a central hub for global cooperation and exchange. Gilead Sciences is the institution with the highest output in this field. Professor Belardinelli, L and Professor Chaitman, BR are the most influential authors in this field. The keywords “efficacy,” “ventricular arrhythmias,” “impact” and “channels” still have a strong influence at present.

Conclusions:

Currently, the research focus in this field primarily centers on 3 key aspects: the anti-angina effect, the electrophysiological characteristics and anti-arrhythmic effect and other effects of ranolazine. The future research direction in this field is likely to focus on the neuroprotective effect of ranolazine, its antitumor metastasis effect and its effect on atrial fibrillation and diabetes patients on the basis of maintaining the current research focus.

1. Introduction

Ranolazine, also known as Ranexa, is a derivative of piperazine with anti-ischemic properties. It is capable of exerting anti-ischemic effects without causing any hemodynamic changes.^[1] It was approved by the FDA as a medication for the treatment of chronic angina in 2006. The research on ranolazine has been developing for over 30 years since the late 1980s, with nearly 2000 articles published on it.

Initially, ranolazine was considered a partial fatty acid oxidase inhibitor. It can inhibit fatty acid oxidation^[2] and increase the activity of pyruvate dehydrogenase to stimulate glucose oxidation,^[3,4] thereby exerting anti-ischemic effects and alleviating symptoms of chronic angina. Scottish researchers have confirmed the cardioprotective effect of ranolazine during ischemia-reperfusion by establishing rabbit models.^[5] Numerous researchers or scholars have also evaluated the efficacy and safety of ranolazine through clinical randomized double-blind controlled trials. Although some researchers have drawn negative conclusions,^[6] the majority of studies have demonstrated positive clinical efficacy and safety in the treatment of chronic angina pectoris.^[7–9] In addition, animal experiments have shown that by the mechanism of inhibiting the oxidation of fatty acid beta and increasing the activity of pyruvate dehydrogenase, ranolazine can reduce the area of myocardial infarction in rats and the release of cardiac troponin T.^[10] It can also improve left ventricular function in dogs with chronic heart failure and increase left ventricular ejection fraction and stroke volume.^[11]

However, with the evolution of the field, researchers have discovered that ranolazine also functions as a late sodium channel inhibitor. It can selectively inhibit late sodium currents to exert cardioprotective effects^[12] and reduce arrhythmias caused by increased late sodium currents.^[13,14] Subsequent experimental results further suggest that ranolazine demonstrates anti-arrhythmic effects,^[15,16] particularly in the management of certain types of arrhythmias and atrial fibrillation associated with acute coronary syndrome, heart failure, or ischemia-reperfusion.^[17,18] According to the mechanism by which ranolazine inhibits late sodium current, some scholars have postulated the hypothesis that it can improve diastolic function. Experimental evidence has confirmed that ranolazine may offer therapeutic benefits for diastolic dysfunction resulting from increased sodium and diastolic calcium currents.^[19] In addition, ranolazine also has a positive effect on long Q-T syndrome type 3 (LQT-3)^[20] and has the ability to inhibit Na+ channel activity caused by genetic mutations in human diseases.^[21] The combination of ranolazine and ivabradine, in conjunction with conventional anti-ischemic therapy, may yield therapeutic benefits for patients with poorly controlled symptoms of microvascular angina.^[22] However, the effect of ranolazine goes far beyond that. Apart from the functions mentioned above, it also has neuroprotective effects^[23] and can prevent contrast-induced nephropathy, among other benefits. In 2024, Yusuf et al conducted a randomized controlled experiment that confirmed the efficacy of ranolazine in preventing contrast-induced nephropathy in humans for the first time.^[24] Also, several researchers have suggested that ranolazine may exhibit an anti-metastatic effect in cancer.^[25] This potential benefit could have significant implications for the treatment of cancer.

Bibliometrics is a comprehensive research system that integrates statistics and bibliometrics. Currently, it has been widely applied in various fields.^[26] It systematically analyzes various aspects of the literature with Lotka law, Bradford law, and Zipf law as its core. This analysis can assist researchers in understanding the research focus and grasping research trends.^[27,28] Since the late 1980s, research on ranitidine has achieved many accomplishments. And based on the current published articles in this field, only one article involved ranitidine when conducting bibliometric analysis.^[29] However, this article focuses more on atrial fibrillation and ion channels, rather than being a specific bibliometric study specifically targeting ranolazine. Overall, at present, there has been no systematic literature analysis on ranolazine in the field of research. Therefore, we believe that now is the optimal time to conduct bibliometric analysis. We anticipate that this study will break the current deadlock in the field and provide scientific guidance for future research endeavors.

2. Data and methods

2.1. Data sources and search strategies

We choose the Science Citation Index Expanded database within the Web of Science Core Collection (WoSCC SCI-E) as our data source. And on September 1, 2025, the search was conducted in the database with TS=(“ranolazine”) OR TS=(“Ranexa”) as the search formula. All articles and review articles published in English prior to 2025 were included in the follow-up study (Excluding all the papers published in 2025, 548 non-article or non-review papers, and 17 non-English papers). The detailed retrieval and screening process is shown in Figure 1.

Figure 1.

The detailed retrieval and screening process.

2.2. Data query and analysis

We downloaded the details of all papers filtered through the above process in “plain text file format.” For the purpose of gathering general information on the papers (including, but not limited to, country, institution, authorship details, journal, quantity of papers, citation frequency, H-index and impact factor [IF]), we opted to directly query the WoSCC SCI-E database and utilized Microsoft Excel for recording and organizing. The H-index was originally proposed by American physicists Hirsch, JE in 2005 as an indicator that comprehensively considers academic output. It can objectively evaluate the academic influence of a certain subject.^[30] The IF is a metric included in Journal Citation Reports (JCR) and serves as a crucial indicator for assessing the influence of academic journals. A high IF typically signifies a higher academic standing and greater influence.^[31]

VOS viewer 1.6.20.0 (Center for Science and Technology Studies [CWTS], Leiden University, Leiden, the Netherlands) and CiteSpace V.6.3.R1 (Drexel University, Philadelphia) Advanced are the most widely utilized analysis software for bibliometric research. Both of these tools offer the advantages of user-friendly operation and robust functionality, allowing for the visual representation of data nodes and their relationships in a clear and comprehensive manner.^[32,33] In this study, the VOS viewer was mainly used to visualize the outcomes of collaborative analysis, keyword occurrence, and co-cited analysis. CiteSpace was primarily used for the analysis of keywords and references. Additionally, we employed CiteSpace to generate a dual journal overlay map in order to enhance our understanding of the research development trajectory pertaining to ranolazine. WeiShengXin (R&D team of Shanghai New Core Biotechnology Co., Ltd., Shanghai, China) is an online tool with multiple mapping templates, and we used it to make the world distribution map of publications on ranolazine in this study.

3. Results

3.1. General trend analysis

There are 935 articles (account for 83.4 percent of all the papers in this study) and 186 (account for 16.6%) review articles, totaling 1121 papers, that meet the aforementioned screening criteria and have been included in our subsequent research. Based on the collected information, we have constructed a bar chart of annual publication volume (Fig. 2). It offers a more comprehensive presentation of the quantity of publications and trends in this field throughout the years. It is evident that research on ranolazine can be roughly categorized into 3 distinct periods. The initial period spanned from 1987 to 2005, during which a total of 71 papers on ranolazine were published. This period laid a robust foundation for the development of this research field. In the second period (from 2006 to 2016), there was an increasing trend in the annual publication volume, which may be attributed to the FDA approval of ranolazine as a drug for treating chronic angina in 2006. The announcement of this approval sparked a notable surge in researchers’ interest within this field. By 2016, the annual publication volume had reached its peak, with a total of 83 papers on ranolazine being published within that year. Afterward, the research in this field appears to have transitioned into a third phase – a period of stagnation. Throughout this phase, there has been an overall decrease in the annual publication volume. This trend may indicate that the study of ranolazine is currently facing a dilemma.

Figure 2.

The bar chart of annual publication volume.

3.2. Distribution of countries and institutions

During the process of writing the manuscript, in order to ensure that no contributions of the country or the author are overlooked, for collaborative papers, they will be re-recognized (for example, a Chinese-US collaborative paper will result in 1 additional paper for both China and the US). Of course, to ensure the scientific nature of the manuscript, we have also added the “independent research papers” item, to analyze the independent output capabilities of each country.

All the papers included in the study encompassed a total of 64 countries/regions and 1512 institutions. The countries and institutions with the highest productivity are delineated in Table 1, showcasing the top 10 performers in this regard. The USA led the field in publication with 557 papers, representing a commanding 50.0% of the total number of papers. Following closely behind were China, contributing 126 papers, and Italy, with 113 papers. In addition, the cumulative citation frequency of the USA has soared to an impressive 21,004 times, securing its position at the forefront among all nations. Although this remarkable achievement may be attributed to the prolific output of scholarly publications by the USA, it still reflects the unparalleled influence

Table 1.

The top 10 countries and institutions with the highest productivity.

Rank	Country/region	Count (all)	Independent published papers	Total citations	H-index	Rank	Productive institution	Count	Total citations
1	USA	557	355	21,004	81	1	Gilead Sciences	103	4364
2	China	126	89	1738	23	2	Harvard University	76	3422
3	Italy	113	70	3015	31	3	Harvard University Medical Affiliates	76	3422
4	Germany	105	58	3612	35	4	Harvard Medical School	54	2397
5	England	87	30	3388	33	5	Brigham & Women’s Hospital	50	2796
6	Canada	75	29	4116	31	6	CV Therapeutics, Inc.	35	3227
7	Greece	39	30	602	14	7	University of California System	35	1203
8	Spain	39	14	1549	19	8	University System of Ohio	35	1144
9	India	37	32	1220	13	9	State University System of Florida	34	2402
10	France	35	20	1105	19	10	University of Florida	34	2402

wielded by the USA in this particular field. Gilead Sciences stands out as the institution with the highest output, publishing a total of 103 papers. It has an H-index of 39. Simultaneously, everyone can clearly see that all the top 10 productive institutions belong to the USA. Figure 3A is a world distribution map of publications on ranolazine created by us using an online tool (WeiShengXin), which clearly displays the publication volume of countries around the world. The different filling colors in the figure represent different numbers of publications. Furthermore, we also used the bibliometric online analysis tool (https://bibliometric.com/app) to draw the national cooperation chord diagram (Fig. 3B). This picture can not only reflect the publication volume of each country, but also vividly show the cooperative relationships among various countries. The area occupied by each country in the image represents its publication volume. The larger the area occupied by a country, the more publications it has. The lines connecting countries indicate cooperative relationships. The more lines there are, the closer the cooperative relationship with other countries. It is very obvious that The USA is the country with the most frequent cooperation with other countries, especially its cooperation with Canada, Italy, Britain, China, and Germany.

Figure 3.

(A) The world distribution map of publications on ranolazine. (B) The diagram of the cooperative relationship between countries.

3.3. Distribution of authors

A total of 5320 authors has contributed to research in this field. The top 10 prolific authors and co-cited authors, who have had the greatest impact in this field, are presented in Table 2. When searching for the top 10 authors, we filtered them by their institution in order to exclude other authors with the same name. Prof Belardinelli, L. has authored 87 papers on ranolazine, placing first among all authors in terms of publication quantity. Additionally, Professor Chaitman, BR holds the record for the most citations with a total of 578 citations. In Table 2, 4 authors are identified as having both high productivity and significant academic influence in this field. These authors are: Professor Belardinelli, L (published 87 papers, cited 323 times), Professor Antzelevitch, C (published 29 papers, cited 519 times), Professor Morrow, DA (published 28 papers, cited 311 times), and Professor Scirica, BM (published 28 papers, cited 252 times). Figure 4 is an author collaboration network visualization drawn using VOS viewer. It includes the top 100 authors who have published at least 5 papers, with different colors in the figure representing different author clusters. It can be found that there is a clear clustering of collaborations among authors, and authors tend to prefer internal collaborations. This may be related to the fact that the authors belong to different countries and institutions. Professor Belardinelli, L, is the author who most frequently collaborates with other authors. His team (represented by red points) has established close cooperation with numerous other teams, serving as a central hub for collaboration and communication among various research groups.

Table 2.

The top 10 prolific authors and co-cited authors.

Rank	Author	Count	Affiliated institutions/countries		Rank	Co-cited author	Co-citations	Affiliated institutions/countries
1	Belardinelli, L	87	Gilead Sciences	USA	1	Chaitman, BR	578	Saint Louis University	USA
2	Rajamani, S	36	Gilead Sciences	USA	2	Antzelevitch, C	519	Masonic Medical Research Laboratory	USA
3	Antzelevitch, C	29	Masonic Medical Research Laboratory	USA	3	Burashnikov, A	460	Masonic Medical Research Laboratory	USA
4	Morrow, DA.	28	Brigham & Women’s Hospital	USA	4	Belardinelli, L	323	Gilead Sciences	USA
5	Scirica, BM.	28	Brigham & Women’s Hospital	USA	5	Morrow, DA	311	Brigham & Women’s Hospital	USA
6	Eckardt, L	26	University of Munster	Germany	6	Sossalla, S	271	University of Gottingen	Germany
7	Frommeyer, G	25	University of Munster	Germany	7	Scirica, BM	252	Brigham & Women’s Hospital	USA
8	Wu, ShN	20	National Cheng Kung University	China	8	Maltsev, VA	228	National Institutes of Health	USA
9	Maier, L	19	University of Gottingen	Germany	9	Sicouri, S	221	Masonic Medical Research Laboratory	USA
10	Verrier, RL	19	Beth Israel Deaconess Medical Center	USA	10	Stone, PH	204	Brigham & Women’s Hospital	USA
11	Braunwald, E	19	Brigham & Women’s Hospital	USA

Figure 4.

The network visualization of collaborating authors. Of the 5320 authors,100 had published at least 5 papers.

Of course, to verify the rationality of choosing 100 nodes as parameters, we also conducted a sensitivity analysis. Author cooperative mesh diagrams with 50 nodes and 150 nodes as parameters were drawn and respectively presented in Figures S1 and S2 (Supplemental Digital Content, https://links.lww.com/MD/Q618). Upon comparing with 100 nodes as a parameter, it was found that the choices of the 3 node parameters yielded largely consistent results. However, figure with 100 nodes as a parameter neither suffered from clutter due to an excessive number of nodes, nor did they lose important information due to too few nodes. To sum up, we believe that it is relatively reasonable to select 100 nodes as parameters for visualization.

3.4. Distribution of journals

As a regularly published medium, academic journals play a crucial role in facilitating the exchange of knowledge within the academic community. Analyzing the distribution of journals is valuable for researchers as it provides insight into current research trends in their respective fields and aids in selecting appropriate publications for future research endeavors. We have collected and organized the top 10 high-yield journals and co-cited journals, and presented them in Table 3. The journal Heart Rhythm published 43 papers on ranolazine, ranking first in terms of publication volume among the journals involved in this study. The journal with the second highest number of papers is J Cardiovasc Pharm, with an IF of 2.2. A total of 27 papers related to ranolazine have been published in this journal. Next is Am J Cardiol (IF2.3), who ranks third with 25 paper outputs. Circulation (IF38.6) is the most cited journal in this field, with a total of 4053 citations. Its total link strength reached 190,623. The journals Heart Rhythm, Am J Cardiol, J Mol Cell Cardiol, Am J Physiol-Heart C, J Am Coll Cardiol, and Circulation have been simultaneously ranked in the top 10 high-yield journals and the top 10 co-cited journals. Furthermore, it was observed that all the journals listed in Table 3 belong to either JCR Q1 or JCR Q2 categories.

Table 3.

The top 10 high-yield journals and co-cited journals.

Rank	High-yield journal	Count	JCR (2024)	IF (2024)	Rank	Co-cited journal	Co-citations	Total link strength	JCR (2024)	IF (2024)
1	Heart Rhythm	43	Q1	5.7	1	Circulation	4053	190,623	Q1	38.6
2	J Cardiovasc Pharm	27	Q2/Q3	2.2	2	J Am Coll Cardiol	2363	105,174	Q1	22.3
3	Am J Cardiol	25	Q3	2.1	3	Circ Res	1649	95,785	Q1	16.2
4	Int J Cardiol	25	Q2	3.2	4	J Mol Cell Cardiol	1178	65,933	Q1	4.7
5	J Mol Cell Cardiol	23	Q1/Q2	4.7	5	Cardiovasc Res	1151	69,628	Q1	13.3
6	Am J Physiol-Heart C	22	Q1	4.1	6	Heart Rhythm	1108	49,022	Q1	5.7
7	J Am Coll Cardiol	22	Q1	22.3	7	Eur Heart J	1058	52,778	Q1	35.6
8	J Pharmacol Exp Ther	21	Q2	3.8	8	New Engl J Med	1044	49,872	Q1	78.5
9	Brit J Pharmacol	19	Q1	7.7	9	Am J Cardiol	1021	49,639	Q3	2.1
10	Circulation	19	Q1	38.6	10	Am J Physiol-Heart C	965	51,705	Q1	4.1

IF = impact factor, JCR = Journal Citation Reports.

In order to understand the knowledge flow path in this field, researchers also conducted a double journal overlay analysis and visualized it in Figure 5. The dual journal overlay map is an overlay of 1 CiteSpace map on top of another. It can show the relationship between the citing journal and the cited journal. It aids researchers in identifying the primary journals for publishing research achievements in this field and the journals that have cited these achievements, thereby uncovering pathways of knowledge flow. In the double journal overlay map, the left side of the graph represents citing journals, indicating the research frontier. On the right side of the graph are the cited journals, which generally represent the research foundation. The lines on the left and right sides represent the citation paths. It can be clearly observed in the figure that there are 4 main citation paths, which are the most important knowledge flow paths in this field. These 4 paths are formed by the cited journal categories as “5. Health, Nursing, Medicale” and “8. Molecular, Biology, Genetics,” respectively, pointing to the citing journal categories as “4. Molecular, Biology, Immunology” and “2. Medical, Medical, Clinical.” Especially the path connecting the cited journal “8. Molecular, Biology, Genetics” and the citing journal cluster “4. Molecular, Biology, Immunology,” its z-value (z = 4.789006) and f-value (f = 3627) are both the largest among the results of this analysis. In addition, it can be observed from our visualization results that each citing journal contains multiple citation paths, indicating that each research frontier is supported by numerous research foundations.

Figure 5.

The dual journal overlay map on the study of ranolazine.

3.5. The results of highly cited papers and the co-cited references

References play a crucial role in the process of academic paper writing, as they provide substantial evidence and theoretical support for scholarly papers. Highly cited papers are those that have been published within the last decade and have received citations ranking among the top 1% of papers worldwide in their respective discipline. To a certain extent, highly cited papers are indicative of the research trends in this field over the past decade.

Table 4 enumerates the top 5 highly cited papers compiled by the researchers. The type of article ranked first in the highly cited papers is the review article. It provides a comprehensive overview of risk factors for coronary artery disease (CAD) and advances in treatment, noting that ranolazine can be used to relieve CAD-related symptomatic angina.^[34] This review article has been cited 736 times since it was published in 2019. The other 4 highly cited papers are all articles, which do not directly investigate ranolazine itself. Instead, they utilize ranolazine as an experimental tool or medium to conduct other studies.^[35–38] The enumeration of the top 5 cited references can be found in Table 5. The article titled “Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties” published in Circulation stands as the most widely cited reference. The authors have conducted animal experiments demonstrating that ranolazine can elicit ion channel effects akin to those of chronic amiodarone, thereby suggesting that ranolazine may possess not only anti-angina efficacy but also potential anti-arrhythmic properties.^[39] The second and third cited references delve into the efficacy and safety of ranolazine in the treatment of chronic angina. Despite employing different methodologies (the former opting for combination therapy, and the latter for standalone therapy), both studies unequivocally demonstrate the effectiveness and safety of ranolazine in managing chronic angina.^[8,9] The research findings, as reported by Scirica et al in their 2007 publication in Circulation, demonstrated that ranolazine functions as a late sodium channel inhibitor and exhibits potential anti-arrhythmic properties. This particular reference has garnered the fourth highest frequency of citations.^[15] The fifth reference was published in 2007 by Morrow et al. This study confirmed that the use of ranolazine was not effective in reducing cardiovascular events in patients with acute coronary syndromes, but also did not increase the risk of death or symptomatic arrhythmias.^[40]

Table 4.

The top 5 highly cited papers.

Rank	Title	Author	Journal	DOI	Citations	Year	Type
1	A review on coronary artery disease, its risk factors, and therapeutics	Malakar, AK	Journal of Cellular Physiology	10.1002/jcp.28350	736	2019	Review
2	A Platform for Generation of Chamber-Specific Cardiac Tissues and Disease Modeling	Zhao, Y	Cell	10.1016/j.cell.2018.11.042	433	2019	Article
3	An evaluation of 30 clinical drugs against the comprehensive in vitro proarrhythmia assay (CiPA) proposed ion channel panel	Crumb, WJ	Journal of Pharmacological and Toxicological Methods	10.1016/j.vascn.2016.03.009	216	2016	Article
4	Cardiac Late Sodium Channel Current Is a Molecular Target for the Sodium/Glucose Cotransporter 2 Inhibitor Empagliflozin	Philippaert, K	Circulation	10.1161/CIRCULATIONAHA.121.053350	151	2021	Article
5	Myocardial perfusion PET for the detection and reporting of coronary microvascular dysfunction: A JACC: Cardiovascular Imaging Expert Panel Statement	Schindler, TH	JACC-Cardiovascular Imaging	10.1016/j.jcmg.2022.12.015	95	2023	Review

Table 5.

The top 5 cited references.

Rank	Title	Author	Journal	DOI	Citations	Year	IF (2024)
1	Electrophysiological effects of ranolazine, a novel antianginal agent with anti-arrhythmic properties	Antzelevitch, C	Circulation	10.1161/01.cir.0000139333.83620.5d	285	2004	3680
2	Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina – A randomized controlled trial	Chaitman, BR	JAMA – J Am Med Assoc	10.1001/jama.291.3.309	225	2004	2667
3	Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina	Chaitman, BR	J Am Coll Cardiol	10.1016/j.jacc.2003.11.045	213	2004	2733
4	Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non-ST-segment-elevation acute coronary syndrome – Thrombolysis in myocardial infarction 36 (MERLIN-TIMI 36) randomized controlled trial	Scirica, BM	Circulation	10.1161/circulationaha.107.724880	173	2007	2644
5	Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes – The MERLIN-TIMI 36 randomized trial	Morrow, DA	JAMA – J Am Med Assoc	doi 10.1001/jama.297.16.1775	167	2007	2226

IF = impact factor.

To gain a deeper understanding of the details of the references, we utilized CiteSpace to conduct cluster analysis on all references and visually presented the top 10 clusters in Figure 6A. The Modularity Q for this cluster analysis is 0.7894, and the Weighted Mean Silhouette is 0.9259. These values indicate that the cluster structure is statistically significant, and the clustering results are highly reasonable. Cluster #0 “angina” contains 100 references, making it the largest reference cluster in this analysis. Cluster #1 is named “patch-clamp” and contains 98 references. Cluster #2, which includes 89 references, is labeled as “pharmacology.” Cluster #3 “reactive oxygen species” and Cluster #4 “atrial fibrillation” respectively include 89 and 87 references. The remaining clusters #5, #6, #7, #8, and #9 are respectively named “lactate,” “hypertrophic cardiomyopathy,” “pyruvate dehydrogenase,” “clinical trial,” and “coronary artery disease.” The timeline view of the references (Fig. 6B) clearly combines the clustering situation with the evolution of time zones. Each node in the figure represents a reference work, and the lines connecting the nodes represent the citation relationship between them. Furthermore, the position where the first node of each cluster appears in the image represents the time when that cluster first emerged. It can be observed that the clusters of references that appeared relatively later are cluster #4, cluster #6, cluster #8 and cluster #9, especially in cluster #4 “atrial fibrillation” and cluster #9 “coronary artery disease.” Besides, the researchers also visualized The Top 25 References with the strongest citation bursts (Fig. 7). The solid blue line in the figure indicates that the reference has been published, while the red line indicates that the reference is in a burst state. It is evident that the last reference in the figure is still in an explosive state and has a significant influence. It was a guideline, published by Knuuti et al in 2020. This paper caused a huge sensation as soon as it was published, and it has been cited more than 4000 times to date.^[41] This guideline introduces the concept of chronic coronary syndrome (CCS) for the first time and comprehensively updates the definition, diagnosis, treatment and management of CCS on the basis of previous ones. Moreover, this guideline is still playing an important role at the current research stage, which seems to indicate that the targets and potential therapeutic effects of ranolazine in CCS are important research contents at present.

Figure 6.

Analysis of reference. (A) Cluster analysis of references. (B) Timeline view of co-cited references.

Figure 7.

The top 25 references with the strongest citation bursts.

3.6. The results of the keywords

In scholarly publications, keywords serve as a means of encapsulating the topic of the article, facilitating rapid comprehension of its core content by readers. A comprehensive analysis of all keywords within a particular field can effectively delineate the research focus and developmental trajectory for scholars.

In this study, we mainly conduct keyword analysis across 3 distinct dimensions. Firstly, we applied VOS viewer for keyword co-occurrence analysis and plotted an overlay visualization of keyword co-occurrence network (Fig. 8A). The figure displays 100 keywords that appear at least 20 times. The size of each dot corresponds to the frequency of the keyword’s appearance, while the color indicates the average year in which the keyword appears. It can be seen that several prominent points in the graph are marked as “ranolazine,” “late sodium current,” “antianginal agent,” “atrial fibrillation” and “arrhythmias,” indicating that these keywords have a high frequency of occurrence. Among them, the color of “atrial fibrillation” is closest to yellow, indicating that it is a newly emerged keyword in recent years. Figure 8B is the density visualization of keyword co-occurrence analysis. In this graph, the size and background color of nodes are related to their importance or relevance. The “ranolazine” node is the largest and most prominent, indicating that it is the core of the entire graph. The sensitivity analysis regarding the selection of keyword node parameters is visualized in Figures S3 and S4 (Supplemental Digital Content, https://links.lww.com/MD/Q618). Secondly, we used CiteSpace software to perform clustering analysis on keywords and drew the clustering view of keywords (Fig. 9A) and the timeline view of keywords (Fig. 9B). The Modularity Q of this cluster analysis is 0.4398 and the Weighted Mean Silhouette is 0.7706. Cluster #0 contains a total of 124 keywords, making it the most informative keyword cluster, and it is named “coronary artery disease.” Cluster #1 is labeled as “atrial fibrillation” and involves 122 keywords. Cluster 2 “late sodium current” contains 95 keywords. Cluster #3 has been marked as the “glucose oxidation” and encompasses a total of 82 keywords. It can be observed that clusters #0, #1, #2, and #3 appeared earlier in time and still maintain a high frequency of occurrence to this day. Cluster #4 has been marked as the “persistent na + current” and encompasses a total of 68 keywords. This particular cluster made its appearance relatively late in the proceedings, yet continues to exhibit a high frequency of occurrence even up to the present day. The following cluster #5 “stable ischemic heart disease,” cluster #6 “oxidation,” cluster #7 “angina pectoris,” and cluster #8 “ischemic injury” contain 52, 25, 19, and 14 keywords respectively. The occurrence frequency of the keywords within clusters has generally been low in recent years, especially in cluster #7 and cluster #8, which have hardly appeared in recent years. This indicates that research pertaining to heart failure and stable ischemic heart disease seems outdated in this field. Finally, we presented the Top 50 keywords with the strongest citation bursts (sorted by intensity) through CiteSpace (Fig. 10). The burst state of keywords and their continuous burst years can reveal research hotspots and development trends in different periods. It can be discovered that “antianginal agent” stands out as the most prominent keyword, exerting a significant impact from 2006 to 2014. And “efficacy,” “ventricular arrhythmias,” “impact” and “channels” are the keywords that are still in the burst state. This seems to indicate that the research on the mechanism of action of ranolazine, as well as its efficacy and effects in treating arrhythmias, are currently hot research areas.^[42,43]

Figure 8.

(A) The overlay visualization of keyword co-occurrence network. (B) The density visualization of keyword co-occurrence network. Of the 4281 keywords,100 had at least 21 occurrences.

Figure 9.

CiteSpace analysis of keywords. (A) Cluster analysis of keywords. (B) Timeline view of keywords.

Figure 10.

The top 50 keywords with the strongest citation bursts.

4. Discussion

4.1. Basic situation analysis

We have analyzed a total of 1121 papers related to ranolazine. Ranolazine was approved by the FDA as a drug for the treatment of chronic angina in 2006. However, research on ranolazine had been conducted for nearly 20 years prior to this approval. This indicates that any newly emerging drug requires a considerable amount of research before it can be approved for clinical application, reflecting the rigorous nature of medicine. Since 2006, there has been a discernible surge in scholarly interest in ranolazine, as evidenced by the burgeoning body of literature dedicated to this subject. In recent years, the fervor of researchers for ranolazine appeared to have waned, suggesting that the advancement of this field has encountered formidable challenges and reached an impasse.

The USA is the country with the most production and citation in this field, and it is also the country with the closest cooperation with other countries or regions. In addition, the top 10 high-yield institutions belong to the USA. These compelling facts collectively underscore the pivotal role that the USA plays in this domain, serving as a trailblazer for the development of this area and a central nexus for global cooperation and exchange. Gilead Sciences is the most prolific institution in this field. The esteemed journal Heart Rhythm has been the major publishing magazine of research papers on ranolazine, boasting a high frequency of citations and thus making a significant contribution to the advancement of this area of study. In addition, the journals Am J Cardiol, J Mol Cell Cardiol, J Am Coll Cardiol, Am J Physiol-Heart C, and Circulation are also characterized by high publication volume and citation frequency. This indicates that their output and academic influence are both at a high level, which significantly promotes the progress of the field.

4.2. Analysis of authors

The authors serve as the primary executive body in academic research, they explore new fields through their research work or scientific research activities, so as to promote the development of a certain discipline. Examining influential authors can offer valuable insights into the progression of a field. In this study, it was found that 7 out of the top 10 prolific authors and 9 out of the top 10 co-cited authors are from the USA. This once again underscores the critical position of the USA in this field, and this may be attributed to the fact that the USA has many mature research institutions.

Prof Belardinelli, L is the most published author in the field and a prominent researcher in multiple areas, including cardiovascular systems and cardiology, cell biology, and physiology. He is a member of the most productive institution “Gilead Sciences,” and his experiments have received financial support from Gilead Sciences. Sufficient funds are very likely to be an important reason for his high productivity. However, the commercial connection between the 2 seems not to affect the objectivity of his research. The subsequent research results of other teams have strengthened and verified the credibility of his research. Moreover, he also disclosed this commercial relationship in the papers he published. So far, Professor Belardinelli, L has published 420 papers. Of all the papers he published, the vast majority were related to the electrophysiology of the heart. In 2009, Professor Belardinelli, L and his colleagues quantified the use-dependent blockade of ranolazine on cardiac peak and late-stage sodium currents using whole-cell patch clamp technology. The experimental results demonstrated that ranolazine decelerated the recovery of late sodium current inactivation, resulting in a use-dependent blockade of late sodium current.^[44] In the following year, his collaborators and he conducted experimental studies on the changes of sodium current in atrial fibrillation and the potential role of ranolazine in atrial fibrillation. Their findings indicated that sodium channels may lead to arrhythmia and atrial fibrillation contractile remodeling, while ranolazine exhibits anti-arrhythmic effects and can also improve diastolic function.^[18] This discovery presents a new therapeutic avenue for ranolazine. In 2011, Professor Belardinelli, L participated in the publication of “Electrophysiologic basis for the antiarrhythmic actions of ranolazine” as the final author. This review article systematically expounds on the role of ranolazine in arrhythmia and the electrophysiological basis of its role.^[16] In 2013, Professor Belardinelli, along with his partner, conducted animal experiments that demonstrated the superior efficacy of GS967 over ranolazine in reducing late sodium currents and combating arrhythmias.^[45] Nevertheless, in spite of this, Professor Belardinelli enthusiasm for ranolazine has not stopped. He actively participates in multiple studies and points out that the combination of ranolazine and dronedarone can reduce atrial fibrillation burden while also emphasizing its favorable tolerance and safety profile.^[46] Together with his colleagues, he also discovered that ranolazine appears to hold promising clinical potential in the treatment of hypertrophic cardiomyopathy (HCM).^[47,48] Although this potential has not been confirmed in human experiments, the excellent safety of ranolazine is beyond doubt.^[49] Certainly, the aforementioned contributions represent only a fraction of Professor Belardinelli research career. Since 2004, he has actively engaged in various studies on ranolazine and has achieved numerous significant results, thereby making substantial contributions to the advancement of this field.

Professor Chaitman, BR from Saint Louis University in the USA, is a highly influential scholar with a personal H-index of 107. In this study, he published a total of 13 papers on ranolazine, but he is the author with the most citations in this field. This situation better reflects his outstanding academic influence. In 2004, Professor Chaitman BR and other researchers validated the efficacy and safety of ranolazine through both monotherapy and combination therapy, and published their research results in 2 journals: JAMA – J Am Med Assoc and J Am Coll Cardiol.^[8,9] Both of these papers are among the top 5 co-cited references, offering significant support for the approval of ranolazine for marketing in 2006. In the same year that ranolazine was granted marketing approval, Professor Chaitman, BR pointed out that ranolazine not only can be used to treat chronic angina, but it is also likely to have therapeutic potential in other cardiovascular diseases.^[50] Professor Chaitman, BR participated in a study on the effects of ranolazine on hyperglycemia in 2009. He and his colleagues demonstrated in a randomized controlled trial that ranolazine significantly improved hemoglobin A (1C) and recurrent ischemia in patients with diabetes. Ranolazine can also reduce the incidence of elevated hemoglobin A (1C) in patients with no prior evidence of hyperglycemia.^[51] He was involved in the publication of “Evaluation of Ranolazine in Patients With Type 2 Diabetes Mellitus and Chronic Stable Angina” as the final author in 2013. In this study, he and his collaborators used ranolazine to compare with placebo, which proved that in patients with diabetes and chronic angina, after treatment with 1 to 2 anti-angina drugs, the addition of ranolazine can reduce the frequency of angina attacks or the frequency of nitroglycerin use.^[52] In addition to exerting a significant influence in this field, Professor Chaitman, BR is also an outstanding scholar in many other fields, especially in the realm of cardiovascular disease.

Upon conducting an analysis of 2 profoundly influential authors in this particular field, it becomes evident that their research predominantly centers on the electrophysiological and anti-angina effects of ranolazine. It is apparent that these 2 research directions are the focal points and critical areas of interest within this field.

4.3. Analysis of research hotspots

Research hotspots refer to topics that are currently receiving widespread attention and in-depth research in the field of scientific research. They are usually able to reflect the cutting-edge dynamics in the current field and hold significant practical significance. In this study, our main focus is on analyzing authors with significant influence, references, and keywords to gain a better understanding of the research hotspots within this field.

Based on the above reference results, keyword results and author analysis, it is believed that the current research hotspots in this field are mainly concentrated in 3 aspects. The first aspect is the anti-angina effect of ranolazine. The second aspect is the electrophysiological properties of ranolazine and its anti-arrhythmic effect. And the third aspect is the use of ranolazine in other applications. Among these aspects, the second one holds particular significance as it represents the most influential research hotspot at present.

4.3.1. The anti-angina effect of ranolazine

The research on the anti-angina effect of ranolazine can be traced back almost to the 1990s. It can be said that it is the earliest research hotspot in this field, and the research enthusiasm for it has continued to this day. However, in these more than 30 years of development, the focus of researchers on its anti-angina effect research was different. At the outset, researchers focused on the application of ranolazine in the treatment of chronic stable angina, and confirmed the efficacy and safety of ranolazine through a large number of experiments.^[8,9,53] Subsequently, researchers began to shift their attention to alternative forms of angina, pointing out that ranolazine can improve symptoms in female angina patients with evidence of ischemia but without obstructive CAD.^[54] In recent years, researchers have used ranolazine more as an anti-ischemia drug, harnessing its anti-angina effect to explore other research content.^[38] However, this does not signify the termination of research on the efficacy of ranolazine in treating angina. On the contrary, research on it has been ongoing.^[55,56]

4.3.2. Electrophysiological characteristics of ranolazine and its anti-arrhythmic effect

Ranolazine is an anti-angina drug, and researchers through in vitro experiments have found that it can elicit ion channel effects similar to those of amiodarone,^[39] and is a late sodium channel inhibitor.^[13] It can selectively inhibit late sodium current and IKr, reduce sodium-dependent calcium overload,^[12] shorten APD and QT interval, and increase negative electrode reserve and negative polarization stability, thereby exerting an anti-arrhythmic effect.^[16] It has been discovered that it has inhibitory effects on various arrhythmias, such as LQT 320, non-ischemic malignant ventricular tachycardia,^[57] reentrant or multifocal ventricular fibrillation,^[58] arrhythmias related to non-ST segment elevation acute coronary syndrome^[15] and atrial fibrillation.^[18] Especially, the effect of ranolazine on atrial fibrillation has been widely studied and is currently the most important research focus. So far, Numerous research results have shown that ranolazine can reduce the incidence of atrial fibrillation after coronary artery bypass grafting^[59] and promote cardioversion in patients with resistance to cardioversion.^[60] Furthermore, ranolazine has the ability to halt the onset of paroxysmal atrial fibrillation, particularly when utilized in conjunction with dronedarone for the treatment of atrial fibrillation.^[61] The combined use of ranolazine and dronedarone has demonstrated greater efficacy compared to either medication used alone.

4.3.3. Ranolazine in other applications

Aside from the previously mentioned antianginal and anti-arrhythmic effects, ranolazine has a range of other uses. It can play a beneficial role in the metabolism of diabetic patients^[51,62] and has been shown to significantly improve blood sugar control in this patient population.^[63–65] And ranolazine seems to have neuroprotective effects,^[66–68] which can enhance the activity of new glial cells, prevent necrosis or apoptosis^[66] and mitigate cognitive decline associated with diabetes.^[69] Additionally, experimental findings have demonstrated that ranolazine has the ability to reverse oxidative damage induced by methotrexate, thereby displaying antioxidant properties.^[70] It should not be ignored that due to voltage-gated sodium channels playing an essential role in cancer metastasis,^[25] ranolazine, as a sodium current inhibitor,^[71] has been shown to inhibit the invasion of cancer cells and reduce the adverse reactions of chemotherapy on the heart and brain.^[25,72–74] The physiological effects of ranolazine are not limited to these, here mentioned are only the physiological effects that are currently concerned more. Recently, a randomized controlled trial conducted in 2024 was the first to confirm in humans the preventive effect of ranolazine in the prevention of mild to moderate renal insufficiency.^[24] This seems to be a new therapeutic direction for ranolazine.

4.4. Advantages and limitations

Advantages: We conducted a comprehensive bibliometric analysis in this field, which allows for the intuitive display of various research information on ranolazine. This analysis delves deeply into current research hotspots and provides scientific guidance for future research directions. Moreover, during the research process, we employed analytical software for data analysis, converting various scattered data into clear and concise charts. This provides excellent convenience for researchers to swiftly comprehend this field.

Limitations: We excluded papers published in 2024 when screening the data, which may lead to some delay in the analysis results. In addition, we also excluded papers published in non-English languages. Although their quantity is relatively small, this could potentially result in incomplete and inaccurate analysis for this study. Furthermore, bibliometric analysis focuses more on the quantity of articles rather than their quality, which may lead to the analysis results being affected by publication bias.

5. Conclusions

Since the late 1980s, this field has undergone 3 stages of development and is currently in the third stage – a period of stalemate. During this period, researchers’ enthusiasm for ranolazine seemed to begin to decline. This study is expected to break the current stalemate and identify new directions for future research.

The USA is the founder and leader of research on ranolazine, serving as the center and intersection of global cooperation and exchange in this field. In the future, researchers in this research field should enhance cooperation with high-quality countries such as the USA, share research resources, data and experience, and promote research progress on a global scale. Gilead Sciences is the main research and development institution for ranolazine. The journals Heart Rhythm, Am J Cardiol, J Mol Cell Cardiol, J Am Coll Cardiol, Am J Physiol-Heart C, and Circulation are characterized by both a high publication volume and significant academic influence, making them the preferred choice for subsequent researchers to submit their papers. Professors Belardinelli, L and Chaitman, BR are scholars with significant influence in this area.

At present, the research focus in this field is primarily on 3 aspects: the anti-angina effect of ranolazine, the electrophysiological characteristics and anti-arrhythmic effect of ranolazine,^[75] and other effects of ranolazine. The future research direction in this field is likely to focus on the neuroprotective effect of ranolazine, its anticancer metastasis effect and its effect on atrial fibrillation and diabetes patients on the basis of maintaining the current research focus. In particular, in 2024, researchers discovered that ranolazine seems to have antioxidant and anti-inflammatory effects,^[76] thus becoming a promising therapy for treating T1DM-related testicular dysfunction.^[77] In addition, according to the function or mechanism of ranolazine, the use of ranolazine as a control variable drug to explore other unknown content seems to be a future development trend in this field.

In terms of guiding significance for clinical practice, future researchers can actively explore the application of ranolazine in other cardiovascular diseases, using the results of this study as an anchor. For instance, researchers can conduct in-depth studies on the therapeutic potential of ranolazine in cardiovascular diseases such as heart failure and arrhythmia, and further verify the efficacy and safety of ranolazine in these diseases through clinical trials and basic research, providing patients with more treatment options. Researchers can also conduct studies on the combined treatment of ranolazine with other drugs. They can explore the therapeutic effects of combining ranolazine with different types of drugs, such as antihypertensive drugs, lipid-lowering drugs, and anti-arrhythmic drugs,^[78] and pay attention to whether this combined treatment can produce synergistic effects, improve efficacy, and reduce drug side effects (e.g., “conduct multicenter randomized trials to verify long-term safety of ranolazine-dronedarone combination in atrial fibrillation”). At present, researchers have discovered that the combination of ranolazine with other anti-arrhythmic drugs such as amiodarone can significantly increase the conversion rate of restoring sinus rhythm, and its safety is also very good.^[75] In addition, researchers can start with emerging keywords (such as “atrial fibrillation”) to actively explore the efficacy and safety of ranolazine in atrial fibrillation. It is also possible to take important key words (such as “channels,” “late sodium current”) as targets to conduct in-depth research on the mechanism of action of ranolazine and provide a theoretical basis for the development of new drugs or treatment methods. At the same time, clinicians should also pay close attention to the research achievements of highly cited papers and co-cited references. These papers typically represent the most significant research advancements and academic viewpoints in the field, providing valuable references for clinical practice.

Acknowledgments

We would like to extend our heartfelt gratitude to all the researchers and healthcare workers who have dedicated their efforts to the advancement of this field.

Author contributions

Conceptualization: Jing Zhang, Jun Wang, Bingju Yan.

Data curation: Jing Zhang.

Resources: Jun Wang, Bingju Yan.

Supervision: Jun Wang, Bingju Yan.

Validation: Jun Wang, Bingju Yan.

Visualization: Jing Zhang.

Writing – original draft: Jing Zhang.

Writing – review & editing: Jun Wang, Bingju Yan.