Due to ongoing lifestyle changes and increasing population ageing, ischaemic diseases, such as acute MI (AMI), and ischaemic stroke have emerged as significant global health concerns. Although conventional therapies, including thrombolysis and interventional treatments, have proven efficacy, their limitations continue to drive the exploration of more effective organ-protection strategies.1 In this context, ischaemic conditioning has garnered significant attention. Ischaemic conditioning is a blanket term that describes the phenomenon whereby brief, sublethal episodes of ischaemia and reperfusion to an organ or tissue confer robust protection against subsequent prolonged ischaemic insults.2 The term encompasses a range of protective strategies, notably ischaemic preconditioning, postconditioning and remote ischaemic conditioning (RIC).3 The study of ischaemic conditioning originated in 1986 when Murry et al. first discovered the phenomenon of ischaemic preconditioning in a canine model of myocardial ischaemia, demonstrating that brief ischaemia could markedly reduce infarct size following subsequent sustained ischaemic injury.4 This seminal finding revealed the inducibility of organ self-protection. In 1993, Przyklenk et al. further proposed remote ischaemic preconditioning, showing that ischaemic stimulation of non-cardiac organs could also induce cardioprotective effects.5 In 2003, ischaemic postconditioning was validated in animal models to attenuate ischaemia–reperfusion injury (IRI).6 Subsequent clinical trials confirmed the ability of ischaemic postconditioning to protect the myocardium.7,8
As research has progressed, the application of ischaemic conditioning has expanded from the heart to multiple organs and tissues, including the brain, kidney, liver, intestines and vessels.9–16 For example, chronic ischaemic conditioning may significantly reduce composite cardiovascular events in patients with symptomatic intracranial atherosclerosis and improve neurological function in patients with acute ischaemic stroke.9,17 Previous studies have demonstrated the multiorgan protective potential of ischaemic conditioning, involving pathways such as phosphatidylinositol 3-kinase/protein kinase B/extracellular signal-regulated kinase, inflammation modulation and mitochondrial regulation.18–22 However, large-scale randomised controlled trials (RCTs) reported no overall benefit of RIC in terms of clinical outcomes in patients with acute heart diseases, such as those with ST-elevation MI undergoing primary percutaneous coronary intervention (STEMI-PPCI).2,23
In the context of cerebrovascular diseases, the benefit of RIC remains in doubt. Chronic RIC may improve functional outcomes after acute ischaemic stroke and there may be a role for RIC in the prevention of recurrent stroke in patients with symptomatic intracranial arterial stenosis.9,24,25 Although RIC did not significantly improve clinical outcomes in patients undergoing organ transplantation (e.g. heart, lung, liver and kidney),26 recent evidence suggests that RIC may reduce the incidence of contrast-associated acute kidney injury following percutaneous coronary intervention (PCI) or coronary angiography.27,28 Although several systematic reviews have assessed RIC and organ protection, there is still a lack of big data revealing research trends and trajectory studies of ischaemic conditions (e.g. ischaemic preconditioning, ischaemic postconditioning and RIC). Thus, the aim of this study was to systematically summarise the research trends and trajectory of ischaemic conditioning for multiple organs and tissues, such as the heart, kidney, brain, lung, intestines, vessels and liver.
Methods
Data Source and Collection
The Web of Science offered high-quality data and extensive coverage, and the search was restricted to the Web of Science Core Collection to ensure data stability. The search strategy included keywords related to ‘ischaemic condition’. Details of the retrieval strategy are presented in Supplementary Table 1. Articles and reviews were included, covering the period from January 2003 to December 2024, restricted to the English language. Conference papers, comments, corrections and correspondence were excluded. In total, 9,967 articles were identified. A study flow chart is provided in Supplementary Figure 1. The collected bibliometric information included the title, publication year, country/region, affiliated institution, journal, authors, keywords, organs/tissues, citation counts, references and abstracts.
Validation
To ensure data accuracy, 100 articles were randomly selected from the initially retrieved literature to assess relevance by reviewing their titles and abstracts. Next, we examined the top 100 most-cited articles from the search results to confirm their alignment with the research topic. This process helped exclude irrelevant articles. In addition, we validated the search by comparing publications from Google Scholar profiles of the top 25 most-cited authors with the results of our search. Significant overlap demonstrates that our approach effectively captured the vast majority of relevant publications without missing any key contributions. This rigorous verification process confirmed the comprehensiveness of this literature research and its alignment with prominent works in the field.
Analysis Methods and Software
For bibliometric analysis, this study used CiteSpace (version 6.3. R1; Drexel University), R Bibliometrix R Packages (University of Auckland) and VOSviewer (version 1.6.20; Leiden University) to visualise and analyse research trends.29,30,31 CiteSpace was used to identify the co-occurrence network of institutions and authors, the temporal evolution of keywords and for dual map overlay analysis. Bibliometrix R Packages quantified collaboration frequencies between countries and created three-field plots. VOSviewer provided visual co-occurrence networks of journals and keywords, whereas the graphical clustering toolkit enabled matrix and mountain visualisation on the basis of word co-occurrence. These tools enabled the construction of collaboration networks among countries, journals, institutions and authors over the study period. The temporal trends and heatmaps of preconditioning, postconditioning and remote conditioning, as well as target organs/tissues (e.g. liver, kidney, intestine, muscle flaps and peripheral tissues), were categorised from the retrieved literature. This classification was primarily achieved through keyword matching using Python (Version 3.11.3). Keywords were predefined by discussion and consensus. Visualisation was implemented using Python package Matplotlib 3.8.4 and Seaborn 0.13.2. To ensure the accuracy and reliability of these automated classifications, the keyword matching process was validated through a manual review of 100 randomly selected articles.
The temporal trends of annual publications (2003–2024) for basic and clinical research were fitted by second-order polynomial regression model. The model parameters were estimated using the least squares method via Python (Version 3.11.3). To assess the research trends of journals, authors and articles in the field accurately, the H-index, G-index and M-index were used. The H-index measures the output and citation impact of a researcher’s published work. An H-index of h means that an author has published h papers that have each been cited at least h times. The G-index enhances the H-index by assigning greater weight to highly cited articles. A G-index of g means that an author’s top g papers have been cited at least g² times, the author’s G-index is g. The M-index adjusts the H-index on the basis of the number of years since the author’s first publication and is calculated by dividing the H-index by the number of years since the author began publishing.
In this study, to describe the independent and collaborative research abilities of each country, single-country publications (used to assess a country’s impact in a specific academic field) and multiple-country publications (used to assess the international influence of different countries in specific fields) were used.
Results
Annual Publications and Citations
Figure 1A illustrates the annual trends in publications and citations on ischaemic conditioning and multiorgan protection research over the past two decades, encompassing a total of 9,967 articles. The number of publications increased steadily, exceeding 500 per year by 2014 and peaking at 560 in 2020, despite a slight decline after 2017. In contrast, citations showed a marked upward trajectory, surpassing 10,000 in 2010 and 20,000 in 2018, with a maximum of 27,233 citations recorded in 2021.
Distribution of Countries
The global distribution of scientific output encompassed contributions from more than 100 countries (Figure 1B). The US ranked first, with 2,895 publications, followed by China (2,302) and Germany (840; Figures 1B and 1D).
In terms of citation impact, the US again led, with 115,177 citations, followed by China (52,307) and Germany (28,849). Notably, the UK achieved the highest average citation rate per article (65.00), with a total of 21,526 citations (Figure 1C). Furthermore, the international collaboration network underscored the central role of the US, followed by China, Germany, the UK and Canada (Figure 1E).
Ischaemic Conditioning Types and Organs/Tissues
Figure 2A illustrates publication trends stratified by ischaemic conditioning types and affected organs/tissues. There was a general upward trend in publications for both clinical and basic research from 2003 to 2024. Ischaemic preconditioning consistently accounted for the highest number of publications, whereas RIC exhibited the most significant increase in publication numbers over this period (Figure 2A). Detailed publication counts for various ischaemic conditioning models across organs/tissues are shown in Figure 2B. The heatmap showed the ‘heart’ organ (5,444) consistently had the highest publication counts across ischaemic conditioning types, followed by the brain (4,650), vasculature (e.g. peripheral arterial disease; 2,027), kidney (1,214), liver (1,156), lung (425), skeletal muscle (261), intestine (214), skin (142), retina (105) and pancreas (34) (Figure 2B). The temporal analysis showed cardiovascular system diseases were most frequently studied across all ischaemic conditioning types over the past two decades, followed by cerebrovascular, kidney and liver diseases (Figure 2C).
Productive Journals and Influential Articles
Journal collaborations revealed strong partnerships, notably among the International Journal of Cardiology, the American Journal of Physiology – Heart and Circulatory Physiology, the Journal of Surgical Research and Brain Research (Figure 3A). The leading journals by publication count include the American Journal of Physiology – Heart and Circulatory Physiology (217 articles), PLoS ONE (120) and the International Journal of Molecular Sciences (90) (Figure 3B). Since 2015, these journals have maintained the highest publication volumes, particularly the American Journal of Physiology – Heart and Circulatory Physiology and PLoS ONE, which consistently lead (Figure 3C). The top influential journals (e.g. American Journal of Physiology – Heart and Circulatory Physiology, Basic Research in Cardiology and Circulation Research) were identified as key sources for understanding the field’s knowledge (Supplementary Table 2). The 25 most cited articles on ischaemic conditioning and organ/tissue protection are presented in Supplementary Table 3, with the most cited being that by Zhao et al. in the American Journal of Physiology – Heart and Circulatory Physiology, with 1,740 citations.6
Most Relevant Affiliations
The co-occurrence network revealed robust collaborative ties among institutions, particularly University College London, Aarhus University Hospital, Capital Medical University and the Medical College of Wisconsin (Figure 4A). The citation network highlighted the influence of the Capital Medical University, University College London, Aarhus University Hospital and University of Toronto (Figure 4B). The top three institutions by publication volume were the Capital Medical University (526), University of Toronto (365) and University of California research university system (359; Figure 4C). The three-field plot in Figure 4D illustrates the close relationships among countries, time and journals. The publication volume of national journal types is closely related to time, among which the US dominates in the publication volume of these types of journals, followed by China and Germany. The journals published are the American Journal of Physiology – Heart and Circulatory Physiology, the Journal of Molecular and Cellular Cardiology and Brain Research.
Author Collaboration Network and Impact
The author collaboration network revealed strong cooperative connections, particularly among G Heusch, DJ Hausenloy, XM Ji and HE Botker, who have significantly influenced research and development in this area (Figure 5A). XM Ji (104) had the highest publication numbers, followed by G Heusch (86) and DJ Hausenloy (64; Figure 5B). The citation network between institutions highlighted the strong relevance of authors, such as G Heusch, XM Ji, DJ Hausenloy and HE Botker (Figure 5C). These authors have made important contributions to the dissemination of knowledge, the discovery of hot topics and the research direction of hot topics in ischaemic conditioning and multiorgan protection. G Heusch has the most citations (3,174), followed by DM Yellon (2,795) and DJ Hausenloy (2,428; Figure 5D). The top 10 influential authors are presented in Supplementary Table 4, with the top 3 being G Heusch, DM Yellon and DJ Hausenloy, indicating that their research results had a high professional level and reference value.
Figure 5E presents the interdisciplinary knowledge flow network for ischaemic conditioning research. The visualisation identified translational pathways connecting basic sciences, such as molecular biology, with clinical cardiology. The connections between these different clusters are less dense than the connections within them, indicating that knowledge flow is more concentrated along specific intercluster pathways. Figure 5F shows the annual number of publications for both basic and clinical research in this field. The number of basic research publications showed a trend of stagnation and subsequent decline over time. In contrast, the volume of clinical research publications exhibited a notable increase, indicating a growing focus on clinical applications.
Keyword Analysis
The top 20 keyword co-occurrences included reperfusion injury (1,319), activation (1,158) and injury (1,132), as well as ischaemic/reperfusion injury (1,040) and protection (745; Supplementary Figure 2A). The word cloud highlighted the most frequently co-occurring keywords. ‘Reperfusion injury’ is prominently displayed. Other key terms showing strong association and significant prominence include ‘neuroprotection’, ‘myocardial infarction’ and ‘stroke’ (Supplementary Figure 2B). ‘Ischaemia’, ‘stroke’, ‘reperfusion injury’, ‘preconditioning’ and ‘postconditioning’ were strongly associated (Supplementary Figure 2C). An evolution timeline of keyword clustering of the research on ischaemic conditioning and organ protection was categorised into five clusters: ‘stroke’, ‘neuroprotection’, ‘percutaneous coronary intervention’, ‘angiogenesis’ and ‘blood flow restriction’ (Supplementary Figure 2D). In later years, terms such as ‘reperfusion injury’ and ‘percutaneous coronary intervention’ emerged.
Discussion
Major Findings
This study revealed that ischaemic conditioning has been an increasingly popular research topic in recent years. The US has led in terms of publication volume and citation frequency, and has played a pivotal role in international collaboration. Institutions such as Capital Medical University, University College London, Aarhus University Hospital and the University of Toronto have made significant contributions to this field, as evidenced by their high publication numbers and citations.
In terms of academic publications, citations and collaborations with other authors, G Heusch, DM Yellon, DJ Hausenloy and XM Ji all had a profound influence. Although countries, institutions and authors have stable cooperative relationships, there is still a need to strengthen these collaborations to promote more systematic and in-depth research.
Extensive studies have demonstrated that ischaemic conditioning activates endogenous protective networks through transient, controlled ischaemic stimuli, exhibiting significant potential in acute MI, ischaemic stroke and other diseases. Ischaemic conditioning’s protective effects rely on complex signalling pathways that may have distinct mechanisms while exhibiting organ-specific regulatory features across the heart, brain, kidney and liver.
In cardiac protection, the core mechanism of ischaemic conditioning involves the cascade activation of protein kinase C, protein kinase and extracellular signal-regulated kinase, coupled with mitochondrial functional regulation to reduce cardiomyocyte apoptosis.18,19,20,21 For example, RIC significantly reduces myocardial infarct size during IRI by activating the phosphatidylinositol 3-kinase/protein kinase B/extracellular signal-regulated kinase pathway in animal models.2 However, these findings did not translate clinically to RIC in myocardial IRI after cardiac surgery: the CONDI-2/EPIC trial showed that RIC did not reduce overall major cardiovascular events in patients with STEMI-PPCI.23 We suggest that RIC may be beneficial in higher-risk patients with heart failure and that less optimal reperfusion may be achieved in patients with acute MI.32 The RIC-AFRICA trial, which will investigate whether RIC improves clinical outcomes in higher-risk STEMI patients in low- and middle-income countries treated with thrombolysis, and the RIP-HIGH trial (NCT04844931) are now under way.33 Another reason, as indicated by the CONDI-2/EPIC trial showing no reduction in major cardiovascular events with RIC in STEMI-PPCI patients, may be the timing of RIC programmes. A post hoc analysis of the LIPSIA CONDITIONING trial revealed a reduced rate of major adverse cardiac events and new congestive heart failure caused by combined intrahospital RIC and ischaemic postconditioning in addition to PPCI in patients with STEMI.34 The i-RIC trial assessed the effect of full disease cycle RIC in patients with STEMI, results are pending.35
Cerebral protection mechanisms share similarities with cardiac pathways but exhibit distinct organ-specific features. Several recently published trials provide promising results for the effects of RIC in improving functional outcomes after acute ischaemic stroke.9,25 The RICA trial demonstrated that adherence to bilateral upper-limb chronic RIC reduces the cumulative incidence of non-fatal or fatal ischaemic stroke recurrence by 24% (HR 0.76; 95% CI [0.59–0.99]) in patients with symptomatic intracranial stenosis compared with the sham group, which may involve activation of adenosine A1 receptors, a reduction in oxidative stress, an immune response, neuroinflammation, an improvement in cerebral perfusion and reconstruction of the collateral circulation.9,36 More recently, another participant-blinded RCT also showed that RIC for 7 days improved functional outcomes at 90 days among patients with acute ischaemic stroke who underwent endovascular thrombectomy compared with sham RIC.25 Notably, although adenosine signalling is central to both cardiac and cerebral protection, downstream targets diverge: protein kinase Cδ dominates in the heart, whereas upregulation of hypoxia-inducible factor 1α mediates cerebral hypoxia tolerance.37,38 Furthermore, RIC suppresses nuclear factor-κB-driven inflammatory cascades via humoral factors (e.g. adenosine and bradykinin), mitigates blood-brain barrier disruption and activates vagal pathways to increase anti-inflammatory cytokine secretion (e.g. interleukin-10), forming a multilayered neuroprotective network.39–42
With respect to renal protection, a meta-analysis of 16 RCTs covering 2,048 patients revealed that RIC reduced the incidence of contrast-induced acute kidney injury (RR 0.50) in patients undergoing PCI or coronary angiography.28 A recent RCT revealed that among high-risk patients undergoing elective cardiac surgery, delayed RIC significantly reduced the occurrence of acute kidney injury (OR=0.68).43 More recently, the same research group demonstrated that, in a multicentre RCT involving at-risk patients undergoing coronary angiography or PCI, the incidence of contrast-associated acute kidney injury was lower in those who received RIC than in the sham group (OR=0.40; 95% CI [0.17–0.94]).27 Gholampour et al. demonstrated that limb RIC inhibits the tumour necrosis factor-α/nuclear factor-κB pathway and reduces neutrophil infiltration in renal tubules.44 Liver protection is another emerging research topic, and several meta-analyses of RCTs have shown potential benefits in terms of postoperative liver function levels and mortality rates in patients undergoing liver surgeries.13,45
Further Directions
Although our analysis of the existing literature has revealed certain patterns, the keyword analysis also points towards specific, promising avenues for future research. Keyword analysis highlighted research hotspots, such as MI, stroke and RIC. RIC has exhibited differential clinical efficacy in cardiovascular and cerebrovascular diseases. Many pivotal clinical trials have demonstrated that RIC has significant benefits in stroke treatment while having limited benefit in terms of cardioprotection. Hausenloy et al. revealed that RIC had no cardioprotective effect in patients with STEMI-PPCI, whereas several RCTs have confirmed that RIC significantly improves neurological function and stroke recurrence in patients with acute stroke.9,10,23,46 This therapeutic divergence may be attributed to several reasons. Optimising RIC protocols is a primary consideration.47 Cardiac trials typically use a single session of four cycles of 5 minutes of ischaemia and 5 minutes of reperfusion. In contrast, some clinical studies on patients with ischaemic stroke have investigated chronic RIC delivered for 1–2 weeks or even several months.9,10 Further research could also focus on the optimal timing of the initiation of RIC in the early stages of cerebral infarction or MI and identify high-risk patient populations (e.g. those experiencing less optimal reperfusion).
Limitations
This study provides a comprehensive overview of the global research status and trends in ischaemic conditioning and organ protection. Using big data via bibliometric analysis sheds light on the growth of research, key contributors and evolving research hotspots. However, this study has several limitations. This study was based solely on data from the Web of Science Core Collection, which means that it may not have captured the full spectrum of research. The search strategy may have targeted some unrelated articles, because comprehensive manual screening of the included citations was not conducted. However, after preliminary verification, most of the articles were found to be relevant to this field. Integrating data from additional databases, such as Scopus, PubMed and Embase, would provide a more comprehensive perspective in this field. Furthermore, academic research is continuously evolving, and the influence of emerging fields may not be adequately captured in bibliometric studies.
Conclusion
This bibliometric analysis revealed rapid advances in research on ischaemic conditioning and organ protection, especially in recent years in the field of neurological protection. To foster a deeper understanding of ischaemic conditioning and its role in organ protection, strengthening global research and multidisciplinary collaboration is essential. This collaborative effort, especially through the refinement of ischaemic conditioning protocols, will be key to unlocking its full potential for multiorgan protection and consequently improving prevention and treatment strategies.
Clinical Perspective
- Ischaemic conditioning reduces reperfusion injury and improves prognosis by protecting multiple organs.
- The focus of ischaemic conditioning research has broadened from protecting the heart and brain to the systemic protective effects of remote ischaemic conditioning on multiple organs.
- Novel therapeutics are needed to protect organs against the detrimental effects of ischaemic reperfusion injury.