Volume 34, Issue 7 (10-2026)
JSSU 2026, 34(7): 10398-10420 |
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Setooni Zadeh Fard S E, Zokaei A, Ghahramani M. A Review of Molecular Mechanisms, Inflammatory Factors, and Emerging Therapeutic Approaches in Atherosclerosis with an Emphasis on Physical Activity. JSSU 2026; 34 (7) :10398-10420
URL: http://jssu.ssu.ac.ir/article-1-6681-en.html
URL: http://jssu.ssu.ac.ir/article-1-6681-en.html
Keywords: Atherosclerosis, Cardiac Rehabilitation, Physical Activity, Inflammatory Markers, Molecular Mechanisms
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Extended Abstract
Introduction
Cardiovascular diseases persist as the primary cause of global mortality, with atherosclerosis serving as the principal pathological process for the majority of these conditions. Modern perspectives on atherosclerosis have shifted; it is now characterized not simply as a lipid-accumulation disorder, but as a chronic, progressive inflammatory-immune disease. This condition involves a numerous molecular and cellular mediators that operate throughout the disease continuum- from initial endothelial injury to the eventual formation and rupture of plaques. Despite progress in clarifying these mechanisms, the literature has either concentrated on basic, laboratory-level pathways or evaluated the clinical efficacy of exercise in isolation, with little attempt to connect the two levels of evidence. It therefore remains unclear through which molecular and inflammatory pathways physical activity produces the clinical benefits observed in cardiac rehabilitation. This narrative review aimed to comprehensively analysis of the impact of physical activity and exercise training on atherosclerosis, focusing specifically on molecular mechanisms, inflammatory markers, and emerging therapeutic approaches, with a focus on exercise-based cardiac rehabilitation.
Methods
This study utilized a narrative review design characterized by a semi-structured search approach, aimed at providing a qualitative synthesis of evidence regarding cardiac rehabilitation, its associated molecular and inflammatory mechanisms, and emerging therapeutic approaches. Although the PRISMA framework was employed only to make the search and selection process transparent; the study was not a full systematic review. PubMed, Scopus, Web of Science, and Google Scholar were searched for English sources, and MagIran, SID, and Noormags for Persian sources. Key terms included atherosclerosis, physical activity, exercise training, cardiac rehabilitation, coronary artery disease, inflammatory markers, cytokines, and molecular mechanisms, combined with Boolean operators (AND, OR, NOT) and database-specific strategies such as MeSH-based queries in PubMed. The inclusion criteria comprised English-language publications from 2020-2025 and Persian-language articles dating from 1400-1405 (SH). Eligible studies were those investigating the nexus between physical activity or exercise-based cardiac rehabilitation and atherosclerosis, focusing specifically on underlying mechanisms, or emerging preventive and therapeutic approaches. Meta-analyses, systematic reviews, clinical trials, quasi-experimental studies, and scientific statements were accepted if peer-reviewed with full text available. Quality was appraised with AMSTAR-2 for systematic reviews, CONSORT for trials, and general criteria (source credibility, methodological rigor, reporting transparency) for other designs. Finally, duplicates, articles, studies lacking full-text availability, investigations focusing exclusively on pharmacological studies, and articles deemed to be of low quality were excluded. The selection process adhered to the four-stage PRISMA protocol and was independently executes by two researchers, with a third reviewer resolving disagreements. From an initial pool of 226 identified records (162 English, and 64 Persian), 61 duplicates were discarded, leaving 165 records for screening by title and abstract. After 108 exclusions, 57 full texts were assessed, and 42 were excluded (28 misaligned with the aims, 9 low qualities, 5 without full text). Fifteen key articles (11 English, 4 Persian) were analyzed by thematic content analysis: they were grouped into three themes, data on design, population, findings, and limitations were extracted and compared, and results were synthesized narratively.
Results
The 15 studies included in this review comprised one meta-analysis, systematic reviews, narrative and comprehensive reviews, one scientific statement, a longitudinal cohort, and quasi-experimental and experimental studies. The strongest clinical evidence came from a meta-analysis of 105 clinical trials involving 14,486 patients, which showed that exercise-based cardiac rehabilitation reduced cardiovascular mortality by 26% (HR 0.74; 95% CI 0.64–0.86; p<0.001) and hospital readmission by 18% (HR 0.82; 95% CI 0.73–0.93; p=0.002). It also reduced recurrent cardiovascular events by 12% (HR 0.88; p=0.021), improved quality of life (SMD 0.45), and increased VO₂max by about 2.3 mL/kg/min. Higher-intensity (70–85% of maximal heart rate) and longer (over 12 weeks) programs were generally more effective, yet an eight-week aerobic program after angioplasty significantly improved femoral artery diameter, elasticity, stiffness, and blood flow. A further trial showed that continuous and interval rehabilitation both altered serum endothelial indices (VEGF and endostatin). The 2024 scientific statement emphasized core CR components, baseline assessment, individualized FITT-based exercise prescriptions, patient education, risk-factor management, and psychological support. Given that only 20–40% of eligible patients currently enroll, there is a growing impetus to adopt home-based and digital delivery programs.
Combined aerobic and resistance training elicited the most pronounced anti-inflammatory response, followed by moderate aerobic exercise. While resistance training, yoga, and tai chi were less potent, high-intensity interval training (HIIT) proved effective, albeit necessitating cautious supervision in cardiac patient populations.
Regarding inflammation profiles, exercise lowered C-reactive protein by 20–40%, interleukin-6 by 15–35%, and tumor necrosis factor-alpha by 20–30%, with additional reductions in IL-1β, VCAM-1, ICAM-1, and fibrinogen. Combined aerobic and resistance training produced the largest anti-inflammatory effect, followed by moderate aerobic training; resistance training and yoga or tai chi were less potent, and high-intensity interval training was effective but required careful supervision in cardiac patients.
Mechanistically, exercise functions through multiple complementary pathways: reduced visceral fat and pro-inflammatory adipokines, increased anti-inflammatory myokines (IL-10, irisin), enhanced eNOS-dependent nitric oxide production driven by shear stress, reduced oxidative stress, improved lipid profile and insulin sensitivity, decreased sympathetic activity, increased autophagy, and macrophage polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype, which stabilizes plaques. While some effects appear within days, whereas macrophage modulation takes 8–12 weeks.
Elite endurance athletes showed the “athlete’s paradox”: higher coronary plaque burden, but plaques that were more calcified, with thicker fibrous caps, smaller lipid cores, and less inflammation, implying a much lower acute event risk. Preventive strategies included coronary CT screening, risk-factor control, and training modification. Emerging approaches included genotype-based exercise, polarized training, myokine therapy, targeted nanoparticles, anti-cytokine immunotherapy, and PCSK9 inhibitors combined with exercise. While clinical findings were consistent across study designs, the current evidence regarding underlying mechanisms primarily relies on narrative reviews, with experimental studies often constrained by small sample sizes and a lack of control groups.
Conclusion
Regular physical activity, particularly within structured cardiac rehabilitation, reduces cardiovascular mortality and readmission by acting simultaneously on several pathogenic pathways of atherosclerosis: systemic inflammation, endothelial dysfunction, oxidative stress, and plaque instability. Exercise is therefore a multi-target intervention, and its benefits extend to people with elevated plaque burden, such as elite athletes, in whom plaque quality matters more than quantity. Exercise-based cardiac rehabilitation should be regarded as a standard component of the clinical management of coronary artery disease. Future research should determine the optimal exercise dose, identify individual factors influencing response to exercise, including genetic variation, and develop digital-technology-based rehabilitation programs to improve access and adherence.
Introduction
Cardiovascular diseases persist as the primary cause of global mortality, with atherosclerosis serving as the principal pathological process for the majority of these conditions. Modern perspectives on atherosclerosis have shifted; it is now characterized not simply as a lipid-accumulation disorder, but as a chronic, progressive inflammatory-immune disease. This condition involves a numerous molecular and cellular mediators that operate throughout the disease continuum- from initial endothelial injury to the eventual formation and rupture of plaques. Despite progress in clarifying these mechanisms, the literature has either concentrated on basic, laboratory-level pathways or evaluated the clinical efficacy of exercise in isolation, with little attempt to connect the two levels of evidence. It therefore remains unclear through which molecular and inflammatory pathways physical activity produces the clinical benefits observed in cardiac rehabilitation. This narrative review aimed to comprehensively analysis of the impact of physical activity and exercise training on atherosclerosis, focusing specifically on molecular mechanisms, inflammatory markers, and emerging therapeutic approaches, with a focus on exercise-based cardiac rehabilitation.
Methods
This study utilized a narrative review design characterized by a semi-structured search approach, aimed at providing a qualitative synthesis of evidence regarding cardiac rehabilitation, its associated molecular and inflammatory mechanisms, and emerging therapeutic approaches. Although the PRISMA framework was employed only to make the search and selection process transparent; the study was not a full systematic review. PubMed, Scopus, Web of Science, and Google Scholar were searched for English sources, and MagIran, SID, and Noormags for Persian sources. Key terms included atherosclerosis, physical activity, exercise training, cardiac rehabilitation, coronary artery disease, inflammatory markers, cytokines, and molecular mechanisms, combined with Boolean operators (AND, OR, NOT) and database-specific strategies such as MeSH-based queries in PubMed. The inclusion criteria comprised English-language publications from 2020-2025 and Persian-language articles dating from 1400-1405 (SH). Eligible studies were those investigating the nexus between physical activity or exercise-based cardiac rehabilitation and atherosclerosis, focusing specifically on underlying mechanisms, or emerging preventive and therapeutic approaches. Meta-analyses, systematic reviews, clinical trials, quasi-experimental studies, and scientific statements were accepted if peer-reviewed with full text available. Quality was appraised with AMSTAR-2 for systematic reviews, CONSORT for trials, and general criteria (source credibility, methodological rigor, reporting transparency) for other designs. Finally, duplicates, articles, studies lacking full-text availability, investigations focusing exclusively on pharmacological studies, and articles deemed to be of low quality were excluded. The selection process adhered to the four-stage PRISMA protocol and was independently executes by two researchers, with a third reviewer resolving disagreements. From an initial pool of 226 identified records (162 English, and 64 Persian), 61 duplicates were discarded, leaving 165 records for screening by title and abstract. After 108 exclusions, 57 full texts were assessed, and 42 were excluded (28 misaligned with the aims, 9 low qualities, 5 without full text). Fifteen key articles (11 English, 4 Persian) were analyzed by thematic content analysis: they were grouped into three themes, data on design, population, findings, and limitations were extracted and compared, and results were synthesized narratively.
Results
The 15 studies included in this review comprised one meta-analysis, systematic reviews, narrative and comprehensive reviews, one scientific statement, a longitudinal cohort, and quasi-experimental and experimental studies. The strongest clinical evidence came from a meta-analysis of 105 clinical trials involving 14,486 patients, which showed that exercise-based cardiac rehabilitation reduced cardiovascular mortality by 26% (HR 0.74; 95% CI 0.64–0.86; p<0.001) and hospital readmission by 18% (HR 0.82; 95% CI 0.73–0.93; p=0.002). It also reduced recurrent cardiovascular events by 12% (HR 0.88; p=0.021), improved quality of life (SMD 0.45), and increased VO₂max by about 2.3 mL/kg/min. Higher-intensity (70–85% of maximal heart rate) and longer (over 12 weeks) programs were generally more effective, yet an eight-week aerobic program after angioplasty significantly improved femoral artery diameter, elasticity, stiffness, and blood flow. A further trial showed that continuous and interval rehabilitation both altered serum endothelial indices (VEGF and endostatin). The 2024 scientific statement emphasized core CR components, baseline assessment, individualized FITT-based exercise prescriptions, patient education, risk-factor management, and psychological support. Given that only 20–40% of eligible patients currently enroll, there is a growing impetus to adopt home-based and digital delivery programs.
Combined aerobic and resistance training elicited the most pronounced anti-inflammatory response, followed by moderate aerobic exercise. While resistance training, yoga, and tai chi were less potent, high-intensity interval training (HIIT) proved effective, albeit necessitating cautious supervision in cardiac patient populations.
Regarding inflammation profiles, exercise lowered C-reactive protein by 20–40%, interleukin-6 by 15–35%, and tumor necrosis factor-alpha by 20–30%, with additional reductions in IL-1β, VCAM-1, ICAM-1, and fibrinogen. Combined aerobic and resistance training produced the largest anti-inflammatory effect, followed by moderate aerobic training; resistance training and yoga or tai chi were less potent, and high-intensity interval training was effective but required careful supervision in cardiac patients.
Mechanistically, exercise functions through multiple complementary pathways: reduced visceral fat and pro-inflammatory adipokines, increased anti-inflammatory myokines (IL-10, irisin), enhanced eNOS-dependent nitric oxide production driven by shear stress, reduced oxidative stress, improved lipid profile and insulin sensitivity, decreased sympathetic activity, increased autophagy, and macrophage polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype, which stabilizes plaques. While some effects appear within days, whereas macrophage modulation takes 8–12 weeks.
Elite endurance athletes showed the “athlete’s paradox”: higher coronary plaque burden, but plaques that were more calcified, with thicker fibrous caps, smaller lipid cores, and less inflammation, implying a much lower acute event risk. Preventive strategies included coronary CT screening, risk-factor control, and training modification. Emerging approaches included genotype-based exercise, polarized training, myokine therapy, targeted nanoparticles, anti-cytokine immunotherapy, and PCSK9 inhibitors combined with exercise. While clinical findings were consistent across study designs, the current evidence regarding underlying mechanisms primarily relies on narrative reviews, with experimental studies often constrained by small sample sizes and a lack of control groups.
Conclusion
Regular physical activity, particularly within structured cardiac rehabilitation, reduces cardiovascular mortality and readmission by acting simultaneously on several pathogenic pathways of atherosclerosis: systemic inflammation, endothelial dysfunction, oxidative stress, and plaque instability. Exercise is therefore a multi-target intervention, and its benefits extend to people with elevated plaque burden, such as elite athletes, in whom plaque quality matters more than quantity. Exercise-based cardiac rehabilitation should be regarded as a standard component of the clinical management of coronary artery disease. Future research should determine the optimal exercise dose, identify individual factors influencing response to exercise, including genetic variation, and develop digital-technology-based rehabilitation programs to improve access and adherence.
Type of Study: Review article |
Subject:
Exercise Physiology
Received: 2026/05/2 | Accepted: 2026/06/30 | Published: 2026/10/7
Received: 2026/05/2 | Accepted: 2026/06/30 | Published: 2026/10/7
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