This review summarizes Coronary Slow Flow (CSF) as a multifactorial syndrome associated with microvascular dysfunction, inflammation, and arrhythmias, highlighting the need for further research into its mechanisms and therapeutic strategies.
Review Article
This review summarizes Coronary Slow Flow (CSF) as a multifactorial syndrome associated with microvascular dysfunction, inflammation, and arrhythmias, highlighting the need for further research into its mechanisms and therapeutic strategies.
Coronary slow flow (CSF) is characterized by recurrent resting angina and delayed distal vessel filling, despite the absence of obstructive coronary artery disease on angiography. With the continuous advancement of coronary interventional techniques, cardiologists have increasingly recognized CSF as a distinct phenomenon, and its pathogenesis has become a major research focus. Arrhythmias, common cardiovascular conditions, often present with clinical manifestations similar to those of CSF. Moreover, both conditions share certain pathogenic factors and pathophysiological processes, including endothelial dysfunction, inflammation, autonomic imbalance, and microvascular abnormalities. A clearer understanding of these overlapping mechanisms may help clinicians manage patients with CSF more scientifically and comprehensively. The present review summarizes the proposed pathogenic mechanisms of CSF, including microvascular disorders, endothelial dysfunction, inflammation, arrhythmias, anatomical factors, early atherosclerosis, and genetic polymorphisms. It also discusses the possible association between CSF and arrhythmias, highlights current uncertainties regarding causality, and considers how these mechanisms may broaden future therapeutic perspectives for this disease.
The incidence of coronary slow flow (CSF) in patients undergoing coronary angiography (CAG) is reportedly between 1% and 7%1,2,3, a range possibly related to differences in the definition of CSF, study populations, diagnostic criteria, and geographic setting. Clinically, CSF often manifests as precordial discomfort, chest tightness, chest pain, panic, and fatigue—symptoms that are difficult to promptly distinguish from other cardiac conditions and may be associated with poor clinical prognosis. Studies have shown that CSF is associated with adverse cardiovascular events, such as acute myocardial infarction4, fatal ventricular arrhythmia5, and sudden cardiac death3,6. For example, Takotsubo syndrome (TTS) patients with CSF had a higher rate of in-hospital complications (66.7%) and overall mortality (50%)6. Therefore, regular follow-up of patients with CSF is strongly recommended. In addition, an understanding of the etiology and pathophysiologic mechanisms of CSF is urgently needed.
Since the phenomenon of coronary slow flow was first reported by Tambe et al. in 19727, research in this field has continuously advanced. Although the etiology and specific pathophysiologic mechanisms of CSF remain unclear, most studies suggest that its pathogenesis is related to coronary endothelial dysfunction and inflammatory response8,9,10,11, early coronary atherosclerosis12, microvascular reserve dysfunction13, anatomical factors14, and genetic factors15,16 (Figure 1). Moreover, some studies have found that cardiac arrhythmias may also affect coronary blood flow17,18,19,20,21,22,23 (Table 1). This review aims to critically evaluate the current evidence on the pathogenesis of CSF, with a specific focus on the relationship between CSF and arrhythmias, and to identify knowledge gaps and future research priorities for this understudied condition. For this narrative review, a literature search was performed in PubMed from inception to February 2026 using keywords including “coronary slow flow,” “microvascular dysfunction,” “endothelial dysfunction,” “inflammation,” “arrhythmia,” and “genetic polymorphism.” Studies were selected if they were relevant to CSF pathogenesis, associated factors, or the relationship between CSF and arrhythmias. Priority was given to larger clinical studies and methodologically robust evidence, while experimental studies and clinically informative case reports were included when they helped explain possible mechanisms or uncommon clinical associations.
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Diagnostic
The current diagnostic criteria for coronary slow flow (CSF) are generally described as follows: (1) the presence of at least one non-diseased coronary vessel (i.e., coronary stenosis <40% on angiography); (2) delayed distal contrast filling; and (3) a Thrombolysis in Myocardial Infarction (TIMI) flow grade of 2 or a corrected TIMI frame count (CTFC) >27 frames (at a standard acquisition rate of 30 frames per second), after excluding secondary causes of slow flow, including coronary vasospasm, coronary embolism, coronary artery ectasia, and exogenous vasoconstrictor agents24,25.
Pathogenesis
To date, a great deal of research has indicated multiple underlying pathogenic mechanisms of CSF, including microvascular disorders, endothelial dysfunction and inflammation, arrhythmia, anatomical factors, early atherosclerosis, and genetic polymorphism. It is important to understand the progress of research on these potential mechanisms and their effects on CSF.
Microvascular disorder
The coronary arteries form a continuous vascular network comprising subepicardial coronary arteries, pre-arterioles, small arterioles, and capillaries. Of these, the pre-arterioles, small arterioles, and capillaries constitute the coronary microcirculation, which plays a pivotal role in the regulation of blood flow25,26.
Several studies have revealed abnormalities in microcirculatory resistance. Fineschi et al. showed that patients with CSF had increased resting microvascular resistance13. Moreover, the presence of microcirculatory deficits in patients with CSF has also been demonstrated based on impairment of subfoveal choroidal thickness, peripapillary retinal nerve fiber layer thickness, and cutaneous microvascular endothelial function14,27. Mayer et al. reported that patients with CSF, as measured by invasive coronary function testing, were more likely to have an abnormal index of microcirculatory resistance28. Furthermore, basic research has found that certain proteins and signaling pathways play a role in regulating CSF. Kochin et al. demonstrated that, in the context of microcirculatory disorders, elevated levels of stress-inducible protein 2 (Sestrin2) are positively correlated with the occurrence of CSF, potentially via the AMPK/mTOR signaling pathway29.
In addition, Beltrame et al. reported that CSF is linked to persistently increased resting coronary microvascular tone, reflected by reduced coronary sinus oxygen saturation30. Yilmaz et al. likewise found that metabolic syndrome, which is associated with a higher incidence of coronary slow flow, may contribute to coronary microvascular dysfunction through multiple mechanisms31. The study by Mangieri et al., which used endocardial myocardial biopsies and histopathologic investigations, found that the vasculature was thickened and the lumen was reduced, which could contribute to increased flow resistance2. These studies suggest that functional and structural microvascular disorders may contribute to CSF. However, the sample sizes of previous studies are small, and larger studies are needed to enhance the credibility of these findings.
Endothelial dysfunction and inflammation
Coronary endothelial cells are the natural barrier between the vessel wall and plasma; they secrete vasoconstrictor and vasodilator factors, which play an important role in maintaining vasoconstriction and vasodilation32,33. Numerous studies have shown that vascular endothelial cell dysfunction may lead to the development of CSF by disturbing the balance between vasoconstrictive and vasodilatory mediators, a process that may contribute to disease onset and progression12,27,34,35.
Currently, nitric oxide (NO) is recognized as one of the most important vasodilatory factors and is one of the most commonly used indicators of endothelial function36,37,38. Under physiological conditions, endogenous NO is produced mainly by endothelial NO synthase (eNOS) via the conversion of L-arginine to citrulline, and is subsequently converted to cyclic guanosine monophosphate (cGMP) in smooth muscle cells, which leads to vasodilation through activation of protein kinases and a reduction of intracellular Ca2+ 39,40,41. Endothelin-1 (ET-1) is one of the most potent vasoconstrictors and has been shown to increase peripheral vascular resistance by facilitating the release of Ca2+ from intracellular stores or the opening of calcium channels, thereby increasing intracellular Ca2+ concentration and inducing vasoconstriction8,42. In studies examining endothelial vasoconstriction and vasodilation, decreased plasma NO levels and increased ET-1 levels were prevalent in patients with CSF, suggesting an imbalance of vasodilatory factors that may be an important factor associated with the development of CSF32,43.
In addition, dysfunction of vascular endothelial cells is also involved in CSF. Nuclear paraspeckle assembly transcript 1 (NEAT1) is an important regulator of atherosclerosis. NEAT1 may affect soluble intercellular adhesion molecule-1 (sICAM-1) expression, suppress the proliferation of human umbilical vein endothelial cells (HUVECs), and promote endothelial cell apoptosis, thereby contributing to vascular endothelial dysfunction and the development of coronary slow flow. Turhan et al. further reported that plasma vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin levels were markedly increased in patients with CSF and showed a significant positive correlation with corrected TIMI frame count (cTFC)44.
Apart from these factors, inflammation is also an underlying pathogenic factor of CSF. Inflammation has been associated with the pathogenesis and development of CSF44,45. Inflammatory cytokines are a diverse group of cytokines, including interleukins (ILs) and C-reactive protein (CRP)46,47,48. CRP has been linked to chronic inflammation through its role in vascular remodeling and increased flow resistance, both of which can contribute to slower blood flow. Several studies have also reported higher levels of Toll-like receptor 4 (TLR4), miR-155, TNF-α, IL-1, and IL-6, along with lower IL-10 levels, in the CSF group compared with controls, suggesting an association between CSF and vascular inflammatory responses49,50,51. Zengin et al. reported that recurrent angina and myocardial infarction were more common in patients with a higher neutrophil-to-lymphocyte ratio (NLR)52. Roshanravan et al. found that patients with CSF had significantly higher expression of IL-1β and NF-κB mRNA, showing that the pathogenesis of the CSF phenomenon may be closely associated with inflammation11. These studies have investigated markers of inflammatory response in patients with CSF and found that inflammatory markers are higher in patients with CSF than in controls, supporting the possibility that inflammation contributes to the pathological process of CSF.
As for systemic inflammation, the systemic immune-inflammatory index (SII) has emerged as a predictor of various cardiovascular complications. This index has also been used to estimate the risk of contrast-induced nephropathy in patients with non-ST-segment elevation myocardial infarction53. Furthermore, systemic inflammation is associated with structural remodeling54 and arrhythmogenesis55, and influences procedural success rates56,57. Recent studies have also revealed that systemic inflammation indicators may help predict CSF. In a retrospective study involving 197 patients, SII, platelet-to-lymphocyte ratio (PLR), NLR, and high-sensitivity C-reactive protein (hsCRP) were found to be positively correlated with CSF. Specifically, SII was identified as an independent predictor of CSF58. Another study found that SII independently predicted coronary slow flow phenomenon (CSFP) and was positively correlated with the mean thrombolysis in myocardial infarction frame count (mTFC) and the number of involved coronary arteries59. Given the central role of endothelial dysfunction, inflammatory cytokines, and adhesion molecules in the pathogenesis of CSF, readily available peripheral blood inflammatory indices—such as SII, NLR, PLR, and hsCRP—offer practical tools for integrating these mechanistic insights into clinical evaluation. Unlike individual cytokines or adhesion molecules that require specialized assays, these composite indices can be derived from routine complete blood counts and have been shown to correlate with the severity of CSF and the mTFC. Therefore, incorporating SII and related inflammatory parameters into the assessment of patients with suspected CSF may enhance risk stratification and provide prognostic information beyond traditional angiographic findings. These inflammatory parameters may also improve the prediction of long-term morbidity and mortality and aid in identifying high-risk individuals who could benefit from anti-inflammatory or endothelial-protective therapies.
Arrhythmia
Ventricular and atrial arrhythmias have been detected in patients with coronary slow flow17,18,19, and the presence of slow flow during coronary angiography may be associated with the occurrence of arrhythmias. In addition, atrial fibrillation (AF) has been suggested to be an independent risk factor for the development of CSF, and the incidence of CSF is significantly correlated with AF episode status60.
Several experimental studies have demonstrated that AF may reduce coronary blood flow by altering the structure and function of the atria60,61. By comparing the mean TIMI frame counts (TFC) of the patients, Luo et al. reported that AF was present in 18% of patients with CSF versus 6% of controls (p < 0.01), and AF was identified as an independent risk factor for CSF (OR: 2.8; 95% CI: 1.5–5.2), suggesting that AF is associated with impaired and attenuated coronary blood flow23. Furthermore, Zhuang et al. demonstrated in a cross-sectional study of atrial fibrillation and slow coronary blood flow that the incidence of CSF was significantly higher in the atrial fibrillation group than in the control group, suggesting that AF is significantly associated with CSF62. Fine fibrillatory waves may be the main pathogenic mechanism of reduced coronary blood flow in patients with AF63.
QT interval dispersion (QTD) reflects differences in cardiac repolarization and areas of cardiac electrophysiological instability. According to previous studies, patients with CSF have longer QT interval dispersion5. Simsek et al. found that the maximum corrected QT interval (QTcmax) and QTc dispersion (QTcD) were significantly prolonged in patients with CSF by comparative analysis between patients with CSF and control subjects5. These changes suggest an increased risk of ventricular arrhythmias in patients with CSF. A recent case report of cardiac sarcoidosis with refractory ventricular tachycardia and coronary slow flow further suggests that myocardial inflammation, microvascular dysfunction, and malignant ventricular arrhythmias may coexist in selected clinical settings64.
Millar et al. showed that premature beats originating from different sites have different hemodynamic effects, with apical premature beats having the greatest effect on coronary blood flow65. This may be related to the fact that the location of pacing affects the cardiovascular system to different extents. In addition, recent studies have shown that autonomic function has an important impact on the cardiovascular system. It has been demonstrated that heart rate variability influences the onset of premature ventricular contractions through the autonomic nervous system, which leads to the phenomenon of slow coronary blood flow66,67. Although previous studies have demonstrated a relationship between CSF and abnormal elevations of electrocardiographic indices of ventricular arrhythmias, there is a paucity of information regarding whether ventricular arrhythmia episodes affect the incidence of CSF. Furthermore, experimental studies are required to elucidate the mechanisms by which arrhythmias affect CSF.
Anatomical factors
Anatomical factors affecting CSF include changes in platelet and erythrocyte characteristics, coronary artery anatomy, and other structural features that may help elucidate the pathogenesis of slow coronary blood flow. It has been shown that patients with CSF have thinner subfoveal choroidal thickness (SFCT)14. Coronary artery anatomy, including luminal index and distal branching of the vessel, has also been implicated in CSF14. A study by Nie et al. on the anatomical characteristics of local coronary arteries in patients with slow coronary flow showed that greater distal branching and coronary tortuosity were associated with slower intracoronary blood flow68. Moreover, it has been shown that the greater the mean corpuscular volume (MCV), the greater the likelihood of CSF. Erythrocytes transport oxygen and carbon dioxide, and their function depends on erythrocyte deformability; an increase in MCV can reduce this deformability, thereby contributing to slow blood flow69. Increased epicardial adipose tissue (EAT) volume, as measured by computed tomography angiography, is strongly associated with CSF70.
Early atherosclerosis
Evidence suggests that vessels in patients with CSF are likely to exhibit morphological changes and increased intima-media thickness as the disease progresses. Therefore, intravascular ultrasound and carotid intima-media thickness assessment may help identify subclinical atherosclerosis. Intravascular ultrasound (IVUS) is useful for detecting early atherosclerotic changes that may not be visible on conventional angiography. Using IVUS evidence of intimal thickening in patients with CSF, Cin et al. proposed that CSF may represent diffuse atherosclerosis involving both the microvascular system and the epicardial coronary arteries71. Research has demonstrated that patients with CSF frequently exhibit substantial levels of coronary artery wall calcification, diffuse intimal thickening, and nonobstructive atherosclerotic coronary changes72. In addition, triglycerides are involved in the atherosclerotic process, and it has been shown that triglyceride levels are elevated in patients with coronary slow flow compared to a non-coronary slow flow group, which is one piece of evidence that CSF may represent an early stage of coronary atherosclerosis73. An increase in carotid artery intima-media thickness (IMT) is an early sign of atherosclerosis. The findings of certain studies demonstrate a correlation between elevated IMT values and CSF12,74. These findings imply that patients with CSF may experience subclinical atherosclerotic changes.
Genetic polymorphism
As research on CSF continues to expand, researchers have begun to recognize associations between CSF and underlying genetic polymorphisms. A study by Sun et al. suggested that three genes closely related to the immune-inflammatory response—formyl peptide receptor 1 (FPR1), formyl peptide receptor 2 (FPR2), and C-X-C chemokine receptor type 4 (CXCR4)—may play an important role in CSF75. In addition, many studies have shown that gene polymorphisms are closely associated with CSF. Mutluer et al., in their study on the correlation between interleukin-1 (IL-1) gene cluster polymorphism and CSF, found that the IL-1β-3954 single-nucleotide polymorphism may contribute to the development of CSF through inflammatory factors that enhance immune system activity76. Liu et al. supported that the IL-6 -634C/G polymorphism is associated with CSF in the Han Chinese population77. Shi et al. showed that the A allele in the IL-10 -592A/C polymorphism is associated with an increased risk of CSF in the Han Chinese population51.
Given that eNOS levels are elevated in patients with CSF, some researchers have proposed a possible association between eNOS genetic polymorphisms and CSF development. Nurkalem et al. reported that the eNOS T-786C polymorphism is a risk factor for CSF and concluded that the C allele is positively correlated with the TIMI frame count78. The findings of a study among Iranians conducted by Karimi et al. indicate that eNOS Asp298Glu (894G/T) gene polymorphism is a possible risk factor for CSF16. However, Caglayan et al. reported no association between the eNOS Glu298Asp polymorphism and CSF risk in a Turkish population79.
Therapy
At present, with advances in research on the mechanisms of CSF, therapeutic drugs for CSF are also being developed. However, since the etiology and pathogenesis of CSF have not yet been fully clarified, most treatments for CSF remain empirical. Dipyridamole may improve left ventricular systolic and diastolic function and exert vasodilatory effects on coronary microvessels in patients with CSF. Trimetazidine can improve ventricular repolarization indices and left ventricular diastolic function and reduce diastolic blood pressure in patients with CSF80. In addition, trimetazidine has been found to reduce heart rate variability, thereby assisting in the treatment of CSF63. Nebivolol improves endothelial function and decreases the risk of ventricular arrhythmias in patients with CSF. Nicorandil elevates NO levels and decreases ET-1 levels, thereby reducing endothelial and microcirculatory dysfunction in the treatment of CSF81,82. A traditional Chinese medicine formulation has been shown to produce antiplatelet, anti-inflammatory, and cardioprotective effects and to improve blood flow in patients with slow coronary flow83,84. After treatment, the CTFC values of patients with CSF were significantly reduced in all three major coronary arteries (LAD, LCX, and RCA), with improvements of 12.92%, 15.25%, and 22.76%, respectively (all P < 0.05). In addition, this formulation attenuates atherosclerotic lesions in the ApoE-deficient mouse model84.
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In recent years, coronary microvascular disorders such as CSF have gained increasing clinical attention. The strongest evidence linking arrhythmias to CSF comes from studies demonstrating that patients with atrial fibrillation (AF) have significantly higher corrected TIMI frame counts and that specific arrhythmic features, such as apical premature beats and prolonged QT dispersion, are associated with reduced coronary flow. Furthermore, systemic inflammation—a central driver of cardiovascular pathophysiology—has emerged ...
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The authors have no conflicts of interest to declare.
The researchers wish to express their gratitude to their colleagues at the School of Clinical Medicine of Shandong Second Medical University and the First People's Hospital of Jining City, China. We acknowledge the use of Grammarly [https://grammarly.com] to grammar-check the manuscript at the final stage of preparation. This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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