Coronary microvascular dysfunction (CMD) is a key contributor to myocardial ischemia and adverse cardiovascular outcomes, particularly in individuals with metabolic disorders such as type 2 diabetes (T2D). While conventional therapies primarily target epicardial coronary disease, effective treatments for CMD remain limited. Glucagon-like peptide-1 receptor (GLP-1R) agonists have emerged as promising agents with cardiovascular benefits extending beyond glycemic control. Preclinical and clinical evidence suggests that GLP-1R activation enhances coronary microvascular function through mechanisms including improved endothelial function, increased nitric oxide bioavailability, attenuation of oxidative stress, and reduced vascular inflammation. Moreover, GLP-1R agonists have been shown to improve myocardial blood flow, myocardial perfusion reserve, and coronary endothelial function, particularly in high-risk populations. Despite these promising findings, inconsistencies remain across studies due to variability in patient populations, study designs, and imaging methodologies. This review summarizes current evidence on the role of GLP-1R agonists in myocardial perfusion, bridging mechanistic insights with clinical outcomes. Further large-scale, well-designed trials are needed to clarify their long-term impact on coronary microcirculation and explore their potential as targeted therapies for CMD.

The association between coronary microcirculation and clinical outcomes in patients with intermediate stenosis remains unclear.

The aim of this study was to assess the prognostic significance of angiography-derived index of microcirculatory resistance (angio-IMR) in patients with intermediate coronary stenosis.

This post hoc analysis included 1,658 patients from the FLAVOUR (Fractional Flow Reserve and Intravascular Ultrasound for Clinical Outcomes in Patients with Intermediate Stenosis) trial, with angio-IMR measured in each vessel exhibiting intermediate stenosis. The primary endpoint was a patient-oriented composite outcome (POCO), a composite of all-cause death, myocardial infarction, or revascularization over a 2-year period.

The median follow-up period was 24.8 months (Q1-Q3: 24.4-26.4 months). Over the 2-year follow-up period, patients with angio-IMR >25 exhibited a significantly higher POCO rate in both the percutaneous coronary intervention (PCI) group (35.06% [27 of 77] vs 7.2% [51 of 708]; P < 0.001) and the non-PCI group (17.95% [21 of 117] vs 4.23% [32 of 756]; P < 0.001). After adjusting for potentially related risk factors, angio-IMR >25 remained an independent predictor of the POCO in the PCI group (HR: 6.235; 95% CI: 3.811-10.203; P < 0.001) and the non-PCI group (HR: 5.282; 95% CI: 2.948-9.462; P < 0.001). The addition of angio-IMR demonstrated incremental prognostic value in both an angiographic risk factor model (C-index 0.710 [95% CI: 0.663-0.756] vs 0.615 [95% CI: 0.563-0.664] [P < 0.001]; net reclassification index 0.268 [95% CI: 0.191-0.362; P < 0.001]; integrated discrimination improvement 0.055 [95% CI: 0.030-0.108; P < 0.001]) and a clinical risk factor model (C-index 0.705 [95% CI: 0.658-0.751] vs 0.594 [95% CI: 0.544-0.644] [P < 0.001]; net reclassification index 0.268 [95% CI: 0.171-0.350; P < 0.001]; integrated discrimination improvement 0.057 [95% CI: 0.027-0.102; P < 0.001]).

In individuals with intermediate coronary stenosis, elevated angio-IMR is linked to an adverse prognosis. Using angio-IMR significantly enhanced the capability to reclassify patients and accurately estimate the risk for the POCO.

Coronary microvascular disease (CMD) comprises a spectrum of conditions characterized by the functional and structural abnormalities of coronary microcirculation, affecting vessels typically smaller than 500 μm. Despite its clinical significance as a contributor to myocardial ischemia, CMD frequently remains underdiagnosed due to the limitations of current diagnostic approaches. Invasive testing, including coronary reactivity assessment, is considered the gold standard, but it is resource-intensive and not always accessible. Non-invasive methods, such as positron emission tomography (PET) and transthoracic Doppler echocardiography (TTDE), offer alternatives but are limited by varying accuracy and accessibility. Amid these diagnostic challenges, there is increasing interest in circulating biomarkers as adjuncts in CMD evaluation. Biomarkers associated with endothelial dysfunction, inflammation, and oxidative stress, detectable through routine blood tests, may assist in CMD diagnosis, risk stratification, and therapeutic monitoring. These biomarkers can offer insights into CMD pathogenesis and enable early, non-invasive screening to identify patients who may benefit from more invasive investigations. This narrative review examines studies assessing biomarkers in CMD patients with diagnoses confirmed through invasive techniques. Our objective is to focus on circulating biomarkers linked to the invasive evaluation of coronary microcirculation, aiming to advance the understanding of the underlying mechanisms of this prevalent condition and enhance diagnostic accuracy and the clinical management of affected patients.

Coronary microvascular disease (CMD) is defined as impaired coronary flow reserve (CFR) and/or increased microvascular resistance (MR) without significant epicardial coronary stenosis. This definition allows for discordant CFR and MR values within patients with CMD. The aim of this meta-analysis is to characterise the prognostic value and pathophysiological backgrounds of CFR and MR con-/discordance.

A systematic search (PROSPERO CRD42024573004) identified studies determining CFR and MR in patients without significant epicardial coronary artery disease. Patients were divided into four groups: (1) normal CFR and MR, (2) abnormal CFR and MR, (3) abnormal CFR with normal MR and (4) normal CFR with abnormal MR and analysed for all-cause mortality and major adverse cardiovascular events (MACE).

We identified four studies representing 2310 total participants. Group B had the highest MACE (OR: 3.23; 95% CI 1.95 to 5.36) and mortality rate (OR: 2.27; 95% CI 1.12 to 4.58) compared with group A. Group C, associated with female sex, showed significantly higher MACE (OR: 2.07; 95% CI 1.25 to 3.45) but not mortality (OR: 1.89; 95% CI 0.92 to 3.88) compared with group A. In group D, associated with high body mass index, MACE and mortality rates did not differ significantly from group A (OR: 1.19; 95% CI 0.67 to 2.11 and OR: 0.55; 95% CI 0.16 to 1.90, respectively).

Abnormal CFR and MR are associated with a high risk of MACE and death. Abnormal CFR and normal MR are associated with an increased MACE-but not death. MACE and mortality risk in discordantly normal CFR and abnormal MR are low. Our findings show the need for tailoring CFR and MR diagnostic thresholds to patient characteristics and raise questions about the presence of CMD in patients with abnormal MR with normal CFR.

Non-obstructive coronary artery disease (NOCAD) is a condition in stable patients that experience angina despite not having significant coronary obstructive lesion. Knowledge on the role of certain biomarkers in patients with NOCAD is still limited. This study aimed to evaluate the roles of inflammation and adhesion molecules in the development of NOCAD. The correlations between the peripheral and coronary levels of the inflammatory biomarkers and adhesion molecules were also investigated.

In this cross-sectional study, symptomatic angina patients scheduled for coronary angiograms were recruited and separated into obstructive coronary artery disease (OCAD) and NOCAD groups based on those angiograms. Peripheral and coronary blood samples were taken to measure inflammation biomarkers [high sensitivity C-reactive protein (hsCRP) and growth differentiation factor 15 (GDF-15)], and adhesion molecules [vascular cell adhesion molecule-1 (VCAM-1)]. Subjects without angina symptoms were recruited for the control group.

The hsCRP, GDF-15, and VCAM-1 levels were higher in the OCAD and NOCAD groups than in the control group. VCAM-1 levels successfully predicted the incidence of NOCAD [p = 0.010, area under the curve (AUC) = 0.716]. All biomarkers' levels in the peripheral and coronary blood were correlated in OCAD and NOCAD patients (p < 0.001).

Elevated levels of the hsCRP, GDF-15, and VCAM-1 were found with NOCAD, despite the absent of significant coronary obstruction. VCAM-1 successfully predicted NOCAD and may thus serve as an early NOCAD biomarker. Significant correlations of hsCRP, GDF-15, and VCAM-1 level in peripheral and coronary blood indicate that the peripheral levels of these biomarkers reflect the levels and changes that occur at the coronary level.

The Systemic Inflammation Response Index (SIRI) and N-terminal Pro-B-type natriuretic peptide (NT-proBNP) have been proposed as reliable predictors of poor prognosis in cardiovascular disease and all-cause mortality, However, their validity has not been extensively evaluated in patients with myocardial infarction with nonobstructive coronary arteries (MINOCA).

259 patients diagnosed with MINOCA were enrolled in this study from January 2015 to December 2022, and serum levels of SIRI and NT-proBNP were detected. The primary endpoints were major adverse cardiovascular events (MACE). According to the occurrence of MACE during the follow-up period, patients were grouped into MACE and Non-MACE groups, and divided by the median values for SIRI and NT-proBNP into groups: low SIRI, high SIRI, low NT-proBNP, and high NT-proBNP.

A statistically significant difference in the levels of SIRI and NT-proBNP was observed between the MACE group and the non-MACE group. Kaplan-Meier survival curve analysis revealed that patients with high SIRI and high NT-proBNP had a significantly higher risk of MACE (log-rank P < 0.001). Furthermore, even after adjusting for covariates, the high SIRI and high NT-proBNP were associated with an increased risk of MACE (P<0.001, HR: 3.188, 95% CI 1.940-5.241; P<0.001, HR: 2.245, 95% CI 1.432-3.519). Additionally, the combined prognosis prediction of SIRI and NT-proBNP was superior to a single prediction, and adding SIRI and NT-proBNP to the traditional risk factor model improved the model's predictive value.

High levels of SIRI and NT-proBNP exhibit a significant correlation with an increased risk of MACE, thereby suggesting that SIRI can be used as a reliable inflammatory indicator for predicting the risk in MINOCA patients, with significantly improved prognostic value when combined with NT-proBNP.

To investigate the role of glucagon-like peptide 1 (GLP-1) in myocardial perfusion, focusing on its effects on coronary microcirculation and cardiovascular outcomes.

Review of foundational research and large-scale clinical trials, including Cardiovascular Outcome Trials (CVOTs), examining the cardiovascular effects of GLP-1. Systematic analysis of trial data to assess the impact of GLP-1 therapy on myocardial infarction, composite cardiovascular events, and stroke incidence.

GLP-1 therapy was found to significantly reduce myocardial infarction and composite cardiovascular events. Additionally, GLP-1 receptor agonists were observed to reduce stroke incidence, suggesting systemic effects on panvascular diseases. While direct protective effects on coronary microvasculature have been less studied, growing evidence supports GLP-1's role in comprehensive myocardial perfusion.

GLP-1 is a promising therapeutic agent for improving myocardial perfusion and reducing cardiovascular events. Its protection is likely associated with comprehensive improvements in myocardial perfusion, including effects on coronary microcirculation. Further research is needed to fully elucidate its mechanisms of action and potential clinical applications.

Takotsubo syndrome (TTS) is a clinical syndrome characterized by a transient left ventricular dysfunction whose diagnosis can be challenging due to its resemblance to acute myocardial infarction (AMI). Despite the growing recognition of TTS, acute complications and long-term mortality rates are comparable to those observed in AMI patients. In this context, a systematic diagnostic approach is imperative for an accurate patient assessment, with due consideration of the distinctive characteristics and optimal timing of each imaging modality. Coronary angiography with ventriculography may be reserved for cases presenting with ST-segment elevation, whereas in all other cases, the use of multimodality noninvasive imaging allows for a comprehensive evaluation of typical diagnostic features and detection of acute complications while also providing prognostic insights. The aim of this review is to evaluate the current research on non-invasive modalities and to propose a diagnostic algorithm that will facilitate the identification and management of TTS.

Subjects who have ischemia with non-obstructive coronary arteries (INOCA) experience angina pectoris with evidence of myocardial ischemia but without coronary stenosis. Few studies have investigated factors associated with its survival, especially insulin resistance. In this study, subjects with angina pectoris, without known diabetes mellites (DM), and with non-invasive tests showing myocardial ischemia were admitted for coronary angiography (CAG). Those whose CAG did not reveal stenosis and agreed to receive an oral glucose tolerance test (OGTT) 2 weeks after hospital discharge were enrolled for analysis. All-cause mortality was recorded, which served as the outcome of the study. A total of 587 subjects with INOCA, without known DM, and with OGTT data were analyzed. After OGTT and HbA1c tests, 86 subjects (14.7%) were newly diagnosed with DM and 59.8% had pre-DM. The median duration of follow-up was 7.03 years. Thirty-nine subjects died during the follow-up period. The incidence rate of mortality was 9.9 /1000 person-year. Those who died had a higher fasting glucose (101 ± 17 vs. 94 ± 13 mg/dl, p = 0.003) but a lower estimated glomerular filtration rate (eGFR) (54 ± 22 vs. 87 ± 30 ml/min, p < 0.001). In the Cox survival analysis, a higher fasting glucose (hazard ratio 1.053, p = 0.007) was associated with worse mortality for INOCA without DM (N = 501). On the contrary, a higher eGFR (hazard ratio 0.967, p = 0.012) was protective of better survival for non-diabetic INOCA (N = 501). In conclusion, for non-diabetic INOCA, higher fasting glucose was associated with worse mortality and higher eGFR was protective for better survival.

Microvascular angina (MVA) is the most common cause of cardiac ischemic chest pain in patients without obstructive coronary artery disease (CAD) and lacks of effective treatment means. Medicine food homology (MFH) involves substances with both nutritional and medicinal qualities that have the potential to improve MVA symptoms as medicines, dietary supplements. However, research on MFH formula (MFHF) for MVA is not available. The study aims to generate a core MFHF for MVA through data mining and offer scientific backing for the utilization of edible medications in the prevention and alleviation of MVA. 11 databases were utilized to construct a database of MFH drugs, and the MFHF was generated through frequency analysis, association rule analysis, and clustering analysis. The composition of the formula is Codonopsis Radix, Astragali Radix, Platycodonis Radix, Persicae Semen, Glycyrrhizae Radix Et Rhizoma, Angelicae Sinensis Radix, and Allii Macrostemonis Bulbus. Through network pharmacology and molecular docking, we identified five major active components of MFHF: Adenosine, Nonanoic Acid, Lauric Acid, Caprylic Acid, and Enanthic Acid, along with nine core targets (NFKB1, ALB, AKT1, ACTB, TNF, IL6, ESR1, CASP3, and PTGS) for the improvement of MVA. These 5 active components have various biological activities, such as reducing oxidative stress, anti-inflammation, analgesia effect, inhibiting platelet aggregation, vasodilatation, vascular endothelial protection, and cardio-protection. GO and KEGG enrichment analyses revealed that MFHF mainly acted on the response to xenobiotic stimulus, integrative component of the plasma membrane, RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding, pathways in cancer, lipid and atherosclerosis, human cytomegalovirus infection, and the PI3K-Akt signaling pathway, which are the main pathogenesis of MVA.

An increasing body of evidence suggests a pivotal role for the microvasculature in the development of cardiovascular disease. A dysfunctional coronary microvascular network, specifically within endothelial cells-the inner most cell layer of vessels-is considered a strong, independent risk factor for future major adverse cardiac events. However, challenges exist with evaluating this critical vascular bed, as many of the currently available techniques are highly invasive and cost prohibitive. The more easily accessible peripheral microcirculation has surfaced as a potential surrogate in which to study mechanisms of coronary microvascular dysfunction and likewise may be used to predict poor cardiovascular outcomes. In this review, we critically evaluate a variety of prognostic, physiological, and mechanistic studies in humans to answer whether the peripheral microcirculation can add insight into coronary microvascular health. A conceptual framework is proposed that the health of the endothelium specifically may link the coronary and peripheral microvascular beds. This is supported by evidence showing a correlation between human coronary and peripheral endothelial function in vivo. Although not a replacement for investigating and understanding coronary microvascular function, the microvascular endothelium from the periphery responds similarly to (patho)physiological stress and may be leveraged to explore potential therapeutic pathways to mitigate stress-induced damage.

Women with angina and non-obstructive coronary artery disease (ANOCA) have a heightened risk for cardiovascular events, and the pathophysiology for ischaemic symptoms may be related to alterations in microvascular structure and function. We examined the use of breathing-enhanced oxygenation-sensitive cardiac magnetic resonance imaging (OS-CMR) using vasoactive breathing manoeuvres to assess myocardial oxygenation in women with ANOCA.

We recruited women (aged 40-65 years) from two sites in Canada who presented to healthcare with persistent retrosternal chest pain and found to have ANOCA, or without a history of cardiovascular disease. All participants were scanned using a clinical 3T MRI scanner, and OS-CMR images were acquired over a breath hold following paced hyperventilation to measure global and regional measurements of heterogeneity. Fifty-four women with ANOCA (age: 55 ± 6.2 years) and 48 healthy controls (age: 51.2 ± 4.8 years) were recruited. There was no significant difference in volume, function, mass, or global myocardial oxygenation between the two groups [mean %Δ in signal intensity (SI): 4.9 (±7.3) vs. 4.5 (±10.1), P = 0.82]. Women with ANOCA had higher regional variations in myocardial oxygenation in circumferential [median %Δ in SI: 5.1 (2.0-7.6) vs. 2.2 (1.4-3.5), P = 0.0004] and longitudinal directions [median %Δ in SI: 11.4 (5.4-16.7) vs. 6.0 (3.0-7.0), P = 0.001], which remained present in a multivariate model.

Heterogeneous myocardial oxygenation may explain ischaemic symptoms without any associated epicardial obstructive coronary artery disease. Regional variations in myocardial oxygenation on OS-CMR could serve as an important diagnostic marker for microvascular dysfunction in women with ANOCA.

Anderson-Fabry disease (AFD), a genetic disorder caused by mutations in the α-galactosidase-A (GLA) gene, disrupts lysosomal function, leading to vascular complications. The accumulation of globotriaosylceramide (Gb3) in arterial walls triggers upregulation of adhesion molecules, decreases endothelial nitric oxide synthesis, and induces reactive oxygen species production. This cascade results in fibrotic thickening, endothelial dysfunction, hypercontractility, vasospasm, and a pro-thrombotic phenotype. AFD patients display increased intima-media thickness (IMT) and reduced flow-mediated dilation (FMD), indicating heightened cardiovascular risk. Nailfold capillaroscopy (NFC) shows promise in diagnosing and monitoring microcirculatory disorders in AFD, though it remains underexplored. Morphological evidence of AFD as a storage disorder can be demonstrated through electron microscopy and immunodetection of Gb3. Secondary pathophysiological disturbances at cellular, tissue, and organ levels contribute to the clinical manifestations, with prominent lysosomal inclusions observed in vascular, cardiac, renal, and neuronal cells. Chronic accumulation of Gb3 represents a state of ongoing toxicity, leading to increased cell turnover, particularly in vascular endothelial cells. AFD-related vascular pathology includes increased renin-angiotensin system activation, endothelial dysfunction, and smooth muscle cell proliferation, resulting in IMT increase. Furthermore, microvascular alterations, such as atypical capillaries observed through NFC, suggest early microvascular involvement. This review aims to unravel the complex interplay between inflammation, oxidative stress, and endothelial dysfunction in AFD, highlighting the potential connections between metabolic disturbances, oxidative stress, inflammation, and fibrosis in vascular and cardiac complications. By exploring novel cardiovascular risk factors and potential diagnostic tools, we can advance our understanding of these mechanisms, which extend beyond sphingolipid accumulation to include other significant contributors to disease pathogenesis. This comprehensive approach can pave the way for innovative therapeutic strategies and improved patient outcomes.

Coronary microvascular disease (CMVD) is common in patients with cardiovascular risk factors and is linked to an elevated risk of adverse cardiovascular events. Although modern medicine has made significant strides in researching CMVD, we still lack a comprehensive understanding of its pathophysiological mechanisms due to its complex and somewhat cryptic etiology. This greatly impedes the clinical diagnosis and treatment of CMVD. The primary pathological mechanisms of CMVD are structural abnormalities and/or dysfunction of coronary microvascular endothelial cells. The development of CMVD may also involve a variety of inflammatory factors through the endothelial cell injury pathway. This paper first reviews the correlation between the inflammatory response and CMVD, then summarizes the possible mechanisms of inflammatory response in CMVD, and finally categorizes the drugs used to treat CMVD based on their effect on the inflammatory response. We hope that this paper draws attention to CMVD and provides novel ideas for potential therapeutic strategies based on the inflammatory response.

Inflammation is an important mechanism in atherosclerosis and plaque formation. C-reactive protein (CRP) is a common inflammatory biomarker associated with the risk of coronary heart disease. We investigated the relationship of CRP with findings from myocardial perfusion imaging (MPI).

In this retrospective study, 102 consecutive patients (mean age 71 years, 68% males) who underwent MPI (for diagnostic reasons or quantification of myocardial ischemia) and CRP determination (upper limit: 6 mg/L) within 1 month from MPI were included. The patients had no infection or recent acute coronary syndrome.

The median CRP level was 4 mg/L (2, 10) among the study population. Patients with raised CRP had higher summed stress score (SSS) (p = 0.006) and summed rest score (SRS) (p = 0.001) and higher risk for SSS > 3 (OR 9.25, 95% CI 2.03-42.13, p = 0.001) compared to those with low CRP. The association of SSS and SRS with CRP levels was more evident in patients over 70 years (p = 0.027 and p = 0.005, respectively). No significant difference in summed difference score was shown. The two groups had no difference in other risk factors (p > 0.05 for all comparisons).

a high level of CRP was associated with the presence and extent of stress-induced myocardial ischemia in MPI.

Perivascular inflammation contributes to the development of atherosclerosis and microcirculatory dysfunction. Pericoronary adipose tissue (PCAT) attenuation, measured by coronary computed tomography angiography, is a potential indicator of coronary inflammation. However, the relationship between PCAT attenuation, microcirculatory dysfunction, and periprocedural myocardial injury (PMI) remains unclear.

Patients with chronic coronary syndrome who underwent coronary computed tomography angiography before percutaneous coronary intervention were retrospectively identified. PCAT attenuation and adverse plaque characteristics were assessed using coronary computed tomography angiography. The extent of microcirculatory dysfunction was evaluated using the angio-based index of microcirculatory resistance before and after percutaneous coronary intervention. Overall, 125 consecutive patients were included, with 50 experiencing PMI (PMI group) and 75 without PMI (non-PMI group). Multivariable analysis showed that older age, higher angio-based index of microcirculatory resistance, presence of adverse plaque characteristics, and higher lesion-based PCAT attenuation were independently associated with PMI occurrence (odds ratio [OR], 1.07 [95% CI, 1.01-1.13]; P=0.02; OR, 1.06 [95% CI, 1.00-1.12]; P=0.04; OR, 6.62 [95% CI, 2.13-20.6]; P=0.001; and OR, 2.89 [95% CI, 1.63-5.11]; P<0.001, respectively). High PCAT attenuation was correlated with microcirculatory dysfunction before and after percutaneous coronary intervention and its exacerbation during percutaneous coronary intervention. Adding lesion-based PCAT attenuation to the presence of adverse plaque characteristics improved the discriminatory and reclassification ability in predicting PMI.

Adding PCAT attenuation at the culprit lesion level to coronary computed tomography angiography-derived adverse plaque characteristics may provide incremental benefit in identifying patients at risk of PMI. Our results highlight the importance of microcirculatory dysfunction in PMI development, particularly in the presence of lesions with high PCAT attenuation.

URL: https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000057722; Unique identifier: UMIN000050662.

The objective of our study was to evaluate the concentrations of pro-inflammatory biomarkers in patients with acute myocardial infarction with non-obstructive coronary arteries (MINOCA) compared to patients with acute myocardial infarction with obstructive coronary arteries (MI-CAD) in the early post-infarction period and after 1 year and to perform a comparative analysis of the relationship between laboratory biomarkers and atherosclerosis progression in patients with MINOCA and MI-CAD.

Samples of peripheral venous blood were collected upon admission and on days 2, 4, and 7 of hospitalization and after 1 year. An extended multiplex analysis was performed in blood serum. Multidetector-computed tomography coronary angiography was performed on day 7 and 1 year after acute myocardial infarction to assess the progression of atherosclerosis.

The level of high-sensitive C-reactive protein (hsCRP) was elevated upon admission in MINOCA patients compared to MI-CAD patients (p = 0.05), but it was comparable in two groups at other time points and did not exceed the reference range after 1 year. Despite comparable levels of cytokines CXCL-6, LIGHT, CCL-8, and endocan-1 in patients in both groups, MINOCA patients had a greater increase in pro-inflammatory cytokines PlGF, oncostatin M, IL-20, and CCL-15 sVCAM-1 in the early post-infarction period and in CCL-21, sVCAM-1, oncostatin M, and PlGF after 1 year. We observed significant differences in the dynamics of the following biomarkers between patients with MI-CAD and MINOCA: the dynamics of concentrations of CCL21 (p = 0.002), LIGHT (p = 0.03), and endocan-1 (p = 0.03) after 1 year compared to day 1 in MI-CAD and MINOCA patients was opposite, while the dynamics of CXCL6 (p = 0.04) and endocan-1 (p = 0.02) differed between groups when evaluated after 1 year compared to day 7 of the early post-infarction period. In the MINOCA group, factors associated with atherosclerosis progression were concentrations of sVCAM-1 and CCL-21, while in the MI-CAD group, concentrations of CCL-8 and CXCL6 were the main determinants of atherosclerosis progression.

This small study showed that MINOCA and MI-CAD patients exhibited differences in a pro-inflammatory biomarker profile in the early post-infarction period and after 1-year follow-up, which implies distinct inflammatory pathways involved in atherogenesis during MINOCA. The key factors that were associated with atherosclerosis progression in MINOCA patients are sVCAM-1 and CCL-21, which may suggest a complex genesis of atherosclerosis progression due to structurally altered plaques and changes in the microcirculatory bed. In MI-CAD patients, CCL-8 and CXCL-6 were the key biomarkers associated with atherosclerosis progression. Further large-scale studies are required to confirm our data.

Myocardial infarction in the absence of obstructive coronary artery disease (MINOCA) is an important subtype of myocardial infarction. Although comprising less than 50% stenosis in the main epicardial coronary arteries, it constitutes a severe health risk. A variety of approaches have been recommended, but definitive diagnosis remains elusive. In addition, the lack of a comprehensive understanding of underlying pathophysiology makes clinical management difficult and unpredictable. This review highlights ongoing efforts to identify relevant biomarkers in MINOCA to improve diagnosis, individualize treatment and better predict outcomes.

Microcirculation is pervasive and orchestrates a profound regulatory cross-talk with the surrounding tissue and organs. Similarly, it is one of the earliest biological systems targeted by environmental stressors and consequently involved in the development and progression of ageing and age-related disease. Microvascular dysfunction, if not targeted, leads to a steady derangement of the phenotype, which cumulates comorbidities and eventually results in a nonrescuable, very high-cardiovascular risk. Along the broad spectrum of pathologies, both shared and distinct molecular pathways and pathophysiological alteration are involved in the disruption of microvascular homeostasis, all pointing to microvascular inflammation as the putative primary culprit. This position paper explores the presence and the detrimental contribution of microvascular inflammation across the whole spectrum of chronic age-related diseases, which characterise the 21st-century healthcare landscape. The manuscript aims to strongly affirm the centrality of microvascular inflammation by recapitulating the current evidence and providing a clear synoptic view of the whole cardiometabolic derangement. Indeed, there is an urgent need for further mechanistic exploration to identify clear, very early or disease-specific molecular targets to provide an effective therapeutic strategy against the otherwise unstoppable rising prevalence of age-related diseases.

The hypertrophic cardiomyopathy phenotype encompasses a heterogeneous spectrum of genetic and acquired diseases characterized by the presence of left ventricular hypertrophy in the absence of abnormal cardiac loading conditions. This "umbrella diagnosis" includes the "classic" hypertrophic cardiomyopathy (HCM), due to sarcomere protein gene mutations, and its phenocopies caused by intra- or extracellular deposits, such as Fabry disease (FD) and cardiac amyloidosis (CA). All these conditions share a wide phenotypic variability which results from the combination of genetic and environmental factors and whose pathogenic mediators are poorly understood so far. Accumulating evidence suggests that inflammation plays a critical role in a broad spectrum of cardiovascular conditions, including cardiomyopathies. Indeed, inflammation can trigger molecular pathways which contribute to cardiomyocyte hypertrophy and dysfunction, extracellular matrix accumulation, and microvascular dysfunction. Growing evidence suggests that systemic inflammation is a possible key pathophysiologic process potentially involved in the pathogenesis of cardiac disease progression, influencing the severity of the phenotype and clinical outcome, including heart failure. In this review, we summarize current knowledge regarding the prevalence, clinical significance, and potential therapeutic implications of inflammation in HCM and two of its most important phenocopies, FD and CA.

Severe inflammatory stress often leads to vessel rarefaction and fibrosis, resulting in limited tissue recovery. However, signaling pathways mediating these processes are not completely understood. Patients with ischemic and inflammatory conditions have increased systemic Activin A level, which frequently correlates with the severity of pathology. Yet, Activin A's contribution to disease progression, specifically to vascular homeostasis and remodeling, is not well defined. This study investigated vasculogenesis in an inflammatory environment with an emphasis on Activin A's role. Exposure of endothelial cells (EC) and perivascular cells (adipose stromal cells, ASC) to inflammatory stimuli (represented by blood mononuclear cells from healthy donors activated with lipopolysaccharide, aPBMC) dramatically decreased EC tubulogenesis or caused vessel rarefaction compared to control co-cultures, concurrent with increased Activin A secretion. Both EC and ASC upregulated Inhibin Ba mRNA and Activin A secretion in response to aPBMC or their secretome. We identified TNFα (in EC) and IL-1β (in EC and ASC) as the exclusive inflammatory factors, present in aPBMC secretome, responsible for induction of Activin A. Similar to ASC, brain and placental pericytes upregulated Activin A in response to aPBMC and IL-1β, but not TNFα. Both these cytokines individually diminished EC tubulogenesis. Blocking Activin A with neutralizing IgG mitigated detrimental effects of aPBMC or TNFα/IL-1β on tubulogenesis in vitro and vessel formation in vivo. This study delineates the signaling pathway through which inflammatory cells have a detrimental effect on vessel formation and homeostasis, and highlights the central role of Activin A in this process. Transitory interference with Activin A during early phases of inflammatory or ischemic insult, with neutralizing antibodies or scavengers, may benefit vasculature preservation and overall tissue recovery.

Rubidium-82 positron emission tomography (82Rb PET) myocardial perfusion imaging is used in clinical practice to quantify regional perfusion defects. Additionally, 82Rb PET provides a measure of absolute myocardial flow reserve (MFR), describing the vasculature state of health. We assessed whether 82Rb PET-derived MFR is associated with all-cause mortality independently of the extent of perfusion defects.

We conducted a multicenter clinical registry-based study of patients undergoing 82Rb PET myocardial perfusion imaging on suspicion of chronic coronary syndromes. Patients were followed up in national registries for the primary outcome of all-cause mortality. Global MFR ≤2 was considered reduced.

Among 7169 patients studied, 38.1% were women, the median age was 69 (IQR, 61-76) years, and 39.0% had MFR ≤2. A total of 667 (9.3%) patients died during a median follow-up of 3.1 (IQR, 2.6-4.0) years, more in patients with MFR ≤2 versus MFR >2 (15.7% versus 5.2%; P<0.001). MFR ≤2 was associated with all-cause mortality across subgroups defined by the extent of perfusion defects (all P<0.05). In a Cox survival regression model adjusting for sex, age, comorbidities, kidney function, left ventricular ejection fraction, and perfusion defects, MFR ≤2 was a robust predictor of mortality with a hazard ratio of 1.62 (95% CI, 1.31-2.02; P<0.001). Among patients with no reversible perfusion defects (n=3101), MFR ≤2 remained strongly associated with mortality (hazard ratio, 1.86 [95% CI, 1.26-2.73]; P<0.01). The prognostic value of impaired MFR was similar for cardiac and noncardiac death.

MFR ≤2 predicts all-cause mortality independently of the extent of perfusion defects. Our results support the inclusion of MFR when assessing the prognosis of patients suspected of chronic coronary syndromes.

Microvascular angina (MVA) substantially threatens human health, and the Shenzhi Tongxin (SZTX) capsule demonstrates a remarkable cardioprotective effect, making it a potential treatment option for MVA. However, the precise mechanism of action for this medication remains unclear. This study utilized network pharmacology and molecular docking technology to investigate the active components and potential mechanisms underlying the efficacy of the SZTX capsule in alleviating MVA.

The main ingredients of the SZTX capsule, along with their targets proteins and potential disease targets associated with MVA, were extracted from public available databases. This study utilized the STRING database and Cytoscape 3.7.2 software to establish a protein-protein interaction network and determine key signaling pathway targets. Subsequently, the DAVID database was utilized to conduct Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes analyses on the intersection targets. To further investigate the molecular interactions, Autodock and PyMOL software were employed to perform molecular docking and visualize the resulting outcomes.

A total of 130 and 142 bioactive ingredients and intersection targets were identified respectively. Six core targets were obtained through protein-protein interaction network analysis. Gene Ontology enrichment analysis showed that 610 biological processes, 75 cellular components, and 92 molecular functions were involved. The results of Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that SZTX capsule molecular mechanism in the treatment of MVA may be related to several pathways, including mitogen-activated protein kinases, PI3K-Akt, HIF-1, and others. The results of molecular docking showed that the 7 key active ingredients of SZTX capsule had good binding ability to 6 core proteins.

SZTX capsule potentially exerts its effects by targeting multiple signaling pathways, including the mitogen-activated protein kinases signaling pathway, PI3K-Akt signaling pathway, and HIF-1 signaling pathway. This multi-target approach enables SZTX capsule to inhibit inflammation, alleviate oxidative stress, regulate angiogenesis, and enhance endothelial function.

Coronary microvascular dysfunction is an underdiagnosed pathologic process that is associated with adverse clinical outcomes. Biomarkers, molecules measurable in the blood, could inform the clinician by aiding in the diagnosis and management of coronary microvascular dysfunction. We present an updated review of circulating biomarkers in coronary microvascular dysfunction representing key pathologic processes, including inflammation, endothelial dysfunction, oxidative stress, coagulation, and other mechanisms.

Myocardial flow reserve (MFR), derived from quantitative measurements of myocardial blood flow during PET imaging, provides prognostic information on patients with coronary artery disease (CAD), but it is not known if this also applies to cancer patients with a competing risk for mortality. Methods: To determine the prognostic value of MFR in patients with cancer, we designed a retrospective cohort study comprising 221 patients with known or suspected CAD (median age, 71 y; range, 41-92 y) enrolled between June 2009 and January 2011. Most patients were referred for perioperative risk assessment. Patients underwent measurement of myocardial blood flow at rest and during pharmacologic stress, using quantitative 82Rb PET imaging. They were divided into early-stage versus advanced-stage cancer groups based on cancer histopathology and clinical state and were further stratified by myocardial perfusion summed stress score, summed difference score, and calculated MFR. Overall survival (OS) was assessed using the Kaplan-Meier estimator, and Cox proportional-hazards regression helped identify independent predictors for OS. Results: During a follow-up of 85.6 mo, 120 deaths occurred. MFR, summed difference score, and cancer stage were significantly associated with OS. In the age-adjusted Cox hazard multivariable analysis, MFR and cancer stage remained independent prognostic factors. MFR combined with cancer stage enhanced OS discrimination. The groups had significantly different outcomes (P < 0.001), with 5-y OS of 88% (MFR ≥ 1.97 and early-stage), 53% (MFR < 1.97 and early-stage), 33% (MFR ≥ 1.97 and advanced-stage), and 13% (MFR < 1.97 and advanced-stage). Conclusion: Independent of cancer stage, MFR derived from quantitative PET was prognostic of OS in our cohort of cancer patients with known or suspected CAD. Combining these 2 parameters enhanced discrimination of OS, suggesting that MFR improves risk stratification and may serve as a treatment target to increase survival in cancer patients.

İNTRODUCTION: Patients with normal coronary arteries in whom increased vasospasm cannot be detected with the stress test should be evaluated in terms of cardiac syndrome x (CSX). İnflammatory systems are effective in endothelial activation and dysfunction in CSX. The systemic immune inflammation index (SII) is thought to be an important factor in determining the course of diseases, especially in infectious diseases or other diseases, as an indicator of the inflammation process. The aim of this study is to determine the role of SII levels in the diagnosis of CSX disease.

The study group included 80 patients who applied to the cardiology department of Fırat University with typical anginal complaints between October 2021 and April 2022, and were diagnosed with ischemia after the myocardial perfusion scan, and then coronary angiography was performed and normal coronary arteries were observed.

When the study and control groups were examined according to age, gender and body mass index, hypertension, smoking, diabetes mellitus, dyslipidemia and family history, no statistical significant difference was observed between the groups. It was observed that there was a significant difference between the high sensitive C- reactive protin levels of the individuals in the study and control groups (p = 0.028). SII levels measured in samples taken from patients were significantly higher than control subjects (p = 0.003). SII cutoff at admission was 582 with 82% sensitivity and 84% specificity (area under the curve 0.972; 95% CI:0.95-0.98;p < 0.001).

It has been demonstrated that systemic SII parameters, which can be simply calculated with the data obtained from the complete blood count and do not require additional costs, can contribute to the prediction of CSX disease.

Coronary microvascular dysfunction (CMD) is a major cause of ischemia with no obstructed coronary arteries.

The authors sought to assess protein biomarker signature for CMD.

We quantified 184 unique cardiovascular proteins with proximity extension assay in 1,471 women with angina and no obstructive coronary artery disease characterized for CMD by coronary flow velocity reserve (CFVR) by transthoracic echo Doppler. We performed Pearson's correlations of CFVR and each of the 184 biomarkers, and principal component analyses and weighted correlation network analysis to identify clusters linked to CMD. For prediction of CMD (CFVR < 2.25), we applied logistic regression and machine learning algorithms (least absolute shrinkage and selection operator, random forest, extreme gradient boosting, and adaptive boosting) in discovery and validation cohorts.

Sixty-one biomarkers were correlated with CFVR with strongest correlations for renin (REN), growth differentiation factor 15, brain natriuretic protein (BNP), N-terminal-proBNP (NT-proBNP), and adrenomedullin (ADM) (all P < 1e-06). Two principal components with highest loading on BNP/NTproBNP and interleukin 6, respectively, were strongly associated with low CFVR. Weighted correlation network analysis identified 2 clusters associated with low CFVR reflecting involvement of hypertension/vascular function and immune modulation. The best prediction model for CFVR <2.25 using clinical data had area under the receiver operating characteristic curve (ROC-AUC) of 0.61 (95% CI: 0.56-0.66). ROC-AUC was 0.66 (95% CI: 0.62-0.71) with addition of biomarkers (P for model improvement = 0.01). Stringent two-layer cross-validated machine learning models had ROC-AUC ranging from 0.58 to 0.66; the most predictive biomarkers were REN, BNP, NT-proBNP, growth differentiation factor 15, and ADM.

CMD was associated with pathways particularly involving inflammation (interleukin 6), blood pressure (REN, ADM), and ventricular remodeling (BNP/NT-proBNP) independently of clinical risk factors. Model prediction improved with biomarkers, but prediction remained moderate.

Coronary microvascular dysfunction (CMD) refers to a group of disorders affecting the structure and function of coronary microcirculation and is associated with an increased risk of major adverse cardiovascular events. At present, great progress has been made in the diagnosis of CMD, but there is no specific treatment for it because of the complexity of CMD pathogenesis. Vascular dysfunction is one of the important causes of CMD, but previous reviews mostly considered microvascular dysfunction as a whole abnormality so the obtained conclusions are skewed. The coronary microvascular function is co-regulated by multiple mechanisms, and the mechanisms by which microvessels of different luminal diameters are regulated vary. The main purpose of this review is to revisit the mechanisms by which coronary microvessels at different diameters regulate coronary microcirculation through integrated sequential activation and briefly discuss the pathogenesis, diagnosis, and treatment progress of CMD from this perspective.

Background The pathobiology of myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) is often uncertain. Investigating biomarker concentrations and their changes may offer novel pathophysiological insights. Methods and Results In this post hoc study of the PLATO (Platelet Inhibition and Patient Outcomes) trial, concentrations of hs-cTnT (high-sensitivity cardiac troponin T), NT-proBNP (N-terminal pro-B-type natriuretic peptide), hs-CRP (high-sensitivity C-reactive protein), and GDF-15 (growth differentiation factor 15) were measured in patients with MINOCA at baseline (n=554) and at 1-month follow-up (n=107). For comparisons, biomarkers were also measured in patients with MI with obstructive (stenosis ≥50%) coronary artery disease (baseline: n=11 106; follow-up: n=2755]). Adjusted linear regression models were used to compare concentrations and their short- and long-term changes. The adjusted geometric mean ratios (GMRs) in patients with MINOCA (median age, 61 years; 50.4% women) indicated lower hs-cTnT (GMR, 0.77 [95% CI, 0.68-0.88]) but higher hs-CRP (GMR, 1.21 [95% CI, 1.08-1.37]) and GDF-15 concentrations (GMR, 1.06 [95% CI, 1.02-1.11]) at baseline compared with patients with MI with obstructive coronary artery disease, whereas NT-proBNP concentrations were similar. Temporal decreases in hs-cTnT, NT-proBNP, and hs-CRP concentrations until 1-month follow-up were more pronounced in patients with MINOCA. At follow-up, patients with MINOCA had lower concentrations of hs-cTnT (GMR, 0.71 [95% CI, 0.60-0.84]), NT-proBNP (GMR, 0.45 [95% CI, 0.36-0.56]), and hs-CRP (GMR, 0.68 [95% CI, 0.53-0.86]). One-month GDF-15 concentrations were similar between both groups with MI. Conclusions Biomarker concentrations suggest greater initial inflammatory activity, similar degree of myocardial dysfunction, and less pronounced myocardial injury during the acute phase of MINOCA compared with MI with obstructive coronary artery disease but also faster myocardial recovery. Registration URL: http://www.clinicaltrials.gov; Unique identifier: NCT00391872.