Ischemic heart disease has long been established as the leading cause of heart failure, typically as a result of hemodynamically significant and obstructive coronary anatomy. Since, the role of dysfunctional coronary microvascular pathophysiologic mechanisms have also been associated with the development of congestive heart failure (CHF), most notably heart failure with preserved ejection fraction (HFpEF) although with limited clinical evidence. Conventional cardiometabolic and behavioral risk factors common to HFpEF such as diabetes mellitus (DM), obesity, hypertension, dyslipidemia, smoking, and chronic kidney disease foster a pro-inflammatory environment conducive to endothelial dysfunction and improper regulation of vasoactive substances. The impaired relaxation and increased vasoconstriction of damaged endothelium gives rise to impaired coronary blood flow and episodes of transient ischemia. Such coronary microvascular dysfunction (CMD) has its own implication on cardiovascular pathophysiologic mechanisms beyond symptomatic coronary and myocardial ischemia, and thus its own potential prevention goals and treatment targets for patients with HFpEF, where previous management had been limited. As such, we conducted a literature review to address the current landscape of data which links CMD to HFpEF. Furthermore, we considered the implications of biopsychosocial elements such as race, ethnicity, sex, gender, and the social determinants of health as they relate to the disparate health outcomes of those most at risk for CMD and HFpEF.

Electrocardiographic (ECG) abnormalities serve as important predictors of future cardiovascular events. However, the specific cardiac abnormalities that bridge the gap between ECG abnormalities and subsequent events remain poorly understood. This study aimed to evaluate the relationship between ECG abnormalities and the prevalence of coronary artery disease (CAD) in propensity score-matched patients with suspected CAD who underwent comprehensive cardiac computed tomography (CT).

A total of 357 patients suspected of CAD underwent ECG and cardiac CT assessments, including calcium scoring, stress dynamic CT perfusion (CTP), coronary CT angiography (CCTA), and CT late enhancement. Propensity score matching based on demographic parameters and CAD risk factors was performed, resulting in 286 matched patients (143 without ECG abnormalities and 143 with ECG abnormalities).

In both unadjusted and propensity score-matched analyses, ECG abnormalities were significantly associated with microvascular dysfunction and myocardial scarring (p < 0.05 for both analyses). However, no significant associations were observed between ECG abnormalities and coronary calcification severity or obstructive CAD (≥ 50% luminal narrowing) in the propensity score-matched patients. Among matched patients without obstructive CAD on CCTA, those with ECG abnormalities exhibited a higher prevalence (30%) of microvascular dysfunction, particularly in the diffuse-transmural pattern, compared to that (14%) of patients without ECG abnormalities (p < 0.01).

ECG abnormalities may not be reliable indicators of the presence of obstructive CAD. However, given their association with microvascular dysfunction, CAD evaluation with comprehensive cardiac CT, including dynamic CTP, is recommended for patients exhibiting ECG abnormalities, particularly to evaluate myocardial perfusion abnormalities.

Question We investigated whether ECG abnormalities in patients suspected of having CAD are linked to epicardial stenosis, microvascular dysfunction, or myocardial scarring. Findings After adjusting for traditional risk factors using propensity-score matching, ECG abnormalities were associated with microvascular dysfunction and myocardial scarring, but not with epicardial coronary stenosis. Clinical relevance These results suggest that ECG abnormalities may offer important insights into tissue-level changes and microvascular pathology, rather than simply reflecting epicardial stenosis, thereby underlining the need for comprehensive cardiac assessment in patients with ECG changes.

Thoracic pain is the most prevalent symptom in patients with cardiovascular diseases. Diagnosis and patient management are guided by the pain attributes, analytical parameters, and several different imaging modalities. Invasive imaging tests and cardiac magnetic resonance are highly relevant in this context, as set out in the 2023 European guidelines for the management of acute coronary syndromes, the 2023 American guidelines for the management of patients with chronic coronary disease, and the 2021 American guidelines for the evaluation and diagnosis of chest pain. This article focuses on the role that these guidelines attribute to non-invasive cardiac imaging (computed tomography and cardiac magnetic resonance) in the management of both acute and chronic coronary syndrome.

Microangiopathy is a key complication of diabetes, adversely effecting several organs including the heart, kidneys, eyes, and nerves. This review focuses on myocardial microvascular dysfunction, a condition characterized by altered vasomotion and long-term structural changes to coronary arterioles, resulting in impaired regulation of blood flow in response to varying oxygen demands of cardiomyocytes. Presence of myocardial microvascular dysfunction is associated with increased risk of cardiovascular disease, even in the absence of obstructive coronary artery disease. Several noninvasive imaging techniques to assess coronary physiology have significantly enhanced our understanding of the myocardial microcirculation. These methods allow for detailed visualization and quantification of blood flow, endothelial function, and inflammation in the microvasculature, providing critical insights into the early stages of microvascular disease in diabetes. A significant area of development is the use of advanced hybrid imaging techniques such as positron emission tomography/computed tomography (PET/CT) and positron emission tomography/magnetic resonance imaging (PET/MRI). The integration of advanced imaging technologies with artificial intelligence is also a key future direction. Overall, these advancements aim to improve the early detection and management of microvascular complications in diabetes, ultimately enhancing outcomes and quality of life. The aim of this review is to provide an overview of both established and emerging noninvasive imaging techniques for assessing myocardial microvascular dysfunction.

Coronary microvascular disease (CMVD), marked by dysfunction of the small coronary vessels, poses significant diagnostic challenges due to the complexity and high cost of current procedures like the index of microcirculatory resistance (IMR). This study aimed to identify metabolomic biomarkers from coronary artery samples to facilitate CMVD diagnosis using advanced bioinformatics techniques-specifically, random forest algorithms and generalized linear models (GLMs)-to develop more cost-effective blood-based diagnostics.

In this prospective study, 68 patients scheduled for coronary angiography and IMR assessment were enrolled. Plasma samples obtained from their coronary arteries were analyzed using untargeted metabolomics with liquid chromatography-mass spectrometry. Advanced bioinformatics methods were applied: random forest algorithms were utilized for feature selection to identify significant metabolites, and GLMs were constructed for predictive modeling. The diagnostic performance of the models was evaluated through receiver operating characteristic (ROC) curve analysis.

The random forest analysis identified the top 10 metabolites that significantly contributed to the classification of CMVD. The GLM built using these metabolites demonstrated excellent diagnostic accuracy, achieving area under the ROC curve (AUC) values of 0.984 in the initial (discovery) cohort and 0.938 in the subsequent (validation) cohort. The use of mathematical modeling enhanced the robustness and interpretability of the biomarker selection process.

Advanced bioinformatics techniques, including random forest algorithms and GLMs, effectively identified key metabolites associated with CMVD. While the collection of coronary artery blood samples is invasive due to the necessity of coronary angiography, this method offers a more practical and cost-effective alternative to IMR measurement, potentially improving the diagnostic approach for CMVD.

Coronary Artery Disease (CAD) is the most common cardiovascular disease worldwide, threatening human health, quality of life and longevity. Aging is a dominant risk factor for CAD. This study aims to investigate the potential mechanisms of aging-related genes and CAD, and to make molecular drug predictions that will contribute to the diagnosis and treatment.

We downloaded the gene expression profile of circulating leukocytes in CAD patients (GSE12288) from Gene Expression Omnibus database, obtained differentially expressed aging genes through "limma" package and GenaCards database, and tested their biological functions. Further screening of aging related characteristic genes (ARCGs) using least absolute shrinkage and selection operator and random forest, generating nomogram charts and ROC curves for evaluating diagnostic efficacy. Immune cells were estimated by ssGSEA, and then combine ARCGs with immune cells and clinical indicators based on Pearson correlation analysis. Unsupervised cluster analysis was used to construct molecular clusters based on ARCGs and to assess functional characteristics between clusters. The DSigDB database was employed to explore the potential targeted drugs of ARCGs, and the molecular docking was carried out through Autodock Vina. Finally, single-cell data (GSE159677) of arterial intima was used to further explore the expression of aging signature genes in different cell subpopulations.

We identified 8 ARCGs associated with CAD, in which HIF1A and FGFR3 were up while NOX4, TCF7L2, HK3, CDK18, TFAP4, and ITPK1 were down in CAD patients. Based on this, CAD patients can be divided into two molecular clusters, among which cluster A mainly involves functional pathways such as ECM receptor interaction and focal adhesion; cluster B mainly involves functional pathways such as amimo sugar and nucleotide sugar metabolism and pyrimidine metabolism. In addition, the molecular docking results showed that retinoic acid and resveratrol had good binding affinity with targets genes. Further single-cell analysis results showed that NOX4, TCF7L2, ITPK1, and HIF1A were specifically expressed in different types of cells in atherosclerotic tissues.

Our study identified several ARCGs that may be involved in the pathogenesis and progression of CAD. Further, retinoic acid and resveratrol were potential candidate molecule drugs for inhibiting these targets.

The triglyceride-glucose (TyG) index is a reliable marker of insulin resistance, and the atherogenic index of plasma (AIP) reflects atherosclerosis. However, the relationship between these biomarkers-particularly AIP-and coronary microvascular dysfunction (CMD) in hypertensive patients has not been systematically studied. This study investigates the association between TyG, AIP, and CMD in hypertensive individuals.

We included 155 hypertensive patients with coronary anatomy confirmed by coronary angiography (CAG) or computed tomography angiography (CTA) within six months of SPECT imaging. CMD was diagnosed with a summed stress score (SSS) ≥4 and a summed difference score (SDS) ≥2. Patients were stratified into tertiles by TyG index and AIP. Logistic regression, adjusted for traditional cardiovascular risk factors, was used to explore the relationship with CMD. The predictive value of TyG and AIP was assessed using receiver operating characteristic (ROC) curves, and decision curve analysis (DCA) evaluated their clinical benefit.

Logistic regression revealed that both TyG and AIP were independently associated with coronary artery disease (CAD) (P<0.05 for both). The area under the ROC curve (AUC) for TyG, AIP, and their combined predictive capacity for CMD was 0.744, 0.707, and 0.748, respectively (P<0.001 for all). The optimal cutoff values for TyG and AIP were 7.012 and 0.5175, respectively. Combining both biomarkers enhanced clinical decision-making and patient benefit.

Higher levels of TyG and AIP are significantly associated with an increased risk of CMD in hypertensive patients. Both biomarkers exhibit strong predictive value, with AIP showing greater specificity and TyG higher sensitivity. Their combined use can improve clinical decision-making and patient outcomes.

Objective: Therefore, the objective of this study was to design hypertension ontology with the aim of improving integration of data, representation of knowledge and better decision making in hypertension management. Methods: First, we performed a systematic literature review (SLR) across ten different databases aiming at capturing the essential concepts. Using this extracted data a Hypertension Ontology (HPO) was created in Protégé which was loaded and published on BioPortal for availability. Results: HPO contains 114 classes and five properties that structure the risk factors, symptoms, diagnosis, and treatment. It improves knowledge discovery, data sharing capabilities, and surpasses existing hypertension-related ontologies in functionality. Conclusion: HPO facilitates standardized hypertension management in a research context and clinical practices. Next Steps will be integration of Real-world data and Interoperability to HER.

Sex differences in ST-segment elevation myocardial infarction (STEMI) due to obstructive coronary artery disease (CAD) are well-established, but limited research exists on sex differences in STEMI patients with nonobstructive coronary arteries (MINOCA) and MINOCA mimickers.

We analyzed 8560 consecutive STEMI patients, enrolled in the Midwest STEMI Consortium from 2003 to 2020. Patients with non-obstructive CAD were classified into MINOCA (defined as < 50% coronary artery stenosis and confirmed or suspected coronary artery plaque disruption, epicardial coronary spasm, or coronary embolism/thrombosis) and MINOCA mimickers (takotsubo cardiomyopathy, myocarditis, or non-ischemic cardiomyopathy). The primary outcome was 5-year all-cause mortality.

Of the 8560 patients, 409 (4.8%) had non-obstructive CAD, including 120 (1.4%) MINOCA and 289 (3.4%) MINOCA mimickers. Females were more likely to have MINOCA and MINOCA mimickers (49.2% and 56.4%, respectively). There were no significant sex differences in in-hospital or 5-year mortality in MINOCA, but females with MINOCA mimickers had higher unadjusted 5-year mortality (HR 2.90, 95% CI 1.53-5.53). After adjusting for age and comorbidities, the long-term mortality risk was similar between sexes (adjusted HR 1.16, 95% CI: 0.61-2.24). Females with obstructive CAD had higher 5-year mortality in unadjusted models (HR 1.66, 95% CI 1.48, 1.86), but the difference was not significant after adjustment (adjusted HR 1.1, 95% CI: 0.98-1.24).

Our findings highlight important sex-based differences in the prevalence, treatment, and long-term outcomes of STEMI patients with MINOCA, MINOCA mimickers, and obstructive CAD. Despite clinical disparities, mortality risks were similar across sexes after adjusting for comorbidities.

Cardiac PET imaging is an important noninvasive modality for the diagnosis and management of heart failure. Cardiac PET myocardial perfusion imaging can identify coronary artery disease with high accuracy and also detect myocardial viability, offering crucial information for the treatment of ischemic cardiomyopathy. Additionally, cardiac PET can help diagnose nonischemic cardiomyopathies including sarcoidosis, amyloidosis, and myocarditis. Improved PET scanner technology combined with emerging radiotracers will, in the future, offer disease-specific molecular imaging that will further assist in the diagnosis, prognosis, and treatment selection for a variety of cardiovascular pathologies.

Coronary microvascular dysfunction (CMD) is a prevalent and often underdiagnosed condition with significant implications for adverse cardiovascular outcomes. The pathophysiology of CMD includes structural and functional abnormalities in the coronary microvasculature and epicardial atherosclerosis contributes to downstream reduction in myocardial perfusion and symptoms. Diagnosis relies on advanced invasive or noninvasive imaging techniques, such as PET and cardiac magnetic resonance, capable of quantifying myocardial perfusion and myocardial blood flow reserve. Effective management includes optimizing cardiovascular risk factors and symptom control. Novel therapeutic strategies recently approved for management of diabetes, obesity, and heart failure with preserved ejection fraction offer potentially powerful options for management of CMD.

Hypertension is a major public health concern and a key risk factor for acute myocardial infarction (AMI), significantly contributing to cardiovascular mortality. Despite advancements in management and treatment, trends in associated mortality remain underexplored.

This study examines U.S. national trends in hypertension- and AMI-associated mortality from 2000 to 2023, focusing on demographics and regions.

Age-adjusted mortality rates (AAMRs) per 100,000 for adults aged ≥ 25 with hypertension and AMI were extracted from the CDC WONDER database. Annual percent changes (APCs) and average APCs (AAPCs) with 95% confidence intervals (CIs) were calculated, stratified by year, sex, race/ethnicity, age, urbanization, and Census region.

From 2000 to 2023, 933,024 hypertension- and AMI-related deaths were recorded. Overall, AAMR declined from 19.84 per 100,000 in 2000 to 16.26 in 2023 (AAPC: -0.93%, 95% CI: -1.18% to -0.76%). However, a sharp rise in mortality occurred between 2018 and 2021, coinciding with the COVID-19 pandemic. Stratified analyses revealed persistently higher mortality rates among menmen, non-Hispanic BlackBlack individuals, and residents of the Southern and rural U.S. regions. Younger adults showed an increasing AAMR trend, indicating a growing burden of hypertension and AMI-associated disease.

While long-term mortality trends show a decline, recent years have seen a rise, particularly among high-risk groups. Targeted public health interventions addressing hypertension management, cardiovascular risk reduction, and healthcare disparities are essential to mitigate the ongoing burden of hypertension and AMI mortality in the U.S.

Splenic switch-off (SSO) is defined as a decrease in splenic radiotracer uptake following pharmacological stress. This study aimed to assess the clinical utility of SSO on adenosine triphosphate (ATP) 13N-ammonia positron emission tomography (PET) in patients without coronary artery disease (CAD).

We analyzed 63 patients (mean age, 67 ± 11 years; 34 males) who underwent ATP 13N-ammonia PET without significant CAD on invasive coronary angiography or cardiac computed tomography within 6 months. Visual assessment of the SSO was conducted by two independent observers, with disagreements resolved by a third observer. We divided the patients into two groups according to the presence (positive) or absence (negative) of SSO and compared global myocardial flow reserve (MFR) and myocardial blood flow (MBF) between the two groups. In addition, the relationship between the reduced MFR and SSO was investigated.

Negative SSO was observed in 15 of 63 patients. Global MFR and global stress MBF were significantly higher in the positive SSO group than in the negative SSO group (2.4 ± 0.6 vs. 1.6 ± 0.6, P < 0.001, and 2.3 ± 0.5 vs. 1.5 ± 0.5 ml min-1 g-1, P < 0.001, respectively). Global rest MBF showed no significant difference between the two groups (1.0 ± 0.2 vs. 1.0 ± 0.3 ml min-1 g-1, P = 0.80). In the negative SSO group, 12 of the 15 (80%) patients had a reduced MFR (<2.0). In contrast, in the positive SSO group, 15 of the 48 (31.3%) patients had a reduced MFR, which was suggestive of coronary microvascular dysfunction (CMD).

The presence of a splenic response based on the visual assessment of SSO may be used to identify an adequate pharmacological response. This can affect the diagnosis of CMD in patients with reduced MFR without CAD. This study showed the clinical utility of splenic switch-off in adenosine triphosphate 13N-ammonia positron emission tomography in patients without coronary artery disease.

Ischemic heart disease (IHD) is a leading cause of morbidity and mortality worldwide, presenting with acute and chronic coronary syndromes. Although coronary atherosclerosis is a major cause of IHD, many patients with angina or myocardial ischemia do not have obstructive coronary heart disease and impairment of the coronary microcirculation has been increasingly implicated as a relevant cause of IHD. Therefore, coronary microvascular dysfunction (CMD) refers to a term covering a wide spectrum of structural and functional alterations which affect the coronary microcirculation leading to myocardial ischemia and angina. The advent of non-invasive and invasive functional tests has exponentially broadened the ability to recognize CMD and delineate related clinical and biochemical features. Despite major advances in diagnosing and stratifying this condition, therapeutic strategies remain limited and poorly defined. In this review, we will provide an overview of the pathophysiology and the diagnostic evaluation of CMD across the spectrum of cardiovascular diseases. Furthermore, we will discuss the novel therapeutic strategies available for these patients in the perspective of a personalized medicine approach.

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.

Skeletal muscle (SM) fat infiltration, or intermuscular adipose tissue (IMAT), reflects muscle quality and is associated with inflammation, a key determinant in cardiometabolic disease. Coronary flow reserve (CFR), a marker of coronary microvascular dysfunction (CMD), is independently associated with body mass index (BMI), inflammation and risk of heart failure, myocardial infarction, and death. The relationship between SM quality, CMD, and cardiovascular outcomes is not known.

Consecutive patients (n = 669) undergoing evaluation for coronary artery disease with cardiac stress positron emission tomography demonstrating normal perfusion and preserved left ventricular ejection fraction were followed over a median of 6 years for major adverse cardiovascular events (MACEs), including death and hospitalization for myocardial infarction or heart failure. Coronary flow reserve was calculated as stress/rest myocardial blood flow. Subcutaneous adipose tissue (SAT), SM, and IMAT areas (cm2) were obtained from simultaneous positron emission tomography attenuation correction computed tomography using semi-automated segmentation at the 12th thoracic vertebra level.

Median age was 63 years, 70% were female, and 46% were nonwhite. Nearly half of patients were obese (46%, BMI 30-61 kg/m2), and BMI correlated highly with SAT and IMAT (r = .84 and r = .71, respectively, P < .001) and moderately with SM (r = .52, P < .001). Decreased SM and increased IMAT, but not BMI or SAT, remained independently associated with decreased CFR (adjusted P = .03 and P = .04, respectively). In adjusted analyses, both lower CFR and higher IMAT were associated with increased MACE [hazard ratio 1.78 (95% confidence interval 1.23-2.58) per -1 U CFR and 1.53 (1.30-1.80) per +10 cm2 IMAT, adjusted P = .002 and P < .0001, respectively], while higher SM and SAT were protective [hazard ratio .89 (.81-.97) per +10 cm2 SM and .94 (.91-.98) per +10 cm2 SAT, adjusted P = .01 and .003, respectively]. Every 1% increase in fatty muscle fraction [IMAT/(SM + IMAT)] conferred an independent 2% increased odds of CMD [CFR <2, odds ratio 1.02 (1.01-1.04), adjusted P = .04] and a 7% increased risk of MACE [hazard ratio 1.07 (1.04-1.09), adjusted P < .001]. There was a significant interaction between CFR and IMAT, not BMI, such that patients with both CMD and fatty muscle demonstrated highest MACE risk (adjusted P = .02).

Increased intermuscular fat is associated with CMD and adverse cardiovascular outcomes independently of BMI and conventional risk factors. The presence of CMD and SM fat infiltration identified a novel at-risk cardiometabolic phenotype.

Background: The soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is linked to the progression of cardiovascular conditions, but its role in coronary microcirculation dysfunction (CMD) is not yet clear. Methods: A cross-sectional observational study from July 2023 to May 2024 was conducted in the China-Japan Friendship Hospital, after registration in the ClinicalTrials database (Registry Name: Coronary Microvascular Dysfunction in Angina Patients With Non-obstructive Coronary Artery Disease (ANOCA-CMD); Registry Number: NCT06503640; Registry Date: 23 September 2022). This cross-sectional study involved 76 subjects, including 55 patients with CMD and 21 without CMD, admitted to the China-Japan Friendship Hospital. CMD was defined by a coronary flow reserve (CFR) < 2.5 or index of microvascular resistance (IMR) ≥ 25. sTREM2 levels were measured using an enzyme-linked immunosorbent assay. Linear correlation analysis assessed the relationship between sTREM2 levels and CFR, IMR, microvascular resistance reserve (MRR), and the resistive reserve ratio (RRR). Univariate and multivariate regression analyses further examined the association between sTREM2 and CMD. Additionally, receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic accuracy of plasma sTREM2 for identifying CMD patients. Results: Elevated sTREM2 levels were found in the CMD group. Correlation analysis showed a significant positive relationship with IMR and an inverse correlation with CFR, MRR, and RRR. After adjusting for confounders, sTREM2 was found to be an independent risk factor for CMD [OR = 1.003, 95% CI 1.001-1.007, p = 0.008]. ROC analysis revealed a sensitivity of 59.46%, specificity of 90.48%, and an AUC of 0.7677 (95% CI: 0.6481-0.8872, p = 0.008) for CMD diagnosis at a threshold of 595.5 pg/mL, indicating good diagnostic performance. Conclusions: Elevated sTREM2 levels in CMD patients indicate its potential as a biomarker.

Depression and coronary heart disease (CHD) are two interconnected diseases that profoundly impact global health. Depression is both a complex psychiatric disorder and an established risk factor for CHD. Sirtuin 1 (SIRT1) is an enzyme that requires the cofactor nicotinamide adenine dinucleotide (NAD+) to perform its deacetylation function, and its involvement is crucial in reducing cardiovascular risks that are associated with depression. SIRT1 exerts its cardioprotective effects via modulating oxidative stress, inflammation and metabolic processes, all of which are central to the pathogenesis of CHD in individuals with depression. Through influencing these pathways, SIRT1 helps to reduce endothelial dysfunction, prevent the formation of atherosclerotic plaques and stabilize existing plaques, thereby decreasing the overall risk of CHD. The present review underscores the important role of SIRT1 in serving as a therapeutic intervention molecule for tackling cardiovascular complications stemming from depression. Furthermore, it highlights the need for further studies to clarify how SIRT1 influences both depression and CHD at the molecular level. The ultimate goal of this research will be to translate these findings into practical clinical intervention strategies.

Data have been inconsistent regarding the association between TIMI frame count (TFC) and coronary function, with data suggesting that the TFC measured after pharmacological stress could correlate better with coronary physiology.

The purpose of this study was to evaluate the correlation of TFC after pharmacological stress with coronary function among women with suspected ischemia and no obstructed coronary arteries (INOCA).

Women with suspected INOCA enrolled in the WISE-CVD (Women's Ischemic Syndrome Evaluation-Coronary Vascular Dysfunction) study (NCT00832702) underwent coronary angiography with coronary function testing, to measure coronary flow reserve to adenosine, change in coronary blood flow and diameter in response to acetylcholine, and change in coronary diameter in response to nitroglycerine (ΔNTG). In a randomly selected subgroup, TFC was quantified at baseline and after pharmacological stress. The association of TFC (postpharmacological stress, rest-to-stress ratio, and percentage change from rest to stress) with measurements of coronary function was assessed with linear regression.

TFC was quantified among 75 women, with a mean age of 54 ± 12 years. Among them, 29 (42%) had hypertension, 7 (10%) had diabetes, 34 (48%) had a previous smoking history, and 33 (49%) women had coronary atherosclerosis. Minor positive correlations were found linking higher TFC poststress with higher coronary flow reserve and higher ΔNTG (P < 0.05). Minor inverse correlations were found when using the TFC rest-to-stress ratio postacetylcholine and ΔNTG (P < 0.05).

Among women with suspected INOCA, measuring the TFC poststress did not help in the identification of abnormal coronary physiology pathways. Other strategies should be developed to improve accessibility to coronary function testing in this population.

Microvascular ischemia, especially in the heart and kidneys, is associated with inflammation and metabolic perturbation, resulting in cellular dysfunction and end-organ failure. Heightened production of adenosine from extracellular nucleotides released in response to inflammation results in protective effects, inclusive of adaptations to hypoxia, endothelial cell nitric oxide release with the regulation of vascular tone, and inhibition of platelet aggregation. Purinergic signaling is modulated by ectonucleoside triphosphate diphosphohydrolase-1 (NTPDase1)/CD39, which is the dominant factor dictating vascular metabolism of extracellular ATP to adenosine throughout the cardiovascular tissues. Excess levels of extracellular purine metabolites, however, have been associated with metabolic and cardiovascular diseases. Physiological estrogen signaling is anti-inflammatory with vascular protective effects, but pharmacological replacement use in transgender and postmenopausal individuals is associated with thrombosis and other side effects. Crucially, the loss of this important sex hormone following menopause or with gender reassignment is associated with worsened pro-inflammatory states linked to increased oxidative stress, myocardial fibrosis, and, ultimately, diastolic dysfunction, also known as Yentl syndrome. While there is a growing body of knowledge on distinctive purinergic or estrogen signaling and endothelial health, much less is known about the relationships between the two signaling pathways. Continued studies of the interactions between these pathways will allow further insight into future therapeutic targets to improve the cardiovascular health of aging women without imparting deleterious side effects.

Heart failure (HF) is a prominent fatal cardiovascular disorder afflicting 3.4% of the adult population despite the advancement of treatment options. Therefore, a better understanding of the pathogenesis of HF is essential for exploring novel therapeutic strategies. Hypertrophy and fibrosis are significant characteristics of pathological cardiac remodeling, contributing to HF. The mechanisms involved in the development of cardiac remodeling and consequent HF are multifactorial, and in this review, the key underlying mechanisms are discussed. These have been divided into the following categories thusly: (i) mitochondrial dysfunction, including defective dynamics, energy production, and oxidative stress; (ii) cardiac lipotoxicity; (iii) maladaptive endoplasmic reticulum (ER) stress; (iv) impaired autophagy; (v) cardiac inflammatory responses; (vi) programmed cell death, including apoptosis, pyroptosis, and ferroptosis; (vii) endothelial dysfunction; and (viii) defective cardiac contractility. Preclinical data suggest that there is merit in targeting the identified pathways; however, their clinical implications and outcomes regarding treating HF need further investigation in the future. Herein, we introduce the molecular mechanisms pivotal in the onset and progression of HF, as well as compounds targeting the related mechanisms and their therapeutic potential in preventing or rescuing HF. This, therefore, offers an avenue for the design and discovery of novel therapies for the treatment of HF.

Ischemia with no obstructive coronary arteries (INOCA) is an increasingly recognized condition in patients presenting with angina and positive stress tests but without significant coronary artery stenosis. This review addresses the pathophysiology, diagnostic approaches, and management strategies associated with INOCA, emphasizing epicardial coronary spasms and coronary microvascular dysfunction (CMD) as underlying mechanisms and myocardial bridging (MB) as a risk factor. Diagnostic modalities include both non-invasive techniques and invasive procedures, such as acetylcholine provocation testing, to differentiate vasospasm from microvascular causes. The paper discusses a potential interference between vasodilators used in trans-radial access and coronary spasm testing. Long-term management approaches for INOCA patients, including pharmacologic therapies and lifestyle interventions, are reviewed.

Coronary artery disease is one of the leading public health problems in the world in terms of mortality and economic burden from the disease. Traditionally, the focus of research and clinical pathways leading to the diagnosis and treatment of coronary artery disease was on the more common variant of the disease resulting from atherosclerosis in the epicardial coronary arteries. However, coronary microvasculature, representing the vast majority of the total heart circulation, has the greatest influence on overall coronary resistance and, therefore, blood flow. Coronary microvascular dysfunction (CMD), characterized by structural or functional abnormalities in the microvasculature, significantly impacts myocardial perfusion. Endothelial dysfunction results in inadequate coronary dilation during exercise or spontaneous spasm in the microvasculature or epicardial arteries. A significant proportion of people presenting for coronary angiography in the context of angina have unobstructed epicardial coronary arteries yet are falsely reassured about the benign nature of their condition. Meanwhile, increasing evidence indicates that patients diagnosed with CMD as well as vasospastic angina (VSA) face an increased risk of Major Adverse Cardiovascular Events (MACEs), including death. The aim of this review is to outline the current practice with regard to invasive and non-invasive methods of CMD and VSA diagnosis and assess the evidence supporting the existing treatment strategies. These include endotype-specific pharmacological therapies, a holistic approach to lifestyle modifications and risk factor management and novel non-pharmacological therapies. Furthermore, the review highlights critical gaps in research and suggests potential areas for future investigation, to improve understanding and management of these conditions.

The growing prevalence in the diagnosis of INOCA (Ischemia with Non-Obstructive Coronary Arteries), ANOCA (Angina with Non-Obstructive Coronary Arteries), and MINOCA (Myocardial Infarction with Non-Obstructive Coronary Arteries) highlights the need to reassess their clinical relevance. Historically regarded as benign syndromes, emerging evidence suggests that these conditions may cause serious cardiovascular events and considerable long-term disability. Additionally, emerging studies suggest that non-obstructive coronary artery disease (CAD) may have a higher prevalence compared to traditional obstructive forms of CAD. This leads to the need to better clarify the underlying pathogenic mechanisms as well as the risk factors associated with these syndromes. This is precisely the aim of this review, which focuses on the complex and heterogeneous mechanisms underlying these syndromes as well as the associated risk factors. This review also sums up the diagnostic steps necessary to achieve an accurate diagnosis, along with the interventional and pharmacological approaches to be implemented in light of the latest evidence.

Patients with abnormal (positive) exercise electrocardiography, but normal stress echocardiography (+ECG/-Echo), have an increased risk of adverse cardiovascular events compared with patients with a normal (negative) ECG and a normal stress Echo (-ECG/-Echo). However, it is unclear if +ECG/-Echo discordance is associated with a greater burden of subclinical coronary atherosclerosis.

Project Baseline Health Study participants who underwent a stress Echo and coronary artery calcium (CAC) scan were stratified by stress Echo result: -ECG/-Echo or +ECG/-Echo. Multivariable regression investigated the association between stress Echo results and CAC burden. Event-free survival from a composite of adverse cardiovascular events was compared between groups.

Among 1630 asymptomatic participants in this observational cohort study, 1503 (92.2%) had a -ECG/-Echo, 105 (6.4%) had a +ECG/-Echo, and 22 (1.3%) had a +Echo. The +ECG/-Echo group had a significantly greater burden of coronary atherosclerosis than the -ECG/-Echo group (mean CAC score, 198±470 versus 53±186; P<0.001; CAClog, 2.2±2.7 versus 1.2±2.0; P<0.001). The -ECG/-Echo group was more likely to have CAC=0 compared with the +ECG/-Echo group (65.9% versus 53.3%; P=0.01), whereas the +ECG/-Echo group more commonly had CAC ≥100 (28.6% versus 11.4%; P<0.001). After adjustment, CAClog scores were 52% higher in the +ECG/-Echo group than in the -ECG/-Echo group (P=0.002). Compared with the -ECG/-Echo group, the +ECG/-Echo group was 4.5× more likely to have a CAC score ≥400 (adjusted odds ratio, 4.54 [95% CI, 1.95-10.05]; P<0.001). After a median follow-up of 4.3 years, a trend toward increased adverse cardiovascular events was observed among participants with +ECG/-Echo.

Individuals with a +ECG/-Echo have a higher burden of subclinical coronary atherosclerosis than those with a -ECG/-Echo, which may explain, at least in part, the increased risk for adverse cardiac events in this population. Further study is needed to determine the optimal strategy for mitigating cardiovascular risk in these patients.

URL: https://www.clinicaltrials.gov; Unique identifier: NCT03154346.

More than 60% of patients undergoing coronary angiography present no coronary artery disease (CAD). Angina and myocardial ischemia are classically determined by epicardial vascular obstruction, but coronary microvascular dysfunction (CMD) may also represent a possible cause for these phenomena. Two endotypes of CMD have been recognized, with two different pathophysiological mechanisms: structural CMD, characterized by low coronary flow reserve (CFR) and high microvascular resistance (MVR) values; and functional CMD, characterized by low CFR and normal MVR values. According to the present data, almost half of patients with non-obstructive CAD have shown signs of CMD. For this reason, further investigations for microvascular function assessment should be considered when evaluating no-CAD patients complaining of angina or presenting signs of myocardial ischemia. The thermodilution method is currently becoming a widespread invasive technique due to its feasibility and high reproducibility for coronary physiology evaluation. Furthermore, a recently introduced technique - called continuous thermodilution - allows for direct measurement of absolute coronary flow and resistances. The role of this brand-new technique in the clinical scenario is however still to be fully investigated and its use is at present limited to research purposes only. Among no-CAD patients, both structural and functional CMD are related to a worse prognosis in term of mortality and major adverse cardiovascular events (MACE). In this review, we will discuss the present evidence supporting the definition, prevalence and clinical implication of the different forms of CMD and the technical aspects of its invasive assessment.

Coronary microvascular dysfunction (CMD) is an important clinical disease spectrum which has gained widespread attention due to chronic anginal symptoms, and worse clinical outcomes, with or without obstructive coronary artery disease (CAD). Coronary microcirculatory dysfunction is due to a wide array of mechanisms such as inflammation, platelet aggregation, vessel wall collagen deposition, imbalance of nitric oxide, free radicals, and sympathetic/parasympathetic simulation. As noted in this supplement, CMD can occur as a primary disease or co-exist with multi-array of diverse cardiac conditions such as CAD (old infarct), hypertrophic cardiomyopathy, Takotsubo cardiomyopathy, hypertension, or infiltrative diseases. CMD, which is often under diagnosed, leads to increase in medical expenses, decrease in quality of life, exacerbation of underlying conditions such as heart failure and even increased mortality. CMD presents a challenge for patients as well as physicians to manage. Here, we review CMD and focus on its endotypes, techniques for microcirculatory assessment, associated tips and tricks and available treatment options.

Microvascular dysfunction (MVD) is increasingly recognized as a critical contributor to the pathogenesis of heart failure (HF), particularly in heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). Coronary microvascular dysfunction (CMD) significantly impacts HFpEF by reducing coronary flow reserve and myocardial perfusion reserve, leading to adverse outcomes such as myocardial ischemia, diastolic dysfunction, and increased risk of major cardiovascular events, including atrial fibrillation. In HFrEF, microvascular impairment is linked to heightened oxidative stress, reduced nitric oxide production, and activation of the renin-angiotensin-aldosterone system, further driving disease progression and contributing to poor prognosis. Advancements in diagnostic techniques, such as positron emission tomography, cardiac magnetic resonance imaging, and biomarker analysis, improve our ability to assess CMD in heart failure patients, enabling earlier diagnosis and risk stratification. Emerging therapies, including sodium-glucose cotransporter-2 inhibitors, angiotensin receptor-neprilysin inhibitors, and endothelial-targeted interventions, enhance microvascular function and improve patient outcomes. The role of personalized medicine is becoming increasingly important, as individualized therapeutic approaches tailored to patient-specific microvascular abnormalities are essential for optimizing treatment effectiveness. This review underscores the pivotal role of MVD in HF. It highlights the urgent need for innovative therapeutic strategies and diagnostic tools to address this complex condition and improve clinical outcomes for HF patients.

Cardiovascular diseases are disorders of the heart and vascular system that cause high mortality rates worldwide. Vascular endothelial cell (VEC) injury caused by oxidative stress (OS) is an important event in the development of various cardiovascular diseases, including ischemic heart disease. This study aimed to investigate the critical roles and molecular mechanisms of long non-coding RNA (lncRNA) SNHG16 in regulating vascular endothelial cell injury under oxidative stress. We demonstrated that SNHG16 was significantly downregulated and miRNA-23a-3p was notably induced in human vascular endothelial cells under OS. Overexpressing SNHG16 or silencing miR-23a-3p effectively mitigated the OS-induced VEC injury. Additionally, glutamine metabolism of VECs was suppressed under OS. SNHG16 protected the OS-suppressed glutamine metabolism, while miR-23a-3p functioned oppositely in VECs. Furthermore, SNHG16 downregulated miR-23a-3p by sponging miR-23a-3p, which direct targeted the glutamine metabolism enzyme, GLS. Finally, restoring miR-23a-3p in SNHG16-overexpressing VECs successfully reversed the protective effect of SNHG16 on vascular endothelial cell injury under OS. In summary, our results revealed the roles and molecular mechanisms of the SNHG16-mediated protection against VEC injury under OS by modulating the miR-23a-3p-GLS pathway.

Angina with non-obstructive coronary artery disease (ANOCA) is commonly observed in patients with stable angina undergoing coronary angiography. Current guidelines recommend non-invasive stress testing as the first step in diagnosing coronary microvascular disease (CMD). This study aims to evaluate the diagnostic value of non-invasive stress testing in patients invasively diagnosed with CMD.

We conducted a retrospective analysis of prospectively collected data. Eligible subjects were patients with angina who underwent NIST evaluation (echocardiography/ electrocardiography stress test or single-photon emission computerized tomography) prior to coronary angiography. All patients underwent invasive evaluation of microvascular function, which included the assessment of Coronary Flow Reserve, Index of Microcirculatory Resistance, and Resistive Reserve Ratio.

Overall, 140 patients (77 women, 67 ± 10 y/o) underwent NIST evaluation prior to coronary angiography, of whom 81 % were positive for ischemia. There was no difference in the prevalence of positive NIST between patients with abnormal compared with normal microvascular function tested invasively (81 % vs 82 %, p = 0.94). The prevalence of CMD was similar between patients with positive versus negative NIST (51 % vs 50 %, p = 0.94). Among 114 patients with positive NIST, 56 (49.2 %) had normal microvascular function, regardless of the type of stress test used (p = 0.94), the suspected territory of ischemia (p = 0.15), or the estimated severity of the ischemia (p = 0.63).

Non-invasive stress testing may have a limited predictive value in the diagnosis of CMD in ANOCA patients. Larger prospective studies are required for better understanding of the role these tests in the diagnosis and definition of CMD.

Coronary microvascular dysfunction (CMD) is an important cause of angina with nonobstructive coronary arteries (ANOCA). It is unclear whether CMD is associated with arrhythmia.

This study aimed to evaluate the prevalence of arrhythmias in patients with ANOCA and CMD compared to those in patients with ANOCA without CMD.

In this observational study of the Coronary Microvascular Disease Registry (NCT05960474), patients with ANOCA who underwent invasive coronary functional assessment for CMD were included. The diagnosis of arrhythmia was based on 12-lead electrocardiography (ECG), or clinical diagnosis accompanied by ECG evidence within 1 year before CMD evaluation.

The study included 262 patients; 66 (25.2%) were CMD-positive. Patients with CMD were older, and there was no difference in history of heart failure and baseline left ventricular ejection fraction compared to those without CMD. Premature atrial contractions (PACs) (25.8% vs. 5.6%; p < 0.001), supraventricular tachycardia (SVT) (24.2% vs. 6.6%; p < 0.001), premature ventricular complexes (PVCs) (43.9% vs. 10.7%; p < 0.001), nonsustained ventricular tachycardia (NSVT) (28.8% vs. 3.1%; p < 0.001), and accelerated idioventricular rhythm (9.1% vs. 2.6%; = 0.02) were more common in CMD-positive patients. In a multivariate analysis adjusting for baseline differences and other variables clinically associated with arrhythmia, CMD was associated with PACs (odds ratio [OR]: 4.7; 95% confidence interval [CI]: 1.8-11.9), SVT (OR: 3.5; 95% CI: 1.5-8.6), PVCs (OR: 5.9; 95% CI: 2.6-13.0), and NSVT (OR: 9.5; 95% CI: 3.2-27.7).

Patients with ANOCA and CMD have a higher likelihood of arrhythmias, especially ventricular arrhythmias.

What is the pathophysiology and clinical findings as well as management of patients presenting with INOCA/MINOCA (Ischemia/Myocardial Infarction with Non-Obstructive Coronary Arteries).

INOCA/MINOCA has a complex pathophysiology. In this review article, we aim to summarize the complex pathophysiology and clinical diagnosis, and review the current management options.

Background: A considerable number of patients with angina undergo invasive coronary angiography, which might reveal non-obstructive coronary arteries (ANOCA). In this setting, they might have coronary microvascular disease (CMD). Its prevalence significantly varies in the literature. This systematic review aims to document the prevalence of CMD over time according to the diagnostic modalities. Methods: A systematic literature review was conducted using PubMed, the Cochrane Library, and Embase, covering publications from inception to 1 May 2024. Among 1471 identified articles, 297 full-text articles were assessed for eligibility. All studies reporting the prevalence of CMD in ANOCA patients based on invasive coronary artery (ICA), positron emission tomography-computed tomography (PET-CT), transthoracic echocardiography (TTE), or cardiac magnetic resonance (CMR) were included. Results: The review included 53 studies (published between 1998 and 2024), encompassing a total of 16,602 patients. Of these studies, 23 used ICA, 15 used PET-CT, 8 used TTE, and 7 used CMR. A statistically significant increase in CMD prevalence over time was observed across all diagnostic modalities (p < 0.05), except for PET-CT, which showed a consistent and stable prevalence over time. Notably, the prevalence rates from all of the diagnostic methods converged towards the 50% prevalence detected by PET-CT. Conclusions: The prevalence of CMD in patients with ANOCA is subject to debate. However, the current data suggest that regardless of the diagnostic method used, the most recent studies tend to converge towards a prevalence value of 50%, which has been consistently reported by PET-CT from the beginning.

We aimed to investigate the correlation between CT-derived fractional flow reserve (CTFFR) and myocardial strain in patients with single coronary artery stenosis and to investigate the diagnostic value of CTFFR in identifying impaired myocardial strain.

We selected 89 patients, categorized into three groups based on the affected coronary artery: 36 with left anterior descending (LAD), 23 with left circumflex (LCX), and 30 with right coronary artery (RCA) stenosis, along with 25 healthy controls. We investigated correlations between CTFFR and both global and regional myocardial strain parameters. Additionally, we assessed the ability of the CTFFR to detect impaired myocardial strain in these patients.

In this study, no significant difference was found in overall myocardial strain between the patient and control groups. However, regional longitudinal strain (LS) and circumferential strain (CS) in the myocardial areas supplied by stenotic coronary arteries was significantly lower in each patient group compared to the others (P < 0.001). The CTFFR exhibited a strong negative correlation with both regional and global myocardial strain, with a stronger association for regional strain. Particularly in group LAD, CTFFR in optimal diastole phase (CTFFR-D) was negatively correlated with Endo-LS (r = -0.66, P < 0.001). Receiver operator characteristic curve (ROC) analysis indicated that CTFFR were effective in diagnosing impaired myocardial strain, particularly LS.

There is a strong correlation between CTFFR, which is a functional measure for assessing coronary artery stenosis, and myocardial strain. CTFFR can identify impaired myocardial strain and can be used as an indirect indicator of myocardial ischemia.

Myocardial ischemia-reperfusion (I/R) injury and coronary microcirculation dysfunction (CMD) are observed in patients with myocardial infarction after vascular recanalization. The antianginal drug trimetazidine has been demonstrated to exert a protective effect in myocardial ischemia-reperfusion injury.

This study aimed to investigate the role of trimetazidine in endothelial cell dysfunction caused by myocardial I/R injury and thus improve coronary microcirculation.

The myocardial I/R mouse model was established, and trimetazidine was administered for 7 days before myocardial I/R model establishment. Echocardiography, 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin-eosin (H&E) staining, and thioflavin S staining were applied to assess myocardial injury and microvascular function. Additionally, the oxygen-glucose deprivation/reperfusion (OGD/R) model was developed in endothelial cells to simulate myocardial I/R injury in vitro. Griess reaction method, immunofluorescence, and western blotting (WB) were employed to detect the expressions of nitric oxide (NO), platelet endothelial cell adhesion molecule-1 (CD31) and vascular endothelial (VE)-cadherin, zonula occludens protein 1 (ZO-1), occludin, vascular endothelial growth factor (VEGF) and adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling-related proteins in endothelial cells and mouse cardiomyocytes. AMPK pathway inhibitor compound C was used for further mechanism validation.

Our research demonstrated that trimetazidine can alleviate myocardial pathological injury and cardiac function injury during myocardial I/R. Trimetazidine was observed to improve microvascular reflux phenomenon and microvascular function and barrier injury in myocardial I/R and OGD/R models. Additionally, the expressions of AMPK signal-related proteins were found to be inhibited in myocardial I/R and OGD/R models, which were then activated in mice administered trimetazidine. However, the effects of trimetazidine on endothelial cell function and barrier damage were attenuated after co-treatment with compound C and trimetazidine.

Trimetazidine ameliorated myocardial I/R-induced CMD by activating AMPK signaling.

Systemic lupus erythematosus (SLE) patients are 90% women and over three times more likely to die of cardiovascular disease than women in the general population. Chest pain with no obstructive cardiac disease is associated with coronary microvascular disease (CMD), where narrowing of the small blood vessels can lead to ischemia, and frequently reported by SLE patients. Using whole blood RNA samples, we asked whether gene signatures discriminate SLE patients with coronary microvascular dysfunction (CMD) on cardiac MRI (n = 4) from those without (n = 7) and whether any signaling pathway is linked to the underlying pathobiology of SLE CMD. RNA-seq analysis revealed 143 differentially expressed (DE) genes between the SLE and healthy control (HC) groups, with virus defense and interferon (IFN) signaling being the key pathways identified as enriched in SLE as expected. We next conducted a comparative analysis of genes differentially expressed in SLE-CMD and SLE-non-CMD relative to HC samples. Our analysis highlighted differences in IFN signaling, RNA sensing and ADP-ribosylation pathways between SLE-CMD and SLE-non-CMD. This is the first study to investigate possible gene signatures associating with CMD in SLE, and our data strongly suggests that distinct molecular mechanisms underly vascular changes in CMD and non-CMD involvement in SLE.

Cardiac rehabilitation, a comprehensive exercise-based lifestyle and medical management, is effective in decreasing morbidity and improving life quality in patients with coronary heart disease. Endothelial function, an irreplaceable indicator in coronary heart disease progression, is measured by various methods in traditional cardiac rehabilitation pathways, including medicinal treatment, aerobic training, and smoking cessation. Nevertheless, studies on the effect of some emerging cardiac rehabilitation programs on endothelial function are limited. This article briefly reviewed the endothelium-beneficial effects of different cardiac rehabilitation pathways, including exercise training, lifestyle modification and psychological intervention in patients with coronary heart disease, and related experimental models, and summarized both uncovered and potential cellular and molecular mechanisms of the beneficial roles of various cardiac rehabilitation pathways on endothelial function. In exercise training and some lifestyle interventions, the enhanced bioavailability of nitric oxide, increased circulating endothelial progenitor cells (EPCs), and decreased oxidative stress are major contributors to preventing endothelial dysfunction in coronary heart disease. Moreover, the preservation of endothelial-dependent hyperpolarizing factors and inflammatory suppression play roles. On the one hand, to develop more endothelium-protective rehabilitation methods in coronary heart disease, adequately designed and sized randomized multicenter clinical trials should be advanced using standardized cardiac rehabilitation programs and existing assessment methods. On the other hand, additional studies using suitable experimental models are warranted to elucidate the relationship between some new interventions and endothelial protection in both macro- and microvasculature.

In patients diagnosed with ST-segment elevation myocardial infarction (STEMI), despite exhibiting normal patency in the culprit arteries following percutaneous coronary intervention (PCI), coronary microvessels do not recover adequately, leading to microvascular dysfunction (MVD). Limited data are available regarding microcirculation assessed through invasive measures during the midterm period. This study aimed to investigate the assessment of MVD in STEMI patients using the index of microvascular resistance (IMR) during the midterm period.We prospectively evaluated 41 patients with STEMI who underwent PCI. IMR was measured by placing a coronary pressure wire with intravenous adenosine at 1 week as the acute phase and at 6 months after primary PCI as the midterm period. An improvement in IMR was observed from baseline to follow-up, with values changing from 30.00 (15.00-45.50) to 19.00 (10.50-30.50) (P = 0.020). The degree of MVD significantly decreased during follow-up (from 61.0% to 34.1%, McNemar's test: P = 0.016). Compared to patients with normal microcirculation, those with MVD (IMR > 25) at midterm follow-up exhibited significantly elevated levels of brain natriuretic peptide (180.25 [68.25-370.65] pg/mL versus 75.90 [18.70-169.70] pg/mL, P = 0.043) and prolonged symptom-onset-to-balloon time (727.00 [213.50-1170.00] minutes versus 186.00 [125.00-316.00] minutes, P = 0.002).These findings indicate that the extent of MVD 6 months post-PCI has significantly diminished compared to discharge levels and is associated with symptom-onset-to-balloon time. Therefore, MVD in patients with STEMI can potentially improve in the midterm under specific circumstances.