Search Results (165)

Background: Systemic sclerosis (SSc) is characterized by endothelial dysfunction leading to progressive vascular injury and fibrosis. While microvascular involvement is well established as an early disease feature, macrovascular disease has been historically underrecognized and poorly investigated in very early disease stages. Integrated assessments across the SSc spectrum, including very early diagnosis of systemic sclerosis (VEDOSS), remain limited. Methods: In this cross-sectional observational study, patients with established SSc, VEDOSS, and primary Raynaud’s phenomenon (PRP) were prospectively enrolled between October 2023 and April 2025. Participants underwent comprehensive microvascular and macrovascular evaluation, including nailfold videocapillaroscopy, multisegmental arterial Doppler ultrasound (carotid, aortic, and lower limb districts), flow-mediated dilation, and measurement of endothelial biomarkers (vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and circulating endothelial cells (CECs)). Traditional cardiovascular risk was estimated using Systematic Coronary Risk Estimation 2 (SCORE2). Results: Sixty-two female subjects were included (34 SSc, 14 VEDOSS, and 14 PRP). Microvascular abnormalities followed the expected disease continuum, with capillaroscopic changes present in 57% of VEDOSS and 91% of SSc patients. Although SCORE2 estimates and carotid intima–media thickness were comparable across groups, macrovascular abnormalities were more frequent in SSc (52.9%) and VEDOSS (50%) compared with PRP (21.4%). VCAM-1, ICAM-1, and CEC levels were significantly increased in SSc compared with PRP, whereas no significant differences were observed between VEDOSS and PRP. Conclusions: These findings support a unified micro- and macro-vascular disease model in SSc and demonstrate that macrovascular involvement is detectable already in the VEDOSS phase. Conventional cardiovascular risk scores underestimate the true vascular burden, highlighting the need for disease-specific risk stratification tools integrating vascular imaging and endothelial biomarkers. Full article

A significant proportion of patients undergoing invasive coronary angiography for angina have no obstructive coronary artery disease (CAD). In such patients, coronary microvascular dysfunction (CMD) and vasospastic angina (VSA) represent key pathophysiological mechanisms. We report a case of a 58-year-old male with exertional chest pain and exercise ECG changes typical of left main or multivessel CAD. Coronary computed tomography angiography (CCTA) showed borderline stenosis of the distal left main coronary artery. Coronary angiography revealed no critical stenosis. A comprehensive functional assessment demonstrated reduced coronary flow reserve (CFR = 2.0) and an elevated index of microcirculatory resistance (IMR = 25), consistent with CMD. An intracoronary acetylcholine provocation test induced severe focal vasospasm of the mid-left anterior descending artery (LAD) with ST-segment elevation and anginal pain, promptly relieved by nitroglycerin, confirming VSA. This case highlights the diagnostic and clinical importance of invasive functional testing in patients with angina and non-obstructive coronary arteries (ANOCA/INOCA). The coexistence of CMD and VSA (two distinct but overlapping pathophysiological endotypes) is increasingly recognized as a marker of adverse prognosis. Functional coronary assessment should be considered in all patients with angina and non-obstructive coronary arteries, as identifying mixed endotypes enables precise, mechanism-guided therapy. Full article

Coronary artery spasm (CAS) is a common endotype in patients with angina with non-obstructive coronary arteries. Pathophysiologically, the presence of CAS among arteries is not normal, as evidenced by several interacting mechanisms involving CAS development, including the endothelium, vascular smooth muscle cells, adventitia, autonomic nervous system, local inflammation, and systemic inflammation. Clinically, CAS is a dynamic process with a threshold effect on presentation; it can present as silent ischemia, atypical chest pain, resting angina, chronic coronary syndrome, acute coronary syndrome, variant angina, and even sudden cardiac arrest. Incomplete intracoronary provocation testing to exclude CAS as the etiology of chronic or acute coronary syndrome leads to an incorrect diagnosis and, subsequently, inappropriate treatment. Identification of the correct endotypes of chronic and acute coronary syndromes is critical for the selection of appropriate therapy, which thus affects disease outcome. Therefore, it is essential to complete intracoronary provocation testing for both the right and left coronary arteries to reach a correct diagnosis regarding CAS, including epicardial vasospasm and microvascular spasm. If CAS is found not to be the cause of myocardial ischemia, then a microvascular functional assessment is the next step to identify the etiology of the ischemic event. A comprehensive assessment of CAS is essential before appropriate treatments can be started. Full article

Periprocedural myocardial infarction after percutaneous coronary intervention (PCI) remains a debated entity, especially in the era of high-sensitivity cardiac troponin assays, which frequently detect biomarker rises even when clinically meaningful ischemia is absent. This review critically examines the main contemporary frameworks used to define these events, including the Fourth Universal Definition of Myocardial Infarction (UDMI), the Academic Research Consortium (ARC)-2 consensus, and the Society for Cardiovascular Angiography and Interventions (SCAI) definition, comparing biomarker thresholds, requirements for objective evidence of ischemia, and procedural criteria. We discuss how differences among definitions shape reported event rates and contribute to heterogeneity in event adjudication across studies. Key pathophysiologic mechanisms of myocardial injury during PCI are summarized, including side-branch compromise, distal embolization, microvascular dysfunction, and mechanical complications. Particular attention is given to the limitations of current criteria, such as incomplete assay standardization, variability in sampling timing, inconsistent reliability of ancillary criteria, including electrocardiography and imaging, and an uneven relationship between biomarker elevation and subsequent outcomes. Finally, we outline priorities for future updates, including harmonization of biomarker thresholds, greater emphasis on relative biomarker dynamics, and structured adjudication that integrates biomarkers with objective ischemic evidence. These steps may improve diagnostic specificity, reduce misclassification, and strengthen the clinical and trial relevance of periprocedural ischemic endpoints. Full article

Background: Coronary slow flow (CSF) is a microvascular disorder characterized by delayed perfusion despite the absence of significant epicardial stenosis. Although its exact pathophysiology remains unclear, endothelial dysfunction, oxidative stress, and atherogenic dyslipidemia have been implicated. Traditional lipid parameters may not fully capture the atherogenic burden, whereas atherogenic indices such as the atherogenic index of plasma (AIP), atherogenic coefficient (AC), and Castelli risk indices (CRI-I and CRI-II) may provide better predictive value. This study aimed to investigate the association between atherogenic indices and CSF in a large real-world angiographic cohort. Methods: This retrospective study included 25,486 patients who underwent coronary angiography between September 2020 and June 2024. A total of 464 patients with CSF (diagnosed by TIMI frame count criteria) and 408 controls with normal coronary flow (NCF) were identified. Atherogenic indices, including AIP, AC, CRI-I, CRI-II, and non-HDL cholesterol (non-HDL-C), were calculated. Multivariate logistic regression analysis identified independent predictors of CSF, while receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic performance of each lipid-related parameter. Results: Patients with CSF had significantly higher AIP, AC, non-HDL-C, and CRI indices and lower HDL-C levels compared to controls (all, p < 0.05). Multivariate analysis identified AIP (OR: 1.73, 95% CI: 1.18–2.44, p = 0.004), age (OR: 1.02, 95% CI: 1.01–1.06, p = 0.014) and smoking (OR: 2.22, 95% CI: 1.36–2.84, p = 0.003) as independent predictors of CSF. ROC analysis showed modest but statistically significant discriminatory capacity for AIP (cut-off: 0.50; AUC: 0.629; 95% CI: 0.591–0.667; p < 0.001). AIP also demonstrated a weak yet significant correlation with mean TIMI frame count (rho = 0.245, p < 0.001), suggesting a potential link to microvascular dysfunction. Conclusions: Among the evaluated atherogenic indices, only AIP demonstrated an independent association with CSF. Despite modest discriminative performance that does not support standalone clinical prediction, AIP may reflect an underlying metabolic phenotype associated with CSF and serve as a complementary marker alongside traditional risk assessment. These findings should be interpreted as hypothesis-generating and warrant prospective validation. Full article

Insulin resistance (IR) promotes a prothrombotic milieu by enhancing platelet hyperactivity, oxidative stress, and endothelial dysfunction, driving both microvascular and macrovascular complications in type 2 diabetes. Our review synthesizes mechanistic evidence showing that insulin-resistant platelets exhibit increased basal activation, elevated sensitivity to agonists, and reduced responsiveness to inhibitory signals, with distinct pro-aggregatory subpopulations amplifying thrombotic risk. Molecular pathways underlying platelet hyperactivation include reactive oxygen species accumulation, advanced glycation end-product signaling, disrupted calcium homeostasis, and impaired nitric oxide/prostacyclin pathways. Clinically, these mechanisms contribute to heightened arterial thrombosis, coronary artery disease, stroke, and microvascular injury, including nephropathy and retinopathy. Nutritional interventions emerge as effective modulators of platelet function and vascular health. Diets such as the Mediterranean, DASH, low-glycemic-index, and plant-based regimens, alongside bioactive compounds—including omega-3 fatty acids, polyphenols, vitamins D, E, C, and minerals like magnesium and zinc—may reduce platelet aggregation, oxidative stress, and systemic inflammation while restoring endothelial function. Clinical and epidemiological evidence demonstrates improvements in flow-mediated dilation, arterial elasticity, and stabilization of atherosclerotic plaques following dietary interventions. Integrating whole-diet strategies with targeted nutrients provides synergistic benefits, suggesting that personalized nutritional approaches can mitigate IR-induced platelet hyperactivity and lower vascular risk. These findings highlight nutrition as a practical, evidence-based adjunct to pharmacotherapy for cardiovascular protection in insulin-resistant populations. Full article

Background/Objectives: Coronary artery disease (CAD) remains one of the leading cardiovascular diseases worldwide. While obstructive CAD is well characterized and managed, identification of patients with non-obstructive CAD (NOCAD) remains challenging. Unlike the coronary vasculature, the eye’s microcirculation can be easily and non-invasively assessed. Therefore, this systematic review summarized the ophthalmological diagnostic methods used to assess microvascular alterations associated with coronary microvascular dysfunction (CMD), angina with non-obstructive coronary arteries (ANOCA), or ischemia with non-obstructive coronary arteries (INOCA). Methods: According to PRISMA guidelines, PubMed/MEDLINE and Embase databases were screened by two independent reviewers from inception to 25 November 2025. Original articles that examined ophthalmological microvascular changes by any method in adults with CMD or its subtypes were included. The quality of the studies was assessed using the JBI Critical Appraisal Checklist. Results: Of 101 identified articles, nine studies met the inclusion criteria, comprising 1894 patients. Optical coherence tomography angiography was the most frequently used imaging modality, followed by optical coherence tomography, slit-lamp smartphone imaging, and fundus photography. Five investigations employed blinded image analysis, three did not, and one study used it partially. Four studies used semi-automated measurements, four employed fully automated methods, and one study applied manual and automated measurements for different parameters. Conclusions: Despite a limited number of studies, retinal and conjunctival microvascular alterations helped differentiate CAD subtypes and may reflect systemic microcirculatory impairment among patients with ANOCA/INOCA. Ophthalmological imaging techniques have the potential to serve as non-invasive tools for detecting microvascular alterations associated with CMD in ANOCA and INOCA patients. PROSPERO Registration Number: CRD420251239875 Full article

Background: The coronary slow flow phenomenon (CSFP) is an angiographic entity increasingly recognized in patients with angina and/or ischemia but non-obstructive coronary arteries (ANOCA/INOCA), associated with systemic inflammation, endothelial dysfunction, and microvascular abnormalities. The hemoglobin, albumin, lymphocyte, and platelet (HALP) score is a novel immunonutritional index that may reflect this multifactorial risk profile. Methods: This retrospective single-center case–control study included 122 patients with CSFP and 126 age- and sex-matched controls with normal coronary flow, all presenting with symptoms of chronic coronary syndrome. CSFP was diagnosed via corrected TIMI frame count. HALP and other inflammatory indices (NLR, PLR, SII, SIRI) were calculated from baseline laboratory values. Associations were evaluated using multivariable logistic regression, ROC analysis, and restricted cubic spline (RCS) modeling. Results: The HALP score was significantly lower in CSFP patients (mean 56.2 vs. 65.9, p < 0.001). In multivariable analysis, HALP was independently associated with CSFP (adjusted OR: 0.951; 95% CI: 0.930–0.972; p < 0.001), whereas NLR lost significance. PLR, SII, and SIRI remained independently associated. HALP showed the highest diagnostic performance (AUC: 0.698), significantly outperforming all other indices (DeLong p < 0.001). A HALP cutoff ≤ 56.4 provided 58.2% sensitivity and 77.0% specificity. RCS analysis demonstrated a significant non-linear inverse relationship (p for non-linearity = 0.034). Subgroup analyses confirmed consistent associations across age, sex, hypertension, and diabetes strata. Conclusions: The HALP score is independently associated with CSFP and outperforms traditional inflammatory indices. Its low cost and accessibility make it a promising tool for clinical risk stratification in ANOCA/INOCA patients, pending validation in multicenter prospective studies. Full article

Heart failure with preserved ejection fraction (HFpEF) accounts for more than half of the cases of HF worldwide. Among the different phenotypes, cardiometabolic HFpEF has the highest prevalence. Cumulative insults related to cardiometabolic comorbidities—obesity, hypertension and type 2 diabetes—create a milieu of metabolic derangements, low-grade systemic inflammation (i.e., metainflammation), endothelial dysfunction, and coronary microvascular disease. Emerging data indicate that the gut–heart axis is a potential amplifier of this process. Cardiometabolic comorbidities promote gut dysbiosis, loss of short-chain fatty acid (SCFA)-producing taxa, and disruption of the intestinal barrier, leading to endotoxemia and upregulation of pro-inflammatory pathways such as TLR4- and NLRP3-mediated signaling. Concomitantly, beneficial gut-derived metabolites (acetate, propionate, butyrate) decrease, while detrimental metabolites increase (e.g., TMAO), potentially fostering myocardial fibrosis, diastolic dysfunction, and adverse remodeling. SCFAs—acetate, propionate, and butyrate—may exert pleiotropic actions that directly target HFpEF pathophysiology: they may provide a CPT1-independent energy substrate to the failing myocardium, may improve lipid and glucose homeostasis via G protein-coupled receptors and AMPK activation, and may contribute to lower blood pressure and sympathetic tone, reinforce gut barrier integrity, and act as anti-inflammatory and epigenetic modulators through the inhibition of NF-κB, NLRP3, and histone deacetylases. This review summarizes current evidence linking gut microbiota dysfunction to cardiometabolic HFpEF, elucidates the mechanistic role of SCFAs, and discusses nutritional approaches aimed at enhancing their production and activity. Targeting gut–heart axis and SCFAs pathways may represent a biologically plausible and low-risk approach that could help attenuate inflammation and metabolic dysfunctions in patients with cardiometabolic HFpEF, offering novel potential therapeutic targets for their management. Full article

Cardiac metabolic flexibility is a key determinant of myocardial energetic resilience. In heart failure with reduced ejection fraction (HFrEF), intrinsic mitochondrial dysfunction and lipotoxicity compromise oxidative capacity. In contrast, heart failure with preserved ejection fraction (HFpEF) is orchestrated primarily by systemic comorbidities and coronary microvascular dysfunction, which decouple glycolysis from glucose oxidation. This review integrates these distinct pathophysiologies into a comprehensive biomarker framework. Beyond core hemodynamic markers, we detail indices of metabolic flux (ketones, acylcarnitines, branched-chain amino acids), endothelial injury, and fibrosis. We further prose a shift from static, isolated measurements to dynamic functional profiling using standardized challenges (e.g., mixed-meal or exercise tests) to quantify metabolic suppression and recovery kinetics. This structured hierarchy enables phenotype-tailored risk stratification and guides mechanism-based precision therapies in the era of personalized medicine. Full article

Post-cardiac arrest syndrome (PCAS) remains a major cause of mortality and neurological impairment following successful resuscitation, yet the mechanisms linking global ischemia–reperfusion injury to microvascular and systemic dysfunction are not yet completely understood. While prior work has focused on inflammation, endothelial injury, and circulatory collapse, the central role of platelets in coordinating these pathological processes has not been comprehensively examined. This review provides the first integrated framework positioning platelets as core modulators, rather than secondary participants, in PCAS pathophysiology. We synthesize emerging evidence demonstrating that ischemia and reperfusion transform platelets into potent thromboinflammatory effectors through oxidative stress, DAMP-mediated pattern recognition signaling, and mitochondrial dysfunction. Hyperactivated platelets drive cerebral microthrombus formation, coronary no-reflow, and peripheral organ hypoperfusion, while platelet–leukocyte aggregates, neutrophil extracellular traps, and platelet-derived microparticles amplify systemic inflammation and endothelial injury. We further highlight the clinical significance of dynamic platelet dysfunction in coagulopathy, prognostication, and responses to post-arrest therapies including targeted temperature management and ECMO. Finally, we outline a novel, platelet-centered therapeutic paradigm, emphasizing selective interventions, such as GPVI inhibition, P-selectin blockade, FXI/XIa inhibition, and NETosis modulation, that target pathological platelet activity while preserving essential hemostatic function. In this review, by reframing platelets as the central determinants of PCAS, we report new mechanistic insights and therapeutic opportunities that are complementary to the existing post-arrest strategies and have the potential to improve survival and neurological outcomes after cardiac arrest. Full article

Background: Recent observational studies suggest that coronary sinus reducer (CSR) implantation may have a beneficial effect on microcirculatory indices in patients with coronary microvascular dysfunction (CMD). However, to date, there is no comprehensive summary of the evidence regarding the impact of CSR in this population. Methods: This systematic review was conducted in accordance with the PRISMA 2020 Statement. The following databases were searched: PubMed, EMBASE, MEDLINE, and ClinicalTrials.gov. Studies assessing microcirculatory indices or primarily involving patients with CMD undergoing CSR implantation were included. Results: After the selection process, 17 studies or trials were included in this systematic review. Across observational studies and case series, CSR implantation was associated with significant improvements in coronary microvascular function, including reductions in the index of microvascular resistance and an increase in coronary flow reserve. These physiological changes were accompanied by consistent improvements in angina severity (CCS class), exercise capacity, and quality-of-life measures, particularly in patients with more severe baseline CMD. Evidence was derived mainly from non-randomized studies involving small patient cohorts, with low procedural complication rates. Ongoing randomized trials are expected to clarify the magnitude of benefit and its clinical relevance in this population. Conclusions: CSR implantation may offer clinical and physiological benefits in patients with refractory angina due to CMD. However, the lack of randomized evidence and uncertainty regarding long-term effects warrant further adequately powered trials. Full article

The pathophysiology of ST-elevated myocardial infarction (STEMI) extends beyond coronary artery occlusion to include microvascular and endothelial dysfunction, both of which critically influence outcomes. Endocan, a soluble dermatan sulfate proteoglycan secreted by endothelial cells, has emerged as a novel biomarker of endothelial activation and dysfunction. Recent studies suggest that elevated endocan levels may carry prognostic significance in patients with STEMI, particularly those undergoing percutaneous coronary intervention (PCI). A comprehensive search of PubMed, Cochrane Library, and Google Scholar was conducted to identify studies evaluating endocan as a prognostic biomarker in STEMI. Review articles, case reports, case series, and experimental studies were excluded. Seven clinical studies, comprising sample sizes ranging from 80 to 320 patients, met the inclusion criteria. Across these studies, endocan levels were analyzed in relation to established prognostic markers and clinical outcomes. Key findings demonstrated that higher endocan levels correlated with stress hyperglycemia (r = 0.21, p < 0.05), higher SYNTAX scores, and worse in-hospital outcomes. A cutoff value of 1.7 ng/mL predicted STEMI with 76.1% sensitivity and 73.6% specificity. Elevated endocan levels also showed positive correlations with the TIMI risk score, major adverse cardiovascular events (MACE), and were identified as independent predictors of incomplete ST-segment resolution (STR) (p = 0.044) and no-reflow phenomenon (NRP) (p < 0.001, OR = 2.39, 95% CI = 1.37–4.15). Collectively, the evidence indicates that endocan is strongly associated with endothelial dysfunction, MACE, NRP post-PCI, and impaired reperfusion. Moreover, traditional prognostic indices such as TIMI and SYNTAX scores appear to correlate with circulating endocan levels. However, variability in reported cutoff values across studies highlights the need for larger, multicenter trials with standardized endpoints to establish endocan’s diagnostic and prognostic utility in STEMI. Full article

Takotsubo syndrome (TTS) is an acute condition involving left ventricular dysfunction that may present clinically as acute coronary syndrome without obstructive coronary disease or congestive heart failure. Initially considered benign, TTS is now recognized as a complex neurocardiac disorder with hospital morbidity rates comparable to those of myocardial infarction, as well as similar long-term risks. Recent evidence establishes TTS as a multifactorial process involving catecholamine overload, coronary microvascular dysfunction, myocardial energetic abnormalities, and dysregulation of the brain and heart axes. Developments in echocardiography, cardiac magnetic resonance imaging, and improvements in diagnostic criteria have enhanced the recognition of syndromic phenotypes. Management of TTS continues to remain primarily supportive; however, recent studies have revealed improved functional outcomes with structured cardiac rehabilitation and cognitive behavioral therapies as the first long-term disease-altering approaches. Future studies should combine neurocardiology, imaging, and therapy-focused research. This review integrates the understanding of the epidemiology, pathophysiology, clinical features, diagnostic work-up, and management of TTS, with particular emphasis on developments emerging from the past decade. Full article

Ischemic heart disease (IHD), the leading causes of cardiovascular morbidity and mortality worldwide, is currently treated though revascularization strategies such as pharmacological thrombolysis, coronary artery bypass grafting (CABG), and percutaneous coronary intervention (PCI). However, the restoration of blood flow often induces cardiac dysfunction, known as myocardial ischemia–reperfusion injury (MIRI). The pathogenesis of MIRI involves a complex, multifactorial process characterized by the interplay of diverse pathophysiological mechanisms, including oxidative stress, intracellular calcium overload, inflammatory cascade activation, apoptosis, autophagy, and microvascular endothelial dysfunction. In recent years, modified RNA (modRNA) technology has emerged as a novel therapeutic strategy for MIRI due to its enhanced molecular stability, reduced immunogenicity, and controllable transient protein expression. Studies have demonstrated that optimized modRNA delivery systems enable efficient, localized expression of therapeutic genes (e.g., antioxidant, anti-apoptotic, and pro-angiogenic factors) at injury sites, significantly mitigating MIRI-associated pathological damage. Nevertheless, significant challenges remain in clinical translation, such as delivery system targeting, transfection efficiency and cytotoxicity. This review focuses on recent advances in the development and application of modRNA-based delivery systems for MIRI treatment. Understanding the molecular mechanisms of MIRI and the structural characteristics and application of modRNA may encourage researchers to explore promising therapeutic modalities for addressing reperfusion-related cardiac injury. Full article