Search

Heart failure with preserved ejection fraction (HFpEF) represents an entity with complex pathophysiologic pathways, among which coronary microvascular dysfunction (CMD) is believed to be an important orchestrator. Research in the field of CMD has highlighted impaired vasoreactivity, capillary rarefaction, and inflammation as potential mediators of its development. CMD can be diagnosed via several noninvasive methods including transthoracic echocardiography, cardiac magnetic resonance, and positron emission tomography. Moreover, invasive methods such as coronary flow reserve and index of microcirculatory resistance are commonly employed in the assessment of CMD. As far as the association between CMD and HFpEF is concerned, numerous studies have highlighted the coexistence of CMD in the majority of HFpEF patients. Additionally, patients affected by both conditions may be facing an adverse prognosis. Finally, there is limited evidence suggesting a beneficial effect of renin-angiotensin-aldosterone system blockers, ranolazine, and sodium-glucose cotransporter-2 inhibitors in CMD, with further evidence being awaited regarding the impact of other pharmacotherapies such as anti-inflammatory agents. [ABSTRACT FROM AUTHOR]

Objective To establish in vivo rat ischemic myocardial injury and in vitro cardiac microvascular endothelial cell (CMEC) hypoxia models so as to investigate the structural and biological changes and probe the angiogenesis basis of coronary microcirculation. Methods In vivo rat myocardial ischemia model was established using the 1/3 ligation of the left anterior descending coronary artery and myocardial tissue structure and ultrastructure were detected using HE, Masson staining, and transmission electron microscopy, respectively. In vitro timegradient hypoxia model of rat CMECs (hypoxia times set at 0 h, 4 h, 8 h, 12 h, 24 h, 48 h, 72 h) was established using a hypoxic incubator. An inverted phase-contrast microscope was used to observe the morphological and growth characteristics of CMECs. The proliferation rate was determined by CCK-8 method, and the survival rate was determined by counting method. The expression of inflammatory factors (IL-1β, IL-6, TNF-α) and angiogenic factors (VEGF, Ang-2) were detected using ELISA method. Results After 72 hours of coronary artery ligation, HE and MASS staining indicated the successful establishment of a rat model of myocardial ischemia and hypoxia. The transmission electron microscopy revealed the ischemic and hypoxic changes in the ultrastructure of cells. . CMECs exhibited the distinct morphological characteristics and adhered to the surface. With the prolonged hypoxia time, the proliferation rate significantly decreased after 48 h (P=0. 042 6), and the survival rate significantly decreased after 24 h (72. 8%). Long-term hypoxia led to significantly higher release levels of IL-1β (24～72 h, P=0. 000 7, 0. 000 7, 0. 001), IL-6 (24～72 h, P=0. 001 5, 0. 000 5, 0. 000 7), and TNF-α (24～72 h, P=0. 001 5, 0. 006 3, 0. 000 8 respectively) compared to short-term hypoxia IL-1β (4～12 h, P=0. 007, 0. 003 4, 0. 000 9 respectively), IL-6 (4～12 h, P=0. 002 6, 0. 001 3, 0. 004 5 respectively), and TNF-α (12 h, P=0. 008 7). In addition, the expression of angiogenic factor VEGF began to increase 8 hours after hypoxia (P＜0. 000 1), decreased at 12-24 hours (P＜0. 000 1 respectively), and then increased rapidly (P＜0. 01); The expression of Ang-2 decreased from 4-12 hours (P＜0. 05), and gradually increased from 24 hours (P＜0. 01). Conclusions Myocardial tissues and CMECs exhibit the different biological changes at different ischemia-hypoxia time points with inflammatory reactions beginning in the early stages and angiogenesis reactions occurring in the late stages. These findings contribute to elucidating the key cellular and molecular mechanisms underlying ischemic myocardial injury. [ABSTRACT FROM AUTHOR]

Multiple common cardiovascular comorbidities produce coronary microvascular dysfunction. We previously observed in swine that a combination of diabetes mellitus (DM), high fat diet (HFD) and chronic kidney disease (CKD) induced systemic inflammation, increased oxidative stress and produced coronary endothelial dysfunction, altering control of coronary microvascular tone via loss of NO bioavailability, which was associated with an increase in circulating endothelin (ET). In the present study, we tested the hypotheses that (1) ROS scavenging and (2) ETA+B-receptor blockade improve myocardial oxygen delivery in the same female swine model. Healthy female swine on normal pig chow served as controls (Normal). Five months after induction of DM (streptozotocin, 3 × 50 mg kg−1 i.v.), hypercholesterolemia (HFD) and CKD (renal embolization), swine were chronically instrumented and studied at rest and during exercise. Sustained hyperglycemia, hypercholesterolemia and renal dysfunction were accompanied by systemic inflammation and oxidative stress. In vivo ROS scavenging (TEMPOL + MPG) reduced myocardial oxygen delivery in DM + HFD + CKD swine, suggestive of a vasodilator influence of endogenous ROS, while it had no effect in Normal swine. In vitro wire myography revealed a vasodilator role for hydrogen peroxide (H2O2) in isolated small coronary artery segments from DM + HFD + CKD, but not Normal swine. Increased catalase activity and ceramide production in left ventricular myocardial tissue of DM + HFD + CKD swine further suggest that increased H2O2 acts as vasodilator ROS in the coronary microvasculature. Despite elevated ET-1 plasma levels in DM + HFD + CKD swine, ETA+B blockade did not affect myocardial oxygen delivery in Normal or DM + HFD + CKD swine. In conclusion, loss of NO bioavailability due to 5 months exposure to multiple comorbidities is partially compensated by increased H2O2-mediated coronary vasodilation. [ABSTRACT FROM AUTHOR]

Background: There are many questions regarding the optimal approach to treating non-culprit lesions in STEMI patients. Several questions still need to be answered, such as identifying the lesions to be revascularized and the optimal timing. Methods: We conducted a single-center analysis. The primary outcome was the incidence of major cardiovascular and cerebral adverse events (MACCE) at 12 months in patients with STEMI and multivessel disease (MVD) who achieved complete revascularization during the index procedure or with a staged procedure. The secondary outcomes were death from any cause, myocardial infarction, target lesion revascularization, stroke, major bleeding events, new angina episodes, new hospitalization, and in-hospital MACCE. Results: From January 2021 to December 2022, a total of 230 patients with STEMI underwent primary PCI in our department; 87 patients had MVD. Fifty-nine patients (67.8%) underwent a non-culprit revascularization strategy during the index procedure strategy, and 28 patients (32.2%) during a staged procedure. The incidence of MACCE at 12 months was 11.9% (seven patients) in the index PCI group, compared with 32.1% (nine patients) in the staged PCI group (odds ratio, 3.52; 95% CI, 1.15 to 10.77; p = 0.022). In-hospital MACCE occurred in five patients (8.5%) of the index PCI group, compared with seven patients (25%) in the staged PCI group (odds ratio, 3.60; 95% CI, 1.03 to 12.61; p = 0.036). A trend towards better outcomes favoring the index PCI group was observed with death from any cause, myocardial infarction, target lesion revascularization, and new angina episodes. Conclusions: Better outcomes were evident with an index PCI strategy than with a staged PCI strategy for complete revascularization in patients with STEMI and MVD. [ABSTRACT FROM AUTHOR]

• Ischemia with non-obstructive coronary arteries (INOCA) encompasses a breadth of structural and functional abnormalities of the coronary circulation causing ischemia (and angina) despite the lack of obstructive epicardial atheroma. • Several diagnostic techniques are available, including invasive and non-invasive ones. At present, invasive functional assessment, using both pressure wire and vasoreactivity tests and also termed #FullPhysiology, is the only one allowing comprehensive evaluation of the pathophysiological mechanisms of INOCA. • Leveraging #FullPhysiology, a stratified medical therapy can be implemented, which can mitigate symptoms and positively affect quality of life in patients with INOCA. Ischemia with non-obstructive coronary arteries (INOCA) is an increasingly recognized entity. It encompasses different pathophysiological subtypes (i.e., endotypes), including coronary microvascular dysfunction (CMD), vasospastic angina (VSA) and mixed entities resulting from the variable combination of both. Diagnosing INOCA and precisely characterizing the endotype allows for accurate medical treatment and has proven prognostic implications. A breadth of diagnostic technique is available, ranging from non-invasive approaches to invasive coronary angiography adjuvated by functional assessment and provocative tests. This review summarizes the strength and limitations of these methodologies and provides the rationale for the routine referral for invasive angiography and functional assessment in this subset of patients. [ABSTRACT FROM AUTHOR]

[Display omitted] [ABSTRACT FROM AUTHOR]

Coronary microvascular dysfunction (CMD) refers to structural and functional abnormalities of the microcirculation that impair myocardial perfusion. CMD plays a pivotal role in numerous cardiovascular diseases, including myocardial ischemia with non-obstructive coronary arteries, heart failure, and acute coronary syndromes. This review summarizes recent advances in CMD pathophysiology, assessment, and treatment strategies, as well as ongoing challenges and future research directions. Signaling pathways implicated in CMD pathogenesis include adenosine monophosphate-activated protein kinase/Krüppel-like factor 2/endothelial nitric oxide synthase (AMPK/KLF2/eNOS), nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE), Angiotensin II (Ang II), endothelin-1 (ET-1), RhoA/Rho kinase, and insulin signaling. Dysregulation of these pathways leads to endothelial dysfunction, the hallmark of CMD. Treatment strategies aim to reduce myocardial oxygen demand, improve microcirculatory function, and restore endothelial homeostasis through mechanisms including vasodilation, anti-inflammation, and antioxidant effects. Traditional Chinese medicine (TCM) compounds exhibit therapeutic potential through multi-targeted actions. Small molecules and regenerative approaches offer precision therapies. However, challenges remain in translating findings to clinical practice and developing effective pharmacotherapies. Integration of engineering with medicine through microfabrication, tissue engineering and AI presents opportunities to advance the diagnosis, prediction, and treatment of CMD. [ABSTRACT FROM AUTHOR]

Objective: Both low serum albumin (SA) concentration and coronary microvascular dysfunction (CMD) are risk factors for the development of heart failure (HF). We hypothesized that SA concentration is associated with myocardial flow reserve (MFR) and implicated in pathophysiological mechanism of HF. Methods: We retrospectively studied 454 patients undergoing dynamic cardiac cadmium‐zinc‐telluride myocardial perfusion imaging from April 2018 to February 2020. The population was categorized into three groups according to SA level (g/dL): Group 1: >4, Group 2: 3.5–4, and Group 3: <3.5. Myocardial blood flow (MBF) and myocardial flow reserve (MFR, defined as stress/rest MBF ratio) were compared. Results: The mean age of the whole cohort was 66.2 years, and 65.2% were men. As SA decreased, stress MBF (mL min−1 g−1) and MFR decreased (MBF: 3.29 ± 1.03, MFR: 3.46 ± 1.33 in Group 1, MBF: 2.95 ± 1.13, MFR: 2.51 ± 0.93 in Group 2, and MBF: 2.64 ± 1.16, MFR: 1.90 ± 0.50 in Group 3), whereas rest MBF (mL min−1 g−1) increased (MBF: 1.05 ± 0.42 in Group 1, 1.27 ± 0.56 in Group 2, and 1.41 ± 0.61 in Group 3). After adjusting for covariates, compared with Group 1, the odds ratios for impaired MFR (defined as MFR < 2.5) were 3.57 (95% CI: 2.32–5.48) for Group 2 and 34.9 (95% CI: 13.23–92.14) for Group 3. The results would be similar if only regional MFR were assessed. The risk prediction for CMD using SA was acceptable, with an AUC of 0.76. Conclusion: Low SA concentration was associated with the severity of CMD in both global and regional MFR as well as MBF. [ABSTRACT FROM AUTHOR]

Background Bolus thermodilution and intravenous adenosine are established methods for coronary microcirculatory assessment. Yet, its adoption remains low, partly due to procedural time and patient discomfort associated with intravenous adenosine. We investigated differences between intracoronary and intravenous adenosine using bolus thermodilution in terms of microcirculatory indices, procedural time, and side effects associated with adenosine in patients with myocardial ischemia and nonobstructive coronary arteries. Methods and Results In this prospective, observational study, 102 patients with suspected myocardial ischemia and nonobstructive coronary arteries underwent measurements of mean transit time, coronary flow reserve, index of microcirculatory resistance, procedure time and patient tolerability with low‐dose intracoronary adenosine, high‐dose intracoronary adenosine (HDIC), and intravenous adenosine. HDIC induced greater hyperemia compared with low‐dose intracoronary IC adenosine and intravenous adenosine with a shorter hyperemic mean transit time, P

Background: Coronary microvascular dysfunction is associated with adverse prognosis after ST-segment elevation myocardial infarction (STEMI). We aimed to compare the invasive, Doppler wire-based coronary flow reserve (CFR) with the non-invasive transthoracic Doppler echocardiography (TTDE)-derived CFR, and their ability to predict infarct size. Methods: We included 36 patients with invasive Doppler wire assessment on days 3–7 after STEMI treated with primary percutaneous coronary intervention (PCI), of which TTDE-derived CFR was measured in 47 vessels (29 patients) within 6 h of the invasive Doppler. Infarct size was assessed by cardiac magnetic resonance at a median of 8 months. Results: The correlation between invasive and non-invasive CFR was modest in the overall cohort (rho 0.400, p = 0.005). It improved when only measurements in the LAD artery were considered (rho 0.554, p = 0.002), with no significant correlation in the RCA artery (rho −0.190, p = 0.435). Both invasive (AUC 0.888) and non-invasive (AUC 0.868) CFR, measured in the recanalized culprit artery, showed a good ability to predict infarct sizes ≥18% of the left ventricular mass, with the optimal cut off values of 1.85 and 1.80, respectively. Conclusions: In patients with STEMI, TTDE- and Doppler wire-derived CFR exhibit significant correlation, when measured in the LAD artery, and both have a similarly strong association with the final infarct size. [ABSTRACT FROM AUTHOR]

The coronary sinus reducer (CSR) is an emerging medical device for treating patients with refractory angina, often associated with myocardial ischemia. Patients implanted with CSR have shown positive outcomes, but the underlying mechanisms are unclear. This study sought to understand the mechanisms of CSR by investigating its effects on coronary microcirculation hemodynamics that may help explain the therapy's efficacy. We applied a validated computer model of the coronary microcirculation to investigate how CSR affects hemodynamics under different degrees of coronary artery stenosis. With moderate coronary stenosis, an increase in capillary transit time (CTT) [up to 69% with near-complete coronary sinus (CS) occlusion] is the key change associated with CSR. Because capillaries in the microcirculation can still receive oxygenated blood from the upstream artery with moderate stenosis, the increase in CTT allows more time for the exchange of gases and nutrients, aiding tissue oxygenation. With severe coronary stenosis; however, the redistribution of blood draining from the nonischemic region to the ischemic region (up to 96% with near-complete CS occlusion) and the reduction in capillary flow heterogeneity are the key changes associated with CSR. Because blood draining from the nonischemic region is not completely devoid of O2, the redistribution of blood to the capillaries in the ischemic region by CSR is beneficial especially when little or no oxygenated blood reaches these capillaries. This simulation study provides insights into the mechanisms of CSR in improving clinical symptoms. The mechanisms differ with the severity of the upstream stenosis. NEW & NOTEWORTHY: Emerging coronary venous retroperfusion treatments, particularly coronary sinus reducer (CSR) for refractory angina linked to myocardial ischemia, show promise; however, their mechanisms of action are not well understood. We find that CSR's effectiveness varies with the severity of coronary stenosis. In moderate stenosis, CSR improves tissue oxygenation by increasing capillary transit time, whereas in severe stenosis, it redistributes blood from nonischemic to ischemic regions and reduces capillary flow heterogeneity. [ABSTRACT FROM AUTHOR]

Diagnosing coronary microvascular dysfunction remains challenging, primarily due to the lack of direct measurements of absolute coronary blood flow (Q) and microvascular resistance (R μ). However, there has been recent progress with the development and validation of continuous intracoronary thermodilution, which offers a simplified and validated approach for clinical use. This technique enables direct quantification of Q and R μ , leading to precise and accurate evaluation of the coronary microcirculation. To ensure consistent and reliable results, it is crucial to follow a standardized protocol when performing continuous intracoronary thermodilution measurements. This document aims to summarize the principles of thermodilution-derived absolute coronary flow measurements and propose a standardized method for conducting these assessments. The proposed standardization serves as a guide to ensure the best practice of the method, enhancing the clinical assessment of the coronary microcirculation. [Display omitted] • Diagnosis of coronary microcirculatory dysfunction requires measurement of coronary blood flow and microvascular resistance. • Absolute coronary blood flow and microvascular resistance can be accurately measured by means of continuous intracoronary thermodilution. • This paper proposes a standardized protocol to perform these measurements. [ABSTRACT FROM AUTHOR]

Background: Myocardial perfusion defect (MPD) is common in chronic Chagas cardiomyopathy (CCC) and is associated with inflammation and development of left ventricular systolic dysfunction. We tested the hypothesis that pentoxifylline (PTX) could reduce inflammation and prevent the development of MPD in a model of CCC in hamsters. Methods and results: We investigated with echocardiogram and rest myocardial perfusion scintigraphy at baseline (6-months after T. cruzi infection/saline) and post-treatment (after additional 2-months of PTX/saline administration), female Syrian hamsters assigned to 3 groups: T. cruzi-infected animals treated with PTX (CH + PTX) or saline (CH + SLN); and uninfected control animals (CO). At the baseline, all groups showed similar left ventricular ejection fraction (LVEF) and MPD areas. At post-treatment evaluation, there was a significant increase of MPD in CH + SLN group (0.8 ± 1.6 to 9.4 ± 9.7%), but not in CH + PTX (1.9 ± 3.0% to 2.7 ± 2.7%) that exhibited MPD area similar to CO (0.0 ± 0.0% to 0.0 ± 0.0%). The LVEF decreased in both infected groups. Histological analysis showed a reduced inflammatory infiltrate in CH + PTX group (395.7 ± 88.3 cell/mm2), as compared to CH + SLN (515.1 ± 133.0 cell/mm2), but larger than CO (193.0 ± 25.7 cell/mm2). The fibrosis and TNF-α expression was higher in both infected groups. Conclusions: The prolonged use of PTX is associated with positive effects, including prevention of MPD development and reduction of inflammation in the chronic hamster model of CCC. [ABSTRACT FROM AUTHOR]

IntroductionInvestigating coronary microvascular perfusion responses after myocardial infarction (MI) would aid in the development of flow preserving therapies. Laser speckle contrast imaging (LSCI) is a powerful tool used for real-time, non-contact, full-field imaging of blood flow in various tissues/organs. However, its use in the beating heart has been limited due to motion artifacts.MethodsIn this paper, we report the novel use of LSCI, combined with custom speckle analysis software (SpAn), to visualise and quantitate changes in ventricular perfusion in adult and aged mice undergoing ischaemia-reperfusion (IR) injury. The therapeutic benefit of inhibiting the actions of the pro-inflammatory cytokine interleukin-36 (IL-36) was also investigated using an IL-36 receptor antagonist (IL-36Ra).ResultsImaging from uncovered and covered regions of the left ventricle demonstrated that whilst part of the LSCI flux signal was derived from beating motion, a significant contributor to the flux signal came from ventricular microcirculatory blood flow. We show that a biphasic flux profile corresponding to diastolic and systolic phases of the cardiac cycle can be detected without mathematically processing the total flux data to denoise motion artifacts. Furthermore, perfusion responses to ischaemia and postischaemia were strong, reproducible and could easily be detected without the need to subtract motion-related flux signals. LSCI also identified significantly poorer ventricular perfusion in injured aged mice following IR injury which markedly improved with IL-36Ra.DiscussionWe therefore propose that LSCI of the heart is possible despite motion artifacts and may facilitate future investigations into the role of the coronary microcirculation in cardiovascular diseases and development of novel therapies.

Introduction: Opening occluded coronary arteries in patients with myocardial infarction (MI) damages the delicate coronary microvessels through a process called myocardial ischaemia-reperfusion injury. Although mesenchymal stromal cells (MSCs) have the potential to limit this injury, clinical success remains limited. This may be due to (i) poor MSC homing to the heart (ii) infused MSCs, even if derived from the same site, being a heterogeneous population with varying therapeutic efficacy and (iii) conventional 2D culture of MSCs decreasing their homing and beneficial properties. This study investigated whether 3D culture of two distinctly different bone marrow (BM)-derived MSC sub-populations could improve their homing and coronary vasculoprotective efficacy. Methods: Intravital imaging of the anaesthetised mouse beating heart was used to investigate the trafficking and microvascular protective effects of two clonallyderived BM-derived MSC lines, namely CD317neg MSCs-Y201 and CD317pos MSCs-Y202, cultured using conventional monolayer and 3D hanging drop methods. Results: 3D culture consistently improved the adhesive behaviour of MSCs-Y201 to various substrates in vitro. However, it was their differential ability to reduce neutrophil events within the coronary capillaries and improve ventricular perfusion in vivo that was most remarkable. Moreover, dual therapy combined with heparin further improved the vasculoprotection afforded by 3D cultured MSCs-Y201 by also modifying platelet as well as neutrophil recruitment, which subsequently led to the greatest salvage of viable myocardium. Therapeutic benefit could mechanistically be explained by reductions in coronary endothelial oxidative stress and intercellular adhesion molecule-1 (ICAM-1)/vascular cell adhesion molecule-1 (VCAM-1) expression. However, since this was noted by both 2D and 3D cultured MSCs-Y201, therapeutic benefit is likely explained by the fact that 3D cultured MSCs-Y201 were the most potent sub-population at reducing serum levels of several pro-inflammatory cytokines. Conclusion: This novel study highlights the importance of not only 3D culture, but also of a specific CD317neg MSC sub-population, as being critical to realising their full coronary vasculoprotective potential in the injured heart. Since the smallest coronary blood vessels are increasingly recognised as a primary target of reperfusion injury, therapeutic interventions must be able to protect these delicate structures from inflammatory cells and maintain perfusion in the heart. We propose that relatively feasible technical modifications in a specific BMderived MSC sub-population could achieve this. [ABSTRACT FROM AUTHOR]

Coronary microvascular dysfunction is a high‐risk factor for many cardiovascular events. However, because of multiple risk factors and limited understanding about its underlying pathophysiological mechanisms, it was easily misdiagnosed. Therefore, its clinical diagnosis and treatment were greatly restricted. Coronary microcirculation refers to microvessels that play an important role in the physiological regulation of myocardial perfusion and regulating blood flow distribution, fulfilling myocardial metabolic needs and moderating peripheral vascular resistance. In coronary microvascular dysfunction, vascular endothelial celldamage is a critical link. The main feature of early coronary microvascular dysfunction is the impairment of endothelial cell proliferation, adhesion, migration, apoptosis, and secretion. Moreover, coronary microvascular dysfunction risk factors include hyperglycemia, lipid metabolism disorders, ischemia‐reperfusion injury, aging, and hypertension, similar to coronary atherosclerosis. There are various mechanisms by which these risk factors harm endothelial function and cause microcirculatory disturbances. Therefore, we reviewed coronary microvascular dysfunction's risk factors and pathogenesis in this article. [ABSTRACT FROM AUTHOR]

This study aimed to construct a large animal model of coronary microvascular embolism, and investigate whether it could mimic the clinical imaging phenotypes of myocardial hypoperfusion in patients with ST-segment elevation myocardial infarction (STEMI). Nine minipigs underwent percutaneous coronary embolization with microspheres, followed by cardiac magnetic resonance (CMR) on week 1, 2 and 4 post operation. Microvascular obstruction (MVO) was defined as the isolated hypointense core within the enhanced area on late gadolinium enhancement images, which evolved during a 4-week follow-up. Fibrotic fraction of the segments was measured by Masson trichrome staining using a panoramic analysis software. Iron deposit and macrophage infiltration were quantified based on Perl's blue and anti-CD163 staining, respectively. Seven out of 9 (77.8%) minipigs survived and completed all of the imaging follow-ups. Four out of 7 (57.1%) minipigs were identified as transmural infarct with MVO. The systolic wall thickening (SWT) of MVO zone was similar to that of infarct zone (P = 0.762). Histopathology revealed transmural deposition of collagen, with microvessels obstructed by microspheres. The fibrotic fraction of infarct with MVO segments was similar to that of infarct without MVO segments (P = 0.954). The fraction of iron deposit in infarct with MVO segments was higher than that of infarct without MVO segments (P < 0.05), but the fraction of macrophage infiltration between these two segments did not show statistical difference (P = 0.723). Large animal model of coronary microvascular embolism could mimic most clinical imaging phenotypes of myocardial hypoperfusion in patients with STEMI, demonstrated by serial CMR and histopathology. [ABSTRACT FROM AUTHOR]

AimsWe previously reported that increased protein O-GlcNAcylation in diabetic mice led to vascular rarefaction in the heart. In this study, we aimed to investigate whether and how coronary endothelial cell (EC) apoptosis is enhanced by protein O-GlcNAcylation and thus induces coronary microvascular disease (CMD) and subsequent cardiac dysfunction in diabetes. We hypothesize that excessive protein O-GlcNAcylation increases p53 that leads to CMD and reduced cardiac contractility.Methods and resultsWe conducted in vivo functional experiments in control mice, TALLYHO/Jng (TH) mice, a polygenic type 2 diabetic (T2D) model, and EC-specific O-GlcNAcase (OGA, an enzyme that catalyzes the removal of O-GlcNAc from proteins)-overexpressing TH mice, as well as in vitro experiments in isolated ECs from these mice. TH mice exhibited a significant increase in coronary EC apoptosis and reduction of coronary flow velocity reserve (CFVR), an assessment of coronary microvascular function, in comparison to wild-type mice. The decreased CFVR, due at least partially to EC apoptosis, was associated with decreased cardiac contractility in TH mice. Western blot experiments showed that p53 protein level was significantly higher in coronary ECs from TH mice and T2D patients than in control ECs. High glucose treatment also increased p53 protein level in control ECs. Furthermore, overexpression of OGA decreased protein O-GlcNAcylation and down-regulated p53 in coronary ECs, and conferred a protective effect on cardiac function in TH mice. Inhibition of p53 with pifithrin-α attenuated coronary EC apoptosis and restored CFVR and cardiac contractility in TH mice.ConclusionsThe data from this study indicate that inhibition of p53 or down-regulation of p53 by OGA overexpression attenuates coronary EC apoptosis and improves CFVR and cardiac function in diabetes. Lowering coronary endothelial p53 levels via OGA overexpression could be a potential therapeutic approach for CMD in diabetes.

Abstract Background The mortality rate of acute ST-segment elevation myocardial infarction (STEMI) remains substantial, despite advances in treatment strategies. Coronary microcirculation dysfunction (CMD) persists after percutaneous coronary intervention (PCI) in a substantial proportion of STEMI patients. The association between CMD assessed using myocardial contrast echocardiography (MCE) and prognosis requires further elucidation. This study aimed to evaluate the impact of CMD after successful PCI on the prognosis of patients with STEMI. Methods We enrolled 167 patients with STEMI after PCI who underwent MCE during hospitalization between January 2018 and March 2022. Patients were classified into the CMD and non-CMD groups according to the results of MCE. The clinical data and MCE results of both groups were analyzed. Follow-up was conducted for major adverse cardiac events. Results MCE detected CMD in 105 patients (62.9%). The CMD group contained fewer hypertensive patients (55.2% versus 74.2%, P = 0.015). Patients with CMD exhibited significantly higher levels of plasma troponin I (TnI) [73.2 (23.0–124.0) versus 28.9 (12.7–80.2) ng/mL, P = 0.004], higher levels of plasma B-type natriuretic peptide [255 (99–641) versus 193 (59–389) pg/mL, P = 0.004], poorer Killip classification (P = 0.038), and different culprit vessels (P

Objective: Recent advances in tissue clearing and high‐throughput imaging have enabled the acquisition of extended‐volume microvasculature images at a submicron resolution. The objective of this study was to extract information from this type of images by integrating a sequence of 3D image processing steps on Terabyte scale datasets. Methods: We acquired coronary microvasculature images throughout an entire short‐axis slice of a 3‐month‐old Wistar–Kyoto rat heart. This dataset covered 13 × 10 × 0.6 mm at a resolution of 0.933 × 0.933 × 1.866 μm and occupied 700 Gigabytes of disk space. We used chunk‐based image segmentation, combined with an efficient graph generation technique, to quantify the microvasculature in the large‐scale images. Specifically, we focused on the microvasculature with a vessel diameter up to 15 μm. Results: Morphological data for the complete short‐axis ring were extracted within 16 h using this pipeline. From the analyses, we identified that microvessel lengths in the rat coronary microvasculature varied from 6 to 300 μm. However, their distribution was heavily skewed toward shorter lengths, with a mode of 16.5 μm. In contrast, vessel diameters ranged from 3 to 15 μm and had an approximately normal distribution of 6.5 ± 2 μm. Conclusion: The tools and techniques from this study will serve other investigations into the microcirculation, and the wealth of data from this study will enable the analysis of biophysical mechanisms using computer models. [ABSTRACT FROM AUTHOR]

IntroductionOpening occluded coronary arteries in patients with myocardial infarction (MI) damages the delicate coronary microvessels through a process called myocardial ischaemia-reperfusion injury. Although mesenchymal stromal cells (MSCs) have the potential to limit this injury, clinical success remains limited. This may be due to (i) poor MSC homing to the heart (ii) infused MSCs, even if derived from the same site, being a heterogeneous population with varying therapeutic efficacy and (iii) conventional 2D culture of MSCs decreasing their homing and beneficial properties. This study investigated whether 3D culture of two distinctly different bone marrow (BM)-derived MSC sub-populations could improve their homing and coronary vasculoprotective efficacy.MethodsIntravital imaging of the anaesthetised mouse beating heart was used to investigate the trafficking and microvascular protective effects of two clonally-derived BM-derived MSC lines, namely CD317neg MSCs-Y201 and CD317pos MSCs-Y202, cultured using conventional monolayer and 3D hanging drop methods.Results3D culture consistently improved the adhesive behaviour of MSCs-Y201 to various substrates in vitro. However, it was their differential ability to reduce neutrophil events within the coronary capillaries and improve ventricular perfusion in vivo that was most remarkable. Moreover, dual therapy combined with heparin further improved the vasculoprotection afforded by 3D cultured MSCs-Y201 by also modifying platelet as well as neutrophil recruitment, which subsequently led to the greatest salvage of viable myocardium. Therapeutic benefit could mechanistically be explained by reductions in coronary endothelial oxidative stress and intercellular adhesion molecule-1 (ICAM-1)/vascular cell adhesion molecule-1 (VCAM-1) expression. However, since this was noted by both 2D and 3D cultured MSCs-Y201, therapeutic benefit is likely explained by the fact that 3D cultured MSCs-Y201 were the most potent sub-population at reducing serum levels of several pro-inflammatory cytokines.ConclusionThis novel study highlights the importance of not only 3D culture, but also of a specific CD317neg MSC sub-population, as being critical to realising their full coronary vasculoprotective potential in the injured heart. Since the smallest coronary blood vessels are increasingly recognised as a primary target of reperfusion injury, therapeutic interventions must be able to protect these delicate structures from inflammatory cells and maintain perfusion in the heart. We propose that relatively feasible technical modifications in a specific BM-derived MSC sub-population could achieve this.

AimsRisks and outcomes of myocardial infarction (MI) are different between men and women and some studies have demonstrated that the latter have a higher risk of mortality. Whilst there are many reasons for this, it may also partially be linked to stronger innate and adaptive immune responses mounted by females compared to males. However, little is known about how sex impacts the coronary microvessels, the site where inflammatory processes take place, after an MI. Intravital and laser speckle microscopy was used to image coronary microvessels and ventricular perfusion in vivo in response to myocardial ischaemia-reperfusion (IR) injury in male and female mice. Interleukin-36 (IL-36) is the latest addition to the IL-1 superfamily of pro-inflammatory cytokines and has recently been shown to mediate inflammation in a number of non-cardiovascular diseases. Its role in mediating potential sex-related microcirculatiory pertubations in the heart are unknown. Therefore, the vasculoprotective efficacy of an IL-36 receptor antagonist (IL-36Ra) was also investigated.Methods and resultsImmunostaining and flow cytometry demonstrated higher expression of IL-36 and its receptor in female hearts, an observation confirmed in human samples. Intravital imaging of the anaesthetised mouse beating heart identified significantly greater neutrophil recruitment in female hearts, but a greater burden of thrombotic disease in male hearts. Male mice had reduced functional capillary density and were unable to restore perfusion to baseline values as effectively as females. However, female mice had significantly larger infarcts. Interestingly, IL-36Ra decreased inflammation, improved perfusion, and reduced infarct size in both sexes despite increasing platelet presence in male hearts. Mechanistically, this was explained by IL-36Ra attenuating endothelial oxidative damage and VCAM-1 expression. Importantly, IL-36Ra administration during ischaemia was critical for vasculoprotection to be realised.ConclusionThis novel study identified notable sex-related differences in the coronary microcirculatory response to myocardial IR injury which may explain why some studies have noted poorer outcomes in women after MI. Whilst contemporary MI treatment focuses on anti-platelet strategies, the heightened presence of neutrophils in female IR injured coronary microvessels necessitates the development of an effective anti-inflammatory approach for treating female patients. We also emphasise the importance of early intervention during the ischaemic period in order to maximise therapeutic effectiveness.

Abstract Background The characteristics of heart failure (HF) with mildly reduced ejection fraction (EF) (HFmrEF) overlap with those of HF with reduced EF (HFrEF) and HF with preserved EF (HFpEF) and need to be further explored. This study aimed to evaluate left ventricular (LV) function and coronary microcirculation in patients with mildly reduced ejection fraction after acute ST-segment elevation myocardial infarction (STEMI). Methods We enrolled 119 patients with STEMI who had undergone speckle tracking imaging and myocardial contrast echocardiography during hospitalization from June 2016 to June 2021. They were classified into normal, HFmrEF, and HFrEF groups according to their left ventricular EF (LVEF): ≥ 50%, 40–50%, and ≤ 40%, respectively. The data of the HFmrEF group were analyzed and compared with those of the normal and HFrEF groups. Results HFmrEF was observed in 32 patients (26.9%), HFrEF in 17 (14.3%), and normal LVEF in 70 patients (58.8%). The mean global longitudinal strain (GLS) of all patients was − 11.9 ± 3.8%. The GLS of HFmrEF patients was not significantly different from that of the HFrEF group (− 9.9 ± 2.5% and − 8.0 ± 2.3%, respectively, P = 0.052), but they were both lower than that of the normal group (− 13.8% ± 3.5%, P

Summary: Background: Coronary microvascular obstruction also known as no-reflow phenomenon is a major issue during myocardial infarction that bears important prognostic implications. Alterations of the microvascular network remains however challenging to assess as there is no imaging modality in the clinics that can image directly the coronary microvascular vessels. Ultrasound Localization Microscopy (ULM) imaging was recently introduced to map microvascular flows at high spatial resolution (∼10 μm). In this study, we developed an approach to image alterations of the microvascular coronary flow in ex vivo perfused swine hearts. Methods: A porcine model of myocardial ischemia-reperfusion was used to obtain microvascular coronary alterations and no-reflow. Four female hearts with myocardial infarction in addition to 6 controls were explanted and placed immediately in a dedicated preservation and perfusion box manufactured for ultrasound imaging. Microbubbles (MB) were injected into the vasculature to perform Ultrasound Localization Microscopy (ULM) imaging and a linear ultrasound probe mounted on a motorized device was used to scan the heart on multiple slices. The coronary microvascular anatomy and flow velocity was reconstructed using dedicated ULM algorithms and analyzed quantitatively. Findings: We were able to image the coronary microcirculation of ex vivo swine hearts at a resolution of tens of microns and measure flow velocities ranging from 10 mm/s in arterioles up to more than 200 mm/s in epicardial arteries. Under different aortic perfusion pressures, we measured in large arteries of a subset of control hearts an increase of flow velocity from 31 ± 11 mm/s at 87 mmHg to 47 ± 17 mm/s at 132 mmHg (N = 3 hearts, P

This study aims to elucidate the association between serum levels of circular RNAs circ_0001879 and circ_0004104 and the occurrence of coronary microcirculation disorders along with post-PCI prognosis in individuals with stable coronary heart disease. A cohort of 92 patients diagnosed with stable coronary heart disease and subjected to PCI between June 2020 and June 2022 at our institution was assembled. Patients were categorized into an exposed group (n = 60) and a non-exposed group (n = 32), predicated on the coronary angiography-derived microcirculation resistance index (caIMR). Comparative analysis revealed significantly elevated levels of circ_0001879 and circ_0004104 in the serum of the exposed group compared to the non-exposed group, with statistical significance (P < 0.05). Post-PCI, both caFFR and caIMR values demonstrated a marked increase in comparison to pre-surgical measurements within both groups, with the exposed group exhibiting lower indices post-surgery relative to the non-exposed group, indicative of superior microcirculatory outcomes (P < 0.05). Furthermore, serum levels of circ_0001879 and circ_0004104 were inversely correlated with favorable prognosis, with lower levels observed in patients with positive outcomes (P < 0.05). The predictive accuracy for poor prognosis, as indicated by the area under the curve (AUC), was enhanced when circ_0001879 and circ_0004104 were considered in tandem (AUC = 0.934), surpassing the predictive power of individual assessments (Z combination vs circ_0001879 = 2.439, Z combination vs circ_0004104 = 2.317, P < 0.05). Elevated serum levels of circ_0001879 and circ_0004104 are observed in stable coronary heart disease patients and are significantly associated with the presence of coronary microcirculation disorders and post-PCI prognosis, underscoring their potential as prognostic biomarkers. • The serum levels of circ_0001879 and circ_0004104 in patients with stable coronary heart disease are obviously elevated. • The serum levels of circ_0001879 and circ_0004104 are related to coronary microcirculation disorders. • Coronary microcirculation disorders is closely related to the prognosis after PCI in patients. [ABSTRACT FROM AUTHOR]

Background: Coronary microcirculation has a fundamental role in the regulation of coronary blood flow in response to cardiac requirements, which has aroused wide concerns in basic science and clinical cardiovascular research. We aimed to analyze coronary microcirculation-associated literatures over 30 years and provide insightful information on the evolutionary path, frontier research hotspots, and future developmental trends. Methods: Publications were retrieved from the Web of Science Core Collection (WoSCC). VOSviewer was used to perform co-occurrence analyses for countries, institutions, authors, and keywords and to generate visualized collaboration maps. CiteSpace was used to visualize the knowledge map derived from reference co-citation analysis, burst references, and keywords detection. Results: This analysis was performed based on 11,702 publications including 9981 articles and 1721 reviews. The United States and Harvard University ranked at the top among all the countries and institutions. The majority of articles were published in Circulation, and it also was the most co-cited journal. Thematic hotspots and frontiers were focused on coronary microvascular dysfunction, magnetic resonance imaging, fractional flow reserve, STEMI, and heart failure. Additionally, keywords burst and co-occurrence cluster analysis showed that management, microvascular dysfunction, microvascular obstruction, prognostic value, outcomes, and guidelines were current knowledge gaps and future directions. Conclusions: Coronary microcirculation presented a research hotspot relevant wide spectrum of cardiovascular diseases. Definite diagnostics and prognostics are particularly valued. The protection of cardiovascular events that influence clinical outcomes should be an insightful concern in the future. Multidisciplinary collaborations will provide significant advances for the development of coronary microcirculation.

BackgroundIt has recently been shown that magnetic resonance (MR) "native T1" mapping is capable of characterizing abnormal microcirculation in patients with obstructive coronary artery disease (CAD). In studies involving women with signs and symptoms of ischemia and no obstructive CAD (INOCA), however, the potential role of native T1 as an imaging marker and its association with indices of diastolic function or vasodilator-induced myocardial ischemia have not been explored. We investigated whether native T1 in INOCA is associated with reduced myocardial perfusion reserve index (MPRI) or with diastolic dysfunction.MethodsTwenty-two female patients with INOCA and twelve female reference controls with matching age and body-mass index were studied. The patients had evidence of vasodilator-induced ischemia without obstructive CAD or any prior infarction. All 34 subjects underwent stress/rest MR including native T1 mapping (MOLLI 5(3)3) at 1.5-Tesla.ResultsCompared with controls, patients had similar morphology/function. As expected, MPRI was significantly reduced in patients compared to controls (1.78 ± 0.39 vs. 2.49 ± 0.41, p

We have previously shown that normoxia serum-starved extracellular vesicle (EV) therapy improves myocardial function, perfusion, and angiogenesis in a swine model of chronic myocardial ischemia. Hypoxia-modified EVs have increased abundance of anti-oxidant, pro-angiogenic, and pro-survival proteins. The purpose of this study is to investigate the differential effects of normoxia serum-starved EVs and hypoxia-modified EVs on myocardial function, perfusion, and microvascular density in chronically ischemic myocardium. Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, the pigs underwent intramyocardial injection of either normoxia serum-starved EVs (NOR, n = 10) or hypoxia-modified EVs (HYP, n = 7). Five weeks later, pigs were euthanized, and ischemic myocardium was harvested. Hypoxia EV treatment was associated with improved contractility compared to NOR, as well as improved capillary density, without changes in arteriolar density. There were trends towards improved perfusion at rest and during pacing in the HYP group compared to NOR. Ischemic myocardium in the HYP group had increased pro-angiogenic Akt and ERK signaling and decreased expression of anti-angiogenic markers compared to the NOR group. In the setting of chronic myocardial ischemia, hypoxia-modified EVs may enhance contractility, capillary density, and angiogenic signaling pathways compared to normoxia serum-starved EVs. [ABSTRACT FROM AUTHOR]

Many clinical trials have attempted to use stem cells to treat ischemic heart diseases (IHD), but the benefits have been modest. Though coronary collaterals can be a "natural bypass" for IHD patients, the regulation of coronary collateral growth (CCG) and the role of endogenous stem cells in CCG are not fully understood. In this study, we used a bone marrow transplantation scheme to study the role of bone marrow stem cells (BMSCs) in a rat model of CCG. Transgenic GFP rats were used to trace BMSCs after transplantation; GFP bone marrow was harvested or sorted for bone marrow transplantation. After recovering from transplantation, the recipient rats underwent 10 days of repetitive ischemia (RI), with echocardiography before and after RI, to measure cardiac function and myocardial blood flow. At the end of RI, the rats were sacrificed for the collection of bone marrow for flow cytometry or heart tissue for imaging analysis. Our study shows that upon RI stimulation, BMSCs homed to the recipient rat hearts' collateral-dependent zone (CZ), proliferated, differentiated into endothelial cells, and engrafted in the vascular wall for collateral growth. These RI-induced collaterals improved coronary blood flow and cardiac function in the recipients' hearts during ischemia. Depletion of donor CD34+ BMSCs led to impaired CCG in the recipient rats, indicating that this cell population is essential to the process. Overall, these results show that BMSCs contribute to CCG and suggest that regulation of the function of BMSCs to promote CCG might be a potential therapeutic approach for IHD. [ABSTRACT FROM AUTHOR]

Coronary flow velocity reserve (CFVR) is defined as the ratio between coronary flow velocity during maximal hyperemia and coronary flow at rest. Gold-standard techniques to measure CFVR are either invasive or require radiation and are therefore inappropriate for large-scale adoption. More than 30 years ago, echocardiography was demonstrated to be a reliable tool to assess CFVR, and its field of application rapidly expanded. Although initially validated to assess the hemodynamic relevance of a coronary stenosis, CFVR by echocardiography was later used to investigate coronary microcirculation. Microvascular dysfunction was detected in many different conditions, ranging from organ transplantation to inflammatory disorders and from metabolic diseases to cardiomyopathies. Moreover, it has been proven that CFVR by echocardiography not only detects coronary microvascular involvement but is also an effective prognostic factor that allows a precise risk stratification of the patients. In this review, we will summarize the many applications of CFVR by echocardiography, focusing on the coronary involvement of systemic diseases. [ABSTRACT FROM AUTHOR]

Following a myocardial infarction (MI), the prognosis of patients is highly dependent upon the re‐establishment of perfusion not only in the occluded coronary artery, but also within the coronary microcirculation. However, our fundamental understanding of the pathophysiology of the tiniest blood vessels of the heart is limited primarily because no current clinical imaging tools can directly visualise them. Moreover, in vivo experimental studies of the beating heart using intravital imaging have also been hampered due to obvious difficulties related to significant inherent contractile motion, movement of the heart brought about by nearby lungs and its location in an anatomically challenging position for microscopy. However, recent advances in microscopy techniques, and the development of fluorescent reporter mice and fluorescently conjugated antibodies allowing visualisation of vascular structures, thromboinflammatory cells and blood flow, have allowed us to overcome some of these challenges and increase our basic understanding of cardiac microvascular pathophysiology. In this review, the elegant attempts of the pioneers in intravital imaging of the beating heart will be discussed, which focussed on providing new insights into the anatomy and physiology of the healthy heart microvessels. The reviews end with the more recent studies that focussed on disease pathology and increasing our understanding of myocardial thromboinflammatory cell recruitment and flow disturbances, particularly in the setting of diseases such as MI. [ABSTRACT FROM AUTHOR]

Background: The mortality rate of acute ST-segment elevation myocardial infarction (STEMI) remains substantial, despite advances in treatment strategies. Coronary microcirculation dysfunction (CMD) persists after percutaneous coronary intervention (PCI) in a substantial proportion of STEMI patients. The association between CMD assessed using myocardial contrast echocardiography (MCE) and prognosis requires further elucidation. This study aimed to evaluate the impact of CMD after successful PCI on the prognosis of patients with STEMI. Methods: We enrolled 167 patients with STEMI after PCI who underwent MCE during hospitalization between January 2018 and March 2022. Patients were classified into the CMD and non-CMD groups according to the results of MCE. The clinical data and MCE results of both groups were analyzed. Follow-up was conducted for major adverse cardiac events. Results: MCE detected CMD in 105 patients (62.9%). The CMD group contained fewer hypertensive patients (55.2% versus 74.2%, P = 0.015). Patients with CMD exhibited significantly higher levels of plasma troponin I (TnI) [73.2 (23.0–124.0) versus 28.9 (12.7–80.2) ng/mL, P = 0.004], higher levels of plasma B-type natriuretic peptide [255 (99–641) versus 193 (59–389) pg/mL, P = 0.004], poorer Killip classification (P = 0.038), and different culprit vessels (P < 0.001) compared to the non-CMD group. Patients with CMD exhibited lower left ventricular ejection fraction [50 (43–58) versus 61 (54–67) %, P < 0.001], poorer wall motion score index values (1.68 ± 0.4 versus 1.31 ± 0.26, P < 0.001) and poorer left ventricular global longitudinal strain [–11.2 (–8.7 to –14.1) versus –13.9 (–11.0 to –17.2) %, P < 0.001] compared to the non-CMD group. Patients underwent follow-up for 13 (7–20) months. After adjusting for hypertension, peak TnI level, culprit vessel, and Killip classification, CMD was an independent predictor of total major adverse cardiac events at 13 months' follow-up [adjusted odds ratio (OR), 2.457; 95% confidence interval (CI), 1.042–5.790; P = 0.040], and patients with CMD had a higher risk of hospitalization for heart failure (adjusted OR, 5.184; 95% CI, 1.044–25.747; P = 0.044) and repeat myocardial infarction (adjusted OR, 2.896; 95% CI, 1.109–7.565; P = 0.030). Conclusions: MCE is a safe and effective method for detecting CMD in patients with STEMI. CMD detected by MCE after successful PCI in patients with STEMI is a common occurrence, which is associated with a significantly worse prognosis, especially hospitalization for heart failure and repeat myocardial infarction. [ABSTRACT FROM AUTHOR]

Background: There are scarce published data reporting the effect of rotational atherectomy (RA) on coronary microcirculation function. Objectives: We aimed to evaluate coronary microcirculation function indicated by the coronary angiography-derived index of microvascular resistance (caIMR) in patients undergoing RA. Methods: RA procedures between January 2013 and December 2021 were retrospectively analyzed. We investigated coronary microcirculation function indicated by caIMR as well as peri-procedural adverse events among the study population. All caIMR measurements were performed using a FlashAngio system. The primary outcome was a composite of post-RA thrombolysis in myocardial infarction (TIMI) flow grade <3 in the target vessel, myocardial injury, procedure-related myocardial infarction, and cardiac death during hospitalization. Results: A total of 155 RA procedures were analyzed. The post-RA caIMRs were significantly higher than pre-RA caIMRs in the target vessels (16.0 ± 7.0 vs. 14.5 ± 7.5, p = 0.029). Patients with post-RA caIMR ≥25 accounted for nearly 12% of those with pre-RA caIMR <25. Patients with post-RA thrombolysis in myocardial infarction (TIMI) flow grade <3 had a significantly higher pre-RA caIMR (23.5 ± 10.2 vs. 13.7 ± 6.6, p = 0.005), and the proportion of patients with pre-RA caIMR ≥25 in the group with TIMI flow grade <3 was greater (61.5% vs. 38.5%, p < 0.001) than that in the group with TIMI flow grade of 3. Maximum RA time of each pass (odds ratio: 1.127, 95% confidence interval: 1.025-1.239, p = 0.014) and pre-RA caIMR ≥25 (odds ratio: 3.254, 95% confidence interval: 1.054-10.048, p = 0.040) were identified to be the independent predictors of the primary outcome for patients who underwent RA. Conclusions: There were significant changes in the coronary microcirculation function of the target vessels after receiving RA as indicated by increased post-RA caIMR compared to pre-RA caIMR. Patients with baseline coronary microcirculatory dysfunction were more likely to have post-RA TIMI flow grade <3, whereas those with pre-RA caIMR ≥25 experienced worse outcomes. [ABSTRACT FROM AUTHOR]

Purpose of Review: Cardiac allograft vasculopathy (CAV) is a late-occurring complication of heart transplantation significantly limiting overall graft survival. In the last few years, evidence has been growing about the use of positron emission tomography (PET) myocardial perfusion imaging with integrated myocardial blood flow (MBF) quantification in heart transplant recipients. Recent Findings: Multiple studies have demonstrated that PET MBF assessment can be utilized to establish the diagnosis of CAV noninvasively and can be employed for prognostication. PET MBF quantification has also helped to define the link between transplant rejection and CAV. In addition, limited data suggests that PET MBF quantification can be used in heart transplant patients for serial monitoring of CAV. Summary: PET myocardial perfusion imaging integrating MBF quantification shows great promise for the evaluation of CAV with good diagnostic and prognostic performance. [ABSTRACT FROM AUTHOR]

The coronary microcirculation plays a cardinal role in regulating coronary blood flow to meet the changing metabolic demands of the myocardium. Coronary microvascular dysfunction (CMD) refers to structural and functional remodeling of the coronary microcirculation. CMD plays a role in the pathogenesis of obstructive and non-obstructive coronary syndromes as well as myocardial diseases, including heart failure with preserved ejection fraction (HFpEF). Despite recent diagnostic advancements, CMD is often under-appreciated in clinical practice, and may allow for the development of novel therapeutic targets. This review explores the diagnosis and pathogenic role of CMD across a range of cardiovascular diseases, its prognostic significance, and the current therapeutic landscape.

Background Sodium‐glucose cotransporter‐2 inhibitors are cardioprotective independent of glucose control, as demonstrated in animal models of acute myocardial ischemia and clinical trials. The functional and molecular mechanisms of these benefits in the setting of chronic myocardial ischemia are poorly defined. The purpose of this study is to determine the effects of canagliflozin therapy on myocardial perfusion, fibrosis, and function in a large animal model of chronic myocardial ischemia. Methods and Results Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, pigs received either no drug (n=8) or 300 mg sodium‐glucose cotransporter‐2 inhibitor canagliflozin orally, daily (n=8). Treatment continued for 5 weeks, followed by hemodynamic measurements, harvest, and tissue analysis. Canagliflozin therapy was associated with increased stroke volume and stroke work and decreased left ventricular stiffness compared with controls. The canagliflozin group had improved perfusion to ischemic myocardium compared with controls, without differences in arteriolar or capillary density. Canagliflozin was associated with decreased interstitial and perivascular fibrosis in chronically ischemic tissue, with reduced Jak/STAT (Janus kinase/signal transducer and activator of transcription) signaling compared with controls. In ischemic myocardium of the canagliflozin group, there was increased expression and activation of adenosine monophosphate‐activated protein kinase, decreased activation of endothelial nitric oxide synthase, and unchanged total endothelial nitric oxide synthase. Canagliflozin therapy reduced total protein oxidation and increased expression of mitochondrial antioxidant superoxide dismutase 2 compared with controls. Conclusions In the setting of chronic myocardial ischemia, canagliflozin therapy improves myocardial function and perfusion to ischemic territory, without changes in collateralization. Attenuation of fibrosis via reduced Jak/STAT signaling, activation of adenosine monophosphate‐activated protein kinase, and antioxidant signaling may contribute to these effects.

Cardioplegic ischemia–reperfusion and diabetes mellitus are correlated with coronary endothelial dysfunction and inactivation of small conductance calcium-activated potassium channels. Increased reactive oxidative species, such as mitochondrial reactive oxidative species, may contribute to oxidative injury. Thus, we hypothesized that inhibition of mitochondrial reactive oxidative species may protect coronary small conductance calcium-activated potassium channels and endothelial function against cardioplegic ischemia–reperfusion-induced injury. Small coronary arteries and endothelial cells from the hearts of mice with and without diabetes mellitus were isolated and examined by using a cardioplegic hypoxia and reoxygenation model to determine whether the mitochondria-targeted antioxidant Mito-Tempo could protect against coronary endothelial and small conductance calcium-activated potassium channel dysfunction. The microvessels or mouse heart endothelial cells were treated with or without Mito-Tempo (0-10 μM) 5 minutes before and during cardioplegic hypoxia and reoxygenation. Microvascular function was assessed in vitro by vessel myography. K+ currents of mouse heart endothelial cells were measured by whole-cell patch clamp. The levels of intracellular cytosolic free calcium (Ca2+) concentration, mitochondrial reactive oxidative species, and small conductance calcium-activated potassium protein expression of mouse heart endothelial cells were measured by Rhod-2 fluorescence staining, MitoSox, and Western blotting, respectively. Cardioplegic hypoxia and reoxygenation significantly attenuated endothelial small conductance calcium-activated potassium channel activity, caused calcium overload, and increased mitochondrial reactive oxidative species of mouse heart endothelial cells in both the nondiabetic and diabetes mellitus groups. In addition, treating mouse heart endothelial cells with Mito-Tempo (10 μM) reduced cardioplegic hypoxia and reoxygenation-induced Ca2+ and mitochondrial reactive oxidative species overload in both the nondiabetic and diabetes mellitus groups, respectively (P <. 05). Treatment with Mito-Tempo (10 μM) significantly enhanced coronary relaxation responses to adenosine 5′-diphosphate and NS309 (P <. 05), and endothelial small conductance calcium-activated potassium channel currents in both the nondiabetic and diabetes mellitus groups (P <. 05). Administration of Mito-Tempo improves endothelial function and small conductance calcium-activated potassium channel activity, which may contribute to its enhancement of endothelium-dependent vasorelaxation after cardioplegic hypoxia and reoxygenation. MT-induced endothelial protection in the setting of CP hypoxia and DM. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: The characteristics of heart failure (HF) with mildly reduced ejection fraction (EF) (HFmrEF) overlap with those of HF with reduced EF (HFrEF) and HF with preserved EF (HFpEF) and need to be further explored. This study aimed to evaluate left ventricular (LV) function and coronary microcirculation in patients with mildly reduced ejection fraction after acute ST-segment elevation myocardial infarction (STEMI).Methods: We enrolled 119 patients with STEMI who had undergone speckle tracking imaging and myocardial contrast echocardiography during hospitalization from June 2016 to June 2021. They were classified into normal, HFmrEF, and HFrEF groups according to their left ventricular EF (LVEF): ≥ 50%, 40-50%, and ≤ 40%, respectively. The data of the HFmrEF group were analyzed and compared with those of the normal and HFrEF groups.Results: HFmrEF was observed in 32 patients (26.9%), HFrEF in 17 (14.3%), and normal LVEF in 70 patients (58.8%). The mean global longitudinal strain (GLS) of all patients was - 11.9 ± 3.8%. The GLS of HFmrEF patients was not significantly different from that of the HFrEF group (- 9.9 ± 2.5% and - 8.0 ± 2.3%, respectively, P = 0.052), but they were both lower than that of the normal group (- 13.8% ± 3.5%, P < 0.001). The HFmrEF group exhibited significantly poorer myocardial perfusion index (1.24 ± 0.33) than the normal group (1.08 ± 0.14, P = 0.005) but displayed no significant difference from the HFrEF group (1.18 ± 0.19, P = 0.486). Moreover, a significant difference in the incidence of regional wall motion (WM) abnormalities in the three groups was observed (P = 0.009), and the WM score index of patients with HFmrEF was 1.76 ± 0.30, similar to that of patients with HFrEF (1.81 ± 0.43, P = 0.618), but poorer than that in the normal group (1.33 ± 0.25, P < 0.001).Conclusions: GLS is a more sensitive tool than LVEF for detecting LV systolic dysfunction. The LV systolic function, coronary microcirculation, and WM in patients with HFmrEF was poorer than that of patients with normal LVEF, but comparable to that in patients with HFrEF. Patients with HFmrEF after STEMI require more attention and appropriate management. [ABSTRACT FROM AUTHOR]

Background and hypothesisThe field of coronary artery physiology is developing rapidly and changing the practice of interventional cardiology. A new functional evaluation technique using the instantaneous wave-free ratio (iFR) has become an alternative to fractional flow reserve. Future research studies need to determine whether physiological indicators play a role in evaluating myocardial perfusion in the catheter room.Materials and methodsThirty-eight patients scheduled for coronary angiography and iFR evaluation underwent a real-time myocardial contrast echocardiography (RT-MCE) examination at rest. The myocardial perfusion parameters (A, β, and A × β) on the myocardial perfusion curve were quantitatively analyzed using Q-Lab software. Coronary angiography and iFR assessment were completed within 1 week after the RT-MCE examination in all patients. Correlation analysis was used to identify iFR- and MCE-related indicators. The sensitivity and specificity of iFR in the quantitative detection of coronary microcirculation were obtained.ResultsThe correlation coefficients between iFR and A, β, and A × β were 0.81, 0.66, and 0.82, respectively. The cut-off value for iFR was 0.85 for microvascular ischemia detection, while the sensitivity and specificity for the diagnosis of myocardial perfusion were 90.7 and 89.9%, respectively. The receiver operating characteristic (ROC) curve area for iFR was 0.946 in the segments related to myocardial blood flow.ConclusionThe iFR is an effective tool for detecting myocardial microcirculation perfusion, with satisfactory diagnostic performance and a demonstrated role in physiological indices used for the perfusion assessment.

BackgroundThe endothelial glycocalyx (EG) is essential for maintaining microvascular homeostasis. However, the relationship between the EG and coronary microcirculation remains to be elucidated. One of the main components of EG is syndecan-1, and its shedding has been claimed to represent the state of the EG. In this study, we aimed to analyze the association between syndecan-1 and the coronary microcirculation.MethodsWe enrolled suspected coronary artery disease (CAD) patients who consecutively underwent coronary angiography (CAG) and angiography-based analysis of physiological indices in the left anterior descending artery (LAD). Serum syndecan-1 was measured by enzyme-linked immunosorbent assay (ELISA). The coronary microcirculation was evaluated by the presence of coronary microvascular dysfunction (CMD) and an impaired microvascular vasodilatory capacity (IMVC), which were quantified by an angiography-derived index of microcirculatory resistance (IMRangio) in the maximum hyperemic state (H-IMRangio) induced by adenosine triphosphate and the ratio (RRRangio) of IMRangio in the non-hyperemic phase to H-IMRangio, respectively.ResultsA total of 528 patients were enrolled in this study. There was no difference in epicardial coronary complexity between patients with high syndecan-1 (HSG) and low syndecan-1 (LSG) levels grouped by the median concentration of syndecan-1 (SYNTAX: 7[3, 10] vs. 9[4, 12], P = 0.15). However, H-IMRangio and RRRangio were different between the LSG and HSG groups (H-IMRangio: 23.64 ± 6.28 vs. 27.67 ± 5.59, P < 0.01; RRRangio: 1.74[1.46, 2.08] vs. 1.55[1.34, 1.72], P < 0.01). Patients with CMD (H-IMRangio > 25) and patients with IMVC (RRRangio below the median value) both had higher syndecan-1 levels (CMD: 86.44 ± 54.15 vs. 55.2 ± 43.72, P < 0.01; IMVC: 83.86 ± 55.41 vs. 59.68 ± 45.06, P < 0.01). After adjustment for confounding factors, HSG remained associated with the presence of CMD and IMVC (CMD: odds ratio [OR]: 2.769, P < 0.01; IMVC: OR: 1.908, P < 0.01).ConclusionHigh levels of syndecan-1 are independently associated with the presence of CMD and IMVC among patients with suspected CAD.

Objective: Preliminary clinical studies have confirmed that Shexiang Tongxin dropping pills (STDPs) could improve angina pectoris and attenuate vascular endothelial dysfunction in patients with slow coronary flow, but the underlying mechanism is not fully unclear. We aimed to investigate the impact of STDP in a swine model of coronary slow flow (SF) and related mechanisms. Methods: SF was induced by coronary injection of 40 μ m microspheres, and pigs were randomly divided into the SF group and SF plus STDP group. Pigs in the STDP group received sublingual STDP for 10 min, followed by 1 g STDP oral administration daily for 6 days. Coronary angiography was performed, the TIMI frame count (TFC) was determined, and hemodynamic measurements were performed before, at 30 min, and 7 days post-SF. Serum levels of total NO, NOS, ET-1, C-TNI, and BNP were measured. Myocardial expressions of TNF and IL-6, eNOS, VEGF, CD31, and α-SMA were analyzed by immunohistochemistry and Western blotting. Results: Compared to the SF group, LVEF and TFC were significantly improved at 7 days post-SF in the STDP group. The serum ET-1 level was significantly reduced at 7 days, and NO and NOS levels were significantly higher in the STDP group. Seven days post-SF, myocardial TNF and IL-6 expressions were significantly downregulated, while the expressions of eNOS and VEGF, CD31, and ɑ-SMA were significantly upregulated in the STDP group. Conclusion: Our results showed that STDP improved cardiac function and coronary flow, possibly through reducing inflammatory responses and upregulating myocardial eNOS and VEGF, CD31, and the ɑ-SMA expression. [ABSTRACT FROM AUTHOR]

Abstract Background Obstruction of coronary microcirculation can lead to myocardial ischemia and poor prognosis. Salvianolate exerts cardiovascular protection at cellular levels. However, no studies have confirmed the effect of salvianolate on stable coronary heart disease (CHD) with high fractional flow reserve (FFR) and myocardial microcirculatory disturbances. Methods/design This study will enroll 78 patients who have stable coronary disease with 50 to 70% stenosis in major coronary arteries and whose FFR > 0.80 and index of microcirculatory resistance (IMR) > 25. Patients will be randomly divided into the salvianolate group or the placebo group. After above evaluations, salvianolate 200 mg will be intravenously dripped immediately for the next 30 min and subsequent 7 days in the salvianolate group, and matching 0.9% normal saline will be arranged in the placebo group. IMR will be reevaluated in immediate phase after first 30 min of salvianolate or placebo treatment. The primary end point will be the IMR change in this phase, and the secondary end points will be the total ischemic burden assessed by the Seattle angina scale, quality of life scale, Holter electrocardiography, and 6-min walk test after 7 days before discharge. Discussion This study will firstly clarify the improvement effect of salvianolate on coronary microcirculation and provide an effective treatment method for stable CHD patients with high FFR and myocardial microcirculatory disturbance. Trial registration Chinese Clinical Trial Registry ChiCTR1800018772 . Registered on 9 October 2018 and updated on 2 March 2020