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Immune checkpoint inhibitors (ICIs) exhibit remarkable antitumor activity and immune-related cardiotoxicity of unknown pathomechanism. The aim of the study was to investigate the ICI class-dependent cardiotoxicity in vitro and pembrolizumab’s (Pem’s) cardiotoxicity in vivo, seeking for translational prevention means. Cytotoxicity was investigated in primary cardiomyocytes and splenocytes, incubated with ipilimumab, Pem and avelumab. Pem’s cross-reactivity was assessed by circular dichroism (CD) on biotechnologically produced human and murine PD-1 and in silico. C57BL6/J male mice received IgG4 or Pem for 2 and 5 weeks. Echocardiography, histology, and molecular analyses were performed. Coronary blood flow velocity mapping and cardiac magnetic resonance imaging were conducted at 2 weeks. Human EA.hy926 endothelial cells were incubated with Pem-conditioned media from human mononuclear cells, in presence and absence of statins and viability and molecular signaling were assessed. Atorvastatin (20 mg/kg, daily) was administered in vivo , as prophylaxis. Only Pem exerted immune-related cytotoxicity in vitro. Pem’s cross-reactivity with the murine PD-1 was confirmed by CD and docking. In vivo, Pem initiated coronary endothelial and diastolic dysfunction at 2 weeks and systolic dysfunction at 5 weeks. At 2 weeks, Pem induced ICAM-1 and iNOS expression and intracardiac leukocyte infiltration. At 5 weeks, Pem exacerbated endothelial activation and triggered cardiac inflammation. Pem led to immune-related cytotoxicity in EA.hy926 cells, which was prevented by atorvastatin. Atorvastatin mitigated functional deficits, by inhibiting endothelial dysfunction in vivo. We established for the first time an in vivo model of Pem-induced cardiotoxicity. Coronary endothelial dysfunction precedes Pem-induced cardiotoxicity, whereas atorvastatin emerges as a novel prophylactic therapy.

Coronary endothelial dysfunction (CED) and coronary artery spasm (CAS) are causes of angina with no obstructive coronary arteries in patients. Both can be diagnosed by invasive coronary function testing (ICFT) using acetylcholine (ACh). This study aimed to evaluate the diagnostic yield of a 3-minute ACh infusion as compared with a 1-minute ACh bolus injection protocol in testing CED and CAS. We evaluated 220 consecutive patients with angina and no obstructive coronary arteries who underwent ICFT using continuous Doppler flow measurements. Per protocol, 110 patients were tested using 3-minute infusion, and thereafter 110 patients using 1-minute bolus injections, because of a protocol change. CED was defined as a <50% increase in coronary blood flow or any epicardial vasoconstriction in reaction to low-dose ACh and CAS according to the Coronary Vasomotor Disorders International Study Group (COVADIS) criteria, both with and without T-wave abnormalities, in reaction to high dose ACh. The prevalence of CED was equal in both protocols (78% vs 79%, p = 0.869). Regarding the endotypes of CAS according to COVADIS, the equivocal endotype was diagnosed less often in the 3 vs 1-minute protocol (24% vs 44%, p = 0.004). Including T-wave abnormalities in the COVADIS criteria resulted in a similar diagnostic yield of both protocols. Hemodynamic changes from baseline to the low or high ACh doses were comparable between the protocols for each endotype. In conclusion, ICFT using 3-minute infusion or 1-minute bolus injections of ACh showed a similar diagnostic yield of CED. When using the COVADIS criteria, a difference in the equivocal diagnosis was observed. Including T-wave abnormalities as a diagnostic criterion reclassified equivocal test results into CAS and decreased this difference. For clinical practice, we recommend the inclusion of T-wave abnormalities as a diagnostic criterion for CAS and the 1-minute bolus protocol for practicality.

Coronary microvascular endothelial dysfunction is both a culprit and a victim of diabetes, and can accelerate diabetes-related microvascular and macrovascular complications by promoting vasoconstrictive, pro-inflammatory and pro-thrombotic responses. Perturbed mitochondrial function induces oxidative stress, disrupts metabolism and activates apoptosis in endothelial cells, thus exacerbating the progression of coronary microvascular complications in diabetes. The mitochondrial quality surveillance (MQS) system responds to stress by altering mitochondrial metabolism, dynamics (fission and fusion), mitophagy and biogenesis. Dysfunctional mitochondria are prone to fission, which generates two distinct types of mitochondria: one with a normal and the other with a depolarized mitochondrial membrane potential. Mitochondrial fusion and mitophagy can restore the membrane potential and homeostasis of defective mitochondrial fragments. Mitophagy-induced decreases in the mitochondrial population can be reversed by mitochondrial biogenesis. MQS abnormalities induce pathological mitochondrial fission, delayed mitophagy, impaired metabolism and defective biogenesis, thus promoting the accumulation of unhealthy mitochondria and the activation of mitochondria-dependent apoptosis. In this review, we examine the effects of MQS on mitochondrial fitness and explore the association of MQS disorders with coronary microvascular endothelial dysfunction in diabetes. We also discuss the potential to treat diabetes-related coronary microvascular endothelial dysfunction using novel MQS-altering drugs.

Myocardial bridging (MB), a congenital variant where a coronary artery segment is tunneled within the myocardium, is increasingly recognized as a contributor to coronary endothelial and vasomotor dysfunction. Beyond the hallmark systolic compression observed on angiography, MB disrupts endothelial integrity, impairs the release of vasoactive substances, and induces vasomotor abnormalities. These effects exacerbate ischemic symptoms and predispose to atherosclerosis in the proximal segment, particularly in conditions such as ischemia/myocardial infarction with nonobstructive coronary arteries. Recent studies underscore MB’s association with coronary vasospasm, microvascular endothelial dysfunction, and adverse cardiovascular outcomes, including sudden cardiac death. These findings highlight the interplay between MB’s structural anomalies and functional impairments, with factors such as the bridge’s length, depth, and orientation influencing its hemodynamic significance. Advances in imaging and coronary physiology assessment, including acetylcholine testing and stress diastolic fractional flow reserve/iFR/RFR, have enhanced diagnostic precision. This review explores the multifaceted impact of MB on coronary physiology, emphasizing its role in endothelial dysfunction and vasomotor regulation. Recognizing MB’s contribution to cardiovascular disease is essential for accurate diagnosis and tailored management strategies aimed at mitigating ischemic risk and improving patient outcomes.

Coronary endothelial dysfunction is an early and critical vascular abnormality in cardiometabolic syndrome, intensified by irregular sleep patterns and excess adiposity. Disruption of circadian rhythm and accumulation of visceral fat impair nitric oxide signaling and promote arterial stiffness through endothelial injury. The gut vascular axis further contributes via microbial imbalance and endotoxin translocation, elevating systemic inflammation and vascular stress. Clinical evidence indicates that probiotics restore microbial equilibrium and attenuate vascular damage. Phytoantioxidants such as curcumin, berberine, and epigallocatechin gallate exert endothelial protective effects by enhancing nitric oxide synthase activity and suppressing inflammatory mediators. These compounds also activate the nuclear factor erythroid two related factor two (Nrf2) pathway, which regulates oxidative balance and promotes vascular resilience. Together, probiotics and phytoantioxidants represent a promising integrative approach to mitigate coronary endothelial dysfunction in populations affected by sleep disturbance and obesity. This review narratively integrates current molecular and clinical findings to delineate precision-guided pathways for endothelial recovery and cardiometabolic risk reduction.

Knowledge about normoxic hypoxia-inducible factor (HIF)-1α stabilization is limited. We investigated normoxic HIF-1α stabilization and its consequences using live cell imaging, immunoblotting, Bio-Plex multiplex immunoassay, immunofluorescence staining, and barrier integrity assays. We demonstrate for the first time that IL-8 and M-CSF caused HIF-1α stabilization and translocation into the nucleus under normoxic conditions in both human coronary endothelial cells (HCAECs) and HIF-1α-mKate2-expressing HEK-293 cells. In line with the current literature, our data show significant normoxic HIF-1α stabilization caused by TNF-α, INF-γ, IL-1β, and IGF-I in both cell lines, as well. Treatment with a cocktail consisting of TNF-α, INF-γ, and IL-1β caused significantly stronger HIF-1α stabilization in comparison to single treatments. Interestingly, this cumulative effect was not observed during simultaneous treatment with IL-8, M-CSF, and IGF-I. Furthermore, we identified two different kinetics of HIF-1α stabilization under normoxic conditions. Our data demonstrate elevated protein levels of HIF-1α-related genes known to be involved in the development of atherosclerosis. Moreover, we demonstrate an endothelial barrier dysfunction in HCAECs upon our treatments and during normoxic HIF-1α stabilization comparable to that under hypoxia. This study expands the knowledge of normoxic HIF-1α stabilization and activation and its consequences on the endothelial secretome and barrier function. Our data imply an active role of HIF-1α in vivo in the vasculature in the absence of hypoxia.

Purpose Smoking cessation has been shown to normalize the coronary endothelial dysfunction in healthy young smokers. However, its effect has not been explored in middle-aged smokers with a longer history of smoking. Therefore, we compared the effects of smoking cessation on coronary vasomotor response between both young and middle-aged smokers and identified the predictor for its improvement. Methods This study investigated 14 young healthy smokers (age 25.2 ± 2.3 years), 13 middle-aged smokers (age 42.0 ± 6.5 years) and 10 non-smokers. Myocardial blood flow (MBF) was measured by using 15 O-water positron emission tomography (PET). Results At baseline, the ratio of MBF during the cold pressor test (CPT) to that at rest (MBF CPT/rest ), the index of coronary endothelial function, was significantly decreased in both young and middle-aged smokers compared to non-smokers (1.24 ± 0.20 and 1.10 ± 0.39 vs 1.53 ± 0.18, p  < 0.05 and p  < 0.001, respectively). The ratio of MBF during adenosine triphosphate infusion to that at rest was significantly decreased in middle-aged smokers compared to young smokers and non-smokers (3.34 ± 1.52 vs 4.43 ± 0.92 and 4.69 ± 1.25, p  < 0.05, respectively). MBF CPT/rest at 1 month after smoking cessation significantly increased in young smokers, but not in middle-aged smokers. By multivariate analysis, baseline serum malondialdehyde-modified low-density lipoprotein (MDA-LDL) was an independent predictor for the changes in MBF CPT/rest after smoking cessation (β = –0.45, p  < 0.05). Conclusion Coronary endothelial dysfunction was reversible by short-term smoking cessation in young smokers, but not in middle-aged smokers, which was associated with serum MDA-LDL levels. Long-term smoking exposure could lead to more advanced coronary endothelial dysfunction and atherosclerosis possibly via oxidative stress.

Objective: The pathophysiology of coronary slow flow phenomenon (CSFP) is poorly understood. Evidence suggesting endothelial dysfunction in patients with slow coronary flow (SCF) led to this evaluation of a possible correlation between microalbuminuria (MAU), as an indicator of endothelial dysfunction, and CSFP in order to investigate a mutual pathophysiology. Methods: In this case-control study, 15786 patients who presented between September 2016 and April 2018 were screened. All patients with CSFP had chest pain and coronary angiography was indicated due to a positive noninvasive test. All cases had a Thrombosis in Myocardial Infarction (TIMI) flow grade of 2 or a corrected TIMI frame count of >27 without any evidence of obstructive coronary artery disease. The patients used as controls had completely normal coronary angiograms. Fasting mid-stream urine samples were analyzed using an immunoturbidimetric assay to determine the albumin-creatinine ratio (ACR) as a surrogate of microalbuminuria (MAU) (ACR: 30–300 mg/g). The prevalence of MAU in the case and control groups was analyzed. Results: A total of 154 individuals with a normal coronary angiogram and 46 patients with SCF were enrolled in the study. The prevalence of MAU was greater in patients with SCF than in the control group (8.7% vs 1.9%, respectively; p=0.048). Even after adjustment for major risk factors, the association between MAU and CSPF remained significant. Conclusion: The results of this study indicated that there was a relationship between MAU and CSFP and confirmed that endothelial dysfunction is a contributing factor to CSFP. These findings are of utmost importance due to the prognostic value of MAU for both all-cause and cardiovascular mortality rates.

Global myocardial ischemia and reperfusion injury play a major role in early postoperative myocardial graft dysfunction. The aim of the present study was to investigate the effects of the nitric oxide (NO) precursor l‐arginine on myocardial and endothelial function after hypothermic ischemia and reperfusion in a heterotopic rat heart transplantation model. After 1 hour ischemic preservation, reperfusion was started after application of placebo (control, n= 12) or l‐arginine (l‐Arg 40 mg/kg, n= 12), a substrate of NO synthesis. Myocardial blood flow (MBF) was assessed by the hydrogen clearance method. An implanted balloon was used to obtain pressure–volume relations of the transplanted heart. Left ventricular developed pressure (LVDP), rate of pressure development (dP/dt), end‐diastolic pressure (LVEDP), isovolumic relaxation constant (TE), and MBF were measured after 60 minutes and 24 hours of reperfusion. Endothelium‐dependent vasodilatation in response to acetylcholine (ACh) and endothelium‐independent vasodilatation in response to sodium nitroprusside (SNP) were also determined. After 1 hour the MBF was significantly higher in the l‐Arg group (3.6 ± 0.6 vs. 1.9 ± 0.2 ml/min/g, p < 0.05). The l‐Arg group showed better recovery of systolic function and myocardial relaxation (LVDP 106 ± 6 vs. 70 ± 7 mmHg, p < 0.05; maximal dP/dt 5145 ± 498 vs. 3410 ± 257 mmHg/s, p < 0.05; TE 12.1 ± 0.9 vs. 16.1 ± 1.5 ms, p < 0.05, at an intraventricular volume of 80 μl). LVEDP was similar in the two groups. After 24 hours no difference was found between the groups for basal MBF, LVP, dP/dt, TE, LVEDP, or the response of MBF to SNP. However, ACh led to a significantly higher increase in MBF in the l‐Arg group (52 ± 8% vs. 29 ± 7%,p < 0.05). These results indicate that (1) NO donation improves myocardial and endothelial functional recovery during early reperfusion after heart transplantation; and (2) initial treatment with l‐Arg has a persisting beneficial effect against reperfusion‐induced graft coronary endothelial dysfunction during late reperfusion.