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PubMed2026

Endothelial function in relation to low-level chronic residential air pollution in a general population: a cohort study.

BACKGROUND: Given the recently updated clean-air targets, this population study assessed endothelial function at low exposure to particulate matter with an aerodynamic diameter of ≤10 µm (PM10) and ≤2.5 µm (PM2.5), nitrogen dioxide (NO2) and black carbon (BC). METHODS: In 453 Flemish participants (47.7% women; mean age, 52.8 years), endothelial function was assessed by finger photoplethysmography after 5 min of ischaemia. The outcome measures were the maximal ischaemic-to-control ratio (Rmax) and the maximal difference (Dmax) in pulse amplitude between the test and control fingers. The air pollutants were related to Rmax and Dmax using mixed models accounting for coresidence, to cardiovascular endpoints by proportional hazards regression, and to residential address by high-resolution spatiotemporal interpolation. RESULTS: From 2010 to 2015, PM10, PM2.5, NO2 and BC decreased (p < 0.0001) with 6-year levels averaging 15.9, 12.8, 14.3 and 1.04 µg/m3. Irrespective of adjustment for risk factors, Dmax was inversely correlated with PM2.5, while associations of Rmax with PM2.5 and associations of both Dmax and Rmax with other pollutants were weaker (p values <0.10), but consistently inverse. Association sizes of Rmax and Dmax with PM10 and PM2.5 weakened over 6 years, paralleling the decreasing air pollutants (p ≤ 0.044). In adjusted analyses, the risk of a composite cardiovascular endpoint decreased (p ≤ 0.043) with higher Rmax and Dmax with hazard ratios ranging from 0.31 to 0.49. Finally, in the geographical analysis, endothelial dysfunction followed the spatial gradients in PM2.5. CONCLUSIONS: Long-term low-level air pollution is associated with subclinical endothelial dysfunction, the initial and critical step leading to adverse cardiovascular outcomes.

Humans↗

PubMed1986

Factors determining the activity of ischemic heart disease.

Transient regional myocardial ischemia appears to underlie symptoms such as angina pectoris and represents a key pathophysiologic step, since it is an objective marker of disease activity and is capable of causing disabling symptoms and damage to left ventricular myocardium. A study of the characteristics of transient ischemia in and out of the hospital has shown that symptoms are an inconsistent underestimation of these events. Ischemia is generally prolonged, mostly asymptomatic, and usually accompanied by a regional decrease in myocardial perfusion. Studies out of the hospital have also shown that these episodes are frequently triggered by a wide range of ordinary everyday activities. These new features of transient ischemia are worth noting when searching for relevant causes that are present during everyday life and when trying to choose more rational therapy. More detailed studies of patient activity have shown that different levels of mental arousal are the most common triggering mechanism causing ischemia out of the hospital. In addition, the occurrence of transient ischemia during everyday life displays a circadian rhythm, with an increase and peak occurrence between 6:00 A.M. and 12 noon each day. The day-to-day variability of ischemia is marked, indicating functional disturbances of coronary stenoses against a background of a severe reduction in cross-sectional area. The examination of proximal stenoses has shown that the reduction in cross-sectional area is usually underestimated by conventional angiography; pressure gradients across coronary stenoses are common and, with reduced poststenotic blood pressure, can jeopardize perfusion; disturbances of vessel caliber and antegrade flow can accompany many of the ordinary everyday activities known to trigger ischemia detected in Holter tapes studied out of the hospital; and there is clear-cut evidence of endothelial dysfunction in these patients, with reversal of the normal dilator response to acetylcholine and paradoxical constriction of stenoses. This evidence of endothelial dysfunction in humans could be central to the problems of atheromatous narrowing, thrombus, and disturbed vasomotion.

Angina Pectoris↗

PubMed1992

Coronary endothelial and cardiac protective effects of a monoclonal antibody to intercellular adhesion molecule-1 in myocardial ischemia and reperfusion.

BACKGROUND: Intercellular adhesion molecule-1 (ICAM-1) is a major ligand on endothelial cells for adherence of activated polymorphonuclear leukocytes (PMNs). The major purpose of this study was to study the effects of RR1/1, a monoclonal antibody against ICAM-1 (i.e., MAb RR1/1), on myocardial injury and endothelial dysfunction associated with myocardial ischemia and reperfusion. METHODS AND RESULTS: Either MAb RR1/1 (2 mg/kg, n = 7), an antibody that was found to bind selectively to endothelial cells in the cat, or MAb R3.1 (2 mg/kg, n = 7), a nonbinding control antibody, was given as an intravenous bolus 10 minutes before reperfusion. Two hundred eighty minutes later, hearts were excised. The left ventricle area-at-risk (AAR) was similar in MAb RR1/1 (29 +/- 2%) and MAb R3.1 (30 +/- 3%) groups. In MAb R3.1-treated cats, 90 minutes of myocardial ischemia plus 4.5 hours of reperfusion induced a significant myocardial injury (necrotic tissue/AAR, 28 +/- 2%), high myeloperoxidase activity (0.65 +/- 0.16 units/100 mg ischemic tissue), and a marked decrease in endothelium-dependent vasorelaxation in isolated left anterior descending coronary arteries (vasorelaxation to acetylcholine, 29 +/- 3%) with no change in endothelium-independent vasorelaxation (relaxation to NaNO2, 91 +/- 3%). However, cats treated with MAb RR1/1 developed significantly less myocardial necrosis (10 +/- 2% of the AAR, p less than 0.01), lower myeloperoxidase activity in ischemic myocardial tissue (0.2 +/- 0.03 units/100 mg ischemic tissue, p less than 0.01), and enhanced vasorelaxant responses to endothelial-dependent relaxation to acetylcholine (53 +/- 5%) compared with ischemic/reperfused cats treated with Mab R3.1. Furthermore, addition of MAb RR1/1 in vitro significantly inhibited unstimulated PMN adherence to ischemic-reperfused coronary artery endothelium. CONCLUSIONS: These results suggest that ICAM-1-dependent PMN adherence plays an important role in reperfusion injury, and that PMN adherence and infiltration contribute significantly to coronary endothelial dysfunction.

Animals↗

PubMed1982

Clinical investigations on the corneal endothelium-XXXVIII Edward Jackson Memorial Lecture.

The normal thickness and transparency of the cornea is maintained by the barrier function and the active fluid pump of the corneal endothelium. The major barrier is the intercellular gap junctions, and the fluid pump depends on the active transport of bicarbonate ions. Three methods are currently available for studying this important cell layer. (1) Endothelial dysfunction produces corneal swelling, and measuring the thickness of the swelling permits the degree of damage and the repair processes to be evaluated. (2) The endothelium's permeability to fluorescein reflects the state of its barrier. (3) The morphometric measurements obtained by specular microscopy of the endothelial cells permit the cell size distribution pattern and any alterations in it to be studied. Although the cell size distribution is normal in the young adult, cellular pleomorphism increases and cell density decreases during the aging process. A follow-up study of cell transformation after surgical trauma disclosed that the human endothelium shows practically no proliferative activity and that the damaged area is covered by means of cell migration. This migration, however, is incomplete, resulting in persistent regional differences in the cell distribution pattern. The traumatized endothelium continues to lose cells at an accelerated rate and endothelial dysfunction may develop many years after injury.

Adolescent↗

PubMed1992

In vivo measurement of endothelium-dependent vasodilation with substance P in man.

Endothelial cells synthesize and metabolize vasoactive substances which are involved in the regulation of vascular tone. Among these factors, the endothelium-derived nitric oxide (NO) appears to be of major importance. Many studies observed an impairment of the generation, release, or the diffusion of endothelial NO across the vascular intima in laboratory animals with various experimental diseases such as hypercholesterolemia, atherosclerosis and hypertension. In human coronary arteries obtained from explanted hearts impaired endothelium-dependent relaxations were measured in atherosclerotic segments. The hypothesis of a decreased NO mediated vasodilation in patients with coronary artery disease was further underscored by in vivo studies in man using intracoronary infusions of the endothelium-dependent vasodilator acetylcholine and quantitative coronary angiographic measurements of the diameter changes. From these observations it was assumed that endothelial dysfunction, in particular a profound inability of the coronary endothelium to relax via NO dependent mechanisms may play an important role in the pathogenesis of abnormal coronary vasomotion. However, further investigations in man reveal that the ability of the coronary endothelium of patients with coronary artery disease or vasospastic angina to produce endothelial NO is less affected as judged from the effects of acetylcholine. In recent investigations a largely preserved endothelial function could be measured in these patients when the endothelium-dependent vasodilator substance P was used as a tool for the measurement of NO dependent relaxation. Thus, endothelial dysfunction does not appear to serve as a major cause of abnormal vasoconstriction in coronary artery disease or vasospastic angina in man.

Acetylcholine↗

PubMed1990

In vivo interleukin-2 activated sheep lung lymph lymphocytes increase ovine vascular endothelial permeability by non-lytic mechanisms.

Therapeutic doses of recombinant interleukin-2 (rIL-2) often result in systemic toxicity consistent with increased vascular permeability. rIL-2 activated lymphocytes (IALs) may produce endothelial dysfunction and have cytolytic potential. However, much of the data on IAL cytotoxicity comes from the use of in vitro activated IALs. Alternatively, rIL-2 may enhance permeability directly or via release of various cytokines by host effector cells. The cytotoxicity of in vivo activated lung lymph lymphocytes has been studied in an ovine model of rIL-2 toxicity. The in vivo IALs had no significant endothelial cytolysis at effector to target ratios of 100:1. However, the in vivo IALs increased endothelial monolayer permeability to albumin, dependent on the concentration of IALs. rIL-2 induced no endothelial cytolysis or permeability alterations at doses of 10(5) and 2 x 10(5) U/ml, respectively. These findings suggest that the acute endothelial dysfunction characteristic of the vascular leak syndrome is not due to rIL-2 directly, but is mediated by in vivo IALs via non-cytolytic mechanisms and/or the release of secondary cytokines in response to rIL-2.

Albumins↗

PubMed1992

Beneficial effects of SPM-5185, a cysteine-containing NO donor in myocardial ischemia-reperfusion.

Intravenous administration of SPM-5185 [N-nitratopivaloyl-S-(N'-acetylalanyl)-cysteine ethyl ester], a cysteine-containing nitric oxide (NO) donor, or SPM-5267 [pivaloyl-S-(N'-acetylalanyl)-cysteine ethyl ester], an analogue of SPM-5185 that lacks the NO moiety, was studied in a feline myocardial ischemia-reperfusion model. Administration of SPM-5185 (1 mg/kg), followed by a 2-mg.kg-1.h-1 infusion starting 10 min before reperfusion, resulted in significant protection 4.5 h postreperfusion. In the myocardial ischemia (MI)+SPM-5267 group, 38 +/- 4% of the area at risk was necrotic, whereas the necrotic area/area at risk was only 7 +/- 2% in the MI+SPM-5185 group (P less than 0.01). Moreover, SPM-5185 treatment markedly attenuated the endothelial dysfunction observed in the left anterior descending coronary artery after reperfusion by 50%. These beneficial effects occurred despite the absence of a significant change in myocardial oxygen demand, as measured by the pressure-rate index. In vitro experiments demonstrated that SMP-5185, but not SPM-5267, decreased adherence of neutrophils to the coronary vascular endothelium and decreased production of superoxide radicals. Therefore, a likely mechanism of the observed cardioprotection by SPM-5185 involves attenuation of polymorphonuclear leukocyte-induced endothelial dysfunction.

Animals↗

PubMed1992

The role of L-arginine in ameliorating reperfusion injury after myocardial ischemia in the cat.

BACKGROUND: Myocardial ischemia followed by reperfusion results in endothelial dysfunction characterized by a reduced release of endothelium-derived relaxing factor (EDRF). Because EDRF has been characterized as nitric oxide, we examined the ability of L-arginine, the substrate for nitric oxide synthesis, to protect in a feline model of myocardial ischemia plus reperfusion. METHODS AND RESULTS: The effects of L-arginine were investigated in a 6-hour model of myocardial ischemia and reperfusion in pentobarbital-anesthetized cats. A bolus administration (30 mg/kg) of L-arginine, or its enantiomer D-arginine, was given followed by a continuous infusion of 10 mg/kg/min for 1 hour starting 10 minutes before reperfusion. Myocardial ischemia plus reperfusion in cats receiving D-arginine resulted in severe myocardial injury and endothelial dysfunction characterized by marked myocardial necrosis, high cardiac myeloperoxidase activity in ischemic cardiac tissue, and loss of acetylcholine- and A-23187-induced endothelium-dependent relaxation in coronary artery rings. In contrast, myocardial ischemia plus reperfusion cats treated with L-arginine exhibited a reduced area of cardiac necrosis (16 +/- 2% versus 41 +/- 5% of area at risk, p less than 0.01), lower myeloperoxidase activity in the ischemic region (0.3 +/- 0.08 versus 0.8 +/- 0.10 units/100 mg tissue, p less than 0.05), and significant preservation of acetylcholine- (p less than 0.01) and A-23187- (p less than 0.01) induced endothelial-dependent relaxation. CONCLUSIONS: These results demonstrate the ability of L-arginine to reduce necrotic injury in a cat model of myocardial ischemia plus reperfusion, and this reduction in infarct size is associated with the preservation of endothelial function and attenuation of neutrophil accumulation in ischemic cardiac tissue.

Animals↗

PubMed1989

Coronary vasomotion in response to sympathetic stimulation in humans: importance of the functional integrity of the endothelium.

The coronary vasomotor response to the cold pressor test was studied with use of quantitative coronary angiography in 32 patients without evidence of coronary artery disease and 55 patients with such disease; in a subset of 22 patients (9 with normal coronary arteries and 13 with coronary artery disease), the effects of the cold pressor test were compared with the effects of the endothelium-dependent vasodilator acetylcholine with simultaneous intracoronary Doppler flow velocity measurements to assess the influence of endothelial dysfunction. The cold pressor test induced vasodilation of 8.9 +/- 5.7% in all 77 analyzed vessel segments of the group with normal arteries (p less than 0.01). In contrast, in patients with coronary artery disease, the 52 analyzed stenotic segments were constricted by -12.1 +/- 9.5% (p less than 0.01), the 57 analyzed vessel segments with luminal irregularities were constricted by -8.9 +/- 5.2% (p less 0.01) and 40 (85%) of 47 angiographically normal segments also were constricted by -7.0 +/- 4.9% (p less than 0.05). Preserved vasodilating capability was demonstrated by intracoronary nitroglycerin in all analyzed segments. In nine patients with normal coronary arteries, the analyzed vessel segments were dilated in response to both the cold pressor test and intracoronary acetylcholine by 10.9 +/- 5.4% and 13.4 +/- 4.7%, respectively. In contrast, in all 13 patients with coronary artery disease, vasoconstriction of identical vessel segments by -9.1 +/- 3.7% and -23 +/- 10.4%, respectively, was observed after both the cold pressor test and intracoronary acetylcholine. Intracoronary propranolol did not significantly affect either the vasodilative response in 11 normal coronary arteries (11.3 +/- 4.4% before and 8.6 +/- 4.3% after beta-blockade) or the vasoconstrictor response in 8 atherosclerotic coronary arteries (-11.4 +/- 4.6% before and -14.6 +/- 5.3% after beta-blockade). The dilation of normal and the constriction of atherosclerotic coronary arteries with cold pressor testing exactly mirror the response to the endothelium-dependent dilator acetylcholine. Endothelial dysfunction in coronary atherosclerosis resulted in a loss of normal dilator function and permitted vasoconstrictor responses to sympathetic stimulation. Thus, coronary vasomotion of large epicardial arteries in response to sympathetic stimulation by the cold pressor test in humans is intimately related to the integrity of endothelial function.

Acetylcholine↗

PubMed1989

Monocrotaline pneumotoxicity in mice.

Lung injury induced in rats by the pyrrolizidine alkaloid monocrotaline is a well-documented model of pulmonary hypertension. To our knowledge, however, monocrotaline-induced cardiopulmonary injury has rarely been described and has never been quantitated in mice. In the present study, adult male mice received 2.4, 4.8, or 24.0 mg monocrotaline/kg body weight/day in the drinking water continuously for 6 weeks. These doses represent 1, 2, and 10 times the severely pneumotoxic regimen in rats. Pulmonary endothelial function was monitored by right lung angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Light and electron microscopy were performed on the left lungs. Cardiac right ventricular hypertrophy was evaluated by the right ventricle to left ventricle plus septum weight ratio (RV/LV + S). Monocrotaline-treated mice exhibited a dose-dependent decrease in lung ACE and PLA activities and an increase in PGI2 and TXA2 production, indicative of endothelial dysfunction. However, these responses were significant only after the highest monocrotaline dose. Light and electron microscopy revealed dose-dependent pulmonary inflammatory and exudative reactions. Unlike previous studies in rats, however, monocrotaline-treated mice developed relatively little lung fibrosis, cardiomegaly, or right ventricular hypertrophy, and no occlusive medial thickening of the pulmonary arteries, even at the highest dose level. These and previous data indicate that there are quantitative biochemical and qualitative morphological differences between mice and rats with respect to monocrotaline pneumotoxicity. Furthermore, in monocrotaline-treated mice (but not in rats) there appears to be a dissociation between lung endothelial dysfunction and inflammation on the one hand, and pulmonary hypertension and fibrosis on the other.

Animals↗

PubMed1992

Impaired endothelium-dependent vasodilation of forearm resistance vessels in hypercholesterolaemia.

Endothelium-dependent vasodilation in response to acetylcholine is impaired in the coronary microvasculature of hypercholesterolaemic subjects. Outside the coronary circulation, however, it has been suggested that hypercholesterolaemia results in a functional abnormality of vascular smooth muscle rather than in endothelial dysfunction. We examined vasodilator responses to acetylcholine, methacholine, and the endothelium-independent vasodilator sodium nitroprusside in the forearm resistance vessels of 12 men with primary hypercholesterolaemia and 12 normocholesterolaemic male controls. Endothelium-dependent vasodilation in response to acetylcholine was impaired in hypercholesterolaemic patients compared with controls: at the highest dose of drug (15 micrograms per min) mean blood flow in the forearms of the hypercholesterolaemic group was only 52% (95% Cl 31-88%) of that in the control group. Responses to sodium nitroprusside and to methacholine in the two study groups were not significantly different. These results indicate that endothelial dysfunction in hypercholesterolaemic subjects is generalised and extends to vascular beds outside the coronary circulation. Selective impairment to acetylcholine suggests that, at a molecular level, the defect is limited to a specific pathway.

Acetylcholine↗

PubMed1992

Aldose reductase and myo-inositol in endothelial cell dysfunction caused by elevated glucose.

A possible relationship between aldose reductase activity and myo-inositol levels and endothelium-dependent relaxations was examined in isolated rabbit aorta incubated with elevated concentrations of glucose (44 mM) for 6 hr to mimic hyperglycemic conditions. Rings of aorta incubated in elevated glucose and contracted submaximally by phenylephrine showed significantly decreased endothelium-dependent relaxations induced by acetylcholine compared with aorta incubated in control (5.5 or 11 mM) glucose. Acetylcholine-induced relaxations of aorta incubated in hyperosmotic mannitol (44 mM) were not different from those incubated in control glucose. Treatment with two structurally unrelated aldose reductase inhibitors, sorbinil or zopolrestat, or supplementation with myo-inositol, prevented the abnormal acetylcholine relaxations of aortic rings caused by elevated glucose. No effects of sorbinil, zopolrestat or myo-inositol were observed on the response to acetylcholine of aorta incubated in control glucose. Neither sorbinil nor myo-inositol affected the increase in release of vasoconstrictor prostanoids caused by elevated glucose. These findings suggest that sorbitol accumulation and myo-inositol depletion contribute to the abnormal endothelial cell function caused by exposure to elevated glucose. The increased release of vasoactive prostanoids is either independent of, or possibly contributes to, the abnormal aldose reductase activity and/or myo-inositol depletion in intact blood vessels exposed to elevated concentrations of glucose.

Acetylcholine↗

PubMed1988

High potassium diets protect against dysfunction of endothelial cells in stroke-prone spontaneously hypertensive rats.

Two lines of evidence strongly support the hypothesis that high potassium diets protect arterial endothelial cells from hypertensive damage. Stroke-prone spontaneously hypertensive rats (SHRSP) fed normal (0.75%) K or high (2.1%) K and normotensive Wistar-Kyoto rats (WKY) were examined in an endothelial function study and a histological study. In the endothelial function study, aortic rings were suspended in tissue baths to monitor isometric tension. Rings contracted with norepinephrine were tested with acetylcholine and sodium nitroprusside. In normal K SHRSP (blood pressure, 156 mm Hg), endothelium-dependent acetylcholine relaxation was severely depressed by 49% (p less than 0.001), whereas in high K SHRSP (blood pressure, 155 mm Hg), normal values were preserved. Endothelium-independent nitroprusside relaxation was virtually the same in both the SHRSP groups (high K vs normal K diet). Since indomethacin did not improve the impaired acetylcholine relaxation in normal K SHRSP, the cyclooxygenase products do not appear to have affected the endothelium-dependent relaxation in the normal K SHRSP. Thus, the endothelium-dependent relaxation response was much decreased in the normal K SHRSP and was preserved in the high K SHRSP. Thus, a high K diet appears to protect the aortic endothelium from a hypertension-induced dysfunction. In the histological study, aortic and mesenteric intimal lesions were assessed blindly under the microscope and graded from 0 to 60 for aortic and from 0 to 40 for mesenteric lesions. Aortic intimal lesion scores were 28 in normal K SHRSP (blood pressure, 209 mm Hg) and 13 in high K SHRSP (blood pressure, 207 mm Hg; -54%; p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1992

Antishock and endothelial protective actions of a NO donor in mesenteric ischemia and reperfusion.

Splanchnic artery occlusion (SAO) of the celiac, superior mesenteric, and inferior mesenteric arteries for 2 hr, followed by a 2-hr reperfusion period in cats produces a severe form of circulatory shock characterized by endothelial dysfunction, increased lysosomal leakage, and severe hypotension resulting from release of proteases, oxygen-derived free radicals, and other humoral mediators into the circulation. Administration of 0.75 mg/kg/hr of C873754, a nitric oxide (NO) donor, 10 min prior to reperfusion, significantly attenuated the accumulation of plasma cathepsin D from 12 +/- 3 U/ml in the SAO + vehicle group to 5 +/- 1 U/ml (P < 0.05) in the C87-3754 treated SAO group. A similar attenuation of plasma myocardial depressant factor (MDF) activity was observed in the C87-3754 treated cats (P < 0.02). Administration of C87-3754 significantly increased short term (i.e., 2-hr) survival rate (P < 0.05, compared to the vehicle group). Moreover, C87-3754 attenuated the SAO shock induced decline in release of endothelium-derived relaxing factor (EDRF) from isolated superior mesenteric artery (SMA) rings stimulated by acetylcholine and A23187. Additionally, C87-3754 significantly decreased PMN adherence to the superior mesenteric venous endothelium in vitro. Thus, treatment with the NO donor, C87-3754 reduced the accumulation of humoral mediators into the plasma while significantly attenuating endothelial dysfunction and improving short term survival.

Animals↗

PubMed1995

Constitutive nitric oxide release is impaired after ischemia and reperfusion.

Myocardial ischemia and reperfusion may result in endothelial dysfunction and reduced release of nitric oxide. With the use of an amperometric sensor, the first direct measurements of constitutive nitric oxide release from a beating heart were measured from the coronary effluent of isolated working rat hearts subjected to ischemia and reperfusion. Rats, six to eight per group, were randomly studied as follows: control (no pretreatment) and pretreatment with the nitric oxide donor L-arginine (3 mmol/L), its enantiomer D-arginine (3 mmol/L), nitric oxide inhibitor N omega-nitro-L-arginine methyl ester (100 mumol/L), and combined N omega-nitro-L-arginine methyl ester/L-arginine. Isolated hearts were pretreated for 10 minutes before 30 minutes of global ischemia and 30 minutes of reperfusion. A nonischemic control group (n = 4) was continuously perfused with oxygenated unsupplemented buffer. After ischemia/reperfusion, hearts supplemented with L-arginine recovered significantly (p < 0.05) increased developed pressure, first derivative of the aortic pressure (dP/dtmax), and aortic flow compared with all other hearts that underwent ischemia/reperfusion. In addition, nitric oxide release was significantly (p < 0.05) increased during reperfusion in the L-arginine group. During reperfusion, the recovery of aortic flow correlated with nitric oxide release (r = 0.81, p < 0.0001). We conclude that after ischemia/reperfusion, endothelial dysfunction results in decreased nitric oxide release, which can be ameliorated with L-arginine pretreatment. The direct cytoprotective properties of nitric oxide may contribute to improved functional recovery in hearts pretreated with L-arginine. Augmentation of the L-arginine/nitric oxide pathway may provide a new approach for improved recovery after cardiovascular operations.

Animals↗

PubMed2026

Phase IIB, Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Intravenous Defibrotide for the Prevention and Treatment of Respiratory Distress and Cytokine Release Syndrome in COVID-19.

INTRODUCTION: Endothelial dysfunction is key in COVID-19 pathogenesis. This randomized, double-blind phase IIb trial investigated continuous intravenous infusion of defibrotide in patients hospitalized with SARS-CoV-2 infection and respiratory failure. METHODS: One-hundred and fifty patients were randomized (2:1) to defibrotide or placebo, stratified by disease severity (WHO COVID-19 severity scale 4/5 vs. 6). The primary endpoint was clinical improvement time (days from first improvement through Day 30). RESULTS: Median clinical improvement time was not significantly different with defibrotide versus placebo (15.0 [IQR: 0-24] vs. 20.0 [IQR: 9-25] days; p = 0.10). Day-30 (23.0% vs. 22.0%) and Day-60 (26.0% vs. 22.0%) mortality, reduction in mean fraction of inspired oxygen during treatment, and median duration of hospitalization did not differ with defibrotide versus placebo. Defibrotide demonstrated favorable safety, with no differences versus placebo in serious adverse events (34.0% vs. 36.0%), hypotension (16.0% vs. 12.0%), or hemorrhage (13.0% vs. 8.0%). Exploratory pre-specified biomarker analyses showed greater early d-dimer reduction and lymphocyte recovery with defibrotide, although these results require validation. CONCLUSION: Continuous intravenous infusion of defibrotide was safe but did not improve clinical outcomes in severe COVID-19. Further analyses will explore mechanistic actions and pharmacokinetics of defibrotide and the pathophysiology of endothelial dysfunction in COVID-19. TRIAL REGISTRATION: EudraCT identifier: 2020-001409-21. CLINICALTRIALS: gov identifier: NCT04348383.

Adult↗

PubMed1992

Preserved endothelium-dependent vasodilation at the vasospastic site in patients with variant angina.

Endothelial dysfunction has been implicated as a cause of coronary vasospasm in patients with variant angina. This study aimed to determine if endothelium-dependent vasodilation evoked with substance P (SP) was altered at the spastic site where vasospasm was induced by acetylcholine (ACH) in patients with variant angina. It has been shown that SP evokes endothelium-dependent vasodilation with no direct effect on vascular smooth muscle in excised human coronary arteries. SP and ACH were infused into the coronary arteries in nine patients with variant angina in whom coronary arteriograms showed normal or mild atherosclerotic lesions. The vasomotor responses of coronary arteries were assessed by quantitative arteriography. ACH at a high dose (100 micrograms/min) provoked coronary vasospasm associated with anginal attack in all patients. In contrast, SP at graded doses (13.5, 40, and 135 ng/min) caused the dose-dependent and comparable increases in the coronary diameter at the spastic and control sites. ACH at a low dose (10 micrograms/min) also caused comparable vasodilation at the spastic and control sites in patients with normal coronary arteries. Coronary vasodilating responses to SP were comparable in patients with variant angina and those with atypical chest pain. The results indicate that endothelium-dependent vasodilation evoked with SP and ACH at the low dose was present at the vasospastic site in patients with variant angina. These findings suggest that the ACH-induced coronary vasospasm in patients with variant angina results from hyperreactivity of vascular smooth muscle to ACH but not from endothelial dysfunction.

Acetylcholine↗

PubMed2026

Association between plasma homocysteine levels and P-wave dispersion in pediatric patients with hyperhomocysteinemia.

UNLABELLED: Hyperhomocysteinemia has been recognized as a cardiovascular risk factor associated with endothelial dysfunction, oxidative stress, and vascular inflammation. Experimental and clinical studies suggest that elevated homocysteine levels may also influence myocardial electrophysiology and contribute to arrhythmogenesis. However, data regarding the relationship between homocysteine levels and electrocardiographic markers of atrial conduction in pediatric populations remain limited. This study aimed to evaluate the association between plasma homocysteine levels and electrocardiographic parameters, particularly P-wave dispersion, in children. This multicenter retrospective case-control study included pediatric patients evaluated in four tertiary pediatric metabolism centers between January 2023 and December 2025. A total of 47 patients with hyperhomocysteinemia (plasma total homocysteine ≥ 15 µmol/L) and 43 age- and sex-matched controls with normal homocysteine levels were included. Controls were selected from the screened population among children with available homocysteine measurements, electrocardiographic and echocardiographic evaluations, and no confirmed inherited metabolic disease or cardiac disorder. Clinical, biochemical, and electrocardiographic parameters, including maximum P-wave duration and P-wave dispersion, were retrospectively analyzed. A total of 90 participants were included, comprising 47 children with hyperhomocysteinemia and 43 healthy controls. P-wave dispersion and maximum P-wave duration were significantly higher in the hyperhomocysteinemia group compared with controls (48.96 [19.48-100.0] vs. 38.57 [10.57-71.19] ms, p < 0.001). Plasma homocysteine levels showed a moderate positive correlation with P-wave dispersion (ρ = 0.441, p < 0.001). These differences were more pronounced in children with higher homocysteine levels and in younger age groups (< 2 years and 2-14 years). In contrast, PR interval (p = 0.790) and QTc interval (p = 0.183) did not differ significantly between groups. Vitamin B12 levels were significantly lower in the hyperhomocysteinemia group (p = 0.013), while folate levels were comparable (p = 0.974). Although sodium, potassium, and magnesium levels differed significantly between groups, all values remained within normal physiological ranges. CONCLUSIONS: Children with hyperhomocysteinemia showed increased P-wave dispersion compared with controls. These findings suggest an association between elevated homocysteine levels and altered atrial conduction parameters in children. Further prospective studies are needed to determine the clinical significance of these findings. WHAT IS KNOWN: • Hyperhomocysteinemia is associated with cardiovascular risk and endothelial dysfunction. • Elevated homocysteine levels have been linked to cardiac electrophysiological alterations in adult populations. WHAT IS NEW: • Elevated homocysteine levels are associated with increased P-wave dispersion in children, with more pronounced effects observed in younger age groups. • These findings support an association between hyperhomocysteinemia and altered atrial conduction parameters in children.

Adolescent↗