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Effects of hyperbaric oxygen on vascular endothelial function in patients with slow coronary flow
Abstract
Background:
To improve therapy for slow coronary flow (SCF), the effects of hyperbaric oxygen (HBO) therapy on vascular endothelial function in SCF patients is the focus of this investigation.
Methods:
Ninety-eight patients who exhibited chest discomfort were retrospectively analyzed, and di-agnosed with SCF by coronary artery angiography at the Third Hospital of Hebei Medical University, Shijiazhuang, China from 2014 to 2016. The patients were divided into two groups according to the following treatment: HBO group (n = 48) and the control group (n = 50). Patients in the control group were administrated with conventional treatment, while those in the HBO group were administrated HBO therapy for 4 weeks in addition to conventional treatment. To evaluate the effects of HBO on vas-cular endothelial functions, plasma levels of nitric oxide (NO), calcitonin gene-related peptide (CGRP), endothelin-1 (ET-1), high sensitivity C-reactive protein (hsCRP) as well as endothelial-dependent flow-mediated vasodilation (FMD) of the brachial artery were measured in both groups before and after their respective treatments.
Results:
There were no significant differences in plasma levels of NO, ET-1, CGRP, hsCRP nor in FMD measurements between the two groups before treatment (p > 0.05). Moreover, the levels of all the parameters measured showed no significant changes before and after treatment in the control group. However, when comparing the control group, FMD and plasma NO and CGRP levels were significantly increased in the HBO group after treatment (p < 0.01), whereas hsCRP and ET-1 levels decreased dramatically (p < 0.001).
Conclusions:
The HBO treatment in addition to conventional therapy may significantly improve the vascular endothelial function in SCF patients. (Cardiol J 2018; 25, 1: 106-112).
... Some studies found that dipyridamole and nicorandil could improve left ventricular systolic and diastolic function in patients with CSF [15,16]. Several other treatments, such as traditional Chinese medicine, hyperbaric oxygen therapy, and cardiac rehabilitation, remain in the exploratory stage [17][18][19]. ...
Background
Studies on coronary slow flow are receiving increasing attention, but objective evaluations are still lacking. The purpose of this study was to visualize the current status and research hotspots of coronary slow flow through bibliometric analysis.
Methods
All relevant publications on coronary slow flow from 2003 to 2022 were extracted from the Web of Science Core Collection database and analyzed by VOSviewer and CiteSpace visualization software. Year of publication, journal, country/region, institution, and first author of each paper, as well as research hotspots were identified.
Results
A total of 913 publications were retrieved. The journal with the most publications was Coronary Artery Disease. The country/region with the most publications was Turkey, followed by China and the United States. The institution with the largest publication volume was Turkey Specialized Higher Education Research Hospital. The author with the largest publication volume was Chun-Yan Ma from China. Keyword analysis indicated that “treatment and prognosis”, “pathogenesis and risk factors” and “diagnosis” were the clustering centers of coronary slow flow, and the research hotspots gradually changed with time, from pathogenesis to treatment and prognosis.
Conclusion
Future research will focus on the search for effective and non-invasive detection indicators and treatments of coronary slow flow. Collaboration needs to be enhanced between different institutions or countries/regions, which would improve clinical outcomes for patients with coronary slow flow.
... These factors are considered to be biomarkers of vascular endothelial function. The ET-1 plasma concentration is the main systolic vascular factor and has been found to be noticeably increased in patients with coronary slow flow [41]. The main diastolic vascular factor, NO-and endothelium-dependent hyperpolarization-mediated digital vasodilatations, have been found to be markedly impaired in microvascular angina patients [42]. ...
Although the prevalence of heart failure with preserved ejection fraction (HFpEF) is growing worldwide, its complex pathophysiology has yet to be fully elucidated, and multiple hypotheses have all failed to produce a viable target for therapeutic action or provide effective treatment. Cardiac remodeling has long been considered an important mechanism of HFpEF. Strong evidence has been reported over the past years that coronary microvascular dysfunction (CMD), manifesting as structural and functional abnormalities of coronary microvasculature, also contributes to the evolution of HFpEF. However, the mechanisms of CMD are still not well understood and need to be studied further. Coronary microvascular endothelial cells (CMECs) are one of the most abundant cell types in the heart by number and active players in cardiac physiology and pathology. CMECs are not only important cellular mediators of cardiac vascularization but also play an important role in disease pathophysiology by participating in the inception and progression of cardiac remodeling. CMECs are also actively involved in the pathogenesis of CMD. Numerous studies have confirmed that CMD is closely related to cardiac remodeling. ECs may serve a critical function in mediating the connection between CMD and HFpEF. It follows that CMECs participate in the mechanism of CMD leading to HFpEF. In this review article, we focus on the role of CMD in the pathogenesis of HFpEF resulting from cardiac remodeling and highlight the subsequent complexity of the EC-mediated correlation between CMD and HFpEF.
... Tambe proposed that the CSF phenomenon might be related to abnormal microcirculation in 1972 [2]. Oğuzhan Çelik et al. identified a correlation between the extent of disruption in endothelial function and the CSF level using the flowmediated dilation (FMD) method [21]. Several studies have found that the imbalance between endothelin-1 and nitric oxide in patients with CSF supports the involvement of endothelial dysfunction in CSF etiopathogenesis [22]. ...
Objective:
Coronary slow flow (CSF) is characterized by delayed opacification of distal epicardial coronary arteries without significant coronary stenosis. In addition, The changes of lipoprotein-associated phospholipase A2 (Lp-PLA2) as a significant predictive factor for CSF remain controversial. The study aims to investigate the association between plasma Lp-PLA2 and CSF.
Methods:
In this retrospective study, 170 consecutive patients who underwent coronary angiography were enrolled in Beijing Anzhen Hospital from January 2017 to September 2019, and were divided into CSF group and normal control groups. According to coronary blood flow rate measured by the thrombolysis in myocardial infarction frame count (TFC) method, CSF was defined as TFC > 27. Serum Lp-PLA2 levels were measured in an enzyme-linked immunosorbent assay.
Results:
Lp-PLA2 levels were higher in the CSF group than in the control group (288.6 ± 50.3 versus 141.9 ± 49.7, P < 0.001) and were significantly correlated with the mean coronary artery thrombolysis in myocardial infarction (TIMI) frame count (r = 0.790, P<0.001). Logistic regression analysis showed that high Lp-PLA2 was independently associated with CSF after adjustment for conventional risk factors (OR = 1.040, CI = 1.022-1.059, P<0.001). Male sex (OR = 2.192, CI = 1.161-4.140, P = 0.016) and hypertension (OR = 1.965, CI = 1.034-3.736, P = 0.039) were also CSF risk factors. Receiver-operating characteristic curve (ROC) analysis showed that Lp-PLA2 levels can predict CSF severity; the predictive power was higher than the other risk factors.
Conclusion:
Our study demonstrated that patients with CSF had higher circulating levels of Lp-PLA2 than normal controls. After adjustment for potential confounders, increased Lp-PLA2 was independently associated with presence of CSF.
Background
The optimum therapy for coronary slow flow phenomenon (CSFP) stays debatable. This study compared the effectiveness of alprostadil with isosorbide dinitrate in alleviating angina episodes in CSFP patients.
Methods
In this prospective, randomized controlled study, 102 patients with CSFP without severe coronary artery stenosis that exhibited stable angina were allocated randomly in a ratio of 1:1 to either the alprostadil group (40 μg, three times per day, n = 51) or the isosorbide dinitrate group (5 mg, three times per day, n = 51). Frequency of angina events, intensity of suffering, and the Canadian Cardiovascular Society (CCS) grading of angina pectoris were evaluated at baseline and one month after. Additionally, the Seattle Angina Questionnaire (SAQ) was assessed.
Results
Baseline characteristics were comparable between the two groups. At 1-month follow-up, patients administered with alprostadil experienced fewer angina episodes [episodes per week, 1 (2) vs. 2 (2), P < 0.001] and less pain intensity [self-evaluated pain score, 2 (3) vs. 3 (4), P < 0.001] than those with isosorbide dinitrate. In the alprostadil group, 78.4% of patients were classified as CCS class I, significantly higher than the 47.1% seen in the isosorbide dinitrate group ( P = 0.001). Furthermore, treatment of alprostadil led to a significant improvement in the SAQ score (7.09 U, 95% CI: 4.22–9.96, P < 0.001) compared to isosorbide dinitrate. Additionally, fewer patients suffered headaches when receiving alprostadil (7.8% vs. 19.6%, P = 0.084).
Conclusion
Alprostadil was more effective in ameliorating angina symptoms in CSFP patients than isosorbide dinitrate.
Clinical trial registration
[ www.chictr.org.cn ], identifier [ChiCTR2000033233].
Introduction
Recently, increased frequency of chronic leg ulcers has been observed. The aim of the study was to compare therapeutic efficacy of combined physical therapy to topical hyperbaric oxygen therapy in the treatment of venous leg ulcers.
Materials and Methods
Participants included 36 patients (14 females and 22 males) between 18 and 80 years of age with chronic venous leg ulcers. They were randomly divided into two study groups. Group I underwent topical hyperbaric oxygen therapy; group II underwent combined physical therapy. Before and after the therapeutic cycle (15 procedures) measurement of ulceration size by planimetry and analysis of laboratory parameters of blood was performed.
Results
In both groups, a statistically significant reduction of ulcer surface area was obtained (25.11±17.8cm ² to 16.93±13.89cm ² , p=0.000196) vs. (34.17±14.82cm ² to 23.99±15.15cm ² , p=0.004337). Blood morphology revealed a statistically significant reduction in patients from group II who underwent combined physical therapy (p=0.01). In both groups, statistically significant reduction of fibrinogen level (p=0.01 and p<0.001), and total protein level (p=0.01) was achieved. In group II reduction of the inflammation marker C-reactive protein (CRP) was noted.
Conclusions
Topical hyperbaric oxygen therapy and combined physical therapy had statistically significant effects on the reduction of surface area of treated venous leg ulcers. The changes in morphological and biochemical parameters may indicate the anti-inflammatory and anti-clotting action effects of combined physical therapy.
Growing life expectancy will contribute to the on-going shift towards a world population increasingly comprised of elderly individuals. This demographic shift is associated with a rising prevalence of age-related diseases, among all age-related pathologies it has become crucial to understand the age-associated cognitive changes that remain a major risk factor for the development of vascular cognitive impairment and dementia (VCID). Furthermore, age-related Alzheimer’s disease and other neurogenerative diseases with vascular etiology are the most prominent contributing factors for the loss of cognitive function observed in aging. Hyperbaric Oxygen Therapy (HBOT) achieves physiologic effects by increasing oxygen tension (PO2), raising oxygen tissue levels, decreasing intracranial pressure and relieving cerebral edema. Many of the beneficial effects of HBOT exert their protective effects at the level of the microcirculation. Furthermore, the microcirculation’s exquisite pervasive presence across every tissue in the body, renders it uniquely able to influence the local environment of most tissues and organs, including the brain. As such, treatments aimed at restoring aging-induced functional and structural alterations of the cerebral microcirculation may potentially contribute to the amelioration of a range of age-related pathologies including vascular cognitive impairment, Alzheimer’s disease, and vascular dementias. Despite the presented evidence, the efficacy and safety of HBOT for the treatment of age-related vascular cognitive impairment and dementia remains understudied. The present review aims to examine the existing evidence indicative of a potential therapeutic role for HBOT-induced hyperoxia against age-related cerebromicrovascular pathologies contributing to cognitive impairment, dementia and decreased healthspan in the elderly.
Hyperbaric oxygen therapy (HBOT) is commonly used as treatment in several diseases, such as non-healing chronic wounds, late radiation injuries and carbon monoxide poisoning. Ongoing research into HBOT has shown that preconditioning for surgery is a potential new treatment application, which may reduce complication rates and hospital stay. In this review, the effect of HBOT on oxidative stress, inflammation and angiogenesis is investigated to better understand the potential mechanisms underlying preconditioning for surgery using HBOT. A systematic search was conducted to retrieve studies measuring markers of oxidative stress, inflammation, or angiogenesis in humans. Analysis of the included studies showed that HBOT-induced oxidative stress reduces the concentrations of pro-inflammatory acute phase proteins, interleukins and cytokines and increases growth factors and other pro-angiogenesis cytokines. Several articles only noted this surge after the first HBOT session or for a short duration after each session. The anti-inflammatory status following HBOT may be mediated by hyperoxia interfering with NF-κB and IκBα. Further research into the effect of HBOT on inflammation and angiogenesis is needed to determine the implications of these findings for clinical practice.
S ummary
Microvascular endothelial cells (MVEC) are plastic, versatile and highly responsive cells, with morphological and functional aspects that uniquely match the tissues they supply. The response of these cells to oxygen oscillations is an essential aspect of tissue homeostasis, and is finely tuned to maintain organ function during physiological and metabolic challenges. Primary MVEC from two continuous capillary networks with distinct organ microenvironments, those of the lung and brain, were pre-conditioned at normal atmospheric (∼ 21 %) and physiological (5 and 10 %) O 2 levels, and subsequently used to compare organ-specific MVEC hypoxia response. Brain MVEC preferentially stabilise HIF-2α in response to hypoxia, whereas lung MVEC primarily accumulate HIF-1α; however, this does not result in significant differences at the level of transcriptional activation of hypoxia-induced genes. Glycolytic activity is comparable between brain and lung endothelial cells, and is affected by oxygen pre-conditioning, while glucose uptake is not changed by oxygen pre-conditioning and is observed to be consistently higher in brain MVEC. Conversely, MVEC mitochondrial activity is organ-specific; brain MVEC maintain a higher relative mitochondrial spare capacity at 5% O 2 , but not following hyperoxic priming. If maintained at supra-physiological O 2 levels, both MVEC fail to respond to hypoxia, and have severely compromised and delayed induction of the glycolytic shifts required for survival, an effect which is particularly pronounced in brain MVEC. Oxygen preconditioning also differentially shapes the composition of the mitochondrial electron transport chain (ETC) in the two MVEC populations. Lung MVEC primed at physioxia have lower levels of all ETC complexes compared to hyperoxia, an effect exacerbated by hypoxia. Conversely, brain MVEC expanded in physioxia display increased complex II (SDH) activity, which is further augmented during hypoxia. SDH activity in brain MVEC primed at 21 % O 2 is ablated; upon hypoxia, this results in the accumulation of near-toxic levels of succinate in these cells. Our data suggests that, even though MVEC are primarily glycolytic, mitochondrial integrity in brain MVEC is essential for metabolic responses to hypoxia; these responses are compromised when cells are exposed to supra-physiological levels of oxygen. This work demonstrates that the study of MVEC in normal cell culture environments do not adequately represent physiological parameters found in situ , and show that the unique metabolism and function of organ-specific MVEC can be reprogrammed by external oxygen, significantly affecting the timing and degree of downstream responses.
Graphical Abstract
In brief
Hypoxia sensing by microvascular endothelial cells (MVEC) is organ-specific, and efficacy of response is affected by external oxygen. While glycolytic capacity is mostly maintained in MVEC regardless of organ or origin, mitochondrial function is required for adequate sensing and timely metabolic shift to glycolysis. Hyperoxygenation of MVEC compromises mitochondrial function, glycolytic shift and survival to hypoxia.
Highlights
Environmental O 2 influences MVEC hypoxia response in an organ-specific fashion
Brain MVEC are unable to respond and survive to hypoxia if hyperoxygenated prior to stress
MVEC glycolytic capacity is not affected by O 2 , but the increase in glucose uptake and shift to glycolytic metabolism stifled and delayed in hyperoxidized MVEC
High O 2 ablates activity of mitochondria complex II in brain MVEC, significantly disturbing succinate levels Disruption of mitochondrial integrity compromises hypoxia sensing irrespective of glycolytic capacity
Atherosclerotic heart disease usually manifests as angina and is diagnosed by stress imaging tests and coronary angiography (1), but some patients with typical angina and documented myocardial ischemia have normal coronary arteries (2), a clinical picture called cardiac syndrome X (3). Endothelial (4) and microvascular (5) dysfunction have been suggested to play a pathogenic role in this situation. Patients with slow coronary flow (SCF) (6) and endothelial dysfunction (7) are both at increased risk for cardiovascular events. Several methods to measure endothelial injury can provide clinical opportunities to identify these patients (8), but the evaluation of endothelial function in arterial and venous vascular beds has not yet been performed. The aim of this study was to evaluate the arterial and venous endothelial functions in patients with stable angina and normal coronary anatomy but SCF on a cardiac angiogram.
Flow mediated brachial dilatation (FMD) and carotid intima-media thickness (IMT) have been a surrogate for early atherosclerosis. Slow coronary flow in a normal coronary angiogram is not a rare condition, but its pathogenesis remains unclear. A total of 85 patients with angina were evaluated of their brachial artery FMD, carotid IMT and conventional coronary angiography. Coronary flow was quantified using the corrected thrombosis in myocardial infarction (TIMI) frame count method. Group I was a control with normal coronary angiography (n = 41, 56.1 ± 8.0 yr) and group II was no significant coronary stenosis with slow flow (n = 44, 56.3 ± 10.0 yr). Diabetes was rare but dyslipidemia and family history were frequent in group II. Heart rate was higher in group II than in group I. White blood cells, especially monocytes and homocysteine were higher in group II. The FMD was significantly lower in group II than in group I. Elevated heart rate, dyslipidemia and low FMD were independently related with slow coronary flow in regression analysis. Therefore, endothelial dysfunction may be an earlier vascular phenomenon than increased carotid IMT in the patients with slow coronary flow.
We studied the effect of hyperbaric oxygen (HBO) treatment on the extent of diet-induced accumulation of lipid oxidation products in rabbit plasma and tissues, on plasma paraoxonase activity, and on the extent of progression and regression of atherosclerotic lesions in the rabbit aorta. HBO treatment of cholesterol-fed rabbits dramatically reduces the development of arterial lesions despite having little or no effect on plasma or individual lipoprotein cholesterol concentrations. Compared with no treatment in cholesterol-fed animals, HBO treatment also substantially reduces the accumulation of lipid oxidation products (conjugated dienes, trienes, and thiobarbituric acid-reactive substances) in plasma, in the low density lipoprotein and high density lipoprotein fractions of plasma, in the liver, and in the aortic tissues. In addition, HBO treatment prevents the decrease in plasma paraoxonase activity observed in rabbits fed cholesterol-rich diets. Similarly, in regression studies, HBO treatment has no effect on the rate of plasma (or lipoprotein) cholesterol decline but significantly accelerates aortic lesion regression compared with no treatment. Direct measures of aortic cholesterol content support these morphological observations. On the basis of these results, we conclude that repeated, but relatively short, exposure to HBO induces an antioxidant defense mechanism(s) that is responsible for retarding the development or accelerating the regression of atherosclerotic lesions.
Adrenomedullin (AM) and calcitonin gene-related peptide (CGRP) are related peptides with distinct pharmacological profiles. Calcitonin-receptor-like receptor (CRLR, now known as CL) can function as either an AM receptor or a CGRP receptor, when cotransfected with receptor-activity-modifying proteins (RAMPs) that define ligand-binding specificity. The aim of the present study was to determine the role of endogenously expressed CL (EndoCL) in generating endogenous AM and CGRP receptors. We raised anti-human CL antibody and identified microvascular endothelial cells (MVECs) as a major CL-expressing cell type in tissues by immunohistochemistry. Cultured MVECs continue to express EndoCL as well as fully active endogenous AM- and CGRP-sensitive receptors in vitro, as demonstrated by the ability of both peptides to induce migration and Akt phosphorylation. We therefore tested the hypothesis that endothelial EndoCL can interact with both AM and CGRP by examining receptor internalisation and desensitisation (loss of the ability to induce Akt phosphorylation). We found that agonist-mediated internalisation of EndoCL occurs in response to AM but not CGRP in MVECs. However, AM-induced EndoCL internalisation was blocked by antagonists of both AM and CGRP receptors: AM(22-52) and CGRP(8-37), respectively. Furthermore, AM-induced EndoCL internalisation resulted in desensitisation not only of AM but also of CGRP receptors. Finally, CGRP also induced desensitisation of both endogenous AM and CGRP receptors, but did not mediate EndoCL internalisation despite interaction with this receptor. Thus, EndoCL interacts with both AM and CGRP, and simultaneously acts as a receptor for both peptides (i.e acting as an endogenous AM/CGRP receptor) in endothelial cells. Interaction with either ligand is sufficient to induce EndoCL desensitisation to both AM and CGRP, but differential mechanisms are involved since only AM induces EndoCL internalisation. These novel findings regarding regulation of EndoCL function in endothelial cells are likely to be of importance in conditions where AM or CGRP levels are elevated, such as cardiovascular disease, diabetes and inflammation.
It is unclear whether changes in plasma levels of inflammatory markers could explain the link between ischemia and slow coronary flow (SCF). The aim of the study was to evaluate the plasma levels of high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, and myeloperoxidase (MPO) during myocardial perfusion imaging (MPI) in SCF patients.
The study population consisted of 53 SCF patients and 30 controls. Coronary flow rates were documented by TIMI frame count (TFC). Plasma levels of hsCRP, IL-6, MPO, and MPI were obtained in all participants.
hsCRP, IL-6 and MPO levels of SCF patients were higher than controls (hsCRP: 4.7 ± 2.5 vs. 1.7 ± 1.1 mg/L, p <0.001; IL-6: 8.2 ± 4.3 vs. 5.2 ± 2.1 pg/mL, p <0.001; and MPO: 75.9 ± 59.6 vs. 24.3 ± 16.7 ng/mL, p <0.001). Twenty-one SCF patients exhibited myocardial perfusion defect (MPD) on MPI. In SCF patients, the highest hsCRP, IL-6 and MPO levels were observed in patients with both MPD and three-vessel slow flow. Mean TFCs were positively correlated with plasma levels of hsCRP (r = 0.424, p = 0.002), IL-6 (r = 0.367, p = 0.007), MPO (r = 0.430, p = 0.001), and reversibility score (r = 0.671, p <0.001) in SCF patients. HsCRP and MPO were the independent variables, which predicted positive MPI results (hsCRP: OR, 2.176; 95% CI, 1.200-3.943; p = 0.010, MPO: OR, 1.026; 95% CI, 1.007-1.046; p = 0.008).
Inflammation may play a crucial role in both the pathogenesis and development of ischemia in SCF. Association of increased levels of inflammatory markers and ischemia suggests that endothelial inflammation may be largely responsible for clinical presentation. New combined treatment regimens should target endothelial activation and inflammation in SCF.
Coronary slow flow phenomenon (CSFP) is defined as delayed coronary opacification in the absence of obstructive coronary artery disease. In the present study, we sought to define its prevalence and clinical features.
The 1,741 consecutive patients who underwent coronary angiography (CAG) were identified. Those with normal left ventricular ejection fraction and normal coronary arteries were included in the study (n=158). TIMI frame counts were calculated, and data on demographics, comorbidities, and medication use were collected. CSFP was defined as frame count > 27. Multivariate logistic regression analysis was used to identify independent predictors of CSFP. CSFP was identified in 96 (5.5%) subjects referred for CAG. Subjects with CSFP were more obese (body mass index [BMI] 33.9 vs. 29.8 kg/m², P=0.003) and had lower high-density lipoprotein levels (39.7 vs. 45.7 mg/dl, P=0.04). In the CSFP group, total cholesterol, low-density lipoprotein and frame counts increased significantly with increasing vessel involvement (1-, vs. 2-, vs. 3-vessel involvement; P<0.05 for each variable). By multivariate analysis, male sex (odds ratio 3.36, 95% confidence interval 1.17-8.61, P=0.02) and higher BMI independently predicted the presence of CSFP (odds ratio 1.09, 95% confidence interval 1.03-1.15, P=0.003).
CSFP is associated with male sex and obesity. Multivessel involvement may be a marker of more severe, diffuse disease. Further studies are needed to investigate this hypothesis.
Stem-cell transplantation to treat acute myocardial infarction (MI) is gaining importance as a minimally invasive and potent therapy to replace akinetic scar tissue by viable myocardium. Our recent studies have shown that stem-cell transplantation marginally improves myocardial oxygenation in the infarct tissue leading to improvement in cardiac function. The aim of the present study was to determine the effect of hyperbaric oxygen (HBO) treatment on myocardial oxygenation and recovery of function in MI hearts. Fisher-344 rats were subjected to MI by permanently ligating the left-anterior-descending (LAD) coronary artery. The rats were then exposed to 100% O(2) at a pressure of 2 atmospheres for 90 minutes, and the exposure was repeated for 5 days a week for 2 weeks. Adult bone-marrow-derived rat mesenchymal stem cells (MSC, 5x10⁵ cells) were mixed with OxySpin (LiNc- BuO, oxygen sensor) and implanted in the infarct and peri-infarct regions of the heart. M-mode ultrasound echocardiography was performed at baseline and at 2 weeks post-transplantation. The myocardial pO(2) in the MSC+HBO group (16.2±2.2 mmHg) was significantly higher when compared to untreated MI (3.8±1.9 mmHg) or MSC (9.8±2.3 mmHg) groups. In addition, there was a significant improvement in cardiac function, increased vessel density, and VEGF expression in MSC+HBO group compared to MSC group (p < 0.05). In conclusion, the results suggested a beneficial effect of HBO administration on stem-cell therapy for MI.
Hyperbaric oxygen (HBO) preconditioning (PC) allows brain protection against transient global ischemia. In the present study, we hypothesize that the mechanism of HBO-PC involves the induction of cyclooxygenase-2 (COX-2) in cerebral tissues before ischemia, which leads to a suppression of COX-2 and its downstream targets after global ischemic insult.
One hundred twenty-nine male Sprague Dawley rats (body weight 280-300 grams) were allocated to the naive control group and the sham operation group, and 3 groups of animals were subjected to 15-minute 4-vessel occlusion: untreated, preconditioned with HBO 2.5 atmospheres absolutes for 1 hour daily for 5 days, preconditioned as mentioned and administered with COX-2 inhibitor NS-398 (1 mg/kg body weight intraperitoneal) before each preconditioning session, and normal rats preconditioned with HBO without ischemia. The mortality, the incidence of seizures, and T-maze scores were recorded. The quantitative cell count in Nissl stain and TUNEL was conducted on day 7 after ischemia. The brain expression of COX-2 was analyzed with Western blotting and immunofluorescence staining.
HBO-PC increased the number of surviving neurons in the Cornu Ammonis area 1, which was associated with the reduced COX-2 expression in the hippocampus and in the cerebral cortex at 1 and 3 days after ischemia. HBO-PC improved functional performance and tended to decrease mortality and the frequency of seizures. These beneficial effects of HBO-PC were abolished by the COX-2 selective inhibitor NS-398.
HBO-PC reduced COX-2 expression and provided brain protection after global ischemia. Administration of COX-2 inhibitor with HBO before ischemia abolished preconditioning effect, thereby implicating COX-2 as a mediator of HBO-PC in the ischemic brain.
We investigated the possibility that transient coronary slow-flow as assessed during coronary angiography in patients with cardiac syndrome X may impair myocardial perfusion and the effects of this phenomenon on long-term prognosis.
From 50 consecutive patients with cardiac syndrome X, we prospectively recruited 16 who exhibited coronary slow-flow during angiography. The remaining 34 patients served as controls. The slow-flow phenomenon was invariably worsened by nitrates and reversed by papaverine. During slow-flow, a dose of 99m-Tc-Methoxy-isobutyl-isonitrile (MIBI) was injected in 12 patients and SPECT imaging performed 1 h later. The perfusion study was repeated after 2 days at rest and, in 9 patients, at peak exercise after 10+/-4 days. Patients were then regularly followed-up.
All 12 patients had a significant MIBI defect in the regions served by the coronary artery that showed slow-flow just prior MIBI injection. After exercise, MIBI tomograms revealed a perfusion defect in 5 out of the 9 patients who underwent stress scanning. At 14+/-2 years follow-up, 1 patient with slow-flow had died and 4 developed significant coronary artery disease (CAD), while all patients of the control group were alive and none had developed significant CAD.
These results show that the slow-flow phenomenon might be the cause of transient myocardial underperfusion in patients with angina and normal coronary arteries. Apparently, this phenomenon is associated with a worse cardiac prognosis. Therefore, patients with coronary slow-flow should be carefully followed-up.
Prolonged untreated diabetes mellitus leads to microangiopathy, tissue hypoxia and ischemic lesions; it increases the risk for stroke and exacerbates brain tissue damage following ischemia. Patients exhibit advanced atherosclerosis in coronary and cerebral arteries as well as enhanced vascular responsiveness to vasoconstrictors, an attenuated response to vasodilators and impaired autoregulation of cerebral blood flow. Altered endothelial function of arterioles and an impaired vasomotor function of resistance vessels could contribute to altered regulation of regional blood flow and insufficient tissue perfusion in diabetes mellitus. Hyperbaric oxygen therapy is shown to contribute to the healing of ischemic ulcerations in diabetic patients and to improvement of several other pathologic conditions. However, information about the mechanism of how this therapy works is still very limited. We postulate that hyperbaric oxygen therapy has an effect on vascular function by modulating mechanisms of vascular responses to various dilator and constrictor agonists in cerebral resistance vessels, leading to restored vascular reactivity. In accordance to this, the therapy affects production of vasodilators and vasoconstrictors, as well as the vessel-sensitivity to these factors. Furthermore, we hypothesize that hyperbaric oxygen therapy would restore cerebral blood flow regulation that is impaired in diabetics, whereas in contrast to that, chronic intermittent hypoxia would lead to impaired cerebral blood flow. These proposed mechanisms would, if confirmed, represent a valuable advancement in the understanding of this subject.
The coronary arteriograms of 6 patients with the anginal syndrome revealed a normal coronary arterial tree. This finding was associated with a strikingly slow flow rate of the angiographic dye through the major vessels. This feature is discussed in detail and a theory of small vessel disease is suggested. The purpose of this paper is to bring into focus a new angiographic finding. Its cause is hypothesized and requires clarification by further studies which should include accurate flow measurements, metabolic determinations, and myocardial biopsics.
Although the Thrombolysis in Myocardial Infarction (TIMI) flow grade is valuable and widely used qualitative measure in angiographic trials, it is limited by its subjective and categorical nature.
In normal patients and patients with acute myocardial infarction (MI) (TIMI 4), the number of cineframes needed for dye to reach standardized distal landmarks was counted to objectively assess an index of coronary blood flow as a continuous variable. The TIMI frame-counting method was reproducible (mean absolute difference between two injections, 4.7 +/- 3.9 frames, n=85). In 78 consecutive normal arteries, the left anterior descending coronary artery (LAD) TIMI frame count (36.2 +/- 2.6 frames) was 1.7 times longer than the mean of the right coronary artery (20.4 +/- 3.0) and circumflex counts (22.2 +/- 4.1, P < .001 for either versus LAD). Therefore, the longer LAD frame counts were corrected by dividing by 1.7 to derive the corrected TIMI frame count (CTFC). The mean CTFC in culprit arteries 90 minutes after thrombolytic administration followed a continuous unimodal distribution (there were not subpopulations of slow and fast flow) with a mean value of 39.2 +/- 20.0 frames, which improved to 31.7 +/- 12.9 frames by 18 to 36 hours (P < .001). No correlation existed between improvements in CTFCs and changes in minimum lumen diameter (r=-.05, P=.59). The mean 90-minute CTFC among nonculprit arteries (25.5 +/- 9.8) was significantly higher (flow was slower) compared with arteries with normal flow in the absence of acute MI (21.0 +/- 3.1, P < .001) but improved to that of normal arteries by 1 day after thrombolysis (21.7 +/- 7.1, P=NS).
The CTFC is a simple, reproducible, objective and quantitative index of coronary flow that allows standardization of TIMI flow grades and facilitates comparisons of angiographic end points between trials. Disordered resistance vessel function may account in part for reductions in flow in the early hours after thrombolysis.
Treatment with hyperbaric oxygen (HBO2) is controversial when treating disorders other than decompression sickness. Still, HBO2 is a treatment modality that has gained recognition in certain situations of ischaemia reperfusion. However, not much is known about its effect on the endothelial cells. Based on earlier studies, the hypothesis was that HBO2 treatment stimulates the release of fibrinolytic factors. The aim of the study was to investigate the effect of HBO2 treatment on cultured endothelial cells in a simulated ischaemia-reperfusion model.
To mimic the clinical situation during ischaemia reperfusion, endothelial cells were subjected to anoxia for 8 h, followed by reperfusion with either HBO2 or normobaric air for 1.5 h, and compared with an untreated control that was not exposed to anoxia. Components investigated were the fibrinolytic stimulator tissue plasminogen activator (t-PA), urokinase plasminogen activator (uPA) and the antagonist. plasminogen activator inhibitor type one (PAI-1).
Immediately after 8 h of total anoxia and reoxygenation with HBO2 (for 1.5 h), the mean (SEM) concentrations of t-PA, PAI-1 and uPA were significantly increased compared to the other groups. The difference between the normobaric and control groups, measured at 1.5 h, 6 h and 24 h post-anoxia, persisted throughout the experiment.
In this ischaemia-reperfusion model. HBO2 stimulates the release of fibrinolytic factors. These observations might be relevant in trauma care in preventing thromboses and/or microembolization following ischaemia-reperfusion.
The aim of the study was to evaluate whether there was an imbalance between endothelin-1 (ET-1) and nitric oxide (NOx) release and diffuse atherosclerotic changes existed in patients with slow coronary flow (SCF). Baseline and post-atrial pacing coronary sinus ET-1 and NOx levels were measured in 19 patients with SCF (11 female, 56 +/- 9 years) and in 14 control subjects (nine female, 54 +/- 7 years). All patients underwent subsequent intravascular ultrasound (IVUS) investigation at the same setting with right atrial pacing. Baseline arterial (12.4 +/- 9.9 vs. 6.3 +/- 5.1 pg/ml, P<0.005) and coronary sinus (12.2 +/- 11.1 vs. 6.4 +/- 6.9 pg/ml, P<0.005) ET-1 plasma levels were higher in patients than in controls. After atrial pacing, concentration of ET-1 level from coronary sinus (24.7 +/- 14.6) significantly increased as compared to baseline (12.4 +/- 9.9, P<0.0001) and control levels (5.3 +/- 6.3, P<0.0001). Additionally, coronary sinus ET-1 level increased significantly with atrial pacing compared to femoral artery ET-1 level (16.3 +/- 8.5, P<0.005) in patients with SCF. After atrial pacing, the femoral artery ET-1 level also increased in patients compared to control level (P<0.0001). No significant differences in arterial and coronary sinus NOx plasma levels were found between the two groups, both at baseline and after pacing. Upon IVUS investigation, the common finding was longitudinally extended massive calcification throughout the epicardial arteries in patients with SCF. Mean intimal thickness was 0.59 +/- 0.18 mm. The data of this study suggest that increased ET-1 levels and insufficient NOx response, as well as the pathological data of IVUS may be associated with coronary microvascular dysfunction and may be the manifestation of early diffuse epicardial atherosclerosis in these patients with SCF.
Acute heart attacks associated with coronary artery disease are collectively referred to as 'acute coronary syndrome' ( ACS). ACS is very common and may lead to severe complications including death. Hyperbaric oxygen therapy (HBOT) involves people breathing pure oxygen at high pressures in a specially designed chamber. It is sometimes used as a treatment to increase the supply of oxygen to the damaged heart in an attempt to reduce the area of the heart that is at risk of dying. We found some evidence that people with ACS are less likely to have major adverse cardiac events, and to have more rapid relief from their pain, if they receive hyperbaric oxygen therapy as part of their treatment. However, there is no good evidence that people are more likely to survive following HBOT. Our conclusions are based on five randomised trials (four of which included only patients with confirmed heart muscle death), and with a limited number of patients. Hyperbaric oxygen may therefore reduce the time to pain relief and the chance of adverse heart events in people with heart attack and unstable angina, but it is not clear if the risk of dying is reduced. Further research is needed.
Slow coronary flow (SCF) in a normal coronary angiogram is a well-recognized clinical entity, but its etiopathogenesis remains unclear. However, previous studies have suggested that microvascular abnormalities and endothelial dysfunction responsible for SCF. Accordingly, we hypothesized that SCF phenomenon may be a form, at least early phase, of atherosclerosis that involve both small vessels and epicardial coronary arteries, and therefore we investigated coronary flow reserve (CFR) reflecting coronary microvascular function in patients with SCF.
Twenty subjects with SCF and 15 control subjects with normal coronary flow were studied. Coronary flow was quantified according to TIMI frame count (TFC). Coronary diastolic peak flow velocities were measured at baseline and after dipyridamole infusion. CFR was calculated as the ratio of hyperemic to baseline diastolic peak velocities.
Demographic features, coronary risk factors, echocardiographic measurements except diastolic function parameters, and biochemical measurements were similar between the groups. CFR values were significantly lower in subjects with SCF than in the control group (1.99+/-0.38 versus 2.99+/-0.47, P<0.0001). In addition, TIMI frame count independently correlated with CFR.
These findings suggest that CFR, which reflects coronary microvascular function, is impaired in patients with SCF, and corrected TFC well correlates with CFR.
Ischemia-reperfusion injury (IRI) occurs following coronary artery revascularization. Reactive oxygen species (ROS) were initially thought to play a role in the pathogenesis of this injury. However, the evidence for this is inconclusive. Recent studies involving ischemic preconditioning have identified ROS as potential mediators for the cardioprotective effects observed following this technique. Furthermore, cardiac studies involving IRI and the use of hyperbaric oxygen (HBO) have demonstrated the ability of HBO to induce cardioprotection and to attenuate IRI. This review suggests the possible role for HBO as a new drug in the arena of myocardial revascularization and cellular protection. While there is mounting clinical evidence for this, a methodological understanding of HBO's cellular mechanisms of actions appears to be lacking. As such, this article attempts to draw the similarity between HBO and other protective oxidative stress mechanisms and then to speculate in an evidence-based manner its possible cellular mechanistic role as a drug via the generation of ROS.
Statins improve endothelial functioning in patients with coronary artery disease and hypercholesterolemia, while substantially little is known about induced changes in myocardial microcirculation. However, although previous studies have suggested that microvascular abnormalities and endothelial dysfunction is responsible for slow coronary flow (SCF), there is no study investigating possible effects of statins on coronary microvascular function in patients with SCF.
We prospectively investigated the effects of short-term lipid-lowering therapy with atorvastatin on coronary flow reserve (CFR) reflecting coronary microvascular function in patients with SCF assessed by transthoracic Doppler echocardiography (TTDE).
In an open clinical trial, CFR was studied in 20 subjects with SCF. TTDE was used to assess CFR at baseline as well as after 8 weeks of atorvastatin therapy. Coronary flow was quantified according to TIMI frame count (TFC). Coronary diastolic peak flow velocities were measured at baseline and after dipyridamole infusion. CFR was calculated as the ratio of hyperemic to baseline diastolic peak velocities.
CFR was independently correlated with TFC. After 8 weeks of atorvastatin therapy, CFR values increased significantly (1.95 +/- 0.38 vs. 2.54 +/- 0.56, (p < 0.001). No change in hemodynamic parameters was noted during the entire study. The improvement in CFR was not correlated to the amount of lipid-lowering effect of atorvastatin.
These findings suggest that short-term lipid-lowering therapy with atorvastatin improved CFR, which reflects coronary microvascular functioning in patients with SCF.
The slow coronary flow (SCF) phenomenon is a coronary microvascular disorder characterized by the delayed passage of contrast in the absence of obstructive epicardial coronary disease. Recent studies showed the possible role of endothelial dysfunction, diffuse atherosclerosis and inflammation in the pathogenesis of this phenomenon. We aimed to investigate the effect of statin on myocardial perfusion in patients with SCF.
The study population consisted of 97 patients with SCF. Coronary flow patterns of the cases are determined by thrombolysis in myocardial infarction (TIMI) frame count method. Single-photon emission computed tomographic myocardial perfusion imaging studies and lipid parameters of the patients were obtained before and after 6 months of simvastatin treatment period. During the study, daily single dose of 40 mg simvastatin has been given to each subject. We found a significant positive correlation between mean TIMI frame count and basal reversibility score (r = 0.84, p = 0.0001). In addition, analysis of the reversibility scores demonstrates that simvastatin treatment has significantly improved the myocardial perfusion abnormality at the end of the follow-up period.
Present findings allow us to conclude that simvastatin improved myocardial perfusion in patients with SCF.
The present study examined the hypothesis that cerebral ischemic tolerance induced by hyperbaric oxygen preconditioning (HBO-PC) is associated with an increase of antioxidant enzyme activity. Male Sprague-Dawley rats (250-280 g, n=74) were divided into sham, middle cerebral artery occlusion (MCAO) for 90 min, and MCAO plus HBO-PC groups. HBO-PC was conducted four times by given 100% oxygen at 2.5 atmosphere absolute (ATA), for 1 h at every 12 h interval for 2 days. At 24 h after the last HBO-PC, MCAO was performed and at 24 h after MCAO, neurological function and Nissl Staining were performed to evaluate the effect of HBO-PC. Malondialdehyde (MDA) content, activity of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) sampled from the hippocampus, ischemic penumbra or core of cortex were measured. HBO-PC decreased mortality rate, improved neurological recovery, lessened neuronal injury, reduced the level of MDA and increased the antioxidant activity of CAT and SOD. These observations demonstrated that an upregulation of the antioxidant enzyme activity by HBO preconditioning plays an important role in the generation of tolerance against brain ischemia-reperfusion injury.
The association of serum albumin with coronary slow flow
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