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The Effect of Cholesterol-Lowering and Antioxidant Therapy on Endothelium-Dependent Coronary Vasomotion
Abstract
Patients with coronary artery disease and abnormalities of serum lipids often have endothelial vasodilator dysfunction, which may contribute to ischemic cardiac events. Whether cholesterol-lowering or antioxidant therapy can restore endothelium-dependent coronary vasodilation is unknown.
We randomly assigned 49 patients (mean serum cholesterol level, 209 +/- 33 mg per deciliter [5.40 +/- 0.85 mmol per liter]) to receive one of three treatments: an American Heart Association Step 1 diet (the diet group, 11 patients); lovastatin and cholestyramine (the low-density lipoprotein [LDL]-lowering group, 21 patients); or lovastatin and probucol (the LDL-lowering-antioxidant group, 17 patients). Endothelium-dependent coronary-artery vasomotion in response to an intracoronary infusion of acetylcholine (10(-8) to 10(-6) M) was assessed at base line and after one year of therapy. Vasoconstrictor responses to these doses of acetylcholine are considered to be abnormal.
Treatment resulted in significant reductions in LDL cholesterol levels of 41 +/- 22 percent in the LDL-lowering-antioxidant group and 38 +/- 20 percent in the LDL-lowering group (P < 0.001 vs. the diet group). The maximal changes in coronary-artery diameter with acetylcholine at base line and at follow-up were -19 and -2 percent, respectively, in the LDL-lowering-antioxidant group, -15 and -6 percent in the LDL-lowering group, and -14 and -19 percent in the diet group (P < 0.01 for the LDL-lowering-antioxidant group vs. the diet group; P = 0.08 for the LDL-lowering group vs. the diet group). (The negative numbers indicate vasoconstriction). Thus, the greatest improvement in the vasoconstrictor response was seen in the LDL-lowering-antioxidant group.
The improvement in endothelium-dependent vasomotion with cholesterol-lowering and antioxidant therapy may have important implications for the activity of myocardial ischemia and may explain in part the reduced incidence of adverse coronary events that is known to result from cholesterol-lowering therapy.
... 4,5 More importantly, CEF responds favorably to therapies that reduce atherosclerotic events. 5,6 While CEF could previously only be measured in the invasive catheterization laboratory during coronary angiography, our group developed a noninvasive magnetic resonance imaging (MRI)-based method to measure changes in coronary cross-sectional area (CSA) and coronary blood flow in response to isometric handgrip exercise, an endothelial-dependent stress. 7 These MRI measures of CEF were shown to be nitric oxide-mediated, thus representing endothelial function, and reproducible. ...
... 4,5 Notably, measurements of peripheral artery endothelial function only modestly correlate with CEF. 6 Our current findings support previous work from our group demonstrating that CEF is impaired in people with HIV without CAD. 9,11 Prior literature suggests a trend towards women with HIV having a higher risk of CVD than men with HIV, although statistical significance was not achieved. ...
Background
Impaired coronary endothelial function (CEF) predicts cardiovascular events and occurs in people living with HIV (PLWH). Women compared with men living with HIV have worse cardiovascular outcomes, but prior CEF studies included few women. The authors aimed to compare CEF in women with HIV versus without HIV, investigate sex differences in CEF and PCSK9 (proprotein convertase subtilisin/kexin type 9) (a proinflammatory biomarker), and evaluate whether increased serum levels of PCSK9 are associated with CEF in PLWH.
Methods and Results
Magnetic resonance imaging was performed to measure CEF (as percent change in coronary cross‐sectional area and coronary blood flow during isometric handgrip exercise, an endothelial‐dependent stressor) and serum PCSK9 levels were measured in 106 PLWH and 76 people without HIV. CEF was significantly reduced in women with versus without HIV (cross‐sectional area change −0.5%±9.7 versus 9.5%±3.2, respectively). After adjustment for age, body mass index, and menopausal status, women with HIV still had reduced CEF (percentage of cross‐sectional area: ß −8.3 [−13 to −3.6], P =0.001) compared with women without HIV. PCSK9 was elevated in women living with HIV versus without (306 ng/mL [200–412 ng/mL] versus 180 ng/mL [154–223 ng/mL], P <0.001), and no sex differences in either CEF or PCSK9 were detected in PLWH. Elevated PCSK9 was associated with impaired CEF in PLWH; however, no significant sex differences in the association were detected.
Conclusions
Among PLWH, coronary endothelial dysfunction is present in women and comparable to men. PCSK9 is higher in women with versus without HIV and a significant inverse relationship between PCSK9 and CEF was shown. Future studies should determine whether PLWH would benefit from interventions to improve endothelial function.
... Moreover, ECD seems reversible after therapeutic intervention (63). For example, cholesterol-lowering and antioxidant therapies improve endothelium-dependent vasomotor functions and reduce CVD incidences (64). Currently, VC treatments focus on improving known risk factors, whereas specific endothelium-targeted therapy is rarely studied. ...
... Statins improve endothelium-dependent vasodilation functions that primarily depend on the upregulation of ECbased KLF2 levels to enhance eNOS activity (138), increase NOS, reduce oxidative stress, and inhibit the effect of endothelin (ET-1) (64,137). Simvastatin significantly increases eNOS expression and activity and restores NO production (139). ...
Vascular calcification (VC) is active and regulates extraosseous ossification progress, which is an independent predictor of cardiovascular disease (CVD) morbidity and mortality. Endothelial cells (ECs) line the innermost layer of blood vessels and directly respond to changes in flow shear stress and blood composition. Together with vascular smooth muscle cells, ECs maintain vascular homeostasis. Increased evidence shows that ECs have irreplaceable roles in VC due to their high plasticity. Endothelial progenitor cells, oxidative stress, inflammation, autocrine and paracrine functions, mechanotransduction, endothelial-to-mesenchymal transition (EndMT), and other factors prompt ECs to participate in VC. EndMT is a dedifferentiation process by which ECs lose their cell lineage and acquire other cell lineages; this progress coexists in both embryonic development and CVD. EndMT is regulated by several signaling molecules and transcription factors and ultimately mediates VC via osteogenic differentiation. The specific molecular mechanism of EndMT remains unclear. Can EndMT be reversed to treat VC? To address this and other questions, this study reviews the pathogenesis and research progress of VC, expounds the role of ECs in VC, and focuses on the regulatory factors underlying EndMT, with a view to providing new concepts for VC prevention and treatment.
... Anti-inflammatory anti-cytokine drugs like ACE inhibitors and statins stabilize the endothelium in addition to interference with viral replication. [108][109][110][111][112] In this way, IL-6 and tumor necrosis factor (TNF)-inhibitors beside antagonists of endothelin receptors, which are antiinflammatory agents supporting endothelial function, are under current investigation for use in patients with COVID-19. 108,[112][113][114] There are drugs like adenosine deaminase and plerixafor that prevent endothelial apoptosis and instigates endothelial proliferation, totally reduce endothelial permeability and improve endothelial function. ...
... [108][109][110][111][112] In this way, IL-6 and tumor necrosis factor (TNF)-inhibitors beside antagonists of endothelin receptors, which are antiinflammatory agents supporting endothelial function, are under current investigation for use in patients with COVID-19. 108,[112][113][114] There are drugs like adenosine deaminase and plerixafor that prevent endothelial apoptosis and instigates endothelial proliferation, totally reduce endothelial permeability and improve endothelial function. [115][116][117] Prophylactic approaches like transfusion of some factors like platelets, fresh frozen plasma, fibrinogen, and prothrombin complex concentrate could also be useful in the COVID-19 treatment plan. ...
The world is in a hard battle against COVID-19. Endothelial cells are among the most critical targets of SARS-CoV-2. Dysfunction of endothelium leads to vascular injury following by coagulopathies and thrombotic conditions in the vital organs increasing the risk of life-threatening events. Growing evidences revealed that endothelial dysfunction and consequent thrombotic conditions are associated with the severity of outcomes. It is not yet fully clear that these devastating sequels originate directly from the virus or a side effect of virus-induced cytokine storm. Due to endothelial dysfunction, plasma levels of some biomarkers are changed and relevant clinical manifestations appear as well. Stabilization of endothelial integrity and supporting its function are among the promising therapeutic strategies. Other than respiratory, COVID-19 could be called a systemic vascular disease and this aspect should be scrutinized in more detail in order to reduce related mortality. In the present investigation, the effects of COVID-19 on endothelial function and thrombosis formation are discussed. In this regard, critical players, laboratory findings, clinical manifestation, and suggestive therapies are presented.
... Statin therapy improves coronary flow reserve (CFR) in patients with coronary atherosclerosis. [1][2][3] Statins also decrease the risk of cardiovascular events among hypertensive patients with average levels of serum total cholesterol and intermediate-risk persons without cardiovascular disease. 4)5) Improvements in CFR may be related to the beneficial effects of statins in such patients, but measurement of CFR was rarely performed in hypertensive patients without coronary artery disease (CAD), because CFR could be invasively measured using Doppler guide wire in a cardiac catheterization laboratory. ...
... Statin therapy decreases cardiac morbidity and mortality in patients with CAD and hypercholesterolemia via pleiotropic effects of statins, including regression of atheroma and stabilization of atherosclerotic plaques. 1 and CFR may be related to the beneficial effects of statins in hypertensive patients without hypercholesterolemia. Because activation of the renin-angiotensin-aldosterone system and sympathetic nervous system may cause endothelial dysfunction, and hypertensive load results in left ventricular hypertrophy, [11][12][13] it is possible that antihypertensive medications may play a role in improving CFR. ...
Background:
It has been unclear whether statin therapy directly improves coronary flow reserve (CFR) in hypertensive patients at cardiovascular risk, independent of lifestyle modification and antihypertensive medications.
Methods:
In this double-blind, randomized controlled trial, we randomly assigned 95 hypertensive patients at cardiovascular risk to receive either rosuvastatin 10 mg or placebo for 12 months, in addition to antihypertensive therapy and lifestyle modification for hypercholesterolemia. Using Doppler echocardiography, coronary flow velocity in the distal left anterior descending artery was measured and CFR was calculated as the ratio of hyperemic to basal averaged peak diastolic flow velocity. The primary end point was change in CFR from baseline to 12 months follow-up.
Results:
Low-density lipoprotein-cholesterol was changed from 157 ± 23 to 84 ± 16 mg/dL in the rosuvastatin group (p < 0.001) and from 152 ± 19 to 144 ± 22 mg/dL in the control group (p = 0.041, but there were no significant differences between the treatment groups in the changes in C-reactive protein, high-density lipoprotein cholesterol, and blood pressures. CFR was changed from 3.03 ± 0.44 to 3.25 ± 0.49 in the rosuvastatin group (p < 0.001) and from 3.15 ± 0.54 to 3.17 ± 0.56 in the control group (p = 0.65). The primary end point of change in CFR was significantly different between the rosuvastatin group and the control group (0.216 ± 0.279 vs. 0.015 ± 0.217; p < 0.001).
Conclusions:
Compared with lifestyle modification alone, addition of rosuvastatin significantly improved CFR in hypertensive patients at cardiovascular risk.
... Another study demonstrated that statin therapy resulted in improvements in CVR in individuals with cerebral small vessel disease, with more pronounced effects in those with the most severe impairments in CVR 42 . Statin therapy has been shown to improve endothelial-dependent vasomotion in the coronary 43,44 and peripheral arteries 45,46 . Statin-induced improvements in endothelial-dependent vasomotion are thought to be mediated by their lipid-lowering properties 47 , and by enhancing NO synthase activity 48 . ...
Introduction
Cerebrovascular reactivity (CVR) provides an index of endothelial function in the brain. Poor CVR is associated with stroke, cerebral small vessel disease, dementia, and even coronary artery disease. Traditional cardiovascular disease (CVD) risk factors are associated with low CVR in patients with known CVD and in older cohorts. However, the relationship between cardiovascular risk profile and reduced CVR in young adults who do not yet have CVD is uncertain.
Methods
This cross-sectional study included adults who underwent a clinically indicated 3-Tesla fMRI scan of the brain with a "breath-hold task." Individuals with intracranial masses or baseline CVD were excluded. Using an axial slice 8 mm superior to the corpus callosum, a mean cerebral t-statistic was calculated as a comparative global measure of CVR. Based on the distribution of these values patients were divided into two groups: high ("normal") and low t-statistic value ("abnormal"). The distribution of cardiovascular risk factors was then compared across groups.
Results
Between January 2014 - December 2023, 76 individuals underwent brain fMRI with a "breath hold task" (mean ± SD age, 35.46 ± 12.09 yrs.; 31.6% female). Mean ± SD global CVR T-statistic was 3.97 ± 1.62. Low CVR was defined as a mean T-statistic ≤ 4.2 (n=44, 57.9%). Individuals with abnormal CVR were older, had a higher frequency of hypertension and hyperlipidemia and had higher systolic and diastolic blood pressures. Age, systolic blood pressure and hyperlipidemia were significantly associated with abnormal CVR in multivariable analyses (age, increase by 10 years OR: 2.00, 95% CI 1.40 - 2.78, p=0.0078; hyperlipidemia OR: 8.54, 95% CI 1.07 - 184.9, p=0.0049, and systolic blood pressure (OR for an increase in 10 mmHg: 1.57, 95% CI 1.10 - 2.10, p=0.0084).
Conclusion
Traditional cardiovascular risk factors are significantly associated with abnormal CVR in young adults without baseline CVD or cerebrovascular disease undergoing fMRI for reasons related to a diagnosis of epilepsy.
... Diketahui bahwa pada keadaan hiperkholesterolemia dapat terjadi peningkatan pembentukan superoksida oleh endotel, superoksida ini secara langsung dapat menginaktivasi nitric oxide dan juga dapat meningkatkan oksidasi LDL dengan membentuk peroksinitrit. Studi terbaru menunjukkan bahwa Probucol dapat meningkatkan respon endotel dependent vasodilator, tidak hanya mencegah oksidasi LDL tetapi juga memberantas radikal bebas oksigen dalam dinding pembuluh darah (Anderson et al., 1995). ...
The obyective of the study was to find out the effect of Probucol as an antioxidant on Malondialdehyde (MDA) level and total circulating endothelial cells of rats exposed to stressor.This study was a post test only control group design using 35 three- months old male wistar rats devided into 5 groups consisting of 7 rats each namely the control groups (Po1, Po2) and the experiment groups (P1,P2, P3). Details of the treatment to each groups ere as follows:Group Po1 were given per oral Probucol dilution solution for 3 weeksGroup Po2 were given per oral Probucol dilution solution and stressor for 3 weeks Group P1 were given per oral Probucol dose I (5 mg/rat) and stressor for 3 weeksGroup P2 were given per oral Probucol dose II (10 mg/rat) and stressor for 3 weeks, andGroup P3 were given per oral Probucol dose III (20 mg/rat) and stressor for 3 weeksMalondialdehyde (MDA) level and total circulating endothelial cells were measured using “Buege and Aust (1978) and Hladovic and Rossman (1973)“ method modified by Wijayanto (1996). Data on MDA level and total circulating endothelial cells were analyzed by using analysis of variant (Anova). The presence of significant difference was confirmed by using LSD test. Correlation between MDA level and total circulating endothelial cells was analysed by using “scarter plot” and r (rho) tests. The results showed a significant increase of MDA level of Po1 compared to Po2 (P less than 0.05). Significant decrease of MDA level (P less than 0,05) was observed in group P1, P2 and P3 compared to that of the Po1 and Po2 control groups. The results also showed a significant increase of total circulating endothelial cells of the control group Po1 compared to that in the control group Po2 (P less than 0,05), while significant decrease of total circulating endothelial cells (P less than 0,05) was observed in group P1, P2 and P3 compared to that of the control group Po2. It can be concluded that stressor may increase MDA level and total circulating endothelial cells
... Atherosclerosis is a chronic immunoinflammatory condition in which endothelial dysfunction plays an early and permissive role. [1][2][3] Atherosclerosis-associated cardiovascular diseases (CVDs) represent a leading cause of death globally, 9 and they progress via cardio-oncological factors including DNA damage, [9][10][11][12][13][14][15] inflammation, 16 apoptosis, 10,12,17,18 and cellular dysfunction. 19 Subendothelial retention of low-density lipoprotein (LDL) and its oxidative modification represent the initial events during atherogenesis. ...
The BReast CAncer type 2 susceptibility protein (BRCA2) responds to DNA damage by participating in homology-directed repair. BRCA2 deficiency culminates in defective DNA damage repair (DDR) that when prolonged leads to the accumulation of DNA damage causing cancer or apoptosis. Oxidative stress promotes DNA damage and apoptosis and is a common mechanism through which cardiovascular risk factors lead to endothelial dysfunction and atherosclerosis. Herein, we show that endothelial BRCA2 plays a protective role against atherosclerosis under hypercholesterolemic stress. We successfully generated and characterized endothelial cell (EC)-specific BRCA2 knockout (BRCA2endo) mice. To study the effect of EC-specific BRCA2-loss in atherosclerosis, we generated and characterized BRCA2endo mice on apolipoprotein E null background (ApoE-/-), fed them with high-fat diet (HFD) and evaluated atherosclerosis. Baseline phenotyping of BRCA2endo mice did not show any adverse effects in terms of DNA damage and apoptosis as well as cardiac and metabolic function. However, using HFD-fed apolipoprotein E knockout (ApoE-/-) background, we demonstrated that EC-specific loss of BRCA2 resulted in aortic plaque deposition and splenomegaly. Comparison of RNA sequencing data from aortas of EC-specific BRCA2-deficient ApoE-/- and BRCA2-intact ApoE-/- mice revealed a total of 530 significantly differentially expressed genes with Protein Folding Response and Lipid Metabolism as the most affected pathways. This study provides foundational knowledge regarding BRCA2 status and function in the cardiovascular system, and highlights the potential of BRCA2 as a novel therapeutic target in prevention and treatment of atherosclerosis. Our data indicate that BRCA2 mutation carriers may be at a previously unrecognized risk of atherosclerosis in addition to breast and ovarian cancer.
... Statins have been shown to increase mRNA levels and the activation of PPAR-α in liver cells. Moreover, statins can positively modulate vasomotor function by limiting acetylcholine-induced vasoconstriction [21,22] as well as improving peripheral NO-mediated vascular relaxation [23]. Nagaoka et al. revealed another positive effect of statins on microcirculation: an increase in blood velocity and flow in the retinal arterioles [24]. ...
Microcirculatory and mitochondrial dysfunction are considered the main mechanisms of septic shock. Studies suggest that statins modulate inflammatory response, microcirculation, and mitochondrial function, possibly through their action on peroxisome proliferator-activated receptor alpha (PPAR-α). The aim of this study was to examine the effects of pravastatin on microcirculation and mitochondrial function in the liver and colon and the role of PPAR-α under septic conditions. This study was performed with the approval of the local animal care and use committee. Forty Wistar rats were randomly divided into 4 groups: sepsis (colon ascendens stent peritonitis, CASP) without treatment as control, sepsis + pravastatin, sepsis + PPAR-α-blocker GW6471, and sepsis + pravastatin + GW6471. Pravastatin (200 µg/kg s.c.) and GW6471 (1 mg/kg) were applied 18 h before CASP-operation. 24 h after initial surgery, a relaparotomy was performed, followed by a 90 min observation period for assessment of microcirculatory oxygenation (μHbO2) of the liver and colon. At the end of the experiments, animals were euthanized, and the colon and liver were harvested. Mitochondrial function was measured in tissue homogenates using oximetry. The ADP/O ratio and respiratory control index (RCI) for complexes I and II were calculated. Reactive oxygen species (ROS) production was assessed using the malondialdehyde (MDA)-Assay. Statistics: two-way analysis of variance (ANOVA) + Tukey’s/Dunnett’s post hoc test for microcirculatory data, Kruskal–Wallis test + Dunn’s post hoc test for all other data. In control septic animals µHbO2 in liver and colon deteriorated over time (µHbO2: −9.8 ± 7.5%* and −7.6 ± 3.3%* vs. baseline, respectively), whereas after pravastatin and pravastatin + GW6471 treatment μHbO2 remained constant (liver: µHbO2 pravastatin: −4.21 ± 11.7%, pravastatin + GW6471: −0.08 ± 10.3%; colon: µHbO2 pravastatin: −0.13 ± 7.6%, pravastatin + GW6471: −3.00 ± 11.24%). In both organs, RCI and ADP/O were similar across all groups. The MDA concentration remained unchanged in all groups. Therefore, we conclude that under septic conditions pravastatin improves microcirculation in the colon and liver, and this seems independent of PPAR-α and without affecting mitochondrial function.
... A large number of clinical trials have demonstrated statins' effect on improving endothelial dysfunction [57][58][59][60]. A systematic review in 2011 also showed significant improvement in both peripheral and coronary endothelial function after statin therapy, highlighting its potential use in MVA [61]. ...
Microvascular angina (MVA), historically called cardiac syndrome X, refers to angina with nonobstructive coronary artery disease. This female-predominant cardiovascular disorder adds considerable health-related costs due to repeated diagnostic angiography and frequent hospital admissions. Despite the high prevalence of this diagnosis in patients undergoing coronary angiography, it is still a therapeutic challenge for cardiologists. Unlike obstructive coronary artery disease, with multiple evidence-based therapies and management guidelines, little is known regarding the management of MVA. During the last decade, many therapeutic interventions have been suggested for the treatment of MVA. However, there is a lack of summarization tab and update of current knowledge about pharmacologic management of MVA, mostly due to unclear pathophysiology. In this article, we have reviewed the underlying mechanisms of MVA and the outcomes of various medications in patients with this disease. Contrary to vasospastic angina in which normal angiogram is observed as well, nitrates are not effective in the treatment of MVA. Beta-blockers and calcium channel blockers have the strongest evidence of improving the symptoms. Moreover, the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, statins, estrogen, and novel antianginal drugs has had promising outcomes. Investigations are still ongoing for vitamin D, omega-3, incretins, and n-acetyl cysteine, which have resulted in beneficial initial outcomes. We believe that the employment of the available results and results of the future large-scale trials into cardiac care guidelines would help reduce the global cost of cardiac care tremendously.
... Many in vitro and in vivo animal studies have implicated AngII within pathways known to contribute to vein graft disease. AngII has been found to promote IH [110] and both SMC hypertrophy [111] and proliferation [112,113], and is evidenced to activate key inflammatory pathways which precipitate vein graft disease. Specifically, AngII has been demonstrated to stimulate release of IL6 from SMCs and macrophages [114] and to activate nicotinamide dinucleotide phosphatase oxidase with resultant production of ROS [115,116], thereby promoting oxidative stress within the vascular microenvironment. ...
Endothelial cells comprise the intimal layer of the vasculature, playing a crucial role in facilitating and regulating aspects such nutrient transport, vascular homeostasis, and inflammatory response. Given the importance of these cells in maintaining a healthy haemodynamic environment, dysfunction of the endothelium is central to a host of vascular diseases and is a key predictor of cardiovascular risk. Of note, endothelial dysfunction is believed to be a key driver for vein graft disease—a pathology in which vein grafts utilised in coronary artery bypass graft surgery develop intimal hyperplasia and accelerated atherosclerosis, resulting in poor long-term patency rates. Activation and denudation of the endothelium following surgical trauma and implantation of the graft encourage a host of immune, inflammatory, and cellular differentiation responses that risk driving the graft to failure. This review aims to provide an overview of the current working knowledge regarding the role of endothelial cells in the onset, development, and modulation of vein graft disease, as well as addressing current surgical and medical management approaches which aim to beneficially modulate endothelial function and improve patient outcomes.
... Indeed, it characterizes lower all-cause mortality and MACE rates (2.38 and 9.24% per year) than observed in OCAD patients (10.1 and 16.8% per year); however, NOCAD patients are still at high risk of death and MACE [31,38]. Not only do statins reduce cholesterol levels, but they also improve endothelium-dependent vasomotion, making them even more beneficial [48]. In addition, statins may decrease all-cause mortality in patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) [34]. ...
No hemodynamically significant atherosclerotic plaques are observed in up to 30% of patients reporting angina and undergoing coronary angiography. To investigate risk factors associated with non-obstructive coronary artery disease (NOCAD), we analyzed the medical records of, consecutively, 136 NOCAD subjects and 128 patients with significant stenosis in at least one coronary artery (the OCAD group). The blood concentrations of the TC (4.40 [3.78–5.63] mmol/L vs. 4.12 [3.42–5.01] mmol/L; p = 0.026), LDL-C (2.32 [1.80–3.50] mmol/L vs. 2.10 [1.50–2.70] mmol/L; p = 0.003), non-HDL-C (2.89 [2.29–4.19] mmol/L vs. 2.66 [2.06–3.39] mmol/L; p = 0.045), as well as the LDL-C/HDL-C ratio (1.75 [1.22–2.60] vs. 1.50 [1.10–1.95]; p = 0.018) were significantly increased in the NOCAD patients compared to the OCAD group due to the lower prevalence and intensity of the statin therapy in the NOCAD individuals (p < 0.001). Moreover, the abovementioned lipid parameters appeared to be valuable predictors of NOCAD, with the LDL-C (OR = 1.44; 95%CI = 1.14–1.82) and LDL-C/HDL-C (OR = 1.51; 95%CI = 1.13–2.02) showing the highest odds ratios. Furthermore, multivariable logistic regression models determined female sex as the independent risk factor for NOCAD (OR = 2.37; 95%CI = 1.33–4.20). Simultaneously, arterial hypertension substantially lowered the probability of NOCAD (OR = 0.21; 95%CI = 0.10–0.43). To conclude, female sex, the absence of arterial hypertension, as well as increased TC, LDL-C, non-HDL, and LDL-C/HDL-C ratio are risk factors for NOCAD in patients reporting angina, potentially as a result of poor hypercholesterolemia management.
... This concept of a spread of virus from endothelium to epithelium explains the vulnerability of those with endothelial instability 29 to worse outcomes and supports interventions to stabilize the vascular endothelium. 30,31 ...
Many SARS-CoV-2 studies have supported the theory that the Type II alveolar epithelial cells (AEC-2) are the primary portal of entry of the virus into the lung following its brief nasal occupation. However, the theory of inhalational transmission of the virus from the ciliated and goblet nasal cells to the lung parenchyma is not supported by the imaging findings on chest computerized tomography (CT), leading the authors to consider an alternative pathway from the nose to the lung parenchyma that could explain the peripheral, basilar predominant pattern of early disease. Imaging supports that the pulmonary capillaries may be an important vehicle for transmission of the virus and/or associated inflammatory mediators to the lung epithelium.
... Острый аферез плазмы LDL-C улучшает эндотелий-зависимую вазодилатацию [199,200,201], предполагая, что статины могут частично восстановить функцию эндотелия за счет снижения уровня холестерина в сыворотке. Однако в некоторых исследованиях статинов восстановление функции эндотелия происходит до значительного снижения уровня холестерина в сыворотке [202,203,204,205], что позволяет предположить наличие дополнительных эффектов на функцию эндотелия помимо снижения уровня холестерина. Действительно, статины увеличивают эндотелиальную продукцию NO, стимулируя и активируя эндотелиальную NO-синтазу (eNOS) [206,207,208,209,210]. ...
... Острый аферез плазмы LDL-C улучшает эндотелий-зависимую вазодилатацию [199,200,201], предполагая, что статины могут частично восстановить функцию эндотелия за счет снижения уровня холестерина в сыворотке. Однако в некоторых исследованиях статинов восстановление функции эндотелия происходит до значительного снижения уровня холестерина в сыворотке [202,203,204,205], что позволяет предположить наличие дополнительных эффектов на функцию эндотелия помимо снижения уровня холестерина. Действительно, статины увеличивают эндотелиальную продукцию NO, стимулируя и активируя эндотелиальную NO-синтазу (eNOS) [206,207,208,209,210]. ...
... Anti-inflammatory anticytokine agents, medications that target ACE2 and its ligand-COVID-19 spike protein, statins and anticoagulants may be beneficial but warrant further studies including clinical trials. [35][36][37][38][39][40] Limitations of the present study include small sample size and involvement of a single center. Though one can examine the associated clinical and imaging findings in this cohort, this prevents the establishment of causality between COVID-19 and bihemispheric stroke. ...
Background:
There is emerging evidence that COVID-19 can trigger thrombosis because of a hypercoagulable state, including large-vessel occlusion ischemic strokes. Bihemispheric ischemic stroke is uncommon and is thought to indicate an embolic source. Here, we examine the findings and outcomes of patients with bihemispheric stroke in the setting of COVID-19.
Methods:
We performed a retrospective cohort study at a quaternary academic medical center between March 1, 2020, and April 30, 2020. We identified all patients with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection who presented with simultaneous bihemispheric ischemic strokes.
Results:
Of 637 COVID-19 admissions during the 2-month period, 13 had a diagnosis of acute ischemic stroke, including 5 who developed bihemispheric cerebral infarction. Three of those 5 (60%) were female, median age was 54 (range 41-67), and all five were being managed for severe COVID-19-related pneumonia complicated by acute kidney injury and liver failure before the diagnosis of cerebral infarction was established. Five presented with elevated ferritin, lactate dehydrogenase, and interleukin-6 (IL-6) levels, and four had lymphopenia and elevated D-dimer levels. All patients underwent neuroimaging with computed tomography for persistent depressed mentation, with or without a focal neurologic deficit, demonstrating multifocal ischemic strokes with bihemispheric involvement. Outcome was poor in all patients: two were discharged to a rehabilitation facility with moderate-to-severe disability and three (60%) patients died.
Conclusions:
Stroke is implicated in SARS-CoV-2 infection. Although causality cannot be established, we present the imaging and clinical findings of patients with COVID-19 and simultaneous bihemispheric ischemic strokes. Multifocal ischemic strokes with bihemispheric involvement should be considered in COVID-19 patients with severe infection and poor neurologic status and may be associated with poor outcomes.
... Thus, COVID-19 endothelium would explain the systemic microcirculatory damage dysfunction in different vascular beds and their clinical sequelae in patients with COVID-19. This evidence reinforces the need to maintain endothelial stability while coping with viral replication, particularly with antiinflammatory anticytokine drugs, ACE inhibitors, and statins (Bansal 2020;Anderson et al. 1995;Feldmann et al. 2020). ...
Despite the recent announcement of the new pathogenic coronavirus to man, SARS-CoV2, a large number of publications are presented to the scientific community. An organized and systematic review of the epidemiological, etiological, and pathogenic factors of COVID-19 is presented. This is a systematic review using the databases MEDLINE, EMBASE, Web of Science, SCIELO; the descriptors coronavirus, SARS-CoV-2, etiology, epidemiology, pathophysiology, pathogenesis, COVID-19, with publications from December 2019 to January 2021, resulting in more than 800 publications and 210 selected. The data suggest that COVID-19 is associated with SAR-CoV-2 infection, with the transmission of contagion by fomites, salivary droplets, and other forms, such as vertical and fecal–oral. The bat and other vertebrates appear to be reservoirs and part of the transmission chain. The virus uses cell receptors to infect human cells, especially ACE2, like other coronaviruses. Heat shock proteins have different roles in the infection, sometimes facilitating it, sometimes participating in more severe conditions, when not serving as a therapeutic target. The available data allow us to conclude that COVID-19 is a pandemic viral disease, behaving as a challenge for public health worldwide, determining aggressive conditions with a high mortality rate in patients with risk factors, without treatment, but with the recent availability of the first vaccines.
... Insulin resistance has been found to be associated with the development of hypertension, and dietary fiber intake might improve blood pressure by modulating insulin metabolism (26,27). Reduced levels of serum cholesterol are associated with improved endothelial function, which mediates vasodilation and reduces blood pressure (28)(29)(30). The weight loss caused by dietary fiber has also been considered the underlying mechanism for the lowering of high blood pressure (31)(32)(33). ...
Background: The possible effects of dietary fiber intake on hypertension have not been clarified fully. The association of dietary fiber intake with hypertension risk in midlife women was analyzed in this study.
Methods: Baseline data were obtained from the Study of Women's Health Across the Nation (SWAN). Smooth curve, linear regression, and logistic regression analyses were performed to investigate the associations of four indices of daily dietary estimate (DDE) of dietary fiber (dietary fiber intake, dietary fiber intake from beans, dietary fiber intake from vegetables/fruit, and dietary fiber intake from grains) with blood pressure in midlife women. For this research purpose, diastolic blood pressure (DBP) ≥90 mmHg was defined as diastolic hypertension, and systolic blood pressure (SBP) ≥140 mmHg was defined as systolic hypertension.
Results: This study included 2,519 participants with an average age of 46. The smooth curve showed approximate negative correlations between three fiber indices (DDE dietary fiber, DDE fiber from vegetables/fruit, and DDE fiber from grains) and blood pressure, including DBP and SBP (all P < 0.005). There were also approximate negative correlations between two fiber indices (DDE dietary fiber and DDE fiber from grains) and the risk of diastolic hypertension and systolic hypertension (all P < 0.05). Furthermore, multiple linear regression analysis suggested that DDE dietary fiber (Sβ = −0.057, 95% CI −0.194 – −0.012, P = 0.027), DDE fiber from vegetables/fruit (Sβ = −0.046, 95% CI −0.263 – −0.007, P = 0.039), and DDE fiber from grains (Sβ = −0.073, 95% CI −0.600 – −0.099, P = 0.006, Model 4) were still negatively correlated with DBP after adjusting for confounding factors. Only DDE fiber from grains was independently and negatively associated with SBP (Sβ = −0.060, 95% CI −0.846 – −0.093, P = 0.015) after these same confounding factors were adjusted for. Importantly, multiple logistic regression analysis suggested that only higher DDE fiber from grains was independently associated with a reduced risk of diastolic hypertension (OR = 0.848, 95% CI 0.770–0.934, P = 0.001, Model 4) and systolic hypertension (OR = 0.906, 95% CI 0.826–0.993, P = 0.034, Model 4) after the adjustments were made for confounding factors.
Conclusions: We found that dietary fiber intake, especially DDE fiber from grains, contributes to a lower risk of systolic hypertension and diastolic hypertension in midlife women.
... 78,79 In 1995, randomized control trial stated that lovastatin can return endothelial function of a coronary artery. 81 Atorvastatin was shown to reduce pro-infl ammatory cytokines (TNF-, IL-1 and IL-6), ICAM-1 and C-reactive protein (CRP) in hypercholesterolemic patients. 82 One study showed that simvastatin produces signifi cant reduction in endothelial dysfunction markers, infl ammation, oxidative stress and endothelial apoptosis; in this study, CRP reduction seemed to have been in relation to the lipid lowering property of simvastatin. ...
Since the fi rst report of pneumonia outbreak in Wuhan by the end of 2019, Coronavirus Disease 2019 (COVID-19) has become a global pandemic; causing millions of deaths globally and aff ecting the rest of worldwide population. The disease is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which enters hosts by inhabiting Angiotensin-Converting Enzyme-2 (ACE-2) receptors expressed in the endothelium layer of not only the respiratory tracts, but also various organs in the body. COVID-19 has been reported to trigger multiple cardiovascular manifestations. Since endothelial dysfunction plays an important role in cardiovascular events and the endothelium is heavily involved in COVID-19 pathophysiology, it is important to investigate their associations and previously established drug potencies to improve endothelial functions as possible treatment options for COVID-19. In this review, we summarize endothelial dysfunction biomarkers involved in COVID-19 and drugs that have shown potential endothelial protective properties to better understand the incidence of endothelial dysfunction in COVID-19 and its future treatment. We searched in PubMed, Wiley Online Library, EBSCO, ScienceDirect databases for literatures containing following keywords: “Endothelial dysfunction”, “COVID-19”, and “biomarkers”. Eligible publications were then assessed and studied to comprise our literature review. A total of 96 studies matched our criteria and provided scientifi c evidences for our review. Materials were then compiled into a review summarizing endothelial biomarkers involved in COVID-19 and potentially repurposed drugs targeting endothelium for COVID-19.Various endothelial dysfunction biomarkers were found to be elevated in COVID19 and is found to be related to its severity, such as adhesion molecules, selectins, PAI-1, and von Willebrand Factors. Multiple drugs targeting the endothelium are also potential and some are under investigation for COVID-19.
... All these mechanisms might be amplified in case of preexisting endothelial dysfunction, such as in patients with CV risk factors and CAD, leading to a heightened risk of ACS and other thrombotic complications. Advances in the understanding of SARS-CoV-2-related endothelial dysfunction, beyond the pathophysiological insights, would encourages the assessment of the utility of pharmacological therapies targeting the endothelium, such as ACE-inhibitors (ACEi) and statins, in large prospective randomized studies [79][80][81][82]. ...
Acute coronary syndromes (ACS) are frequently reported in patients with coronavirus disease 2019 (COVID-19) and may impact patient clinical course and mortality. Although the underlying pathogenesis remains unclear, several potential mechanisms have been hypothesized, including oxygen supply/demand imbalance, direct viral cellular damage, systemic inflammatory response with cytokine-mediated injury, microvascular thrombosis, and endothelial dysfunction. The severe hypoxic state, combined with other conditions frequently reported in COVID-19, namely sepsis, tachyarrhythmias, anemia, hypotension, and shock, can induce a myocardial damage due to the mismatch between oxygen supply and demand and results in type 2 myocardial infarction (MI). In addition, COVID-19 promotes atherosclerotic plaque instability and thrombus formation and may precipitate type 1 MI. Patients with severe disease often show decrease in platelets count, higher levels of d-dimer, ultralarge von Willebrand factor multimers, tissue factor, and prolongation of prothrombin time, which reflects a prothrombotic state. An endothelial dysfunction has been described as a consequence of the direct viral effects and of the hyperinflammatory environment. The expression of tissue factor, von Willebrand factor, thromboxane, and plasminogen activator inhibitor-1 promotes the prothrombotic status. In addition, endothelial cells generate superoxide anions, with enhanced local oxidative stress, and endothelin-1, which affects the vasodilator/vasoconstrictor balance and platelet aggregation. The optimal management of COVID-19 patients is a challenge both for logistic and clinical reasons. A deeper understanding of ACS pathophysiology may yield novel research insights and therapeutic perspectives in higher cardiovascular risk subjects with COVID-19.
... Endothelial cells (EC) mediate vasodilation through the regulated release of nitric oxide (NO) in response to changes in blood flow and various pharmacologic interventions. [1][2][3][4][5] Beyond its effects on smooth muscle cell relaxation, NO regulates platelet and leukocyte adherence, hemostasis/thrombosis and fibrinolysis. [6,7] In a highly coordinated fashion, EC also produces potent vasoconstrictors, including endothelin-1, angiotensin II, thromboxane A 2 (TXA 2 ), and prostaglandin H2. ...
Treatment with high dose icosapent ethyl (IPE), an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA), significantly reduced ischemic events in patients with either cardiovascular disease (CV) or diabetes plus other risk factors (REDUCE-IT) but the mechanism is not well understood. We compared the effects of EPA, docosahexaenoic acid (DHA), and the omega-6 fatty acid arachidonic acid (AA) on bioavailability of nitric oxide (NO) and fatty acid composition. Human umbilical vein endothelial cells (HUVECs) were pretreated with EPA, DHA, or AA (10 µM). Cells were stimulated with calcium ionophore and NO and peroxynitrite (ONOO⁻) were measured using porphyrinic nanosensors. Levels of EPA, DHA, AA and other fatty acids were measured by gas chromatography (GC). EPA treatment caused the greatest NO release (18%, p<0.001) and reduction in ONOO⁻ (13%, p<0.05) compared to control; the [NO]/[ ONOO⁻] ratio increased by 35% (p<0.001). DHA treatment increased NO levels by 12% (p<0.01) but had no effect on ONOO⁻ release. AA did not affect either NO or ONOO⁻ release. Fatty acid treatments increased their respective levels in ECs. EPA levels increased 10-fold to 4.59 mg/g protein (p<0.001) with EPA treatment and the EPA/AA ratio increased by 10-fold (p<0.001) compared to vehicle. Only EPA increased docosapentaenoic acid (DPA, n3) levels by 2-fold (p<0.001). AA alone decreased the EPA/AA ratio 4-fold (p<0.001). These findings support a preferential benefit of EPA on endothelial function and n-3 fatty acid content.
... Normal aralık dahilinde olsa bile yüksek serum P konsantrasyonunun, normal böbrek fonksiyonu olan hastalarda ateroskleroz ve mortalite gelişiminde ön gördürücü olduğu bildirilmiştir (8,10). Bu elementlerin dengede tutulması ile kardiyovasküler risk faktörlerinin azaltılması sonucunda, KVH tedavisinde önemli terapötik fayda sağlayabileceği öne sürülen endotel fonksiyonları düzeltilebilmektedir (11,12). Akım aracılı vazodilatasyon testi (AAD) ise endotel fonksiyonları değerlendirmede kabul görmüş yöntemlerden birisidir (13 13), ortalama değeri ise 0,62 (minimum 0,20-maksimum 1,03) olarak bulunmuştur. ...
Amaç: Aterosklerotik değişikliklerin ve endotel disfonksiyonunun patogenezi karmaşık ve çok faktörlüdür. Kandaki elektrolitlerden magnezyum ve fosfat mineralleri aterogenez ve endotel fonksiyon bozukluğunun patofizyolojisinde yer alan önemli minerallerdir. Endotel fonksiyonu değerlendirmede en çok kabul görmüş akım aracılı vazodilatasyon testidir. Çalışmamızda, koroner arter hastalığı olan hastalarda magnezyum/fosfat oranı ile endotel fonksiyonları arasındaki ilişkinin değerlendirilmesi amaçlanmıştır. Gereç ve Yöntem: Koroner anjiyografi ile belgelenmiş koroner arter hastalığı olan ardışık 61 hasta çalışmaya dahil edildi. Radial arterden akım aracılı vazodilatasyon testi ile endotel fonksiyonları poliklinik kontrolünde incelendi. Magnezyum/fosfat oranı ile akım aracılı vazodilatasyon yüzdelik değişimi arasındaki korelasyonu değerlendirmek için Spearman korelasyon analizi kullanıldı. Bulgular: Hastaların ortalama yaşı 61,2±10,1 yıl olup hastaların %72’si erkek ve ortalama vücut kitle indeksi 27,8±5,4 kg/m2’dir. AAD testinde ortalama radial arter bazal çapı 0,25±0,03 cm, test sonrası ortalama radial arter çapı 0,28±0,03 cm olarak saptandı. Magnezyum/fosfat oranları ile endotel fonksiyonlarını gösteren arter çapındaki yüzdelik değişim arasında pozitif yönde bir ilişki saptandı (r = 0,268, p = 0,037). Sonuç: Koroner arter hastalığı olan hastalarda, magnezyum/fosfat oranı endotel fonksiyonlarının bir göstergesi olarak kullanılabilir.
... [69,70]. Lovastatin inhibits oxidation of LDL, and this improves the vascular endothelial function (vasoconstrictor reaction) in hyperlipidemia, and in particular, the combined use of an antioxidant can significantly improve the function [64,71]. Antioxidant activity has also been reported in red yeast rice pigments [72,73]: monascin and ankaflavin suppressed LDL-cholesterol oxidation [74]. ...
Red yeast rice has been used to produce alcoholic beverages and various fermented foods in China and Korea since ancient times; it has also been used to produce tofuyo (Okinawan-style fermented tofu) in Japan since the 18th century. Recently, monacolin K (lovastatin) which has cholesterol-lowering effects, was found in some strains of Monascus fungi. Since statins have been used world-wide as a cholesterol-lowering agent, processed foods containing natural statins are drawing attention as materials for primary prevention of life-style related diseases. In recent years, large-scale commercial production of red yeast rice using traditional solid-state fermentation has become possible, and various useful materials, including a variety of monascus pigments (polyketides) that spread as natural pigments, in addition to statins, are produced in the fermentation process. Red yeast rice has a lot of potential as a medicinal food. In this paper, we describe the history of red yeast rice as food, especially in Japan and East Asia, its production methods, use, and the ingredients with pharmacological activity. We then review evidence of the beneficial effects of red yeast rice in improving lipid metabolism and the circulatory system and its safety as a functional food.
... The role of the immune system must be examined to better understand the molecular mechanisms of SARS-CoV-2 pathogenesis and to evaluate therapeutic intervention strategies that target the immune system response and complications due to endotheliitis in several organs. For this reason, therapies should focus on stabilizing the endothelium while tackling viral replication, particularly with anti-inflammatory anti-cytokine drugs, ACE inhibitors, and statins (Anderson et al., 1995;David et al., 2002;Fang et al., 2020;Feldmann et al., 2020;Flammer et al., 2008;Taddei et al., 1998). ...
Objective
There is an urgent need for effective treatments to prevent or attenuate lung and systemic inflammation, endotheliitis, and thrombosis related to COVID-19. The aim of this study was to assess the effectiveness of a multidrug-therapy consisting of Ivermectin, Azithromycin, Montelukast and Acetylsalicylic Acid (“TNR4” therapy) to prevent hospitalization and death among ambulatory COVID-19 cases in Tlaxcala, Mexico.
Design and Methods
A comparative effectiveness study was performed among 768 confirmed SARS-CoV-2 cases aged 18 to 80 years, who received ambulatory care at the Ministry of Health of Tlaxcala. A total of 481 cases received the TNR4 therapy, while 287 received another treatment (comparison group). All participants received home visits and/or phone calls for clinical evaluation during the 14 days after enrollment.
Results
Nearly 85% of cases who received the TNR4 recovered within 14 days compared to 59% in the comparison group. Likelihood of recovery within 14 days was 3.4 times greater among the TNR4 group than in the comparison group. Patients treated with TNR4 had a 75% and 81% lower risk of being hospitalized or death, respectively, than the comparison group.
Conclusions
TNR4 therapy improved recovery and prevented risk of hospitalization and death among ambulatory COVID-19 cases.
... Recent studies have shown that cholesterollowering therapy improves endothelium-dependent vasodilation in coronary [17,18] and systemic [19] arteries due to an increased bioavailability of nitric oxide (NO) [20], the most important endothelium derived vasodilating substance. Apart from vasodilating effects, NO has been found to be a principal factor involved in the antiatherosclerotic properties of the endothelium [21]. ...
Objective: Cardiovascular disease(CVD) or Heart atherosclerosis is a chronic disease of the arterial wall associated with inflammation and an imbalance in lipid metabolism, CVD increased with risk factors including high cholesterol, low-density lipoprotein (LDL) in the blood, low levels of high-density lipoprotein (HDL) in the blood, high blood pressure (hypertension), tobacco smoke, diabetes, Obesity, lifeless lifestyle, age-family history of heart disease is also a risk factor and uncontrollable factor. The study was designed to identify and compare lipid profile levels, NO in Atherosclerosis disease and healthy individuals. Materials and Methods: Nitric Oxide levels and Blood lipid profile were determined in 114 CVD divided into [38 of single vessel disease] (SVD), [38 of (2 vessel disease)](2VD) and [38 of (3 vessel disease or complex)](3VD),and 114 healthy subjects, and comparing the concentration of (NO) with the rest of the biochemical parameters. Results: Nitric Oxide and high-density lipoprotein(HDL) levels in the blood showed a significant decrease in CVD patients as compared to control group (P ≤ 0.05).. while shown biochemical markers of blood lipid profile (serum TG, TCH, LDL, VLDL) were showing significant increase in CVD patients as compared to control group (P ≤ 0.05), and the results indicate a significant decrease in the concentration of nitric oxide (NO) and HDL in (3 vessel disease or complex) (3VD) compared to (2 vessel disease)(2VD), which in turn less than (single vessel disease)(SVD) compared to the control groups. The results showed a significant increase in the levels of lipid profile (TG , TCH , LDL, VLDL) in (3VD) compared to (2VD), which in turn higher than (SVD).We also identified the correlation between (NO) and lipid profile and the results showed a negative correlation between (NO) and (TG,TCH.LDL.VLDL) .and positive correlation between (NO) and HDL. Conclusion: In atherosclerosis, we find a significant reduction in levels of nitric oxide, and a significant rise in cholesterol levels, triglycerides, LDL and VLDL during atherosclerosis and significant decrease in HDL level. Especially when the type of occlusion increases (3VD), (2VD) and (SVD).
... LDL (low-density lipoprotein) cholesterol disturbs this homeostasis via several means that include the impairing production of the vasodilator nitric oxide (NO) by inactivating endothelial nitric oxide synthase (eNOS) in endothelial cells (ECs), disrupting the vasomotor tone (Hermida & Balligand, 2014;Noor et al., 2007;Steinberg et al., 1997). Accordingly, cholesterol-lowering drugs have been shown to reduce the burden of CAD, in part due to improved endothelial vasomotor tone and reduced coronary artery dilatation (Anderson et al., 1995;Ward et al., 2019). ...
Objective:
Atherosclerosis is the main cause of the cardiovascular disease (CVD). Elevated blood cholesterol and inflammation of the endothelium are two major mechanisms contributing to the establishment of atherosclerotic plaques. Statins, such as pravastatin, are blood-cholesterol lowering drugs commonly prescribed for patients with or at risk for CVDs. In addition to lowering blood cholesterols, statins have recently been shown to improve endothelial function in both hyper- and normocholesterolemic patients with atherosclerosis. To understand the molecular mechanisms underlying the endothelial function improvement by statins, we assessed the RNA profile of pravastatin-treated endothelial cells, particularly their mRNAs and long non-coding RNAs (lncRNAs).
Methods:
Human umbilical vein endothelial cells (HUVECs) treated with pravastatin (10 µM) for 24 hr were profiled for lncRNAs and mRNAs using the Arraystar Human lncRNA Expression Microarray V3.0.
Results:
Of the 30,584 different lncRNAs screened, 95 were significantly upregulated, while 86 were downregulated in HUVECs responding to pravastatin. LINC00281 and BC045663 were the most upregulated (~8-fold) and downregulated (~3.5-fold) lncRNAs, respectively. Of the 26,106 different mRNAs screened in the pravastatin-treated HUVEC samples, 190 were significantly upregulated, while 90 were downregulated. Assigning the differentially expressed genes by bioinformatics into functional groups revealed their molecular signaling involvement in the following physiological processes: osteoclast differentiation, Rap1 signaling pathway, hematopoiesis, immunity, and neurotrophin signaling pathway.
Conclusions:
This is the first lncRNA and mRNA expression profiling of pravastatin-mediated changes in human endothelial cells. Our results reveal potential novel targets and mechanisms for pravastatin-mediated vascular protection in atherosclerosis.
... The causative factor and/or promoting mechanism of atherosclerosis is the effective reduction of nitric oxide (NO) availability, and it requires an early therapeutic intervention for the recovery of EDF. EDF therapy includes 1) the use of pharmacological drugs, such as beta blockers, calcium channel blockers, erythropoietin, renin-angiotensin inhibitors [5,6] and/or 2) a non-pharmacological therapy approach in the form of lifestyle changes such as aerobic exercise and healthy diet [7]. IS has been shown to have a higher prevalence and mortality in Asian countries when compared with the rest of the world with unclear reasons [8][9][10]. ...
Endothelial dysfunction has been implicated in atherosclerosis, ischemic heart disease, and stroke. Endothelial progenitor cells (EPCs), found in the bone marrow and peripheral blood as rare cell population, demonstrated a high proliferation and differentiation capacity. Understanding how such diseases influence the quantity and functionality of EPCs is essential for the development of novel therapies. This study aims to investigate the factors that affect the quantity and functionality of circulating EPCs in stroke patients and healthy controls. Blood samples were collected once from healthy donors (n = 30) and up to 3 times (within 7 days (baseline), 3 and 12 months post-stroke) from stroke patients (n = 207). EPC subpopulations were isolated with flow cytometry for characterization. The Matrigel tubular formation assay was performed as a measure of functionality. An increased amount of circulating EPCs was observed in stroke patients over 45 years when compared to age-matched healthy individuals. EPCs showed a rising trend in stroke patients over the 12-month post-stroke period, reaching statistical significance at 12 months post-stroke. Isolated CD34⁺KDR⁺ cells from stroke patients showed impairment in tubular formation capability when compared to cells from healthy donors. The quantity and vasculogenic function of circulating EPCs in peripheral blood have been effectively evaluated in stroke patients and healthy control donors in this study. Age and stroke are found to be 2 influencing factors on the angiogenic capacity. It is suggested that the increase in EPC number is triggered by the recovery response following ischemic stroke.
Graphical abstract
... 47 Reactive oxygen species can impair endothelial function and increase systemic and intrarenal proinflammatory and fibrogenic factors, possibly triggering a complex sequence of mechanisms involved in atherosclerosis. [48][49][50][51][52] In our study, TBARS levels were significantly increased in the atherogenic diet and Triton-induced rats, while the catalase level was decreased in both groups. However, treatment with PF showed decreased levels of TBARS and increased levels of catalase compared with those in Group II for both models. ...
Atherosclerosis is no longer a disease attributed mainly to high cholesterol content in the body; it has come to be regarded as a chronic inflammatory disease with an autoimmune component. The purpose of this study was to investigate the effect of the prunin fraction (PF) isolated from the ethanolic extract of Bauhinia variegata against the release of various proinflammatory mediators in rats fed an atherogenic diet. The diet was administered orally to Sprague Dawley rats for 60 days to induce atherosclerosis. The blood serum of the rats was used to estimate the levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), thiobarbituric acid reactive substance, catalase, total cholesterol, triglyceride, low-density lipoprotein, and high-density lipoprotein using assay kits. Other physical parameters, such as body weight, feed intake, and systolic blood pressure, were also determined during the study. The results showed a significant protective effect of the PF against diet-induced atherosclerosis by decreasing the levels of proinflammatory mediators such as TNF-α and IL-6. Rats treated with PF (20 and 40 mg/kg) showed a change in systolic blood pressure and a reduction in oxidative stress induced by the atherogenic diet. Reduction in body weight and modulation of food intake were observed in PF-treated rats, which indicated atheroprotective, hypolipidemic, and antioxidant effects. The study concludes that the atheroprotective properties of PF are due to effects on the initial phase of plaque formation to thrombus formation. This study may help researchers to find a better alternative for selecting optimal therapies and preventing plaque formation. Future Significance: This article focuses on the molecular mechanisms involved in the evolution of atherosclerotic plaques and different targets that act at the starting stage of the plaque to thrombus formation. This may pave the way for selecting optimal therapies and preventing plaque complications.
... Esta hipótesis justifica la utilización de los diferentes tratamientos para estabilizar el endotelio mientras exista replicación viral, particularmente con antiinflamatorios, drogas anticitoquinas, inhibidores de la ECA y estatinas. 9,13,14 Esta estrategia es particularmente relevante para pacientes vulnerables con preexistencia de disfunción endotelial, que está asociada con el sexo masculino, tabaquismo, hipertensión arterial, diabetes mellitus, obesidad y enfermedad cardiovascular establecida, todas asociadas con resultados adversos en COVID-19. ...
SARS-CoV-2 affects the host using the angiotensin-converting enzyme 2 receptor (ACE2). The first step in virus entry is the binding of the virus trimeric protein S (spike) to the human ACE2 receptor. which is expressed in multiple organs, including the lung, heart, kidney and intestine, and more importantly in endothelial tissue. Within the main pathophysiology is the cytokine storm, it is the uncontrolled systemic inflammatory response that results from the release of large amounts of pro-inflammatory cytokines and chemokines by immuno-effector cells. The cytokine storm binds to the metabolic response to surgery trauma, causing an inflammatory hyper response, which can lead to multiple organ failure. The management of the patient with COVID-19 disease and surgery involves different medical and surgical specialties.
... It shows anticancer, antidiabetic, antimicrobial, hepatoprotective, cardioprotective, analgesic and diaphoretic actions etc., (30)(31)(32). Major active constituents of tulasi includes, carvocrolursolic acid, rosmarinic acid, eugenol, oleic acid etc. (33)(34)(35). ...
... Two large, adult trials reported improvement in endothelial function with the use of cholesterol-lowering therapy (96,97). HMG-CoA reductase inhibitors (statins) exhibit antioxidant, anti-inflammatory, and NO restorative properties (98), and beneficial effect on endothelial function has been shown in a broad range of patients (99)(100)(101). ...
Pediatric obesity is increasing in prevalence and is frequently an antecedent to adult obesity and adult obesity-associated morbidities such as atherosclerosis, type II diabetes, and chronic metabolic syndrome. Endothelial cell activation, one aspect of inflammation, is present in the early stages of atherosclerosis, often prior to the onset of symptoms. Endothelial activation is a pathological condition in which vasoconstricting, pro-thrombotic, and proliferative mediators predominate protective vasodilating, anti-thrombogenic, and anti-mitogenic mediators. Many studies report poor outcomes among obese children with systemic endothelial activation. Likewise, the link between childhood obesity and poor outcomes in critical illness is well-established. However, the link between obesity and severity of endothelial activation specifically in the setting of critical illness is largely unstudied. Although endothelial cell activation is believed to worsen disease in critically ill children, the nature and extent of this response is poorly understood due to the difficulty in measuring endothelial cell dysfunction and destruction. Based on the data available for the obese, asymptomatic population and the obese, critically ill population, the authors posit that obesity, and obesity-associated chronic inflammation, including oxidative stress and insulin resistance, may contribute to endothelial activation and associated worse outcomes among critically ill children. A research agenda to examine this hypothesis is suggested.
Background and purpose:
Cerebral vasomotor reactivity (VMR) is vital for regulating brain blood flow and maintaining neurological function. Impaired cerebral VMR is linked to a higher risk of stroke and poor post-stroke outcomes. This study explores the relationship between statin treatment intensity and VMR in patients with ischemic stroke.
Methods:
Seventy-four consecutive patients (mean age 69.3 years, 59.4% male) with recent ischemic stroke were included. VMR levels were assessed 4 weeks after the index stroke using transcranial Doppler, measuring the breath-holding index (BHI) as an indicator of the percentage increase in middle cerebral artery blood flow (higher BHI signifies higher VMR). Multistep multivariable regression models, adjusted for demographic and cerebrovascular risk factors, were employed to examine the association between statin intensity treatment and BHI levels.
Results:
Forty-one patients (55%) received high-intensity statins. Patients receiving high-intensity statins exhibited a mean BHI of 0.85, whereas those on low-intensity statins had a mean BHI of 0.67 (mean difference 0.18, 95% confidence interval: 0.13-0.22, p-value<.001). This significant difference persisted in the fully adjusted model (adjusted mean values: 0.84 vs. 0.68, p-value: .008). No significant differences were observed in BHI values within patient groups on high-intensity or low-intensity statin therapy (all p-values>.05). Furthermore, no significant association was found between baseline low-density lipoprotein (LDL) levels and BHI.
Conclusions:
High-intensity statin treatment post-ischemic stroke is linked to elevated VMR independent of demographic and clinical characteristics, including baseline LDL level. Further research is needed to explore statin therapy's impact on preserving brain vascular function beyond lipid-lowering effects.
Background
The world is confronted with the threat of a pandemic driven by a novel coronavirus, namely Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The disease was spread in December 2019 in Wuhan (China). The virus has spread to 216 nations, regions, and territories around the world. There were around 510306 confirmed cases and 333401 deaths by May 2020. Patients with cardiovascular diseases and other co-morbidities were at a high risk of SARS-CoV-2 infection that ultimately resulted in the death of the patient.
Objective
This review highlights the impact of COVID-19 on cardiovascular diseases and other comorbidities.
Methods
This review was completed using different sources of search sites like Google Scholar, Pub- Med, ScienceDirect, Scopus, etc.
Result
The diseases associated with the cardiovascular system include myocarditis, heart failure, cardiac injury, and microangiopathy. The mechanisms that cause cardiovascular problems in COVID-19 are myocardial injury pathways, systemic inflammation, altered myocardial demand and supply ratios, plaque rupture, coronary thrombosis, adverse effects of various therapies, and electrolyte imbalances. Several studies provide an important clinical and molecular clue to cardiac involvement during COVID-19. The high cytokine concentrations may contribute to myocardial lesions and a poor disease prognosis. In an earlier study, autopsy reports of COVID-19 found the SARS-CoV-2 genome in myocardial tissues. This also demonstrates that cytokine-induced organ dysfunction contributes to the disease process.
Conclusion
This review concludes that the impact of coronavirus on the cardiac system has shown a harmful effect, and patients with co-morbidities are likely to be more affected by COVID-19 infection.
An unprecedented global social and economic impact as well as a significant number of fatalities have been brought on by the coronavirus disease 2019 (COVID-19), produced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Acute SARS-CoV-2 infection can, in certain situations, cause immunological abnormalities, leading to an anomalous innate and adaptive immune response. While most patients only experience mild symptoms and recover without the need for mechanical ventilation, a substantial percentage of those who are affected develop severe respiratory illness, which can be fatal. The absence of effective therapies when disease progresses to a very severe condition coupled with the incomplete understanding of COVID-19’s pathogenesis triggers the need to develop innovative therapeutic approaches for patients at high risk of mortality. As a result, we investigate the potential contribution of promising combinatorial cell therapy to prevent death in critical patients.
Traumatic brain injuries (TBIs) are associated with high morbidity and mortality due to both the original insult as well as the destructive biological response that follows. Medical management aims to slow or even halt secondary neurological injury while simultaneously laying the groundwork for recovery. Statins are one class of medications that is showing increased promise in the management of TBI. Used extensively in cardiovascular disease, these drugs were originally developed as competitive inhibitors within the cholesterol production pipeline. They are now used in diverse disease states due to their pleiotropic effects on other biological processes such as inflammation and angiogenesis. Preclinical studies, retrospective reviews, and randomized clinical trials have shown a variety of benefits in the management of TBI, but to date, no large-scale randomized clinical trial has been performed. Despite this limitation, statins' early promise and well-tolerated side effect profile make them a promising new tool in the management of TBIs. More bench and clinical studies are needed to delineate proper treatment regimens as well as understand their true potential.
In Deutschland und in den anderen westlichen Industrienationen steht die koronare Herzkrankheit (KHK) in der Morbiditäts- und Mortalitätsstatistik an erster Stelle. In Deutschland erleiden jährlich etwa 250.000 Menschen einen akuten Myokardinfarkt, der in etwa 35 % der Fälle tödlich verläuft; 34 % der Patienten mit akutem Myokardinfarkt sterben vor Erreichen der Klinik. Die koronare Herzkrankheit stellt die Manifestation der Atherosklerose im Bereich der Herzkranzgefäße dar. Zur Therapie der Myokardischämie bei Patienten mit stabiler chronischer koronarer Herzkrankheit stehen medikamentöse sowie revaskularisierende Maßnahmen wie z. B. die aortokoronare Bypassoperation und nichtchirurgische Interventionen (Ballondilatation, Stentimplantation, direktionale Atherektomie und Rotationsangioplastie) zur Verfügung. Weitere therapeutische Maßnahmen zur Behandlung der Myokardischämie bei diesem Patientenkollektiv sind die Implantation von antitachykarden Schrittmachersystemen (mit Defibrillatoren), die Anwendung der intraaortalen Gegenpulsation bei kardiogenem Schock bzw. bei kardiologischen Interventionen mit primär deutlich erhöhtem Risiko, ferner die Herztransplantation.
Acute coronary syndromes (ACS) may complicate the clinical course of patients with Coronavirus Disease 2019 (COVID-19). It is still unclear whether this condition is a direct consequence of the primary disease. However, several mechanisms including direct cellular damage, endothelial dysfunction, in-situ thrombosis, systemic inflammatory response, and oxygen supply-demand imbalance have been described in patients with COVID-19. The onset of a prothrombotic state may also be facilitated by the endothelial dysfunction secondary to the systemic inflammatory response and to the direct viral cell damage. Moreover, dysfunctional endothelial cells may enhance vasospasm and platelet aggregation.
The combination of these factors promotes atherosclerotic plaque instability, thrombosis and, consequently, type 1 myocardial infarction.
Furthermore, severe hypoxia due to extensive pulmonary involvement, in association with other conditions described in COVID-19 such as sepsis, tachyarrhythmias, anemia, hypotension, and shock, may lead to mismatch between oxygen supply and demand, and cause type 2 myocardial infarction.
A deeper understanding of the potential pathophysiological mechanisms underlying ACS in patients with COVID-19 could help the therapeutic management of these very high-risk patients.
The omega-3 fatty acids (n3-FAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) rapidly incorporate into cell membranes where they modulate signal transduction pathways, lipid raft formation, and cholesterol distribution. Membrane n3-FAs also form specialized pro-resolving mediators and other intracellular oxylipins that modulate inflammatory pathways, including T-cell differentiation and gene expression. Cardiovascular (CV) trials have shown that EPA, administered as icosapent ethyl (IPE), reduces composite CV events, along with plaque volume, in statin-treated, high-risk patients. Mixed EPA/DHA regimens have not shown these benefits, perhaps as the result of differences in formulation, dosage, or potential counter-regulatory actions of DHA. Indeed, EPA and DHA have distinct, tissue-specific effects on membrane structural organization and cell function. This review summarizes: (1) results of clinical outcome and imaging trials using n3-FA formulations; (2) membrane interactions of n3-FAs; (3) effects of n3-FAs on membrane oxidative stress and cholesterol crystalline domain formation during hyperglycemia; (4) n3-FA effects on endothelial function; (5) role of n3-FA-generated metabolites in inflammation; and (6) ongoing and future clinical investigations exploring treatment targets for n3-FAs, including COVID-19.
Coronavirus has been spreading rapidly around the world since it broke out in China in 2019. Respiratory diseases caused by coronavirus infection cause various diseases ranging from asymptomatic subclinical infections to severe pneumonia and cardiovascular complications, leading to death. In this regard, natural products are being studied to prevent various diseases caused by COVID-19. In current review, we would like to present mechanisms related to the inhibition of heart disease in ginseng and ginsenoside against SARS-CoV-2. In many previous studies, ginseng and ginsenoside are known to have antioxidant, blood flow improvement, improvement of vascular and heart function, blood pressure control, suppression of myocardial infarction and heart failure, and antiarrhythmia. Therefore, ginseng and ginsenoside have a possibility to suppress cardiovascular complications caused by COVID-19. Many of research provide evidence for ginseng and ginsenoside as treatments for the risk of cardiovascular complications. However, in this review, more specific contents on the proposition of the efficacy of ginseng and ginsenoside for COVID-19 should be presented. Therefore, we hope that researches to reduce cardiovascular complications of ginseng and ginsenoside for COVID-19 should be presented to reduce mortality for COVID-19.
Aims: Inflammation plays a critical role in the pathogenesis of coronary artery disease (CAD), however the impact of anti-inflammatory therapies to reduce those processes which promote atherosclerosis in CAD patients is unknown. We aimed to test the hypothesis that anti-inflammatory approaches improve impaired coronary endothelial function (CEF), a driver of coronary atherosclerosis, in stable CAD patients.
Methods and Results: We performed a single-center, randomized, placebo-controlled, double-blinded trial to assess whether low dose methotrexate (MTX), low dose colchicine (LDC), and/or their combination (MTX+LDC), improves CEF using non-invasive MRI measures in patients with stable CAD ( N = 94). The primary endpoint was the MRI-detected change in coronary cross-sectional area from rest to isometric handgrip exercise (IHE), a predominantly nitric oxide-dependent endothelial dependent stressor. Coronary and systemic endothelial endpoints, and serum inflammatory markers, were collected at baseline, 8 and 24 weeks. Anti-inflammatory study drugs were well-tolerated. There were no significant differences in any of the CEF parameters among the four groups (MTX, LDC, MTX+LDC, placebo) at 8 or 24 weeks. Serum markers of inflammation and systemic endothelial function measures were also not significantly different among the groups.
Conclusion: This is the first study to examine the effects of the anti-inflammatory approaches using MTX, LDC, and/or the combination in stable CAD patients on CEF, a marker of vascular health and the primary endpoint of the study. Although these anti-inflammatory approaches were relatively well-tolerated, they did not improve coronary endothelial function in patients with stable CAD.
Clinical Trial Registration: www.clinicaltrials.gov , identifier: NCT02366091.
Amaç: Aterosklerotik değişikliklerin ve endotel disfonksiyonunun patogenezi karmaşık ve çok faktörlüdür. Kandaki elektrolitlerden magnezyum ve fosfat mineralleri aterogenez ve endotel fonksiyon bozukluğunun patofizyolojisinde yer alan önemli minerallerdir. Endotel fonksiyonu değerlendirmede en çok kabul görmüş akım aracılı vazodilatasyon (AAD) testidir. Çalışmamızda, koroner arter hastalığı olan hastalarda magnezyum/fosfat oranı ile endotel fonksiyonları arasındaki ilişkinin değerlendirilmesi amaçlandı. Gereç ve Yöntem: Koroner anjiyografi ile belgelenmiş koroner arter hastalığı olan ardışık 61 hasta çalışmaya dahil edildi. Radial arterden akım aracılı vazodilatasyon (AAD) testi ile endotel fonksiyonları poliklinik kontrolünde değerlendirildi. İstatistiksel analiz için IBM SPSS Statistics 25.0 Programı kullanıldı. Mg/P oranı ile AAD yüzdelik değişimi arasındaki korelasyonu değerlendirmek için Spearman korelasyon analizi kullanıldı. Bulgular: Çalışmaya alınan 61 hastanın ortalama yaşı 61.2±10.1 yıl olup hastaların %72’ si erkek ve ortalama vücut kitle indeksi 27.8±5.4 kg/m2’ dir. AAD testinde ortalama radial arter bazal çapı 0.25±0.03 cm, test sonrası ortalama radial arter çapı 0.28±0.03 cm olarak saptandı. Magnezyum/ fosfat oranları ile endotel fonksiyonlarını gösteren arter çapındaki yüzdelik değişim arasında pozitif yönde bir ilişki saptandı ( r = 0.268, p = 0.037). Sonuç: Koroner arter hastalığı olan hastalarda, magnezyum/fosfat oranı endotel fonksiyonlarının bir göstergesi olarak kullanılabilir.
In 1980, Furchgott and Zawadzki demonstrated the release of an endothelium-derived relaxing factor in isolated rabbit aorta with exposure to acetylcholine (ACh) (1). This factor has subsequently been identified as nitric oxide (NO·) (2) or a closely related redox form of NO· (3). It is now known that NO· is synthesized enzymatically from L-arginine and O2 by a family of FAD- and FMN-containing enzymes, the nitric oxide synthases (NOSs), that require NADPH and tetrahydrobiopterin (BH4) as cofactors (4). As a class of enzymes, the NOSs appear ubiquitous and have been identified in a number of mammalian cell types and tissues including endothelium (5), epithelium (6), neurons skeletal muscle (8), ventricular myocardium (9), and cytokine-stimulated inflammatory cells (10,11).
Endothelial dysfunction is an early abnormality in the process of atherosclerosis and cardiovascular disease and has been associated with worse clinical outcome. Cardiac rehabilitation (CR) has been reported to be helpful to reduce cardiovascular events in various types of cardiac disease, but the mechanisms of its beneficial effects remain only partially known. In this article, we review the studies that assessed the effect of CR on endothelial function in patients with various cardiac conditions. Available data show that CR significantly improves impaired endothelial function in these patients, which may contribute to the beneficial effects of CR on clinical outcome.
Mental stress can cause angina in patients with coronary artery disease, but its effects on coronary vasomotion and blood flow are poorly understood. Because atherosclerosis affects the reactivity of coronary arteries to various stimuli, such as exercise, we postulated that atherosclerosis might also influence the vasomotor response of coronary arteries to mental stress.
We studied 26 patients who performed mental arithmetic under stressful conditions during cardiac catheterization. (An additional four patients who did not perform the mental arithmetic served as controls.) Coronary segments were classified on the basis of angiographic findings as smooth, irregular, or stenosed. In 15 of the patients without focal stenoses in the left anterior descending artery, acetylcholine (10(-8) to 10(-6) mol per liter) was infused into the artery to test endothelium-dependent vasodilation. Changes in coronary blood flow were measured with an intracoronary Doppler catheter in these 15 patients.
The response of the coronary arteries to mental stress varied from 38 percent constriction to 29 percent dilation, whereas the change in coronary blood flow varied from a decrease of 48 percent to an increase of 42 percent. The direction and magnitude of the change in the coronary diameter were not predicted by the changes in the heart rate, blood pressure, or plasma norepinephrine level. Segments with stenoses (n = 7) were constricted by a mean (+/- SE) of 24 +/- 4 percent, and irregular segments (n = 20) by 9 +/- 3 percent, whereas smooth segments (n = 25) did not change significantly (dilation, 3 +/- 3 percent; P less than 0.0002). Coronary blood flow increased by 10 +/- 10 percent in smooth vessels, whereas the flow in irregular vessels decreased by 27 +/- 5 percent. The degree of constriction or dilation during mental stress correlated with the response to the infusions of acetylcholine (P less than 0.0003, r = 0.58).
Atherosclerosis disturbs the normal vasomotor response (no change or dilation) of large coronary arteries to mental stress; in patients with atherosclerosis paradoxical constriction occurs during mental stress, particularly at points of stenosis. This vasomotor response correlates with the extent of atherosclerosis in the artery and with the endothelium-dependent response to an infusion of acetylcholine. These data suggest that in atherosclerosis unopposed constriction caused by a local failure of endothelium-dependent dilation causes the coronary arteries to respond abnormally to mental stress.
Hypercholesterolemia was induced in New Zealand white rabbits by feeding them a 0.5% cholesterol-enriched rabbit chow for 2 wk. Half of the cholesterol-fed rabbits were given lovastatin, a potent inhibitor of hydroxymethylglutaryl-coenzyme A reductase (HMG-CoA reductase), the rate limiting enzyme in cholesterol biosynthesis, and the other half were given its vehicle (i.e., DMSO). At the end of 2 wk, the rabbits underwent experimental myocardial ischemia or a sham ischemia procedure. Ischemic animals fed the cholesterol-enriched diet for 2 wk experienced much greater cardiac damage than ischemic rabbits fed the control diet, despite the absence of any atherosclerosis. Lovastatin was shown to protect the ischemic rabbit myocardium by three different indices of ischemic damage: (a) maintenance of creatine kinase (CK) activity in the ischemic myocardium; (b) reduced loss of free amino-nitrogen containing compounds from the ischemic myocardium; and (c) blunting the rise of plasma CK activity. These effects were not due to differences in myocardial oxygen demand between the groups. Arteries isolated from animals fed the cholesterol-enriched diet developed defects in endothelium-dependent relaxation in both large vessels as well as coronary resistance vessels. Acute hypercholesterolemia increases the severity of myocardial ischemia while at the same time impairing endothelium-dependent relaxation. These deleterious changes can be significantly attenuated by treatment with lovastatin.
Atherosclerosis results in impaired relaxation to acetylcholine, thrombin, and the calcium ionophore A23187, all agents that require the presence of endothelium. We now report that dietary treatment of atherosclerosis in monkeys not only produces morphological improvement of the atherosclerotic lesion but restores endothelium-dependent vascular relaxation to normal. Because the intima remains thickened after regression of atherosclerosis, these studies suggest that intimal thickening which is present in both atherosclerotic vessels and after regression of atherosclerosis does not prevent the endothelium-derived relaxing factor from reaching the underlying vascular smooth muscle.
Indirect evidence suggests accelerated degradation of endothelium-derived nitric oxide (ENDO) by superoxide anion (O2-) in hypercholesterolemic vessels (HV). To directly measure O2- production by normal vessels (NV) and HV, we used an assay for O2- based on the chemiluminescence (CL) of lucigenin (L). HV (1 mo cholesterol-fed rabbits) produced threefold more O2- than NV (1.47 +/- 0.20 nM/mg tissue/min, n = 7 vs. 0.52 +/- 0.05 nmol/mg tissue/min, n = 8, P < 0.001). Endothelial removal increased O2- production in NV (0.73 +/- 0.08, n = 6, P < 0.05), while decreasing it in HV (0.76 +/- 0.15, n = 5, P < 0.05). There was no difference between denuded HV and denuded NV. Oxypurinol, a noncompetitive inhibitor of xanthine oxidase, normalized O2- production in HV, but had no effect in NV. In separate isometric tension studies treatment with oxypurinol improved acetylcholine induced relaxations in HV, while having no effect on responses in normal vessels. Oxypurinol did not alter relaxations to nitroprusside. Thus, the endothelium is a source of O2- in hypercholesterolemia probably via xanthine oxidase activation. Increased endothelial O2- production in HV may inactivate endothelium-derived nitric oxide and provide a source for other oxygen radicals, contributing to the early atherosclerotic process.
The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), a multicenter, randomized, double-blind study, tested the efficacy of cholesterol lowering in reducing risk of coronary heart disease (CHD) in 3,806 asymptomatic middle-aged men with primary hypercholesterolemia (type II hyperlipoproteinemia). The treatment group received the bile acid sequestrant cholestyramine resin and the control group received a placebo for an average of 7.4 years. Both groups followed a moderate cholesterol-lowering diet. The cholestyramine group experienced average plasma total and low-density lipoprotein cholesterol (LDL-C) reductions of 13.4% and 20.3%, respectively, which were 8.5% and 12.6% greater reductions than those obtained in the placebo group. The cholestyramine group experienced a 19% reduction in risk (P<.05) of the primary end point—definite CHD death and/or definite nonfatal myocardial infarction—reflecting a 24% reduction in definite CHD death and a 19% reduction in nonfatal myocardial infarction. The cumulative seven-year incidence of the primary end point was 7% in the cholestyramine group v8.6% in the placebo group. In addition, the incidence rates for new positive exercise tests, angina, and coronary bypass surgery were reduced by 25%, 20%, and 21%, respectively, in the cholestyramine group. The risk of death from all causes was only slightly and not significantly reduced in the cholestyramine group. The magnitude of this decrease (7%) was less than for CHD end points because of a greater number of violent and accidental deaths in the cholestyramine group. The LRC-CPPT findings show that reducing total cholesterol by lowering LDL-C levels can diminish the incidence of CHD morbidity and mortality in men at high risk for CHD because of raised LDL-C levels. This clinical trial provides strong evidence for a causal role for these lipids in the pathogenesis of CHD.
Abnormal constriction of the epicardial coronary arteries contributes to the pathogenesis of myocardial ischemia, not only in variant angina but also in patients with stable and unstable forms of angina. This augmented vasoconstrictor responsiveness associated with atherosclerosis can in large part be attributed to an impairment in endothelium-dependent relaxation. When the endothelium is removed experimentally or is dysfunctional (as in atherosclerosis), normal vasodilation is replaced by paradoxical vasoconstriction. Infusion of acetylcholine into normal coronary arteries of humans results in vasodilation, which is mediated by endothelium-derived relaxing factor (EDRF), presumably nitric oxide or a closely related substance. When acetylcholine is infused into coronary arteries of patients with atherosclerosis, loss of dilation and paradoxical constriction are observed. This abnormal coronary response to acetylcholine reflects impairment of EDRF due to either its diminished release and/or increased inactivation. Similar reductions in endothelium-dependent coronary dilation in patients with atherosclerosis have been observed in response to other pharmacological or physiological stimuli-serotonin, blood flow, and catecholamines-and to a lesser degree in response to substance P. Normal human epicardial coronary arteries dilate during daily activities such as exercise, mental stress, or exposure to cold. This dilation is mediated by increases in blood flow (and thereby EDRF) in response to increasing metabolic demand. In healthy vessels, this dilation overcomes the constrictor influences of catecholamines (predominantly norepinephrine) that are released locally from nerve endings during these activities. Atherosclerosis, by impairing EDRF, leaves the vasoconstrictor influence of catecholamines unopposed. The resultant abnormal coronary constriction, when superimposed on stenoses, is likely to be an important contributing mechanism of myocardial ischemia by further reducing the available coronary blood flow reserve. The setting of exertion-related coronary constriction is of greatest importance among patients with stable angina. Episodes of unstable angina may occur at rest, unrelated to physical exertion. The pathological findings in this condition include the presence of a complex, degenerated plaque; intracoronary platelet aggregates; and thrombus. Serotonin, a product released from aggregating platelets, and thrombin, formed by the coagulation cascade, have been shown to dilate normal coronary arteries by the release of EDRF. Atherosclerotic arteries, which are deficient in EDRF, are paradoxically constricted by serotonin and thrombin. Thus, although the underlying culprit in the pathogenesis of abnormal coronary vasoconstriction is an impairment of endothelium-dependent dilation, the specific triggering mechanisms that lead to the unopposed vasoconstriction may differ in various forms of angina. Abnormal responses to catecholamines and blood flow are more germane in patients with stable angina, whereas responses to serotonin and possibly to thrombin are more relevant to patients with unstable forms of angina. Recent experimental and clinical studies have suggested that the abnormalities of endothelium-dependent relaxation in atherosclerosis may extend to the microvasculature even though these vessels are free of overt pathology. In patients with nonobstructive coronary atherosclerosis, the flow responses of small vessels to acetylcholine, substance P, and rapid pacing have been shown to be markedly blunted. These findings may have profound implications regarding the ability of atherosclerotic arteries to regulate their blood flow, as the small vessels are where metabolic regulation normally resides.
Oxidative modification of LDL may very well play a significant role in atherogenesis. At some point this hypothesis will have to be tested critically in a clinical setting. At this time, however, our knowledge is incomplete, and it is not really possible to make fully informed decisions about how such a trial should be conducted: that is, with which antioxidant, in which population, for how long, etc. It would be best to await results of further basic studies in animal models and the results of pilot studies in humans before launching what will necessarily be a very expensive and time consuming project. It would be especially unfortunate if such a study were conducted in a less than optimal manner and yielded a negative or an inconclusive result. That might make it more difficult to obtain the necessary enthusiasm and financial support at a later time for a more appropriate clinical trial.
In animals, acetylcholine dilates normal arteries and produces vasoconstriction in the presence of hypercholesterolemia, hypertension, or atherosclerosis, reflecting endothelial cell dysfunction. In patients with angiographically smooth coronary arteries, acetylcholine has been reported to produce both vasodilation and constriction. To test the hypothesis that the acetylcholine response relates to risk factors for coronary artery disease, acetylcholine 10(-8) to 10(-6) M was infused into the left anterior descending or circumflex coronary artery, and diameter changes were assessed with quantitative angiography in 34 patients with angiographically smooth coronary arteries. The acetylcholine response ranged from +37% (dilation) to -53% (constriction) at the peak acetylcholine dose. All coronary arteries dilated in response to nitroglycerin (26 +/- 17%), suggesting an abnormality of endothelial function in the patients with a constrictor response to acetylcholine. By multiple stepwise regression analysis, serum cholesterol (p less than 0.01), male gender (p less than 0.001), family history (p less than 0.05), age (p less than 0.05), cholesterol level (p less than 0.01), and total number of risk factors (p less than 0.0001) were independently associated with the acetylcholine response. Thus, coronary risk factors are associated with loss of endothelium-dependent vasodilation. The development of vasoconstriction is likely to be an abnormality of endothelial function that precedes atherosclerosis or an early marker of atherosclerosis not detectable by angiography.
Atherosclerosis in animals and humans is associated with an unresponsiveness of arteries and arterioles to endothelium-dependent vasodilators--agents acting on smooth muscle indirectly by stimulating the release from endothelial cells of a vasodilator principle (endothelium-derived relaxing factor). Altered vasomotor regulation in atherosclerosis could partly reflect an injurious action of abnormal lipoproteins on endothelium. Recently, 'cell-modified' or 'oxidized' low-density lipoprotein (EC-LDL) has received increasing attention because of its potential cytotoxic and atherogenic properties. We report here that arteries exposed to EC-LDL in vitro show an endothelium-dependent vasoregulatory impairment closely resembling that of atherosclerotic arteries. Our results indicate that transfer of lysolecithin from EC-LDL to endothelial membranes produces a selective unresponsiveness to receptor-regulated endothelium-dependent vasodilators.
The effect of intensive lipid-lowering therapy on coronary atherosclerosis among men at high risk for cardiovascular events was assessed by quantitative arteriography. Of 146 men no more than 62 years of age who had apolipoprotein B levels greater than or equal to 125 mg per deciliter, documented coronary artery disease, and a family history of vascular disease, 120 completed the 2 1/2-year double-blind study, which included arteriography at base line and after treatment. Patients were given dietary counseling and were randomly assigned to one of three treatments: lovastatin (20 mg twice a day) and colestipol (10 g three times a day); niacin (1 g four times a day) and colestipol (10 g three times a day); or conventional therapy with placebo (or colestipol if the low-density lipoprotein [LDL] cholesterol level was elevated).
The levels of LDL and high-density lipoprotein (HDL) cholesterol changed only slightly in the conventional-therapy group (mean changes, -7 and +5 percent, respectively), but more substantially among patients treated with lovastatin and colestipol (-46 and +15 percent) or niacin and colestipol (-32 and +43 percent). In the conventional-therapy group, 46 percent of the patients had definite lesion progression (and no regression) in at least one of nine proximal coronary segments; regression was the only change in 11 percent. By comparison, progression (as the only change) was less frequent among patients who received lovastatin and colestipol (21 percent) and those who received niacin and colestipol (25 percent), and regression was more frequent (lovastatin and colestipol, 32 percent; niacin and colestipol, 39 percent; P less than 0.005). Multivariate analysis indicated that a reduction in the level of apolipoprotein B (or LDL cholesterol) and in systolic blood pressure, and an increase in HDL cholesterol correlated independently with regression of coronary lesions. Clinical events (death, myocardial infarction, or revascularization for worsening symptoms) occurred in 10 of 52 patients assigned to conventional therapy, as compared with 3 of 46 assigned to receive lovastatin and colestipol and 2 of 48 assigned to receive niacin and colestipol (relative risk of an event during intensive treatment, 0.27; 95 percent confidence interval, 0.10 to 0.77).
In men with coronary artery disease who were at high risk for cardiovascular events, intensive lipid-lowering therapy reduced the frequency of progression of coronary lesions, increased the frequency of regression, and reduced the incidence of cardiovascular events.
The direct vasoactive effects of native and oxidatively modified low density lipoproteins as well as their effects on endothelium-dependent relaxations to 5-hydroxytryptamine were studied in isolated rings of pig right coronary artery. Slowly developing contractions were caused by native low density lipoproteins (100 micrograms protein/ml). The contractions were more pronounced in the absence than in the presence of the trace metal chelator, EDTA, and coincided with the formation of lipid peroxides during the response. The lipophilic antioxidant, butylated hydroxytoluene, prevented the oxidation of, and contraction to, native low density lipoproteins. Low density lipoproteins oxidized by exposure to copper contracted coronary arteries more rapidly with a threshold of only 1 micrograms protein/ml, but with a similar maximal contraction at 100 micrograms protein/ml. Superoxide dismutase inhibited the contraction to native low density lipoproteins, but not to oxidized low density lipoproteins. Catalase blocked contractions to both native and oxidized low density lipoproteins. Contractions to oxidized low density lipoproteins were unaffected by indomethacin, but were abolished by removal of the endothelium or by inhibitors of endothelium-derived relaxing factor. Oxidized low density lipoproteins but not native low density lipoproteins inhibited endothelium-dependent relaxations to 5-hydroxytryptamine. Thus, oxidized low density lipoproteins caused endothelium-dependent coronary artery contractions which are mediated by a hydroperoxide. Contractions to native low density lipoproteins are due to their oxidation in the organ chamber by the superoxide anion radical. Oxidized, but not native, low density lipoproteins impair normal endothelial cell vasodilator function in vitro. Oxidized low density lipoproteins, important in the pathogenesis of atherosclerosis, may directly contribute to the increased risk of vasospasm seen in hypercholesterolemia and atherosclerosis.
To study the vasomotility of normal and diseased coronary arteries during dynamic exercise, symptom-limited supine bicycle exercise during cardiac catheterization was performed by 18 patients with classic angina pectoris. The cardiovascular response was assessed by hemodynamic measurements and computer-assisted determination of normal and stenotic coronary artery luminal areas from biplane coronary angiograms made before, during, and after exercise. After baseline measurements were recorded, 12 patients (group 1) performed bicycle exercise for 3.4 min (mean), reaching a maximum workload of 81 W (mean); at the end of exercise they received 1.6 mg sublingual nitroglycerin. After measurements at rest in six other patients (group 2), 0.1 mg intracoronary nitroglycerin was given, followed by exercise (3.8 min, 96 W; NS) and sublingual nitroglycerin as in group 1. During exercise in group 1, luminal area of the coronary stenosis decreased to 71% of resting levels (p less than .001), while area of the normal coronary artery increased to 123% of control (p less than .001). After sublingual nitroglycerin at the end of exercise, area of the normal vessel further increased to 140% of control (p less than .001), while luminal area of the stenosis dilated to 112% of resting levels (p less than .001 vs exercise, NS vs rest). Pretreatment with intracoronary nitroglycerin increased both normal (121%; p less than .05) and stenotic (122%; p less than .05) luminal areas, while preventing the previously observed narrowing of stenosis during exercise (114%; NS). Exercise resulted in a similar heart rate-systolic pressure product and caused angina pectoris in two-thirds of the patients in each group. However, patients pretreated with intracoronary nitroglycerin (group 2) had a lower mean pulmonary arterial pressure during maximum exercise (35 mm Hg) than those patients (group 1) not receiving pretreatment (47 mm Hg; p less than .001). Group 2 patients reached a percentage of their predicted work capacity (65%) that was about the same as that during previous upright bicycle exercise (71%; NS), while group 1 patients had a significantly lower work capacity (51% of predicted) than that before catheterization (82%; p less than .001). Hence, narrowing of coronary artery stenosis during dynamic exercise is attributable to active vasoconstriction due to its reversibility by preexercise intracoronary nitroglycerin. Patients who did not experience narrowing of stenosis during exercise (group 2) had less evidence of myocardial ischemia (lower mean pulmonary arterial pressure) and maintained their work capacity.(ABSTRACT TRUNCATED AT 400 WORDS)
Previous studies have established that low density lipoprotein (LDL) incubated with endothelial cells (EC) undergoes extensive oxidative modification in structure and that the modified LDL is specifically recognized by the acetyl LDL receptor of the macrophage. Thus, in principle, EC-modified LDL could contribute to foam cell formation during atherogenesis. Oxidatively modified LDL is also potentially toxic to EC. The present studies show that addition of probucol during the incubation of LDL with EC prevents the increase in the electrophoretic mobility, the increase in peroxides, and the increase in subsequent susceptibility to macrophage degradation. It has also been shown that oxidation of LDL catalyzed by cupric ion induces many of the same changes occurring during EC modification. Addition of probucol (5 microM) also prevented this copper-catalyzed modification of LDL. Most importantly, samples of LDL isolated from plasma of hypercholesterolemic patients under treatment with conventional dosages of probucol were shown to be highly resistant to oxidative modification either by incubation with endothelial cells or by cupric ion in the absence of cells. The findings suggest the hypothetical but intriguing possibility that probucol, in addition to its recognized effects on plasma LDL levels, may inhibit atherogenesis by limiting oxidative LDL modification and thus foam cell formation and/or EC injury. Other compounds with antioxidant properties might behave similarly.
Despite its very potent vasodilating action in vivo, acetylcholine (ACh) does not always produce relaxation of isolated preparations of blood vessels in vitro. For example, in the helical strip of the rabbit descending thoracic aorta, the only reported response to ACh has been graded contractions, occurring at concentrations above 0.1 muM and mediated by muscarinic receptors. Recently, we observed that in a ring preparation from the rabbit thoracic aorta, ACh produced marked relaxation at concentrations lower than those required to produce contraction (confirming an earlier report by Jelliffe). In investigating this apparent discrepancy, we discovered that the loss of relaxation of ACh in the case of the strip was the result of unintentional rubbing of its intimal surface against foreign surfaces during its preparation. If care was taken to avoid rubbing of the intimal surface during preparation, the tissue, whether ring, transverse strip or helical strip, always exhibited relaxation to ACh, and the possibility was considered that rubbing of the intimal surface had removed endothelial cells. We demonstrate here that relaxation of isolated preparations of rabbit thoracic aorta and other blood vessels by ACh requires the presence of endothelial cells, and that ACh, acting on muscarinic receptors of these cells, stimulates release of a substance(s) that causes relaxation of the vascular smooth muscle. We propose that this may be one of the principal mechanisms for ACh-induced vasodilation in vivo. Preliminary reports on some aspects of the work have been reported elsewhere.
The role of human plasma lipoproteins as carriers in the blood transport of the cholesterol-lowering and water-insoluble drug, probucol, was investigated in in vitro studies. [14C]Probucol was incubated in whole human blood, a serum pool, individual diluted sera, and isolated protein and lipoprotein fractions. In whole blood, about 90% partitioned in plasma. Following ultracentrifugal fractionation of the serum, it was found that less than 5% distributed in the d greater than 1.20 protein fraction (albumin-rich fraction) and more than 95% in the lipoprotein fractions. The distribution of probucol in the lipoprotein fractions correlated with the lipoprotein total lipid volume under saturation conditions (incubation of isolated lipoprotein fractions) as well as nonsaturation conditions (fractionation of serum exposed to [14C]probucol). Incubation of the albumin-rich fraction and of apolipoproteins originating from the isolated lipoprotein fractions showed that they account for a negligible part in the interaction of probucol with blood components. The probucol uptake of individual sera was shown to be correlated to the lipid content of the serum. When probucol was incubated in erythrocyte suspensions containing variable amounts of lipoproteins, probucol partitioned less in erythrocytes as the lipoprotein concentration increased in the suspension.
The discovery that mammalian cells generate nitric oxide, a gas previously considered to be merely an atmospheric pollutant, is providing important information about many biologic processes. Nitric oxide is synthesized from the amino acid L-arginine by a family of enzymes, the nitric oxide synthases, through a hitherto unrecognized metabolic route -- namely, the L-arginine-nitric oxide pathway1–8. The synthesis of nitric oxide by vascular endothelium is responsible for the vasodilator tone that is essential for the regulation of blood pressure. In the central nervous system nitric oxide is a neurotransmitter that underpins several functions, including the formation of memory. . . .
Oxidized low-density lipoproteins (LDL), which may play an important role in atherogenesis, inhibit endothelium-dependent relaxations of normal arteries in vitro. The effects of probucol, an inhibitor of LDL oxidation, on endothelium-dependent relaxations in thoracic aorta of rabbits that received a cholesterol-rich (0.5%) or standard diet for 10 weeks were determined. In some rabbits in each group, the diet was supplemented with probucol (1%) for the last 6 weeks. The cholesterol-rich diet markedly increased plasma cholesterol and resulted in increased plasma lipid peroxides. Probucol prevented the increase in lipid peroxides, but had no effect on plasma cholesterol. Rings of aorta were mounted in organ chambers for measurement of isometric tension and contracted with phenylephrine. Endothelium-dependent relaxations to acetylcholine and A23187 were significantly impaired in aortic rings from cholesterol-fed rabbits. Aortic rings from rabbits fed cholesterol and treated with probucol relaxed normally to both vasodilators. Relaxations to acetylcholine and A23187 were not significantly changed in rings from rabbits that received probucol-supplemented standard diet. Endothelium-independent relaxations to sodium nitroprusside (SNP) were not influenced by the cholesterol diet or probucol. Thus, probucol preserves endothelium-dependent relaxations of hypercholesterolemic rabbit aorta without reducing plasma cholesterol. As demonstrated by the reduction in plasma lipid peroxides, the effect of probucol may be related to its antioxidant properties and may imply that oxidized lipids have a role in endothelial cell dysfunction of atherosclerotic arteries in vivo.
Since hypercholesterolaemia is associated with impaired endothelium-dependent vasodilation, a study was conducted to find out whether cholesterol reduction will improve endothelial function in patients with hypercholesterolaemia and normal coronary arteries. 25 men (mean age 51 [SD 8] years) with total serum cholesterol > 6.2 mmol/L) and angiographically normal coronary arteries had their coronary vasomotor responses to intracoronary acetylcholine and nitroglycerin assessed by computer-assisted quantitative angiography at baseline and after 6 months of cholesterol-reducing diet and cholestyramine. Between baseline and follow-up mean total serum cholesterol level fell by 28.7 (SD 5.6)% (p < 0.001); mean low-density lipoprotein (LDL) cholesterol level by 35.6 (8.7)% (p < 0.001); and mean total cholesterol to high-density lipoprotein (HDL) cholesterol ratio by 29.4 (10.6)% (p < 0.001). Acetylcholine significantly reduced the mean segment diameter at baseline, by 21.7 (14.0)% (p < 0.01), but it increased the diameter at follow-up, by 6.16 (13.3)% (p < 0.01), the difference between the two occasions being significant (p < 0.001). Nitroglycerin significantly increased the mean segment diameter, both at baseline, by 18.7 (11.5)% (p < 0.01), and at follow-up, by 19.3 (12.1)% (p < 0.01), the difference between the two responses being not significant. At baseline total cholesterol and LDL cholesterol did not correlate with acetylcholine response, but they did at follow-up (total cholesterol, r = 0.67, p < 0.01; LDL cholesterol, r = 0.64, p < 0.01). Impairment of endothelium-dependent (acetylcholine-induced) dilation of the epicardial coronary arteries in hypercholesterolaemic patients with angiographically normal coronary arteries is thus reversible by reducing serum cholesterol. In addition, the degree of impairment of acetylcholine-induced vasomotor response is related to the cholesterol concentrations after therapy.
Vasoconstrictor responses to serotonin are augmented in monkeys with diet-induced atherosclerosis and improve after 18 months of normal diet. We tested the hypothesis that functional improvement may occur early during regression, before evidence of structural improvement.
Responses of the iliac artery to serotonin were measured by quantitative angiography and a Doppler flow probe in several groups of monkeys: (1) normal monkeys, (2) monkeys fed an atherogenic diet for 2 years (atherosclerotic), and (3) monkeys fed an atherogenic diet for 2 years (preregression) followed by a normal diet for 4, 8, or 12 months (regression). In normal monkeys, serotonin produced minimal constriction of the iliac artery, and blood flow to the legs increased. In atherosclerotic monkeys, there was pronounced constriction of the iliac artery, and blood flow to the legs decreased markedly. After 4 months of regression diet, four of eight monkeys demonstrated marked reduction in hyperresponsiveness to serotonin angiographically, and by 8 months, six of eight monkeys had significant improvement. After regression, serotonin produced minimal changes in flow. There was no reduction in intimal area (ie, atherosclerotic lesion) in iliac arteries from regression monkeys compared with atherosclerotic monkeys, but there was a marked reduction in cholesteryl ester in arteries from regression monkeys.
Abnormal vasoconstrictor responses to serotonin usually return to or toward normal within a few months during regression of atherosclerosis. Functional improvement occurs in conjunction with early resorption of lipid from the arterial wall and occurs before detectable changes in mass of the atherosclerotic lesion.
It has been shown that there is impairment of the vasodilatory response to acetylcholine in patients with hypercholesterolemia and angiographically normal coronary arteries. Moreover, in patients with angiographically smooth coronary arteries, the number of coronary risk factors is associated with a loss of endothelium-dependent vasodilation. The purpose of the present analysis was to evaluate in patients with and without coronary artery disease coronary vasomotor response to dynamic exercise in angiographically normal and stenosed coronary arteries and to relate the response to serum cholesterol levels as well as to other coronary risk factors.
Luminal area change during exercise (delta-ex, percent change compared with rest = 100%) was determined by biplane quantitative coronary arteriography in three groups: Group 1 consisted of 14 patients with normal total serum cholesterol of < 200 mg/100 mL; mean, 173 mg/100 mL (mean age, 51 years). Group 2 comprised 23 patients with a slightly elevated cholesterol of 200 to 250 mg/100 mL; mean, 223 mg/100 mL (mean age, 53 years). Group 3 had 24 patients with markedly elevated cholesterol of > 250 mg/100 mL; mean, 288 mg/100 mL (mean age, 54 years). Serum cholesterol levels and categorical risk factors such as positive family history, history of hypertension, smoking, obesity, and diabetes were related to exercise-induced vasomotor response. The three groups did not differ with regard to clinical characteristics, exercise work load, and hemodynamic data measured during exercise. However, delta-ex in normal vessels was significantly different between all three groups (ANOVA, P < .01): +31% (group 1), +18% (group 2), and +4% (group 3). Delta-ex in stenotic vessels did not differ between the groups: -5% (group 1), -13% (group 2), and -12% (group 3). Delta-ex of the nonstenosed vessel correlated significantly and inversely with total cholesterol, with low-density lipoprotein cholesterol, with the ratio of total to high-density lipoprotein cholesterol, and with the number of coronary risk factors present in a patient. High total cholesterol and a history of hypertension were independent risk factors for impaired coronary vasomotion.
In patients with and without coronary artery disease, hypercholesterolemia and a history of hypertension independently impair exercise-induced coronary vasodilation in angiographically normal coronary arteries. In the stenotic vessel, vasomotion during exercise does not appear to be influenced by the actual serum cholesterol. The precise mechanism by which the impaired vasomotion of the angiographically normal coronary arteries is mediated is unknown, but a direct negative effect of hypercholesterolemia on endothelial function or early undetected atherosclerosis appears to be the most likely explanation.
Hypercholesterolaemia and atherosclerosis impair responses to endothelium-derived nitric oxide (EDRF) in human and animal coronary arteries, a dysfunction that correlates with elevated low density lipoproteins (LDL). Previous studies show that native LDL immediately and reversibly inhibit acetylcholine-evoked EDRF responses in rabbit aortic ring precontracted with noradrenaline or serotonin whereas Cu(2+)-oxidised LDL (oxLDL) inhibit relaxations after 30 min with a potency that varies with the donor. We now show that antioxidants, probucol (10 microM) and ascorbic acid (100 microM) in vitro, prevent the inhibition by native LDL, indicating that this effect involves free radicals. As expected, the antioxidants had no influence on the inhibition by oxLDL. Superoxide dismutase appeared to have no effect on the inhibition by native or oxLDL. The oral administration of probucol to selected volunteers also prevented the inhibition of relaxation by their native LDL. These preparations showed a diminished susceptibility to oxidation and their oxLDL caused a markedly reduced and always reversible inhibition of relaxation compared to the potent and sometimes irreversible inhibition prior to administration of the drug. We conclude that antioxidants such as probucol reduce the formation of free radicals and the oxidative modification of LDL that lead to the impairment of EDRF responses and may prevent this same dysfunction in hypercholesterolaemia and atherosclerosis.
Peroxynitrite is an oxidant which could be formed in the vasculature by the reaction of superoxide with nitric oxide. It is capable of modifying amino acid residues and of initiating lipid peroxidation. In the present study we have shown that peroxynitrite converts low density lipoprotein to a form recognized by the macrophage scavenger receptor and that this process is associated with modification of the protein and lipid, and with the oxidation of alpha-tocopherol to alpha-tocopherol quinone.
Exposure of isolated arteries to oxidatively modified low density lipoprotein (LDL) has been reported to suppress endothelium-dependent relaxation (EDR). To determine whether lipid degradation products in oxidized LDL contribute to impaired relaxation, we have tested the responsiveness of isolated rabbit aortas to endothelium-dependent relaxants (acetylcholine, ATP, and calcium ionophore A23187) and nitroglycerin before and after 2-hour incubations with selected lipids and LDL preparations. Concentrations (10 microM) of lecithin, phosphatidylserine, lysophosphatidylserine, sphingomyelin, phosphatidic acid, palmitate, arachidonate, and auto-oxidized arachidonate had no effect on EDR. Concentrations (10 microM) of lysolecithin, lyso-platelet activating factor, and sphingosine significantly suppressed endothelium-dependent relaxation. Native LDL (100 micrograms/ml incubation buffer) containing only small amounts of lysophosphatidylcholine exerted no effect on EDR. In contrast, LDL preparations oxidatively modified by exposure to cultured endothelial cells or copper inhibited EDR. When modified LDL was depleted of its lysolecithin by treatment with a selective phospholipase B (lysolecithinase), the inhibitory effects were attenuated. In contrast, native LDL accumulating lysolecithin under the influence of a phospholipase A2 (lecithinase) exerted inhibitory effects mimicking those of oxidized LDL. Lipids and lipoproteins had no effect on the responsiveness to nitroglycerin, an endothelium-independent vasodilator. We conclude that lysolecithin in oxidatively modified LDL contributes importantly to its vasomotor effects.
The consensus of evidence from angiographic trials demonstrates both coronary artery and clinical benefits from lowering of lipids by a variety of regimens. The findings of reduced arterial disease progression and increased regression have been convincing but, at best, modest in their magnitude. For example, among those treated intensively in FATS, the mean improvement in proximal stenosis severity per patient was < 1% stenosis, and only 12% of all lesions showed convincing regression. In view of these modest arterial benefits, the associated reductions in cardiovascular events have been surprisingly great. For example, coronary events were reduced 75% in FATS; this was entirely a result of a 93% reduction in the likelihood that a mildly or moderately diseased arterial segment would experience substantial progression to a severe lesion at the time of a clinical event. We believe that the magnitude of the clinical benefit is best explained in terms of this observation, according to the following lines of reasoning. Clinical events most commonly spring from lesions that are initially of mild or moderate severity and then abruptly undergo a disruptive transformation to a severe culprit lesion. The process of plaque fissuring, leading to plaque disruption and thrombosis, triggers most clinical coronary events. Fissuring is predicted by a large accumulation of core lipid in the plaque and by a high density of lipid-laden macrophages in its thinned fibrous cap. Lesions with these characteristics constitute only 10-20% of the overall lesion population but account for 80-90% of the acute clinical events. In the experimental setting, normalization of an atherogenic lipid profile substantially decreases the number of lipid-laden intimal macrophages (foam cells) and depletes cholesterol from the core lipid pool. In the clinical setting, intensive lipid lowering virtually halts the progression of mild and moderate lesions to clinical events. Thus, the reduction in clinical events observed in these trials appears to be best explained by the relation of the lipid and foam cell content of the plaque to its likelihood of fissuring and by the effects of lipid-lowering therapy on these "high-risk" features of plaque morphology. The composite of data presented here supports the hypothesis that lipid-lowering therapy selectively depletes (regresses) that relatively small but dangerous subgroup of fatty lesions containing a large lipid core and dense clusters of intimal macrophages. By doing so, these lesions are effectively stabilized and clinical event rate is accordingly decreased.
Probucol and other anti-oxidants prevent the inhibition of endothelium-dependent relaxation by low density lipoproteins For personal use only. No other uses without permission
- Jacobs F M Plane
- Mcmanus D Bruckdorfer
- Kr
Plane F, Jacobs M, McManus D, Bruckdorfer KR. Probucol and other anti-oxidants prevent the inhibition of endothelium-dependent relaxation by low density lipoproteins. Atherosclerosis 1993;103:73-9. The New England Journal of Medicine Downloaded from nejm.org on December 1, 2014. For personal use only. No other uses without permission. Copyright © 1995 Massachusetts Medical Society. All rights reserved.
impairing the vasodilator response to acetylcholine
- The New England Journal Of Medicine
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THE NEW ENGLAND JOURNAL OF MEDICINE Feb. 23, 1995 impairing the vasodilator response to acetylcholine. 9,21
2 Multiple Risk Factor Intervention Trial Research Group Multiple Risk Factor Intervention Trial: risk factor changes and mortality results
- Multiple Risk Factor Intervention Trial Research Group
Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries
- Ludmer PL
- Selwyn AP
- Shook TL