Pathology,Assessment and Treatment of Endothelial Dysfunction
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Since the introduction of insulin in 1922, vascular disease has emerged as the major burden of diabetes and consumes the greatest proportion of health service funding attributed to diabetes care in the UK.1 Unfortunately, the atherosclerotic process that is largely responsible for these vascular changes progresses in a silent, relentless manner and is not usually clinically evident until the development of an acute devastating event such as myocardial infarction or stroke. Longitudinal studies have identified factors that confer greater vascular risk such as diabetes, smoking, dyslipidaemia and hypertension, and it is recognised that these factors can interact synergistically to promote atherosclerotic deposits. Valiant attempts have been made to quantify vascular risk2, 3 to provide the health care professional with a logical basis for intervening with treatment aimed at modifying these risk factors. Disappointingly, however, the sensitivity of these approaches for the diabetic individual is relatively low. In other words, there are many diabetic patients developing vascular events whom hitherto, have not been recognised as being at ‘significant’ vascular risk using traditional treatment approaches. Conversely, we may be treating unnecessarily diabetic patients deemed at high vascular risk since the natural history for a given individual may not ultimately lead to the development of a clinical vascular event. Moreover, pharmacological intervention aimed at modifying traditional risk factors in patients with diabetes does not reduce vascular risk to the extent seen in the non-diabetic population. For instance, the hypercholesterolaemic diabetic patient with coronary artery disease (CAD) treated with a statin remains at greater risk of a further vascular event compared with an untreated non-diabetic patient with CAD and a similar level of hypercholesterolaemia.4 In summary therefore, more sensitive and specific markers of vascular disease in the diabetic patient need to be identified as well as additional approaches to reduce vascular events. Can our current knowledge of the pathophysiology of the vascular endothelium assist? The vascular endothelium contributes to the control of vascular tone and endothelial dysfunction has been implicated in the pathogenesis of diabetic vascular disease.5, 6 Vascular tone is influenced by a number of potent vasoactive substances that are released by the endothelium. These include vasodilatory compounds such as nitric oxide (NO) and prostacyclin, and vasoconstrictor compounds such as angiotensin II or prostaglandin endoperoxide.7 Much research has focused on the role of NO, also known as endothelium-derived relaxing factor. NO is continually secreted by the endothelium8 but its production may be increased by shear stress, or pharmacologically by agonists such as acetycholine (ACh)9 or Substance P.10 Infusion of these agonists result in vasodilation, therefore, in part due to the synthesis of NO and probably other vasoactive substances.8 Infusion of ACh and other pharmacological stimuli have been used over the last decade to examine endothelial function. It was first demonstrated in 1986 that ACh caused dose-dependent vasodilation in non-diabetic patients with angiographically normal coronary arteries whilst, paradoxically, vasoconstriction occurred in patients with atherosclerosis.11 Subsequent studies using inhibitors of the L-arginine–NO pathway have confirmed that these observed ACh-induced vasodilatory responses are principally mediated by NO.12 Several studies have also demonstrated the close relation of endothelial function in the human coronary and peripheral circulation13 and it is now well established that examination of vasodilatory responses in the brachial artery is a useful surrogate in assessing the predisposition to atherosclerosis in patients with cardiac risk factors. Techniques commonly used to examine endothelial function are those of venous plethysmography and high resolution ultrasound. Several investigations have shown abnormalities of endothelial function in atherosclerosis-free subjects with dyslipidaemia, 14 hypertension, 15 in smokers16 and type 2 diabetes mellitus.17 A number of studies have demonstrated the presence of endothelial dysfunction in type 1 diabetes mellitus;18-20 however, these findings have not been wholly consistent, 21 which may relate to differing patient populations, methodology and study conditions. Although it would appear that the vascular endothelium may demonstrate these physiological abnormalities before the development of measureable atherosclerotic deposits, it is not practical to measure endothelial responses using these biophysical techniques in day to day clinical practice. However, if the endothelium becomes damaged, it releases certain markers in the circulation that may be quantified. Examples of these markers include von Willebrand's factor, thrombomodulin, E-selectin and homocysteine (HCY). The use of these novel markers of endothelial damage in the clinical setting is perhaps most advanced with HCY. Circulating levels of HCY have been shown to be higher in men with established CAD in the general population22 and in patients with diabetes.23 It has also been demonstrated that acute hyperhomocysteinaemia causes endothelial dysfunction in vivo.24 Furthermore, homocysteine-lowering treatment with folic acid and vitamin B6 has been shown to reduce the progression of subclinical atherosclerosis.25 It is tempting to speculate, therefore, that such treatment may provide additional armoury by which to halt the progression of vascular disease. Studies such as the SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) project are already under way, attempting to address this question. Whilst studies of the endothelium have generated much enthusiasm in the world of vascular medicine, several caveats need to be applied since this research is still is its infancy. Firstly, the association between the development of endothelial dysfunction and atherosclerosis has been extrapolated from animal work and cross-sectional studies in humans, with no longitudinal studies demonstrating a clear progression from physiological disturbance of the endothelial behaviour to atherosclerotic formation. Secondly, although endothelial dysfunction is a consistent finding in type 2 diabetes, the situation needs to be clarified in type 1 diabetes, where these abnormalities may be confined to certain sub-groups of patients. Furthermore and most importantly, studies need to clarify the relative sensitivity and specificity of these novel biochemical markers of endothelial damage to detect vascular disease in the diabetic patient, and whether normalising the levels of these circulating markers will have any impact on reducing this risk. Nevertheless, the potential of reducing the burden of diabetic vasculopathy by halting the progression of endothelial dysfunction to clinical disease remains an exciting (if currently speculative) prospect.
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Cardiac allograft vasculopathy remains the principal limitation to the long-term survival of cardiac transplant patients.1Uretsky BF Murali S Reddy PS et al.Development of coronary artery disease in cardiac transplant patients receiving immunosuppressive therapy with cyclosporine and prednisone.Circulation. 1987; 76: 827-833Crossref PubMed Scopus (487) Google Scholar Nearly half of these individuals have angiographically detectable atherosclerosis 5 years after transplantation, and half of this group will develop graft failure.2Gao SZ Alderman EL Schroeder JS et al.Accelerated coronary vascular disease in the heart transplant patient: coronary arteriographic findings.J Am Coll Cardiol. 1988; 12: 334-340Abstract Full Text PDF PubMed Scopus (431) Google Scholar Accelerated coronary atherosclerosis is related to the interplay of nonimmune and immune processes, which leads to endothelial injury and the subsequent development and progression of transplant coronary vasculopathy. The development of allograft vasculopathy is inversely correlated with the aggressiveness of the immunosupression.3Laden AM The effects of treatment on the arterial lesions of rat and rabbit cardiac allografts.Transplantation. 1972; 13: 281-290Crossref PubMed Scopus (22) Google Scholar4Addonizio LJ Hsu DT Douglas JF et al.Decreasing incidence of coronary disease in pediatric cardiac transplant recipients using increased immunosuppression.Circulation. 1993; 88: 224-229Google Scholar It is well known that the development of coronary atherosclerosis is associated with abnormal risk factor profiles. Therefore, prediction of the development and progression of transplant coronary atherosclerosis should identify a higher risk population who warrant closer monitoring, aggressive risk factor modification, and more intense immunosuppression. The coronary endothelium plays an integral role in the regulation of arterial tone, vessel permeability, smooth muscle cell proliferation, leukocyte and platelet adhesion, and platelet aggregation.5Furchgott RF Vanhoutte PM Endothelium-derived relaxing and contracting factors.FASEB J. 1989; 3: 2007-2018Crossref PubMed Scopus (1693) Google Scholar Coronary endothelial dysfunction is an early marker of atherosclerosis. Previous studies demonstrate that an intracoronary acetylcholine infusion produces constriction of atherosclerotic coronary arteries as well as angiographically normal vessels in patients with risk factors for coronary artery disease.6Vita JA Treasure CB Nabel EG et al.Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease.Circulation. 1990; 81: 491-497Crossref PubMed Scopus (1095) Google Scholar A normal coronary vasodilator response to acetylcholine is seen in patients with normal coronary arteries and is mediated by the local release of endothelial-derived relaxation factor (EDRF), which overrides the direct constrictor effect of acetylcholine on the vascular smooth muscle. The coronary endothelial response to acetylcholine mimics that seen in response to common vasomotor stimuli such as sympathetic stimulation, mental stress, the cold pressor test, or exercise.7Gordon JB Ganz P Nabel EG et al.Atherosclerosis influences the vasomotor response of epicardial coronary arteries to exercise.J Clin Invest. 1989; 83: 1946-1952Crossref PubMed Scopus (312) Google Scholar In this issue of Chest (see page 1266), Aptecar and colleagues investigated whether coronary vasomotor responses measured early after cardiac transplantation predict the development of future graft vasculopathy. Using a carefully designed protocol in a small patient cohort, they found that paradoxic constriction to acetylcholine within 2 months of transplantation failed to predict the development of graft atherosclerosis detected by quantitative coronary angiography performed at 1 year posttransplantation. The authors cautioned, however, that they could not exclude the presence of angiographically undetectable atherosclerosis on the baseline or 1-year follow-up angiograms. Intravascular ultrasound (IVUS) is more sensitive than coronary angiography for diagnosing allograft vasculopathy.8Goar St. FG Pinto FJ Alderman EL et al.Intravascular ultrasound imaging of angiographically normal coronary arteries: an in vivo comparison with quantitative angiography.J Am Coll Cardiol. 1991; 18: 952-958Abstract Full Text PDF PubMed Scopus (155) Google Scholar9Pinto FJ Chenzbraun A Botas J et al.Feasibility of serial intracoronary ultrasound imaging for assessment of progression of intimal proliferation in cardiac transplant patients.Circulation. 1994; 90: 2348-2355Crossref PubMed Google Scholar In the early stages of coronary atherosclerosis, subintimal atheroma development may be accompanied by enlargement of the medial and adventitial layers, and compensatory vascular dilation.10Glagov S Weinsenberg E Zarins CK et al.Compensatory enlargement of human atherosclerotic coronary arteries.N Engl J Med. 1987; 316: 1371-1375Crossref PubMed Scopus (3043) Google Scholar At the recent American Heart Association Scientific Sessions, Davis et al11Davis SF Yeung AC Meredith IT et al.Early endothelial dysfunction predicts the development of transplant coronary artery disease at one year post-transplant [abstract].Circulation. 1994; 90: I-294Google Scholar presented an elegant study of 20 cardiac transplant patients, which examined the relationship between early endothelial function and the subsequent development of intimal thickening detected by IVUS. Coronary segments that constricted to acetylcholine early (ie, 15±3 days) after transplantation demonstrated a significantly greater increase in intracoronary ultrasound detected initimal thickening 1 year later, as compared to segments with normal responses to acetylcholine. The authors concluded that early endothelial dysfunction does indeed predict the development of transplant coronary atherosclerosis as manifested by changes in ultrasound-detected intimal thickness. Inappropriate coronary vasoconstriction due to endothelial damage and circulating vasoactive factors released from platelets may precipitate episodes of myocardial ischemia. We, and others, have demonstrated that the acute administration of intravenous estrogen reverses the abnormal vasoconstrictor response to endothelial-dependent stimuli in postmenopausal women.12Reis SE Gloth ST Blumenthal RS et al.Ethinyl estradiol acutely attenuates abnormal coronary vasomotor responses to acetycholine in postmenopausal women.Circulation. 1994; 89: 52-60Crossref PubMed Scopus (489) Google Scholar Recent investigations have shown that lipid-lowering therapy may make diseased coronary arteries dilate more like healthy ones in response to a provocative stimulus such as acetylcholine.13Egashira K Hiroka Y Kai H et al.Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia.Circulation. 1994; 89: 2519-2524Crossref PubMed Scopus (630) Google Scholar It was recently reported that the use of pravastatin, a lipid-lowering agent, in cardiac transplant recipients suppresses natural killer cell cytotoxicity and may be associated with a reduced incidence of allograft rejection.14Katznelson S Kobashigawa JA Wang XM et al.Pravastatin use in heart transplant patients suppresses natural killer cell (NKC) cytotoxicity and may be associated with reduced allograft rejection [abstract].Circulation. 1994; 90: I-200Google Scholar This suggests that comprehensive risk factor modification may reduce the clinical manifestations of early coronary atherosclerosis by improving endothelial function as well as retarding the progression of atherosclerosis in high-risk patients, such as those who have undergone cardiac transplantation. Therefore, further large-scale clinical studies are needed to identify early markers of coronary atherosclerosis in cardiac transplant patients.
Immunosuppression
Coronary atherosclerosis
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Conclusions: ESWT-induced coronary neovascularization can provide a useful alternative modality to treat severe CAD cases not suitable for or willing to have surgical intervention.
Endothelial Dysfunction
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Purpose. To study the effect of a single hemodialysis (HD) session on the endothelial structure and function by analyzing the contents of nitric oxide (NO) stable metabolites and circulating endothelial cells (CECs) number, and to establish the interrelation between the oxidative stress (OS) marker malondialdehyde (MDA) and endothelial dysfunction indices in patients with end-stage renal disease (ESRD). Material and methods. The study included 20 chronic HD patients (9 men aged 41,0±3,0 years; HD duration, (40,4±4,8) months). Patients with chronic glomerulonephritis (65%) dominated. Plasma content of MDA, the activity of superoxide dismutase (SOD) and catalase (CT) in erythrocytes, blood content of SH-groups were measured before and after the HD session by standard methods. Plasma content of nitrite-( NO2-) and nitrate anion (NO3-) was estimated by the spectrophotometric method, and CEC amount in platelet-rich plasma ss described by Hladovec J. et al., 1978 in our modification. Results. After the HD session NO2- content decreased by 18,4% (p<0,001), NO3- by 13,4% (p=0,007), while CEC number did not significantly change (p=0,478). Due to HD the content of MDA increased by 10,5% (p=0,007), the activity of SOD, CT increased by 8,9% (p=0,005) and 16,2% (p=0,016) respectively, and the concentration of SH-groups decreased by 20,8% (p<0,001). Significant correlation between the content of MDA and NO2- (Rs=-0,56, p=0,010), CECs amount (Rs=0,52, p=0,018) was established; the CEC number was in turn related to the level of NO2- (Rs=-0,58, p=0,007). Conclusions. The HD session is associated with the development of OS, lack of NO and possibly endothelial damage which confirms practicability of endothelial protection, in particular modulation of the L-arginine-NO system, during HD session in patients with ESRD.
Malondialdehyde
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Introduction: Endothelial Dysfunction(ED), well documented in essential hypertension, is produced by oxidation stress, breakdown and inactivation of NO, release of Endothelium D erivedConstricting Factor, prostanoids, endothelin -1 leading to decreased bioavailability of NO sustained SBP and high mean BP blunts Flow Mediated Dilatation (FMD) response in brachial artery.Hence present study has been designed to measure flow mediated vasodilatation of brachial artery by high resolution ultrasonographic imaging and pulse Doppler study.Material and Methods: This study has been carried out in the Department Of General Medicine & Radio-Diagnosis during the session August 2018 to December 2019, in GIMSR, Visakhapatnam,Andhra Pradesh.Fifty hypertensive patients diagnosed as per JNC-VIII recommendation have been studied.Equal number of 50 healthy persons as 30 male and 20 female in the age group of 40-70 have been taken as control for comparison.Evaluation of their endothelial function was done in terms Resting Brachial Artery Diameter (RBAD)and FMD% in hypertension group.Results: RBAD was found to be 4.07 + 0.28 in control, 3.98 + 3.4 in hypertension group (n=31) where SBP > 160mmHg.4.15 +0.37 mm (SBP 140-159 mmHg).Correlated with DBP the RBAD data were 90-109 = 3.84 + 0.34,>= 100 = 3.88 + 0.32.HBAD values in study group in relation to SBP and DBP showed:SBP 140 -159 = 3.95 + 0.33,DBP 90 -109 = 4.08 + 0.37, SBP>160 = 4.15 + 0.37 and DBP > 110 = 4.02 + 0.7.FMD% (flow Mediated dilation) is designated as an endothelial dependant process reflecting relaxation of an artery in response to increase flow and shear stress.Hyperemia is associated with increased blood flow, velocity and diameter.Conclusion: FMD% may not be useful for therapeutic purpose because large number of physiological factor alters this.It is a functional bioassay for, in vivo, endothelial function in human.
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Rome and L'Aquila$
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