Minimizing myocardial ischemia-reperfusion injury has broad clinical implications and is a critical mediator of cardiac surgical outcomes."Ischemic injury" results from a restriction in blood supply leading to a mismatch between oxygen supply and demand of a sufficient intensity and/or duration that leads to cell necrosis, whereas ischemiareperfusion injury occurs when blood supply is restored after a period of ischemia and is usually associated with apoptosis (i.e.programmed cell death).Compared to vascular endothelial cells, cardiac myocytes are more sensitive to ischemic injury and have received the most attention in preventing myocardial ischemia-reperfusion injury.Many comprehensive reviews exist on various aspects of myocardial ischemia-reperfusion injury.The purpose of this review is to examine the role of vascular endothelial cells in myocardial ischemia-reperfusion injury, and to stimulate further research in this exciting and clinically relevant area.Two specific areas that are addressed include: 1) data suggesting that coronary endothelial cells are critical mediators of myocardial dysfunction after ischemia-reperfusion injury; and 2) the involvement of the mitochondrial permeability transition pore in endothelial cell death as a result of an ischemia-reperfusion insult.Elucidating the cellular signaling pathway(s) that leads to endothelial cell injury and/or death in response to ischemia-reperfusion is a key component to developing clinically applicable strategies that might minimize myocardial ischemia-reperfusion injury.
Anti-atherogenic effects of high density lipoprotein (HDL) and its major protein component apolipoprotein A-I (apoA-I) are principally thought to be due to their ability to mediate reverse cholesterol transport. These agents also possess anti-oxidant properties that prevent the oxidative modification of low density lipoprotein (LDL) and anti-inflammatory properties that include inhibition of endothelial cell adhesion molecule expression. Results of the Framingham study revealed that a reduction in HDL levels is an independent risk factor for coronary artery disease (CAD). Accordingly, there has been considerable interest in developing new therapies that specifically elevate HDL cholesterol. However, recent evidence suggests that increasing circulating HDL cholesterol levels alone is not sufficient as a mode of HDL therapy. Rather, therapeutic approaches that increase the functional properties of HDL may be superior to simply raising the levels of HDL per se. Our laboratory has pioneered the development of synthetic, apolipoprotein mimetic peptides which are structurally and functionally similar to apoA-I but possess unique structural homology to the lipid-associating domains of apoA-I. The apoA-I mimetic peptide 4F inhibits atherogenic lesion formation in murine models of atherosclerosis. This effect is related to the ability of 4F to induce the formation of pre-β HDL particles that are enriched in apoA-I and paraoxonase. 4F also possesses anti-inflammatory and anti-oxidant properties that are independent of its effect on HDL quality per se. Recent studies suggest that 4F stimulates the expression of the antioxidant enzymes heme oxygenase and superoxide dismutase and inhibits superoxide anion formation in blood vessels of diabetic, hypercholesterolemic and sickle cell disease mice. The goal of this review is to discuss HDL-dependent and -independent mechanisms by which apoA-I mimetic peptides reduce vascular injury in experimental animal models.
Currently, abdominal aortic aneurysms (AAAs), which are a permanent dilation of the aorta, are treated surgically when the maximum transverse diameter surpasses 5.5cm.AAA rupture occurs when the locally acting wall stress exceeds the locally acting wall strength.There is a need to review the current diameter-based criterion, and so it may be clinically useful to develop an additional tool to aid the surgical decision-making process.A Finite Element Analysis Rupture Index (FEARI) was developed.Ten patient-specific AAAs were reconstructed, and the corresponding wall stress computed.Previous experimental work on determination of ultimate tensile strengths (UTS) from AAA tissue samples was implemented in this study.By combining peak wall stress along with average regional UTS, a new approach to the estimation of patient-specific rupture risk has been developed.Ten cases were studied, all of which were awaiting or had previously undergone surgical AAA repair.A detailed examination of these ten cases utilising the FEARI analysis suggested that there was a possibility that some of the AAAs may have been less prone to rupture than previously considered.It is proposed that FEARI, used alongside other rupture risk factors, may improve the current surgical decision-making process.The use of FEARI as an additional tool for rupture prediction may provide a useful adjunct to the diameter-based approach in surgical decision-making.
The aim of this trial was to test the feasibility of a screening method based on the well-known risk factors of cardiovascular disease (CVD), and to evaluate the efficacy of 2 preventive strategies to lower the level of risk factors.Participants (n = 755) were female employees contacted during their health check visit at the age of 40, 45, 50, or 55 years.The risk-index consisted of body mass index, total serum cholesterol level, blood pressure, smoking and exercise activity.Psychosocial factors (e.g.vital exhaustion, optimism-hopelessness) were assessed with self-report questionnaires.Highrisk women were invited to participate in a preventive intervention.Simple crossover design was used to evaluate the efficacy of personal feedback and health education as compared with feedback and group-based intervention programme.Follow-ups were completed at 6 and 12 months.Nearly one third (29.0 %) of the participants scored over the previously established risk-limit.Indicators of negative affectivity, i.e. vital exhaustion and hopelessness, associated significantly with the risk index after controlling for age and education.The feasibility of the screening method in an occupational health care setting proved to be good.The proportion of high-risk women was higher than expected but remained clearly lower than the 41 % prevalence in corresponding male cohorts.Results suggest that the screening method offers a good starting point for prevention.
Background: Vascular complications are uncommon (1-3%) in kidney transplantation. Recipient morbidities may result in loss of the allograft. Early and middle-term vascular complications include external iliac artery iatrogenic or spontaneous lesions and drainage vein thrombosis. Percutaneous transluminal angioplasty (PTA) is proposed as a valid, less invasive and alternative treatment to surgical repair. Material and Methods: Three patients, in the last two years, referred to our Institute: one affected by dissection secondary to the site clamp and suture stenosis of the external iliac artery, one spontaneous pseudoaneurysm with uncontained rup- ture of the same artery and another with pseudoaneurysm at the site of previous transplantation. All patients were treated by endovascular PTA approach. Patients with pseudo-aneurysm were treated by self-expandable stent-graft PTFE endo- prostheses (Hemobahn-Gore) release whereas in the other a balloon-expandable covered stent (Advanta V12 Boston Sci- entific) was used. Results: After treatment clinical, ultrasonographic and Doppler parameters showed a complete functional recovery of ileo- femoral axis as well renal function. All patients were discharged 5 days after the procedure. At an average follow-up of 12 months, by angio-CT scan, no recurrence of stenoses or aneurysms were found. Conclusion: PTA followed by stent placement is safe, effective and less invasive than surgical repair. Short and middle- term follow-up showed the benefit of the procedure, moreover the hospital stay is dramatically reduced. All renal allograft recipients, with vascular complications, should undergo to PTA procedure as a first option.
Endothelial dysfunction has been characterized by decreased nitric oxide (NO) synthesis or reduced NO bioavailability, which relates to inflammation, proliferation of smooth muscle cells, deposition of extracellular matrix, vasoconstriction, and a prothrombotic state within the vessel lumen. The endothelium is the site of the final step of synthesis of both NO and angiotensin II (Ang II) and is a major site for their countervailing interaction. Evidence suggests that renin-angiotensin system (RAS) blockade may have an impact on early mechanisms of vascular disease, such as endothelial dysfunction and vascular remodeling that underlie clinical manifestations of cardiovascular disease. This article reviews the current views on the biologic organization of RAS. Evidence supports a pathologic role of RAS activity in promoting endothelial dysfunction characterized by the impairment of NO bioavailability, and provides the basis for considering inhibition of RAS activity as a major target for therapeutic intervention.
The usefulness of lupus anticoagulant (LA) and several antibodies for predicting thrombosis was assessed in patients with idiopathic thrombocytopenic purpura (ITP), systemic lupus erythematosus (SLE), lupus like disease (LLD), recurrent abortion and primary antiphospholipid syndrome (APS).LA was measured using the diluted Russell Viper Venom test (DRVVT) and the diluted prothrombin time (dPT).In healthy volunteers, the median (range) of the DRVVT and dPT ratio were 0.97 (0.88 -1.08) and 1.05 (0.85 -1.29), respectively.The positive percent of dPT ratio was high in patients with ITP, SLE, recurrent abortion and primary APS.The sensitivity for thrombosis was highest for the dPT ratio and the specificity for thrombosis was highest for the DRVVT ratio.The sensitivity and the Odd's ratio for both the dPT and DRVVT ratio were high.A positive predictive value in DRVVT and a negative predictive value in dPT were high.The receiver operating characteristic (ROC) curve analysis indicates that the dPT ratio might be more useful for predicting thrombosis than the DRVVT ratio.The DRVVT and dPT ratios are useful for both the diagnosis of APS as well as predicting thrombosis.
Atherothrombosis, ischaemic heart disease (IHD), cerebrovascular disease (CVD) and peripheral arterial dis- ease (PAD) are a major cause of mortality and are predicted to be the leading cause of death world-wide by 2020. It is now recognised that CVD is part of a family of atherothrombotic diseases such as PAD and IHD. However, despite receiving contemporary evidence-based preventative drug therapy, patients with established arterial disease and those with multiple risk factors for atherothrombosis both experience high cardiovascular (CV) event rates with a 4.7% yearly rate of hard events. People with symptomatic atherosclerosis in 1 vascular bed are at a higher risk of subsequent events in other beds, e.g. patients who suffer a stroke are at a high risk of going on to suffer a coronary event, with a 10 year CV event risk of 42.8%. These findings support the need for increased awareness among physicians and patients for the amount of vascular cross-risk that is related to the overlap between the various beds of atherothrombosis. Atherothrombosis in stroke patients should be considered as a global arterial disease. We present a systematic review of the literature relating to the risk of non-cerebral (especially sub-clinical) atherothrombotic events in ischaemic stroke pa- tients.
Auditory Brainstem Responses (ABRs) is an electrophysiologic technique that represents the synchronized activity of the brainstem and the auditory nerve.Nerve conduction velocity (NCV) is part of electrodiagnostic procedures that help in evaluating the type and degree of abnormalities of the peripheral nerves.The aim of our study was to assess whether central or peripheral nerves are involved in hypertensive patients.20 patients of primary hypertension were selected between the ages of 40-60 years of either sex along with 20 age-and sex-matched normotensives.ABRs along with NCV, both sensory and motor components of the median nerve were performed using standard techniques.Auditory threshold increased significantly in the hypertensive group compared with controls (p < 0.05).There was a significant prolongation of absolute peak latencies of waves I, II and V and interpeak latency III-V.However, no significant difference was observed in the NCV between the hypertensives and controls.We conclude that there was a significant correlation of rise in systolic and diastolic blood pressure with absolute peak latencies of ABRs in hypertensive patients.However, no significant difference in nerve conduction velocity was seen.
Chronic kidney disease (CKD) is now widely recognized as a significant risk factor for cardiovascular disease (CVD). Chronic angiotensin II (Ang II) stimulation facilitates tissue hyperplasia, hypertrophy, and inflammation, and the current medical strategy for CKD is primarily based on the suppression of rein-angiotensin system. Since Ang II induces hypertension through both vasoconstriction and sodium retention, the understanding of vascular and renal actions of Ang II is essential for the better management of CKD and CVD. Ang II is coupled to a variety of intracellular signaling path- ways depending on cell types, and Ang II type 1 receptor (AT1) is thought to be responsible for most, if not all, of the car- diovascular effects of Ang II. Recent studies have suggested that the MEK/ERK pathway plays an important role in Ang II-mediated vascular smooth muscle contraction, where cytosolic phospholipase A2 (cPLA2)/P450 pathway has a positive feedback effect. Interestingly, the MEK/ERK pathway has been also shown to mediate the stimulatory effect of Ang II on renal proximal transport. However, the cPLA2/P450 pathway has a negative feedback effect on the Ang II-mediated ERK activation in renal proximal tubules. Thus, arachidonic acid metabolites seem to play quite contrasting roles in the Ang II- mediated ERK activation in vascular and renal tissues. This article will be focused on the roles of MEK/ERK pathway in vascular and renal tubular actions of Ang II.
Scaling up research is essential to prevent and contain the rapidly growing epidemic of cardiovascular diseases (CVD) in low- and middle- income (LMIC) countries. Research funds are generally limited and need to be invested pri- marily to generate new knowledge on how to translate existing evidence into action and not for the discovery of novel causes and treatments. Problem-oriented health policy and systems research have a critical role to play in the effective im- plementation of a policy framework for addressing cardiovascular diseases. Research need to identify effective multistakeholder regulatory approaches that impact on diet, tobacco use and physical activity. Policy interventions that have the potential to reduce social gradient of major noncommunicable diseases (NCD) through the reduction of social stratification, vulnerability and exposure to risk factors also merit research. Macro and micro economic appraisals are re- quired to assess the economic impact of risks and diseases and cost effectiveness of different types of health interventions in different settings. Appropriate resource allocation for medical technology need to be researched in order to maximize health benefits and equity in low resource environments. Important modifiers of health system effectiveness such as ad- herence of patients and performance of providers also need to be studied. Further, the widening gap between the need for long-term care and the capacity of welfare programs to fulfill that need and the limited economic capacity of LMIC, calls for research into new public financing mechanisms to provide financial protection care. Finally, the research agenda need to be pro-poor so that the social gradient related to CVD can be narrowed to contribute to progress towards the Millen- nium Development Goals.
Preeclampsia is a major cause of maternal and perinatal mortality.Although preeclampsia may be caused by several factors, endothelial cell dysfunction has been proposed as the main pathophysiological cause.Dysfunctional endothelium in the uteroplacental circulation not only increases peripheral vascular resistance, but also affects generalized vasoconstriction via humoral factors released from the placenta.A standard method for predicting and preventing preeclampsia has yet to be developed; however, the analysis of a combination of biochemical markers, particularly markers related to vascular dysfunction, may enhance our ability to predict and prevent preeclampsia in the near future.
There is much evidence regarding autonomic dysfunction in obesity in adults, but information on autonomic status in obese children is scant. In the present study autonomic function tests were conducted in 30 normal and 30 obese children aged between 5 and 10 years. We performed tests for parasympathetic function (resting heart rate, S:L ratio (standing to lying ratio), 30:15 ratio and Valsalva ratio) and tests to assess sympathetic function (blood pressure response to hand grip test and cold pressor response). The children were classified as normal and obese on the basis of BMI (body mass index). Children with BMI between 20 to 24.9 were classified as normal and those with BMI > 30 as obese. The mean values of hand grip test and cold pressor response were significantly lower in the study group compared with controls (P < 0.05), however the Valsalva ratio was higher in the obese compared with normal children. Hence, our study showed compromised autonomic nervous system functions in the obese group compared with controls
Treatment with oral anti-platelet agents constitutes a cornerstone in the therapy of coronary artery disease. Coronary angioplasty and stent implantation improved the therapy of coronary artery disease and especially the treatment of acute myocardial infarction. Implementation of glycoprotein IIb/IIIa inhibition further advanced anti-platelet therapy as a central component in the treatment of acute coronary syndromes. Sustained prevention of reocclusion was achieved when dual anti-platelet therapy had been introduced and reduced the risk of stent thrombosis to ~1% following elective stenting in stable coronary artery disease. However, targeting more complex lesions or performing the intervention in states of increased platelet reactivity such as in acute coronary syn- dromes or in diabetic patients is still associated with a higher risk of stent thrombosis. Additionally, incomplete ADP- receptor inhibition by thienopyridine treatment contributes to increased cardiovascular events and mortality after coronary intervention. This review describes the underlying pathophysiology leading to coronary atherothrombosis and contributing to stent thrombosis as well as the pharmacological approach to prevent it by dual anti-platelet therapy. It summarizes the assess- ment of anti-platelet therapy by different analytical methods such as platelet aggregation, platelet function analyzers, and the platelet reactivity index. Impaired clopidogrel responsiveness and its implication for adverse cardiovascular events and stent thrombosis are discussed. Current strategies in improving the efficacy of clopidogrel treatment as well as the next generation of anti-platelet substances such as novel thienopyridines and non-thienopyridine P2Y12-receptor blocking agents are addressed. Finally, we discuss the potential of von-Willebrand factor aptamers compared to glycoprotein IIb/IIIa inhibitors in acute coronary syndromes.
It is clear that dietary factors can induce epigenetic changes - i.e. can alter patterns of DNA methylation and histone posttranslational modifications in the genome. At least part of the epigenetic effects elicited by diet in infants may result in long-lasting changes in gene expression within an individual's lifetime and, at least in animal models, transgen- erationally. Therefore, these epigenetic modifications can be regarded as early molecular events of potentially critical relevance to vascular disease prevention. A comprehensive description of dietary factor-induced changes in the epige- nome - including both protective and risk-generating factors - is needed to appreciate the extent and relevance of these early molecular events. A second critical goal yet to be achieved is the description of the epigenome of cell types partici- pating in atherogenesis. By combining these two approaches, research promises to generate information that can be trans- lated into improved vascular disease prevention. Here, we review recent advances in the field of epigenetics, dietary fac- tors and vascular disease.
Diabetes mellitus (DM) is one of the most potent independent risk factors for the development of coronary artery disease (CAD) and is recognized as a cardiovascular disease equivalent.Compared with individuals without DM, those with DM have a higher prevalence of CAD, a greater extent of coronary ischemia, and are more likely to have a myocardial infarction and silent myocardial ischemia.The vasculature of diabetic patients is more vulnerable in developing atherosclerotic plaques in comparison with the vasculature of the non diabetic individuals.Microvascular and macrovascular effects are observed in the majority of organs of diabetic patients.Endothelial dysfunction, increased stiffness of the aorta, renal artery stenosis, diabetic nephropathy, carotid artery stenosis leading to cerebrovascular insufficiency, CAD and heart failure are the main complications of DM on the vasculature.Therapeutic modalities such as angiotensinconverting enzyme inhibitors, angiotensin II receptor blockers, thiazolidinediones (glitazones), statins, and antioxidants may be useful in these patients.
Endothelial cells form the lining of the vasculature. Despite the continuity of this layer throughout the body, endothelial cells exhibit remarkable heterogeneity in structure, molecular composition and activity: between sites; and in response to different exposures. One important consequence of endothelial diversity is the localized nature of many vascu- lar disorders. To date a limited number of studies have attempted to define unique phenotypic features of the different in- traocular endothelial subpopulations, which include the endothelial cells of vascular beds in the iris, the choroid and the retina. Differences that distinguish endothelial cells in the circulations of the choroid and the retina, in particular, are be- lieved to be major etiological factors controlling the specific involvement of the two tissues in some of the most common blinding diseases. Age-related macular degeneration involves choroid, and diabetic retinopathy and posterior uveitis are primarily diseases of the retina. Development of effective targeted therapies for these ocular disorders will require a de- tailed understanding of the heterogeneity of ocular endothelia. Our review summarizes the existing literature relating to diversity of the ocular endothelial cells. We highlight structural, metabolic and functional characteristics that distinguish intraoocular endothelial subtypes from each other and from extraocular endothelial cells, and we consider the implications of these differences for the design of novel biological therapeutics for eye diseases.
Serum aldosterone levels are often elevated in patients with heart failure and are associated with poor clinical outcomes. Aldosterone can be produced in extra-adrenal tissues including the heart, and the local increase in aldosterone exerts deleterious effects on heart structure and function. Aldosterone has 2 types of effects on intracellular ion milieu and cellular function. One is the classical genomic effect in which aldosterone combines with the intracellular mineralocorti- coid receptor, transfers to the nucleus, and stimulates synthesis of various proteins. Another is the non-genomic effect that expresses within minutes without synthesizing proteins. The non-genomic effects of aldosterone are less proved in the heart, but it has been shown that aldosterone rapidly activates Na + influxes via Na + -K + -2Cl - co-transport and Na + /H + ex- change, resulting in an increase in intracellular Na + concentration and intracellular alkalinization. These changes in intra- cellular ion milieu cause positive inotropy, cell swelling, and generation of reactive oxygen species. Thus, the non- genomic effects of aldosterone may contribute, in concert with the genomic effects, to cardiac hypertrophy, fibrosis, and remodeling. This review will discuss the experimental studies examining the mechanisms and physiological/patho- physiological relevance regarding the non-genomic effects of aldosterone in the heart.
Although initial experimental data and results of observational studies suggest that hormone replacement ther- apy (HRT) is associated with a reduction in the risk of heart disease, the results for events such as stroke or thromboem- bolism are less clear. Randomized secondary and primary prevention studies have found that HRT is not protective against the risk of coronary heart disease, stroke or progression of atherosclerosis. Therefore, HRT therapy should not be initiated to prevent vascular disease among postmenopausal women. There are numerous explanations for the divergent findings of observational and randomized clinical trials of HRT. For example, study design and differing biological effects of HRT on vascular risk factors. The use of HRT for young postmenopausal women with moderate to severe menopausal vasomotor symptoms appears to be safe. The absolute risk of vascular event associated with HRT is low and varies depending on factors like age or years since the menopause. The presence or absence of cardiovascular risk factors determines the differences in vascular risk linked to HRT. Further studies should identify the mechanisms involved and determine whether and how different regimens of HRT in- fluence vascular risk as well as the influence of individual patient characteristics.
Vascular endothelial cells regulate the passage of fluids, solutes, and cells from the vascular space to the tis- sues. Disruption of vascular integrity is involved in the pathogenesis of inflammatory diseases including transfusion- related acute lung injury (TRALI), a most severe nonhemolytic transfusion reaction with symptoms such as dyspnea and/or hypotension and fever. Pulmonary edema, due to increased vascular permeability for macromolecules and plasma, is a hallmark of TRALI. The mortality rate of TRALI ranges from 5 to 10%. While donor antibodies (Abs) against human leukocyte antigen (HLA) class I and granulocytes are regarded as causative factors, various clinical studies have demon- strated the roles of anti-HLA class II-Ab on the etiology of TRALI, although the detailed mechanisms have not been clari- fied. Over several years we have investigated to clarify the underlying mechanism by which anti-HLA class II Abs cause an increase in endothelial permeability. In this review, we show that anti-HLA class II Ab generates proinflammatory cy- tokines and chemokines from HLA class II positive mononuclear cells of peripheral blood in an Fc R-dependent manner. As a result, the produced interleukin-1 and tumor necrosis factor- lead to increased endothelial permeability via the nu- clear factor- B pathway but not apoptosis of endothelial cells. These findings provide a better understanding of the roles of anti-HLA class II Ab in the etiology of TRALI.
