Vascular Disease Prevention (Discontinued) - Volume 2, Issue 1, 2005

We investigated the development of pulmonary inflammation and pulmonary vascular hypertrophy induced by continuous catecholamine (CA) infusion in rats. We studied the role of proinflammatory cytokines in this pathogenetic process and their relationship to pulmonary injury and to cardiac hypertrophy. Female Sprague-Dawley rats (n=251) received a continuous intravenous infusion of norepinephrine (NE), phenylephrine (PE), isoproterenol (ISO) or NaCl 0.9% (as control) over time intervals between 20 min and 72 h. We analysed cardiac function and hypertrophy as well as activation of proinflammatory cytokines in lung, serum, pleural fluid and bronchoalveolar lavage (BAL) fluid. Additionally, BAL cytology and histologic changes in the lung were investigated. Lung histology showed pulmonary oedema, inflammation and vascular hypertrophy after stimulation with all types of CA. In the lung, mRNA of IL-1α, IL-1β and IL-6, but not of TNFα, increased transiently after 45 min of PE and, to a lower degree, ISO infusion. Only PE infusion induced accumulation of neutrophils and macrophages in BAL. The degrees of pulmonary inflammation and vascular hypertrophy were similar with different stimulation types, and there was a significant positive correlation between these two processes. Right ventricular (RV) hypertrophy was induced by ISO but not by PE. These results demonstrate that CA elicit pulmonary inflammation and thereby, pulmonary vascular hypertrophy. Both α- and β-adrenergic mechanisms have been shown to contribute to this pathogenesis. However, it is likely that RV hypertrophy developed as a consequence of direct CA effects rather than of pulmonary vascular hypertrophy.

This study aimed to determine whether the influence of the lipid profiles as a risk factor was different between patients with and without diabetes mellitus (DM). Two hundred and fifty-six consecutive patients who underwent coronary angiography because of suspected coronary artery disease (CAD) were retrospectively analyzed. They included 188 patients with CAD and 68 patients with chest pain syndrome (controls). Multiple logistic regression analysis showed that DM, low density lipoprotein-cholesterol (LDL-C) / high density lipoprotein-cholesterol (HDL-C) ratio, remnant-like lipoprotein particle-cholesterol (RLP-C) and RLP-C / HDL-C ratio could discriminate CAD patients from the controls. The most powerful discriminating factor was DM (OR: 4.17, 95% CI: 1.82-9.57, p=0.0007). In the subgroup of non-diabetic patients, hypertension, LDL-C / HDL-C ratio, RLP-C and RLP-C / HDL-C ratio could discriminate CAD. In diabetic patients, however, only TG could discriminate CAD. These results suggest that the contribution of dyslipidemia in the development of CAD may be different in patients with and without DM, at least in the Japanese population.

Several individual pharmacologic agents such as antiplatelet drugs, beta-blockers, angiotensin converting enzyme inhibitors and lipid lowering agents have proven efficacy in reducing mortality in patients with vascular diseases. We review the efficacy of combination evidence-based medical therapies in patients with vascular diseases and demonstrate that secondary prevention therapies used in combination are associated with significantly improved survival. Such therapies, most of which are generic and inexpensive today, appear to offer a marked survival advantage in patients with cardiovascular diseases.

In man prosthetic vascular grafts fail to develop an endothelial lining, no matter how long they have been implanted for. As a result, these grafts remain permanently thrombogenic and have poorer patency rates than grafts constructed using autologous vessels. Attempts have been made to artificially place endothelial cells on prosthetic grafts and this is termed “endothelial seeding”. The aim has been to produce an antithrombogenic surface similar to that possessed by normal vessels. In addition there have been attempts to produce artificial biological grafts or grafts lined with genetically modified cells. This approach of combining prosthetic materials and biologically active cells is usually referred to as “tissue-engineering”. Graft seeding and tissue-engineered grafts have shown definite advantages in animal studies as well as in some of the clinical trials, and are worthy of further study. Unfortunately they cannot, currently be recommended for routine clinical use. However, if the techniques could be successfully transferred to the clinical situation, they would represent a real advance in vascular surgery. Present research is directed to developing methods of accelerating endothelialization by pharmacological means, to enhance fallout of endothelial cell progenitors and the use of endothelial cells genetically engineered in order to make them produce more of desirable substances such as tissue plasminogen activator or growth factors to stimulate angiogenesis.

Obstructive sleep apnoea syndrome (OSAS) is a clinical disorder associated with hypertension; recent guidelines suggest that it should be considered as one of the causes of refractory hypertension. Good clinical practice indicates that a patient with suspected sleep apnoea should undergo 24 h blood pressure (BP) monitoring as well as polysomnography. Several studies have investigated a causal role of OSAS in hypertension and if these two conditions were linked by some possible confounding factor, such as obesity; recently, it has been observed that OSAS is an independent risk factor for hypertension and predisposes to a markedly increased incidence of cardiovascular disease. The physiopathological link between OSAS and high BP is not clear yet. Nevertheless it is possible to propose the hypothesis of a causal role of hypoxia, which characterizes sleep apnoea. In turn, hypoxia causes sympathetic activation, systemic vasoconstriction, endothelial dysfunction and increased serum leptin levels. All these factors may exacerbate the hypertensive state. Therapeutic strategies for hypertensive patients with OSAS include: continuous positive airway pressure (CPAP) treatment, which can reduce BP values and improve the autonomic control of BP and heart rate, and weight loss in obese patients, who represent about 70% of all patients with OSAS. In contrast, a pharmacological approach to treat sleep apnoea in hypertensives is not worthwhile at present. In conclusion, identification and treatment of OSAS in hypertensive patients is important to reduce the cardiovascular risk of these subjects.

Nitric oxide (NO) is a molecule that mediates key physiological and pathophysiological mechanisms. The intracellular availability of L-arginine, the precursor for NO synthesis, is limited by plasma concentration, metabolism and L-arginine transport. The membrane transport of extracellular L-arginine seems to be a rate-limiting step for NO synthesis even when the intracellular levels of L-arginine are available in excess. A clear explanation for the phenomenon ´´Larginine paradox´´ has not yet been found. In mammalian cells, four transport systems for L-arginine have been described: y+, y+L, Bo,+ and bo,+. Chronic renal failure (CRF), chronic heart failure (CHF) and essential hypertension are characterised by endothelial dysfunction, elevated concentration of pro-inflammatory circulating cytokines and alteration in platelet function and coagulation factors. Due to these pathological alterations they comprise groups of patients at very high risk for atherothrombotic events. Accumulating evidence suggests that a disturbance of the L-arginine-NO pathway is involved in the pathophysiology of CRF, CHF and hypertension, perhaps reflecting a response to the hormonal imbalance and increased production of inflammatory mediators common to these diseases. The current review provides an overview of L-arginine transport and NO production in endothelium and blood cells in patients with cardiovascular and renal diseases.

Nitric oxide (NO) and endothelin-1 (ET-1) are the prototype of endothelium-derived relaxing (EDRFs) and constricting factors (EDCFs), respectively. They have been studied extensively in relation to cardiovascular disease, but there is limited information on their interaction. Nonetheless, compelling evidence indicates that in several conditions with excess cardiovascular risk, blunted NO affects are coupled with enhanced ET-1 synthesis, thus suggesting a reciprocal regulation of these two factors. Consistent with this contention is the evidence that NO inhibits the synthesis of ET-1 in different cell types and that ET-1 blunts NO release in response to stimulation by cytokines. However, it is likely that ET-1 can play an ambivalent role since it enhances NO release, both directly, via ETB receptors on endothelial cells, and indirectly, by causing vasoconstriction and, thereby, increasing laminar shear stress. A number of in vitro and in vivo studies have unravelled the complexity of the mechanisms underlying the regulation of NO and ET-1 synthesis. Several factors can affect in opposite directions the transcription of the NO synthase and preproET-1 genes. The family of NF-kB transcription factors, peroxisome proliferator-activated receptors and reactive oxygen species appear to play a major role in this regulation, as well as in triggering early events of atherogenesis. The purpose of this review is, therefore, to examine the molecular mechanisms regulating the interplay between NO and ET-1, and to discuss their implications for arterial and pulmonary hypertension, and for atherosclerosis.

Selective serotonin re-uptake inhibiting drugs (SSRIs) are widely used for endogenous depression. In addition to depleting the nerve terminals of serotonin they also lower blood platelet serotonin levels. Platelet aggregation is a major component of acute coronary syndromes, including sudden death, and also of limb ischaemia. Platelet-released serotonin causes constriction of diseased blood vessels. The recent literature has revealed a number of reports of association between the treatment of depression with SSRIs and reduced events caused by intra-arterial thrombosis. The effects of serotonin and serotonin depletion upon intracoronary thrombosis, diseased blood vessels, blood platelets and bleeding are discussed with recommendations for future research into the potential cardiovascular benefits of SSRIs and serotonin 5HT2A antagonists.

The endothelium of the coronary arteries has been identified as the important organ that locally regulates coronary perfusion and cardiac function by paracrine secretion of nitric oxide (NO) and other vasoactive peptides. Therefore, also in cardiac transplantation, the established organ procurement with hypothermic storage in solutions designed to preserve myocytes but not endothelial cells, has to be critically discussed. Heart transplantation is a treatment for end-stage heart failure. This intervention has promising survival rates: 84% oneyear and 65% five-year survival. However, these survival rates offer plenty of room for improvement and further research in the areas of organ preservation and perioperative management. This review will focus on possible strategies to improve donor and recipient management in regard to a functional endothelium and NO. We briefly address the following topics: (1) NO pathway and effects, to lay the ground for possible therapeutic strategies and interventions; (2) NO and ischaemia / reperfusion, to understand the mechanisms that lead to NO depletion and its consequences; (3) NO and hypothermia, to understand the effects of hypothermia on the endothelium; (4) Current status of donor and recipient management, to describe the strategies used today; (5) Possible new approaches: NO-scavenging and NO-substitution, to describe the recent research that is performed in this area including some of our own results; (6) Outlook in donor and recipient management, to suggest possible new directions, based on our current knowledge.

Ultrasound measurements of the carotid wall are widely used surrogate markers for atherosclerosis with the intima-media thickness [IMT] being the most commonly measured variable. However, ultrasound has recently defined carotid artery wall structures in higher spatial dimensions, such as total area of carotid plaques [TPA] and total volume of carotid plaques [TPV]. It is possible that IMT, TPA and TPV measure different aspects of the atherosclerotic process and thus have different clinical implications. IMT, TPA and TPV have never been correlated in the same individuals. We had a unique dataset in which IMT, TPA and TPV were measured concurrently in 272 subjects. We evaluated the left and right carotid arterial systems in each subject as independent variables and performed three pairwise correlation analyses between IMT and transformed TPA and TPV from the 544 carotid arterial systems. We found pairwise correlations between IMT and square root TPA, IMT and cubic root TPV and square root TPA and cubic root TPV; these correlation coefficients were 0.667, 0.586 and 0.963, respectively [all P<0.0001]. However, correlation graphs showed marked scatter of individual data points. Thus, IMT was only moderately well correlated with TPA and TPV, but TPA and TPV were very strongly correlated with each other. This suggests that IMT is less related to TPA and TPV than they are to each other and could reflect somewhat different aspects of atherosclerosis. Furthermore, the high correlation between TPA and TPV suggests that both might not need to be measured together in future analyses.