Vascular Disease Prevention (Discontinued) - Volume 4, Issue 2, 2007

Aims: To determine whether a short period of intensive monitoring and optimization of antihypertensive therapy according to a target-driven treatment protocol can improve blood pressure (BP) control in high-risk patients with type 2 diabetes. Methods: Consecutive patients (n=28, mean age 66 years) with type 2 diabetes and sub-optimal BP (>145/85 mm Hg) who were already receiving two or more antihypertensive drugs were studied for an 8-week period by a single investigator in a university hospital clinic. Current antihypertensive therapy was reviewed and optimized using a pre-defined step-wise treatment algorithm. The end-points were (a) attainment of the British Hypertension Society Audit standard BP of <140/80 mm Hg or (b) the end of the 8-week intervention period, whichever was reached first. Patients were subsequently discharged back to routine clinical care and re-assessed at >6 months. A control group received standard treatment shared between the hospital clinic and primary care by general practitioners. Results: In the intervention group, a significant improvement in both systolic (169 ± 3 to 149 ± 4 mm Hg; p<0.001) and diastolic (88 ± 2 to 80 ± 2 mmHg; p<0.01) BP was observed at 8 weeks with 43% of patients achieving the audit standard (p<0.01). The improvement in systolic BP was partially sustained at > 6 months (164 ± 3 mm Hg; p<0.005 vs. baseline). The mean daily number of antihypertensive drugs was 2.6 at entry and 3.0 at > 6 months (p=NS). There was no improvement in either systolic (175 ± 6 vs. 178 ± 7 mm Hg) or diastolic BP (84 ± 4 vs. 82 ± 6 mm Hg) in the control group. Conclusions: A significant improvement in BP can be achieved through a short period of intensified monitoring and optimization of drug therapy according to a predefined protocol of logical drug combinations. This improvement, which is partially sustained over a longer period, can be attained without a significant increase in the mean daily number of antihypertensive drugs.

Chronic venous insufficiency (CVI) of the lower extremities is a complicated disorder that affects the productivity and well-being of millions of people worldwide. Management requires careful differential diagnosis and a systematic long-term multidisciplinary care effort directed toward realistic goals within the context of the patient's lifestyle. Patients suffering from any class of the Clinical, Etiological, Anatomical, Pathophysiological (CEAP) classification of chronic venous disease (CVD) may be symptomatic (C0s-C6s). Leg heaviness, discomfort, itching, cramps, pain, paresthesia and oedema (C3) are the most frequent manifestations of CVD and a major reason for medical consultation. The standard treatments for venous disease of the lower limb include compression bandaging and stocking as well as surgical removal of varicose veins. Drugs for the venous system were initially called phlebotonics as they were believed to act on venous tone. They are still largely used in the symptomatic treatment of CVI and to make patients more comfortable. Phlebotropic drugs, in their modern form, are aimed at a wide range of processes. They are naturally occurring, seminatural or synthetic substances, some of them combining two or more active principles to improve the efficacy. Most of these belong to the flavonoid family (such as diosmine, esperidine, troxoerutine, oxoerutine, etc.) and others are capillary protecting substances as escine, centella asiatica, bilberry anthocyanosides. Flavonoid drugs have been widely used in the management of the symptom of venous disease for many years and have recently been studied in some detail to assess their effects on the microcirculation. Phlebotropic drugs are widely prescribed and marketed in Italy, France, Germany and other parts of Europe. Their mechanisms of action vary, but their main property is activation of venous and lymphatic return. The effects of phlebotropic drugs on physiological parameters such us venous tone, venous haemodynamics, capillary permeability and lymphatic drainage have been studied by many well-conducted randomized, double-blind clinical trials. In particular, phlebotropic drugs participate in the heamodynamic re-equilibrium of the microvascular system consisting in reducing capillary permeability by increasing its resistance with the consequent reduction of interstitial fluid. A series of drugs have been recently introduced for the treatment of severe CVI (CEAP 4/5/6), as co-adjuvants. They are antithrombotic drugs (sulodexide, heparan sulfate, defibrotide) and vasodilators (pentoxifyllin and prostaglandin E1) for their specific action on endothelial alterations and blow flow patterns, and on microthrombi and their oxygen barrier effect.

The accumulated wisdom of the last decade has fuelled a view of diabetes as an unusually severe form of cardiovascular disease (CVD) with a poor prognosis. Diabetic patients expect an up to 3-fold increase in coronary heart disease (CHD) events, independent of other traditional CVD risk factors, but those with CVD fair worse than their nondiabetic counterparts. The available therapeutic agents with the strongest current evidential support in prevention of CVD in diabetes are not those which primarily reduce blood glucose levels but rather those which reduce low density lipoprotein cholesterol or blood pressure. Current results from clinical trials are rather disappointing in reducing CVD events. Despite important reductions in relative risk in trials of statins, antihypertensive agents and those targeting the renin-angiotensin system there is a desperate need for new effective agents that can combat atherogenic factors including low high density lipoprotein cholesterol and raised triglyceride-rich particles, hyperinsulinaemia and notably the effects of high glucose on the arterial wall; not only to prevent CVD (macrovascular) but also the microvascular complications that are the cause of so much morbidity. To achieve this goal we must elucidate the pathophysiological role of glucose in endothelial dysfunction and atherogenesis, and begin to explain how elevated blood glucose itself (independent of other atherogenic features of the metabolic syndrome) might damage the arterial wall. Finally, we need to know to what extent any adverse effects of elevated glucose may be reversed if blood glucose levels are normalised. Unique model systems will contribute to understanding the direct and isolated effect of hyperglycaemia on the atherogenic process. We hope that this knowledge will help correct the anomalous situation whereby glucose-lowering drugs fail to demonstrate significant benefits in prevention of CVD.

The presence of K+ channels that are sensitive to intracellular ATP concentration ([ATP]i) was first described for ventricular myocytes and referred to as ATP-sensitive K+ channels (i.e. KATP channels). Subsequently, K+ channels with similar physiological characteristics were demonstrated to be expressed by many other cells types including pancreatic β-cells, skeletal muscle fibres, central neurons, cortical neurons and smooth muscle. It is now apparent that these channels play important roles in coupling cellular electrical activity to the metabolic status of cells. Molecular biological approaches have been employed to clone the protein subunits which form KATP channels. These studies indicate that the channels are composed of at least two protein subunits: (i) inwardly-rectifying K+ channel (Kir) subunits of the Kir6.x family that form the ion conducting pore and (ii) modulatory, sulphonylurea receptor (SUR) subunits, a member of the ATP-binding cassette (ABC) protein super-family, which accounts for several pharmacological properties of the channels. Determination of the molecular basis of native vascular KATP channels and smooth muscle-specific KATP subunit composition is essential for a comprehensive understanding of the physiological and pathophysiological roles of the channels in controlling smooth muscle contractility, sulphonylurea drug- and KATP channel opener-sensitivity and control of channel gating (opening and closing) by kinase-mediated phosphorylation. The purpose of this review is to briefly to overview the current knowledge available concerning KATP channels, with the primary focus being the molecular basis of native KATP channels and their possible linkage to pathophysiological function in vascular smooth muscle.

Blood pressure (BP) is one of the major determinants of cerebrovascular morbidity and mortality in individuals. Cell culture and animal model studies suggest the involvement of the renin-angiotensin system (RAS) in cerebral damage in stroke. Further, recently, interruption of the RAS with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II (Ang II) type 1 receptor blockers (ARBs) has been shown to reduce the risk for de novo or recurrent strokes in hypertensive patients. However, whether BP lowering independent effects of this class of agents could partly contribute to cerebral protection in stroke remains to be elucidated. In this study, ARBs, telmisartan and losartan, were given concomitantly for 5 weeks in spontaneously hypertensive rats stroke-prone (SHR-SP) infused with Ang II, and the effects of these agents on neurological deficits and survival were evaluated up to 25 weeks. There was no significant difference of BP levels among four groups (not-treated, Ang II-treated, Ang II plus telmisartan-treated, and Ang II plus losartan-treated rats) during the Ang II infusion period. Although both ARBs protected against neurological deficits and prolonged survival in Ang II-infused SHR-SP, the protective effects of telmisartan were stronger than those of losartan. Cumulative neurological deficit and death rates were significantly less in telmisartan-treated than in non-treated SHR-SP. The present findings suggest that ARBs could partly exert cerebral protection in a BP lowering independent manner and that inhibition of the RAS by telmisartan may become a promising strategy for the treatment of high-risk stroke-prone hypertensive patients.

Caffeine (1,3,7-trimethylxanthine), a natural alkaloid present in many beverages such as coffee, tea and cola drinks, is the most widely consumed pharmacological compound. Due to its common use and frequent intake in stressful conditions, a great deal of data have been produced by epidemiological surveys and experimental mammal studies to evaluate its direct and side effects on the cardiovascular system. There are controversies concerning the possible adverse effects induced by the normal use of caffeine (200-600 mg/day), but a number of negative consequences have been associated with the caffeine present in herbal supplements, beverages and junk food. In this review, we discuss the possible mechanisms involved in the beneficial and detrimental cardiovascular effects of caffeine.

Many studies promote both diagnostic and prognostic roles for single photon emission computed tomography (SPECT) functional brain imaging in patients with cerebrovascular disease (CVD). SPECT allows in vivo non-invasive imaging and quantification of regional cerebral blood flow (rCBF). Main indications include stroke, transient cerebral ischaemia (TIA), intracranial haemorrhage and arteriovenous malformation (AVM). In all types of CVD, significant changes in brain perfusion occur. SPECT-rCBF imaging may be useful in defining stroke subtypes-pathogenesis and add critical information regarding patients' therapy and clinical outcome. Moreover, calculation of regional cerebrovascular reserve (rCVR) at rest and during acetazolamide vasodilation reflects the brain's autoregulatory process. In acute stroke, SPECT imaging is superior to CT and MRI in demonstrating cerebral ischaemia in the early hours of onset. Recent studies illustrate the prognostic value of early SPECT-rCBF imaging, in comparison with CT. Additionally, SPECT-rCBF studies are useful in identifying appropriate candidates for thrombolytic treatment and therapy monitoring. In patients with chronic symptoms and signs of CVD, but negative CT, a positive SPECT study indicates cerebral ischaemia correlated with arterial stenosis. Anatomic imaging contributes little to the diagnosis of TIA, while SPECT may be useful in determining the cause and in identifying patients at high risk for early stroke following a TIA. SPECT also has a clinical application in monitoring ischaemia associated with vasospasm following subarachnoid haemorrhage. Brain SPECT has an important role for steal documentation in patients with AVM, while the evaluation of CVR seems to be prognostic for postoperative outcome. In the future, more studies are needed, to answer focused clinical questions.

Venous thromboembolic disease (VTE) is a well known risk in orthopaedic and trauma surgery. There is no unified opinion on the best method of prophylaxis and so most orthopaedic departments use very different regimes. We provide an overview of the best prophylactic methods available at present and an insight into the future of VTE prevention.

In addition to increasing the risk of diabetes, the metabolic syndrome increases the risk for cardiovascular disease and stroke. For the atherogenic dyslipidemia associated with the metabolic syndrome, the primary aims for therapy is to lower triglycerides, raise High Density Lipoprotein (HDL)-cholesterol, and reduce Low Density Lipoprotein (LDL)-cholesterol. The Scandinavian Simvastatin Survival Study and Cholesterol and Recurrent Events trials showed that reducing LDL-cholesterol with a statin decreased total and cardiovascular mortality in patients with coronary artery disease. In these trials, similar benefits were obtained with the metabolic syndrome subgroup as for the groups as a whole. Part of the Prevention of Renal and Vascular Endstage Disease Intervention Trial (PREVEND IT) involved pravastatin 40 mg in patients with persistent microalbuminuria, and in the metabolic syndrome subgroup, pravastatin lowered the incidence of major adverse cardiac events. The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study was in patients admitted to hospital with unstable angina or non-Q-wave acute myocardial infarction, and showed that intensive lipid lowering with atorvastatin reduced ischemic events, and this was similar in patients with and without the metabolic syndrome. The Bezafibrate Infarction Prevention (BIP) study enrolled patients with a previous myocardial infarction or stable angina to bezafibrate, to increase HDL-cholesterol while lowering triglycerides, and in the subjects with the metabolic syndrome, bezafibrate reduced the incidence of new myocardial infarction. Nicotinic acid is more potent than fibrates in raising the levels of HDL-cholesterol and lowering LDL-cholesterol, but slightly less potent than fibrates in reducing triglycerides. In the Coronary Drug Project of patients with coronary artery disease, nicotinic acid/niacin decreased the occurrence of myocardial infarction and mortality similarly in subjects with and without the metabolic syndrome. The combination of a statin and fibrate/niacin is probably beneficial in the metabolic syndrome, but this is yet to be clearly demonstrated in clinical trial.

Objective: Familial Combined Hyperlipoproteinemic (FCH) is a disorder of lipid metabolism characterized by an increased risk of premature coronary heart disease. Our aim is to estimate the prevalence of FCH subjects in a large North-Italian rural population monitored for 32 years (1972-2004). Methods: In the 2004 Brisighella Heart Study (BHS) survey, 1303 subjects were tested in five or more four-yearly surveys (mean age: 63.7±14.9 years). The individual plasma lipid phenotype by Fredrickson classification was attributed for each survey on the basis of low density lipoprotein (LDL)-cholesterol and triglycerides. A primary dyslipoproteinemia was suspected on the basis of personal and family history, body mass index and dietary habits. Results: At the end of the longitudinal study, the subjects with variable phenotype in the studied population were 17.2% and among primary hyperlipoproteinemics 36.3%. Mean IIb phenotype prevalence was 12.3 ± 6.3% in all hyperlipoproteinemics, while it was 33.4 ± 11.9% in potential FCH subjects. Only 7 subjects were constantly IIb during the observation time and four of them are certainly secondary hyperlipoproteinemics. The Ilb phenotype prevalence was significantly more variable than the Ila phenotypes. The 3.1% of the studied subjects have been selected as candidates for a FCH diagnosis without significant differences between sexes. Conclusion: Our data suggest the existence of a long-term primary variability of the individual plasma lipid phenotype. The prevalence of FCH in the general population appears to be near 2%.