Atheromatous Vascular Disease Research Articles

Prevention of Osteoarthritis Progression by Statins, Targeting Metabolic and Inflammatory Aspects: A Review.

Background and purpose:Several traditional risk factors of atherosclerosis such as age, obesity, and altered lipid metabolism are shared with osteoarthritis (OA). Metabolic abnormalities and atheromatous vascular disease are linked with systemic inflammation and progression of OA. Hence, treatment of OA with statins is expected to improve metabolic abnormalities and prevent OA progression. Many studies which have addressed this issue found inconsistent results. This review aims to elucidate the effect of statins in OA by summarizing the existing data.Methods:Potential studies in English language published in Medline/PubMed, Scopus and Google Scholar since 2000 were searched by using keywords such as osteoarthritis, statins, progression, treatment, prevalence, synovitis, pain. Fourteen papers were found to be relevant and were summarised.Results:Data regarding symptomatic effect of statins in OA are scarce and the results varied from no effect to a small improvement or even increased risk of pain in knee OA. However, most studies on the incidence and progression of OA found a significant decreased risk of incident OA, as well as reduced risk of radiographic progression in statin users vs. non-users. Factors such as patient adherence, duration of treatment, and higher cumulative statin doses were associated with greater efficacy.Conclusion:Existing data indicate a preventing effect of statin therapy on OA progression. However, unless a formal meta-analysis with weight analysis is made, a conclusion cannot be drawn.

Efficacy and Safety of PCSK9 Inhibitors in Hypercholesterolemia Associated With Refractory Nephrotic Syndrome

IntroductionTreatment of hypercholesterolemia in refractory nephrotic syndrome remains a therapeutic challenge. There is not enough evidence supporting the efficacy of statins, and these drugs can be associated with an increased incidence of adverse effects. Herein we summarize our clinical experience with 12 patients suffering from refractory nephrotic syndrome with associated vascular disease and uncontrolled hypercholesterolemia despite treatment with statins who were treated with proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors.MethodsTwelve adult patients with primary nephrotic syndrome refractory to multiple lines of immunosuppressive treatment who suffered from clinical atheromatous vascular disease were treated with PCSK9 inhibitors according to the prescription guidelines for secondary prevention of cardiovascular events. Eight patients with refractory nephrotic syndrome without vascular disease treated with atorvastatin comprised the control group.ResultsFour weeks after treatment with PCSK9 inhibitors, a statistically significant decrease in total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels was observed without significant changes in serum albumin levels or proteinuria. The mean LDL-C decrease was 36.8% ± 4.9% mmol/L at 4 weeks and remained unchanged throughout the follow-up period. In the control group, there were no significant changes in the levels of total cholesterol or LDL-C during the follow-up period. At the diagnosis of nephrotic syndrome, plasma PCSK9 levels were 334 ± 40 ng/mL and correlated significantly with serum LDL-C levels (r = 0.49, P = 0.023). Six months after starting treatment with PCSK9 inhibitors, plasma PCSK9 levels were significantly reduced to values of 190 ± 36 ng/mL (P = 0.001) with a mean relative reduction of 42.3% ± 12.6%. No local adverse effects were seen at the injection site and no significant changes were seen in the levels of transaminase, creatine phosphokinase, or aldolase.ConclusionPCSK9 inhibitors may be an effective and safe alternative for the treatment of hypercholesterolemia associated with refractory nephrotic syndrome.

Correction: The modality of dialysis does not influence atheromatous vascular disease progression or cardiovascular outcomes in dialysis patients without previous cardiovascular disease.

[This corrects the article DOI: 10.1371/journal.pone.0186921.].

The modality of dialysis does not influence atheromatous vascular disease progression or cardiovascular outcomes in dialysis patients without previous cardiovascular disease.

BackgroundThere is limited and inconclusive information regarding the influence of the modality of renal replacement therapy on the atherosclerotic burden of patients on dialysis. The aim of this study was to compare the prevalence of asymptomatic atheromatous carotid disease, as also its rate of progression and cardiovascular outcomes, in two matched populations of patients treated with hemodialysis (HD) and peritoneal dialysis (PD).MethodsFollowing a prospective, observational and multicenter design, we compared 237 PD and 237 HD patients without previous cardiovascular disease, included in the NEFRONA study, and matched for age, sex, diabetes and time on dialysis. Carotid ultrasound study was performed at baseline and after two years of follow-up in 6 carotid territories. Atheromatous vascular disease (AVD) progression was defined as any increase in the number of territories with plaques after 2 years. Fatal and non fatal cardiovascular events were also recorded during 36-month of follow-up.Main resultsAt baseline, PD patients presented a worse general cardiovascular risk profile than HD patients. On the contrary, some markers of prevalent atherosclerotic disease (common carotid intima-media thickness and ankle-brachial index) were more favorable in PD patients. During follow-up, we observed no differences either in the rate of progression of atheromatous vascular disease (OR 1.78, 95% CI 0.80–4.06, p = 0.161) or in the incidence of cardiovascular events (OR 1.51, 95% CI 0.85–2.66, p = 0.159), according to the modality of dialysis.ConclusionDialysis modality did not impact on atherosclerotic carotid disease progression or cardiovascular outcomes, in two groups of patients treated with PD or HD.

Carbon dioxide insufflation in open-chamber cardiac surgery: A double-blind, randomized clinical trial of neurocognitive effects

The aims of this study were first to analyze neurocognitive outcomes of patients after open-chamber cardiac surgery to determine whether carbon dioxide pericardial insufflation reduces incidence of neurocognitive decline (primary end point) as measured 6 weeks postoperatively and second to assess the utility of carbon dioxide insufflation in cardiac chamber deairing as assessed by transesophageal echocardiography. A multicenter, prospective, double-blind, randomized, controlled trial compared neurocognitive outcomes in patients undergoing open-chamber (left-sided) cardiac surgery who were assigned carbon dioxide insufflation or placebo (control group) in addition to standardized mechanical deairing maneuvers. One hundred twenty-five patients underwent surgery and were randomly allocated. Neurocognitive testing showed no clinically significant differences in z scores between preoperative and postoperative testing. Linear regression was used to identify factors associated with neurocognitive decline. Factors most strongly associated with neurocognitive decline were hypercholesterolemia, aortic atheroma grade, and coronary artery disease. There was significantly more intracardiac gas noted on intraoperative transesophageal echocardiography in all cardiac chambers (left atrium, left ventricle, and aorta) at all measured times (after crossclamp removal, during weaning from cardiopulmonary bypass, and at declaration of adequate deairing by the anesthetist) in the control group than in the carbon dioxide group (P < .04). Deairing time was also significantly longer in the control group (12 minutes [interquartile range, 9-18] versus 9 minutes [interquartile range, 7-14 minutes]; P = .002). Carbon dioxide pericardial insufflation in open-chamber cardiac surgery does not affect postoperative neurocognitive decline. The most important factor is atheromatous vascular disease.

Mediterranean diet for combating the metabolic syndrome

The increasing prevalence of the metabolic syndrome poses a major public health issue for the 21st century. By far the most significant impact the metabolic syndrome has on health is the increased incidence of atheromatous vascular disease.

The role of insulin and proinsulin in the regulation of triglyceride metabolism.

The mechanisms underlying the associations between abnormal glucose tolerance and myocardial infarction are poorly understood. It has often been suggested that an increased plasma insulin concentration is causally linked to many of the metabolic abnormalities that are associated with abnormal glucose tolerance, although this suggestion remains controversial. Recently it has been proposed that proinsulin and proinsulin-like molecules may also be involved in the atherogenic process. Both hyperinsulinaemia and insulin resistance are associated with fasting hypertriglyceridaemia and both increased VLDL production and increased plasma triglyceride concentrations commonly occur in association with abnormal glucose tolerance and atheromatous vascular disease. In order to study the effects of insulin, proinsulin and proinsulin-like molecules on hepatic triglyceride secretion we have undertaken experiments in vitro using the liver cell line HepG2. In conjunction with these in vitro experiments we have also studied, in vivo, the associations between insulin, proinsulin, proinsulin-like molecules and plasma triglyceride concentrations in subjects with both normal and abnormal glucose tolerance. Our results in vitro show that proinsulin and proinsulin-like molecules have similar and not different effects to insulin but are less biologically active. In vivo, our results show that concentrations of insulin, proinsulin and proinsulin-like molecules per se are not an important determinant of plasma triglyceride concentrations. Both abnormal NEFA suppression during an oral glucose tolerance test and increased central adiposity are closely linked to poor glucose tolerance and are the most important determinants of plasma triglyceride concentrations. Taken together these results suggest that it is not insulin nor proinsulin concentrations per se that are causally linked to hypertriglyceridaemia. We suggest that abnormal NEFA suppression plays an important part in the increase in risk of vascular disease associated with insulin resistance.

Sténoses de l’artère rénale athéromateuses et fibrodysplasiques

Renal artery stenosis may be due to atheromatous disease or renal fibromuscular dysplasia (FMD). Management of both diseases requires treatment of hypertension usually observed in such patients; however, clinical presentation, mechanism and treatment of these 2 diseases are usually different. Renal FMD is now considered as a systemic disease, the cause of which may be genetic (although the exact cause is still elusive). Renal arteries are the most frequent localizations of FMD, but extra renal arteries may also be involved (usually carotid arteries). Risk factors of hypertension-induced renal FMD include estrogen treatment and smoking. Renal FMD are mostly found in young women and in children who present with recent severe and/or refractory symptomatic hypertension. Diagnosis is usually easy (Doppler, CT-scan), and treatment of renal FMD is angioplasty in most cases. Atheromatous renal artery stenosis is usually found in patients with other atheromatous disease (peripheral artery disease, carotid, coronary artery disease...). Clinical presentation include severe or refractory hypertension, recurrent flash pulmonary edema in a patient with hypertension, progressive renal dysfunction spontaneously or after medical treatment with converting-enzyme inhibition or angiotensin II blockade, hypertension in a patient (usually smoker or ex-smoker) with diffuse atheromatous vascular disease. Management of atheromatous renal artery disease is medical treatment in all patients (aggressive treatment of cardiovascular risk factors, control of arterial pressure); revascularization is required in some patients only since it rarely cures hypertension: the goal of revascularization is mostly renal function protection, which may be observed in selected patients. Revascularization must be decided by physicians or teams involved in the care of such patients. Patients with atheromatous renal artery disease are at very high renal and cardiovascular risk : aggressive management of cardiovascular risk factors is crucial.

An Unusual Case of Intra-Abdominal Apoplexy

Abdominal apoplexy is an uncommon disorder typically due to atheromatous vascular disease, inflammatory processes such as pancreatitis eroding into large blood vessels or vasculitis. We describe an unusual case due to unrecognised syphilis masquerading as pancreatitis.

Detection of Occult Renovascular Disease in Unexplained Chronic Kidney Disease

Atherosclerotic renal artery stenosis (RAS) is a recognized cause of renal impairment. RAS is often overlooked in unexplained chronic kidney disease (CKD). A retrospective analysis of renal angiograms was performed to determine the prevalence of occult renovascular disease in 64 (M:F, 46:18; ages 21-81 years [median 60 years]) patients with unexplained CKD. Twelve patients had diabetes mellitus (type II: 11) and 43 were smokers. Median serum creatinine was 5.2 mg/dl (range 1.5-10.6 mg/dl). Group A included patients with unexplained CKD and with no risk factors for RAS and Group B had patients with increased risk for RAS. A narrowing of the renal vessel, main artery or branch, by >50% on renal arteriography was used as diagnostic criteria for RAS. 31/64 patients had positive angiographic findings. Thirteen patients had unilateral RAS, 9 had bilateral RAS, 5 had unilateral stenosis with occlusion on the opposite side, 3 had unilateral occlusion and 1 had a solitary kidney with RAS. 19/34 (54%) in Group A and 12/30 (40%) in Group B had a positive renal angiogram. In 10 patients with a rise in serum creatinine on recent introduction of ACE inhibition, 2 had evidence of RAS on renal arteriography. Eleven patients underwent angioplasty and 2 reconstructive surgeries. In 4 patients, blood pressure control improved and anti-hypertensive drug requirements were reduced, whilst renal replacement therapy was postponed in 4, by 2-24 months. In 18 patients, the lesions were not amenable to angioplasty or reconstructive surgery. Four patients did not benefit in any form with intervention. Occult atheromatous renal vascular disease is a common, not readily predictable and potentially correctable etiology of unexplained CKD.

Implications of recent heart failure trials for patients with hypertension.

There are two major reasons why hypertension is an important risk factor for heart failure. The first is that an elevated blood pressure increases the wall stress in the left ventricle. The second is that hypertension, in a complex manner, contributes to the development of atheromatous vascular disease. Among the more common causes of heart failure are the sequelae of coronary heart disease. The treatment of hypertension modifies the progression to heart failure and the occurrence of coronary events. In patients who have heart failure, hypotension rather than hypertension is a predictor of a poor outcome, likely because low blood pressure is a consequence of damage to the myocardium. The clinical message is that hypertension should be treated aggressively. Where heart failure is a likely outcome, or where hypertension occurs in the presence of heart failure, there is a strong case for using drugs that have been shown to be beneficial in the treatment of both hypertension and heart failure.

Effects of exercise training of 8 weeks and detraining on plasma levels of endothelium-derived factors, endothelin-1 and nitric oxide, in healthy young humans

Vascular endothelial cells produce nitric oxide (NO), which is a potent vasodilator substance and has been proposed as having antiatherosclerotic property. Vascular endothelial cells also produce endothelin-1 (ET-1), which is a potent vasoconstrictor peptide and has potent proliferating activity on vascular smooth muscle cells. Therefore, ET-1 has been implicated in the progression of atheromatous vascular disease. Because exercise training has been reported to produce an alteration in the function of vascular endothelial cells in animals, we hypothesized that exercise training influences the production of NO and ET-1 in humans. The purpose of the present study was to examine whether chronic exercise could influence the plasma levels of NO (measured as the stable end product of NO, i.e., nitrite/nitrate [NOx]) and ET-1 in humans. Eight healthy young subjects (20.3 ± 0.5 yr old) participated in the study and exercised by cycling on a leg ergometer (70% VO 2 max for 1 hour, 3–4 days/week) for 8 weeks. Venous plasma concentrations of NOx and ET-1 were measured before and after (immediately before the end of 8-week exercise training) the exercise training, and also after the 4th and 8th week after the cessation of training. The VO 2 max significantly increased after exercise training. After the exercise training, the plasma concentration of NOx significantly increased (30.69 ± 3.20 vs. 48.64 ± 8.16 μmol/L, p < 0.05), and the plasma concentration of ET-1 significantly decreased (1.65 ± 0.14 vs. 1.23 ± 0.12 pg/mL, p < 0.05). The increase in NOx level and the decrease in ET-1 level lasted to the 4th week after the cessation of exercise training and these levels (levels of NOx and ET-1) returned to the basal levels (the levels before the exercise training) in the 8th week after the cessation of exercise training. There was a significant negative correlation between plasma NOx concentration and plasma ET-1 concentration. The present study suggests that chronic exercise causes an increase in production of NO and a decrease in production of ET-1 in humans, which may produce beneficial effects (i.e., vasodilative and antiatherosclerotic) on the cardiovascular system.

Homocysteine and thiol metabolites in vitamin B12 deficiency

Homocysteine metabolism is increasingly implicated in a diverse group of clinical disorders, including atheromatous vascular disease. We studied the disposition of homocysteine via the trans-sulphuration pathway, plasma glutathione peroxidase (GPx) activity and plasma levels of the sulphated hormone dehydro-epiandrosterone sulphate (DHEAS) in six vitamin B(12)-deficient human subjects before and after 2 weeks of vitamin B(12) repletion, both in the fasting state and following an oral methionine load (0.1 g/kg body weight). Fasting plasma total homocysteine concentrations fell (P=0.03) and total cysteine concentrations rose significantly (P=0.048) after treatment for 2 weeks with vitamin B(12) injections. The magnitude of the mean fall in the fasting concentration of homocysteine (38.8 micromol/l) was similar to the mean rise in cysteine levels (36.0 micromol/l) following vitamin B(12) therapy. Circulating levels of homocysteine were increased at 4 h after a methionine load when compared with fasting levels, both before and after vitamin B(12) repletion (P=0.003 for both). Total cysteinyl-glycine was lower post-methionine than in the fasting state following vitamin B(12) therapy (P=0.007). Fasting plasma GPx fell significantly after 2 weeks of vitamin B(12) therapy (P=0.05). The change in plasma GPx between the fasting state and 4 h after methionine loading was significantly different pre- and post-vitamin B(12) therapy (P=0.05). The present study provides indirect support to the hypothesis that defects in the trans-sulphuration and remethylation of homocysteine produce hyperhomocysteinaemia in vitamin B(12) deficiency in human subjects. Elevated homocysteine levels directly or indirectly may up-regulate GPx. Sulphation status, as measured by plasma DHEAS, was unchanged.

Decreased circulating plasma lipids in patients with homocystinuria.

Premature vascular disease and thrombosis are recognized complications in homocystinuria. Vascular disease in patients with homocystinuria affects both arterial and venous systems, with venous thrombosis as the major cause of death (Mudd et al 1985). Histologically, the arterial disease is characterized by intimal and medial smooth-muscle hyperplasia, with fibrosis and thickening of the elastic lamina, but lipid deposition is usually not observed (Gibson et al 1964). This contrasts with the classical appearance of atheromatous vascular disease in the general population. Relatively little is known about possible disturbances to lipid metabolism in patients with homocystinuria. We report observations on lipids and lipoproteins in a group of patients being treated and monitored for homocystinuria.

The kidney as a target of hypertension.

In spite of improvement in blood pressure control during the last decades, the incidence of hypertension-related end-stage renal disease (ESRD) is reported to have increased and has become a common cause of renal failure, especially in the United States, but also in several other countries. The clinical diagnosis of hypertensive nephrosclerosis is usually presumptive, and an important differential diagnosis in older hypertensive persons is atheromatous renal vascular disease. Many studies of renal function in treated essential hypertension have shown a small and clinically insignificant decline in glomerular filtration rate (GFR). Recent long-term studies indicate that the change in GFR may be nonlinear, with a greater fall in GFR after initiation of antihypertensive treatment, followed by a phase of minimal or normal loss of GFR. There are no available prospective studies indicating that well-treated essential hypertension leads to renal failure, but there are new data indicating that patients with nonmalignant essential hypertension without any underlying renal disease and with early and good blood pressure control do not develop renal failure.

ACE inhibitors, diabetes and cardiovascular disease.

Treatment of hypertension with beta blockers or thiazide diuretics reduces the risk of stroke more than that of myocardial infarction [1, 2]. This may be due in part to adverse effects of these drugs on serum lipids and insulin resistance ‐ both independent risk factors for cardiovascular disease. Newer antihypertensive agents with neutral or beneficial effects on these parameters may offer greater protection against atheromatous vascular disease, particularly in high-risk groups such as patients with non-insulindependent diabetes mellitus (NIDDM) where hypertension, dyslipidaemia and insulin resistance often coexist. Interest has focused on angiotensin converting enzyme inhibitors (ACEI) because of mounting evidence that they may improve impaired vascular endothelial function, an early surrogate marker of atheroma.

Apolipoprotein (a) concentrations and susceptibility to coronary artery disease in patients with peripheral vascular disease.

To investigate the relation between apolipoprotein(a) concentrations and angiographically defined coronary artery disease in patients with atheromatous peripheral vascular disease. 40 consecutive patients were recruited at the time of admission for peripheral vascular surgery. All underwent clinical assessment and coronary arteriography. Apolipoprotein(a) concentrations were measured by an immunoradiometric assay. Tertiary referral centre. Patients requiring surgical intervention for large vessel peripheral vascular disease. Presence or absence and severity and distribution of angiographically defined coronary artery disease. Measurement of circulating contractions of apolipoprotein(a) and other lipid indices. Coronary artery disease was absent in 11 patients (group 1), mild to moderate in 12 (group 2), and severe in 17 (group 3). The distribution of peripheral vascular disease and of standard lipid indices was similar in these three groups of patients. There was a significant difference in apolipoprotein(a) concentrations between the three groups, with concentrations progressively increasing with the severity of coronary artery disease (mean (95% confidence interval): group 1, 112 U/1 (52 to 242); group 2, 214 U/1 (129 to 355); group 3, 537 U/1 (271 to 1064) (analysis of variance p < 0.005). The prevalence of coronary artery disease was increased 7.4 fold in patients with apolipoprotein(a) concentrations that were greater than the cohort median (206 U/1) (p < 0.01). The results show an association between apolipoprotein(a) concentrations and angiographically defined coronary artery disease in patients with large vessel peripheral vascular disease. The findings imply differences in the pathogenesis of coronary and peripheral atheroma and suggest that the measurement of apolipoprotein(a) may prove a useful additional tool in the risk factor assessment of patients undergoing peripheral vascular surgery.

Audit of a decade of continuous ambulatory peritoneal dialysis

We have reviewed the results of continuous ambulatory peritoneal dialysis (CAPD) in a single renal unit over the period from December 1979 to the end of 1990. Case records of 211 of the 222 patients treated by CAPD over this period were obtained and age, sex, diagnoses, duration of CAPD, and cause of death determined. We found marked effects of age and a diagnosis of atheromatous vascular disease at the start of CAPD on patient survival. For patients aged under 45 years 5-year patient survival was 78%, for those aged 45-65 it was 29% and for those aged over 65 years it was 32%. Patients with a diagnosis of atheromatous vascular disease at the start of CAPD had a 3-year survival of 25% compared with 69% for age- and sex-matched CAPD patients without such a diagnosis. Five-year technique survival was 67% if failure was defined as transfer to haemodialysis or death as a direct result of CAPD, but only 11% of patients were on CAPD continuously for 5 years. Attempts to compare our results with those from other reports were hindered by the variety of methods used to calculate patient and technique survival; we suggest that standard methods should be agreed.

Relation of Lipid Peroxides to Macrovascular Disease in Type 2 Diabetes

Lipid peroxides are thought to be formed by free radicals and may play an important role in the development of atheromatous vascular disease. We have investigated the relationship between lipids, lipoproteins, coagulation factors, and lipid peroxides (measured as thiobarbituric acid reacting species (TBARS) in Type 2 diabetic patients with macrovascular disease. Eighteen diabetic and 20 non-diabetic subjects with clinical evidence of ischaemic heart disease and/or peripheral vascular disease were investigated, together with 28 healthy subjects without evidence of vascular disease. TBARS concentrations in non-diabetic (mean 5.0 (95% Cl 4.5-5.7) mumol l-1) and diabetic groups (5.6 (5.1-6.0) mumol l-1) with macrovascular disease were not significantly different although values were higher in both groups of patients with vascular disease by comparison with control subjects (2.7 (2.4-3.1) mumol l-1, p less than 0.001). Significant univariate correlations between TBARS concentrations and measures of blood glucose control (fructosamine, blood glucose and HbA1) were found for all 66 subjects (r = 0.35-0.42, p less than 0.01-p less than 0.001), although no independent association between these parameters and TBARS was demonstrated in multiple regression analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

The Apo(a) gene: Structure/function relationships and the possible link with thrombotic atheromatous disease

The last 25 years have witnessed an exponential increase of interest in the lipoprotein Lp(a). The structure of the gene encoding for its unique apo protein, Apo(a) has been determined resulting in possible structure/function relationships which may explain the close association between elevated levels of Lp(a) and atheromatous vascular disease. These findings may have profound therapeutic implications for the future treatment of the hyperlipidaemias and hypercholesterolaemia in particular.