Resistance and intolerance to statins.

BACKGROUND AND AIMS: Many patients treated with statins are considered statin-resistant because they fail to achieve adequate reduction of low density lipoprotein cholesterol (LDL-C) levels. Some patients are statin-intolerant because they are unable to tolerate statin therapy at all or to tolerate a full therapeutic statin dose because of adverse effects, particularly myopathy and increased activity of liver enzymes. RESULTS: The resistance to statins has been associated with polymorphisms in the 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA-R), P-glycoprotein (Pg-P/ABCB1), breast cancer resistance protein (BCRP/ABCG2), multidrug resistance-associated proteins (MRP1/ABCC1 and MRP2/ABCC2), organic anion transporting polypeptides (OATP), RHOA, Nieman-Pick C1-like1 protein (NPC1L1), farnesoid X receptor (FXR), cholesterol 7alpha-hydroxylase (CYP7A1), Apolipoprotein E (ApoE), proprotein convertase subtilisin/kexin type 9 (PCSK9), low density lipoprotein receptor (LDLR), lipoprotein (a) (LPA), cholesteryl ester transfer protein (CETP), and tumor necrosis factor α (TNF-α) genes. However, currently, there is still not enough evidence to advocate pharmacogenetic testing before initiating statin therapy. Patients with inflammatory states and HIV infection also have diminished LDL-C lowering as a response to statin treatment. Pseudo-resistance due to nonadherence or non-persistence in real-life circumstances is probably the main cause of insufficient LDL-C response to statin treatment. CONCLUSIONS: If a patient is really statin-resistant or statin-intolerant, several other treatment possibilities are nowadays available: ezetimibe alone or in combination with bile acid sequestrants, and possibly in the near future mipomersen, lomitapide, or monoclonal antibodies against PCSK9.

Managing the residual cardiovascular disease risk associated with HDL-cholesterol and triglycerides in statin-treated patients: a clinical update.

Cardiovascular disease (CVD) is a significant cause of death in Europe. In addition to patients with proven CVD, those with type 2 diabetes (T2D) are at a particularly high-risk of CVD and associated mortality. Treatment for dyslipidaemia, a principal risk factor for CVD, remains a healthcare priority; evidence supports the reduction of low-density lipoprotein cholesterol (LDL-C) as the primary objective of dyslipidaemia management. While statins are the treatment of choice for lowering LDL-C in the majority of patients, including those with T2D, many patients retain a high CVD risk despite achieving the recommended LDL-C targets with statins. This 'residual risk' is mainly due to elevated triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) levels. Following statin therapy optimisation additional pharmacotherapy should be considered as part of a multifaceted approach to risk reduction. Fibrates (especially fenofibrate) are the principal agents recommended for add-on therapy to treat elevated TG or low HDL-C levels. Currently, the strongest evidence of benefit is for the addition of fenofibrate to statin treatment in high-risk patients with T2D and dyslipidaemia. An alternative approach is the addition of agents to reduce LDL-C beyond the levels attainable with statin monotherapy. Here, addition of fibrates and niacin to statin therapy is discussed, and novel approaches being developed for HDL-C and TG management, including cholesteryl ester transfer protein inhibitors, Apo A-1 analogues, mipomersen, lomitapide and monoclonal antibodies against PCSK9, are reviewed.

Haptoglobin genotype 2-2 associated with atherosclerosis in patients with ischemic stroke.

AIM: Ischemic stroke (IS) is multifactorial disease and therefore different genes and proteins play a role in its development. Haptoglobin (Hp) removes free hemoglobin and protects from iron-induced oxidative damage, inflammatory response, atherosclerosis and cerebrovascular diseases. The aim of this study was to investigate Hp genetic variants in patients with carotid atherosclerotic lesions and IS. MATERIAL AND METHODS: A total of 121 subjects with IS participated in the study, 81 male and 40 female. RESULTS: Among 121 patients with IS, 79 had diffuse atherosclerotic plaques and stenosis. Hp genotype was statistically significantly associated with CDFI neck carotid artery stenosis findings (p = 0.006). Patients with Hp1-2 genotype had statistically significantly larger odds for atherosclerotic changes compared to those with Hp1-1 genotype, as well as those with Hp2-2 genotype. CONCLUSION: This study has shown an association of the Hp2-2 genotype and atherosclerosis in patients with IS, indicating Hp2-2 genotype as a genetic biomarker for precision medicine and personalized healthcare.

Renal transplantation in patients with Balkan endemic nephropathy.

BACKGROUND: Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial disease prevalent in Croatia, Romania, Bulgaria, Bosnia and Herzegovina, and Serbia. In addition to renal disease, an increased incidence of upper urothelial carcinomas (UUCs) has been observed in the foci of BEN. Carcinoma may occur alone or in combination with BEN. Immunosuppression is associated with an increased risk for development of different malignancies. There are no data in the literature about the outcome of patients with BEN after transplantation. METHODS: We performed a retrospective evaluation of the database and review of the charts and pathology reports of 601 renal transplant recipients treated at our institution. RESULTS: From January 1995 to December 2004, kidney transplantations were performed in nine patients with BEN. One-year graft survival was 100%. A man, who was transplanted in 1997 died 2 years after transplantation with a functioning graft due to disseminated cancer from the pelvis of his own kidney. A female patient developed UCC 2 years after transplantation. They were both treated with a bolus of methylprednisolone before transplantation, because of four HLA-mismatches. A male patient developed UCC in the native and transplanted kidneys. He underwent a native nephroureterectomy with partial nephroureterectomy of transplanted kidney. His graft function was preserved with decreased immunosuppression. Three years later a urinary bladder carcinoma was discovered on a regularly performed multislice computed tomography. One patient developed a skin malignancy. Other patients have had uneventful posttransplantation courses with excellent graft function. Thus, 33.3% of patients with BEN developed UUC, compared with a 0.67% prevalence of urinary tract tumors among transplanted patients with other causes of end-stage renal disease. CONCLUSION: Patients with BEN are at increased risk for the development of UCC after transplantation. Regular screening for early detection of malignancy is mandatory. Longer follow-up and results from other transplant centers are needed to further investigate the relationship between BEN and UCC after renal transplantation.

Lipid lowering drug therapy in patients with coronary heart disease from 24 European countries--Findings from the EUROASPIRE IV survey.

OBJECTIVE: Since dyslipidaemia is one of the most important risk factors for coronary heart disease (CHD), lowering of LDL-cholesterol (LDL-C) causes significant reduction in morbidity and mortality, particularly in patients with established CHD. The aim of this survey was to assess how statins were prescribed in CHD patients at discharge after a coronary event from hospitals throughout Europe and how the intake of these drugs was reported by the patients when they were seen more than one year later in relationship with their achieved LDL-C levels. METHODS: 6648 CHD patients' data from centres in 24 European countries were gathered using standardized methods. Lipid measurements were performed in one central laboratory. Patients were divided in three groups: high-intensity statin therapy, moderate or low intensity statin therapy and no statin therapy at all. RESULTS: 90.4% CHD patients were on statin therapy at the time of discharge from the hospital which decreased to 86% one year later. Only 37.6% of these patients were prescribed a high-intensity statin at discharge which even decreased to 32.7% later. In only 6 countries (all of them high-income countries) the number of patients on a high-intensity statin therapy increased substantially after the hospital discharge. It is worrying that statin therapy was discontinued in 11.6% and that only 19.3% of all CHD patients achieved target values of LDL-C < 1.8 mmol/L at the time of interview. CONCLUSIONS: Too many CHD patients with dyslipidaemia are still inadequately treated and most of these patients on statin therapy are not achieving the treatment targets. Therapeutic control of LDL-C is clearly related to the intensity of lipid lowering drug regimen after the CHD event indicating that a considerable potential still exists throughout Europe to reduce CHD mortality and morbidity rates through more efficient LDL-C lowering.

Characterization of a monoclonal antibody that binds equally to all apolipoprotein and lipoprotein forms of human plasma apolipoprotein B. I. Specificity and binding studies.

A stable mouse hybridoma cell line has been developed that produces monoclonal antibody to human plasma apolipoprotein B. This antibody was proven to be specific for apolipoprotein B immunoblotting and an enzyme immunoassay using apolipoprotein B and other apolipoproteins. The antibody bound with comparable affinities to soluble apolipoprotein B, chylomicrons, very-low-density (VLDL) and low-density lipoproteins (LDL). Coupled to agarose, this antibody allowed complete removal of apolipoprotein B-containing lipoproteins from normolipidemic, hypertriglyceridemic and hypercholesterolemic plasma. Desialyzation and deglycosylation had no effect on its binding to LDL. The described antibody had no effect on the receptor-mediated binding of radiolabeled LDL to the human hepatoma cells (HepG2) in culture. Analysis of 25 different samples of human plasma indicated identical expression of the corresponding epitope in these individuals. The described monoclonal antibody, most likely, binds to a rather stable domain of apolipoprotein B that is not altered by the interaction with lipids or polymorphism of the apolipoprotein B. We propose that this antibody be called 'Pan B' antibody.

Alirocumab: targeting PCSK9 to treat hypercholesterolemia.

Lowering of low-density lipoprotein (LDL) cholesterol reduces coronary heart disease morbidity and mortality, not only in secondary but also in primary prevention. Statins are generally accepted as a treatment of choice for this. However, still many high-risk and very-high-risk patients fail to achieve target LDL cholesterol values. Therefore, a new class of lipid-lowering drugs was recently developed-inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9). Alirocumab was the first drug in this class to be approved by the U.S. Food and Drug Administration (FDA) and recently also by the European Medicines Agency (EMA). Alirocumab has been shown to lower LDL cholesterol by up to 60% with a safety profile comparable to that of placebo. Large outcome studies are still on the way and their first results will be available in 2017. This review focuses on alirocumab, discussing currently available hard evidence on the beneficial effects of this drug in the treatment of hypercholesterolemia.

Effect of simvastatin on micropulmonary red cell mass in patients with hyperlipoproteinemia.

The purpose of this study was to compare the macrocirculatory and microcirculatory effects of simvastatin in hyperlipemic patients. In vitro measurements of lipoprotein levels and macrocirculatory hemorheology were complemented by in vivo measurements of the pulmonary capillary red cell volume (RCVpc) before and after 6 weeks of treatment with 40 mg of simvastatin daily in 30 male patients with hyperlipoproteinemia type IIa. RCVpc was assessed from the vascular component of the lung diffusing capacity for carbon monoxide, using the modification of the Roughton-Forster's method. RCVpc was increased in patients (60.9+/-9 versus 40+/-9 ml in healthy controls) and it decreased to 47+/-6 ml after treatment (P=5x10(-11)). The decreases in RCVpc correlated to concomitant decreases in peripheral hematocrit (R=0.68) and serum total cholesterol (-34% on average; R=0.59). Membrane diffusing capacity was normal in patients and not affected by the therapy; suggesting that increased RCVpc was due to increased micropulmonary hematocrit. Thus, it appears that viscosity in microcirculation is greatly increased in hyperlipemic patients and that simvastatin is able to normalize it. Since microcirculatory conditions can only partly be inferred from in vitro measurements the use of lung diffusional parameters was advocated, which enable in vivo assessment of hemorheology in microcirculation.

Triglyceride-poor very low density lipoprotein in human serum.

The chemical and physical properties of very low density lipoproteins, isolated from the pool of the sera of 60 persons with high pre-beta and normal triglyceride and cholesterol concentrations, have been studied. These very low density lipoproteins, a designated as triglyceride-poor very low density lipoproteins, consist of 20.5% phospholipids, 30.8% free cholesterol, 15% cholesterol esters and 33.7% triglycerides. Their protein content consists of 54.5% apo B, 26% apo A, 11.5% apo E and only 8% apo C, so they differ from any serum lipoprotein described until now. Triglyceride-poor very low density lipoproteins consist of spherical particles 300-450 A in diameter as revealed by electron microscopy.

The effects of cortisol, 11-epicortisol, and lysine vasopressin on DNA and RNA synthesis in isolated human adrenocorticotropic hormone-secreting pituitary tumor cells.

The effects of cortisol, its steric analog 11-epicortisol, and lysine vasopressin (LVP) on DNA and RNA synthesis in isolated adrenocorticotropic hormone-secreting human pituitary tumor cells obtained by transsphenoidal surgery were studied using [3H]thymidine incorporation in DNA and [3H]uridine in RNA. Cortisol suppressed RNA and, to a greater extent, DNA synthesis in these cells. This could explain the slow growth of pituitary tumors in patients with Cushing's disease and the rapid growth of Nelson's pituitary tumors after bilateral adrenalectomy. 11-Epicortisol also suppressed RNA synthesis, but it had a stimulatory effect on DNA synthesis, which indicates a high specificity of glucocorticoid receptors. When applied together with cortisol, 11-epicortisol antagonized the suppressive effects of cortisol on DNA synthesis. Although LVP stimulated RNA synthesis, it suppressed DNA synthesis in most of the tumor cells.

Changes in serum lipid and lipoprotein levels in postmenopausal patients with node-positive breast cancer treated with tamoxifen.

Tamoxifen has been used for a long time as an adjuvant hormonal treatment in breast cancer patients. We studied 62 newly diagnosed postmenopausal women, aged 50-79 years, with node-positive breast cancer and receiving adjuvant tamoxifen (20 mg per day). Total serum cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol, apo AI, apo AII, apo B and Lp(a) were determined before the surgery and 3, 6, 9, 12 and 24 months after starting tamoxifen treatment. Tamoxifen significantly reduced total serum cholesterol (6.13+/-1.20 mmol/L vs 5.21+/-1.05 mmol/L) (P <0.01), LDL-cholesterol (3.72+/-0.70 mmol/L vs 2.93+/-0.51) (P <0.01) and Lp(a) (0.11+/-0.07 g/L vs 0.02+/-0.01 g/L) (P < 0.01). There were no changes in triglycerides or HDL-cholesterol serum levels during tamoxifen treatment. The results indicate that an additional beneficial effect of adjuvant tamoxifen therapy may be that it decreases cardiovascular risk in such patients.

Endocrine responses to head and neck surgery in men.

It has been well established that surgical stress leads to profound changes in endocrine function and metabolism. However, the endocrine response varies depending upon the type and the extent of surgery. As no data were available about the endocrine changes during and following major head and neck surgery, this study was performed. Plasma levels of adrenocorticotropin (ACTH), cortisol, thyroid-stimulating hormone (TSH), thyroxin (T4), triiodothyronine (T3), growth hormone (GH), prolactin (PRL), gonadotropins (LH and FSH), oestradiol and testosterone were determined in 17 patients one day before, immediately after, as well as 2 and 4 days after head and neck surgery. An increase in ACTH, cortisol, PRL and GH, and a decrease in plasma oestradiol and testosterone values occurred immediately after surgery. There was a slow fall in cortisol levels after surgery, but they remained elevated even on the fourth postoperative day, whereas GH values returned on the fourth day to the initial level. There were no changes in gonadotropins, TSH and T3, but T4 values were found to be increased on the second and fourth postoperative day. The prolonged cortisol stimulation which was not described by other researchers after other kinds of surgery might be caused by vagal stimulation during and/or after head and neck surgery. Increased needs after a major head and neck surgery could explain the increment of T4 values.

Is lipoprotein(A) a risk factor for atherosclerosis of the retinal arteries?

Elevated plasma Lp(a) has been linked to development of coronary artery disease (CAD). There is no data about plasma Lp(a) and atherosclerosis of the retinal arteries. Therefore the purpose of this study was to assess the risk of retinal vessels atherosclerosis conferred by elevated plasma Lp(a) levels in 73 adult males. The results were compared with those in 45 matched apparently healthy males with no retinal vessel changes. The atherosclerotic changes of the retinal vessels were determined by direct ophthalmoscopy and graded (1-4) according to Scheie. Plasma levels of Lp(a) were measured by radial immunodiffusion. The results were compared using chi-square test. Although a very weak correlation between plasma Lp(a) levels and the incidence of retinal atherosclerosis was found, no significant association between the degree of atherosclerotic changes and plasma Lp(a) levels could be proven. Thus it could be concluded that plasma Lp(a) level is not a significant risk factor for atherosclerosis of the retinal arteries.

Plasma cortisol in men--relationship with atherosclerosis of retinal arteries.

The production of cortisol increases in acute stress but the effects of chronic stress on plasma cortisol are still controversial. Stress on the other hand plays a role in coronary artery disease (CAD) and carotid atherosclerosis. Since there is no data about plasma cortisol and atherosclerosis of the retinal arteries, the purpose of this study was to explore the relationship between plasma cortisol in 101 adult males with the degree of their retinal vessels atherosclerosis. The results were compared with those in 47 matched apparently healthy men with no retinal vessels changes. The atherosclerotic changes of retinal vessels were determined by direct ophthalmoscopy and graded (1-4) according to Scheie. Morning plasma cortisol levels were determined by radioimmunoassay using commercial kits. The results were compared by using chi-square test. No association between morning plasma cortisol concentrations and retinal vessels atherosclerosis could be found. The results of this study do not support a role for physiological levels of plasma cortisol in the development of atherosclerosis, at least of the retinal arteries, in men.

Extracorporeal treatment for refractory hyperlipidemia.

Radical, non-pharmacological, methods of treatment should never be used until it has first been shown that conventional therapy either fails to control hyperlipidemia or cannot be tolerated by the patient. In general, the use of extracorporeal techniques will be restricted to patients with severe familial hypercholesterolemia, although occasionally they may be resorted to in other categories of hyperlipidemia. Seven different procedures are available today for routine clinical practice: unselective plasma exchange, semi-selective double filtration and its modifications as well as the highly selective procedures of immunoadsorption, chemo-adsorption onto dextran sulfate, heparin induced LDL precipitation lipoprotein(a) column, and LDL hemoperfusion (direct adsorption of lipids--DALI). Large-scale regression studies were performed with five highly selective treatment modalities. Control coronary angiograms obtained after about two years of treatment showed that atherosclerotic plaques on coronary arteries had not enlarged or had even been reduced in 80% to 90% of patients.

Dialyzer reprocessing with peroxyacetic acid as sole cleansing and sterilizing agent.

In a prospective study, the effectiveness of a newly available peroxyacetic acid solution (Dialox) as a cleansing and sterilizing agent for the reuse of conventional hollow-fiber hemophan dialyzers was evaluated. The effects of reprocessing dialyzers with peroxyacetic acid on leukocyte and platelet counts, dialyzer performance, acute intradialytic symptoms and cost effectiveness were studied. A total of 250 sessions using new dialyzers and 3,227 sessions employing reused dialyzers were monitored. Dialyzers were withdrawn after a maximum of 21 sessions, and the mean number of uses was 13.9 +/- 5.1. It was found that peroxyacetic acid reprocessing of hemophan dialyzer membranes improved hemodialysis leucopenia and thrombocytopenia. It was also proved that, compared to new ones, the reused dialyzers were associated with significantly fewer intradialytic symptoms. Clearances of small molecules and ultrafiltration rate after multiple dialyzer reprocessing remained within the acceptable limits. The duration of hemodialysis has been prolonged 30 min after the 10th dialyzer reuse and dialysis adequacy remained unaffected. About 100,000 DEM were saved during the one year due to the reuse procedure. The authors conclude that automated dialyzer reprocessing with peroxyacetic acid as a sole cleansing and sterilizing agent is a safe, efficacious and money-saving method.

Plasma lipids, lipoprotein Lp(a), apolipoproteins, and hemostatic risk factors distributions in postmenopausal women.

In the present study, the effect of hormone replacement therapy on lipid metabolism, apolipoproteins and hemostatic risk factors for cardiovascular disease was assessed in 216 Croatian postmenopausal women. There were 156 current users divided in to two groups according to the duration of therapy. The short-term study of < 10 months (X +/- SD 5.31 +/- 2.69) included 49 users, and long-term study of > 11 months (X +/- SD 22.06 +/- 10.95) included 107 users of hormone replacement therapy. Sixty nonusers served as a control group. In the short-term study, current users had a significant increase in serum HDL cholesterol, apolipoprotein A-I, A-II and a decrease in total/HDL cholesterol ratio, apoB and antithrombin III (p < 0.05). No significant differences were recorded for total cholesterol, triglycerides, LDL cholesterol, lipoprotein Lp(a) and plasminogen. In the long-term study, a significant increase in HDL cholesterol, apo A-I and total/HDL cholesterol ratio, and a decrease in AT III were observed. Results of the study showed favorable effects of hormone replacement therapy on serum lipid profile and apolipoproteins as a protective regimen from cardiovascular disease in both treatment groups of postmenopausal women. There are conflicting reports regarding increased fibrinolytic activity. The clinical relevance of the observed changes in antithrombin III concentrations as an important coagulation inhibitor is doubtful and should be considered in a more extensive evaluation of the potential hemostatic risk factors for cardiovascular risk and thromboembolism.

[The effects of androgens and other sex hormones on serum lipoproteins]. / Ucinci androgena i drugih spolnih hormona na serumske lipoproteine.

This review summarizes recent data on the effects of endogenous and exogenous androgens, estrogens and progesterone on serum lipoproteins levels and composition in humans. Sex steroid hormones modulate serum lipoprotein metabolic mechanisms and influence atherosclerosis and coronary heart disease. In general, androgens lower HDL and raise LDL levels and Lp(a) thus promoting the atherogenic process. As it is true with estrogens, the lipoprotein effects of androgens are more pronounced with oral than with parenteral administration. Millions of women use oral contraception and postmenopausal women use more and more some form of hormone replacement therapy. The HDL-raising effect of estrogen replacement seems to be mediated by an increase in apoprotein AI production and not by a decrease in the clearance rate. Estrogens lower LDL levels by accelerating the rate of LDL catabolism which is due to an increase in the number of hepatic LDL receptors. They also improve endothelium-dependent vasodilatation which might be mediated by an antioxidant action of estrogens. These facts could explain well known cardioprotective effects of estrogens. Androgen progestins, especially older such as norgestrel, lower HDL and raise LDL thus diminishing or eliminating the benefits of estrogens on cardiovascular system while newer progestins have a lesser effect on circulating lipoproteins.

[Lipids and cardiovascular diseases]. / Lipidi i kardiovaskularne bolesti.

There are many evidences suggesting a direct relationship of hyperlipoproteinemia, particularly hypercholesterolemia, and coronary heart disease. Therefore, in this paper an up-to-date review of lipoprotein metabolism, the biochemical basis of atherogenic hyperlipoproteinemia and current concepts of etiology and pathogenesis of atherosclerosis are presented. A detailed explanation is given to what extent and why will reduction of blood cholesterol levels reduce the prevalence and severity of coronary heart disease as well as under what circumstances and at what level of blood cholesterol should dietary or drug treatment be started. Since diet is the cornerstone of therapy for hyperlipoproteinemia instructions concerning dietary treatment are given in details. If diet alone proves insufficient, drugs should be added to the regimen. A detailed review of all major forms of drug therapy is also given together with dosage and adverse effects of all hypolipidemic agents used until now.