Anthony S. Wierzbicki

The lipid and non-lipid effects of statins.

The 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors, more commonly known as statins, are a class of drug widely used for the treatment of hypercholesterolaemia in patients with established cardiovascular disease as well as those at high risk of developing atherosclerosis. Their predominant action is to reduce circulating levels of low-density lipoprotein (LDL) cholesterol; to a smaller degree, they also increase high-density lipoprotein (HDL) cholesterol and reduce triglyceride concentrations. In recent years, however, there has been an increasing body of evidence that their effects on lipid profile cannot fully account for their cardiovascular protective actions: their beneficial effects are too rapid to be easily explained by their relatively slow effects on atherogenesis and too large to be accounted for by their relatively small effects on plaque regression. Experimental models have revealed that statins exert a variety of other cardiovascular effects, which would be predicted to be of clinical benefit: they possess anti-inflammatory properties, as evidenced by their ability to reduce the accumulation of inflammatory cells in atherosclerotic plaques; they inhibit vascular smooth muscle cell proliferation, a key event in atherogenesis; they inhibit platelet function, thereby limiting both atherosclerosis and superadded thrombosis; and they improve vascular endothelial function, largely through augmentation of nitric oxide (NO) generation. The relative importance of the lipid- and non-lipid-related effects of the statins in the clinical situation remains the subject of much continuing research.

Relation of Erectile Dysfunction to Angiographic Coronary Artery Disease

I t is estimated that over 152 million men worldwide experience erectile dysfunction (ED).1 Although the incidence and severity of ED increases with age, the most common pathologic risk factor for organic ED is believed to be diabetes. Other vascular diseases are also known to cause ED; the main link is insult to the vascular endothelium, which plays a major role in the regulation of arterial patency. Hyperlipidemia, smoking, hypertension, and diabetes cause endothelial cell dysfunction, which precedes the formation of atherosclerotic plaques. This study assesses the prevalence and severity of ED in a cohort of men who underwent coronary angiography and identifies any correlaton of ED and the severity of plaque burden found on coronary angiography. • • • The study received ethical committee approval and recruited 132 men attending day case coronary angiography, who agreed and consented to take part in the study. Baseline demographic data were determined with an emphasis on cardiovascular risk factors (Table 1). All men were asked to complete the International Index of Erectile Function-5 (IIEF) questionnaire to ascertain erectile performance. In addition, they were specifically asked about the temporal relation of their ED to their date of onset of cardiovascular symptoms. The diagnosis of coronary artery disease was defined either by a history of myocardial infarction (48%), percutaneous coronary angioplasty (12%), coronary artery bypass grafting (7%), or by angiographic results. Stenosis of 50% in a coronary artery on angiography was considered significant. Formal stratification of plaque burden was assessed by calculation of a Gensini score2 for each angiogram. The relation between the number of coronary arteries with significant stenosis and IIEF score was assessed by chi-square test. Linear regression analysis was performed to ascertain the relation between plaque burden as quantified by the Gensini score and IIEF score. Multiple regression analysis was used to investigate the association between IIEF score and established cardiovascular risk factors and drug therapies. Symptoms of ED were volunteered by 45% (n 59) of all men who admitted to having ED, although 65% (n 86) scored 21 on the IIEF, suggesting a diagnosis of ED. Of those 59 men who subjectively admitted to having ED, 58% (n 34) admitted to experiencing ED before their diagnosis of coronary artery disease. Angiography was performed for progression of disease in 44% (n 58) and established a diagnosis in 41% (n 54). Coronary angiographic findings demonstrated that 30% (n 39) had singlevessel disease, 21% (n 28) had 2-vessel disease, and 27% (n 36) had 3-vessel disease. The median Gensini score (median 34, range 0 to 192) showed an inverse correlation with IIEF score (r 0.17; p 0.05), although there were no significant differences between the number of diseased arteries observed and the incidence of ED (p 0.34). Backward stepwise multiple regression analysis demonstrated an inverse correlation of IIEF score with cardiovascular risk factors (r 0.54; p 0.001) and identified age ( 0.51; p 0.001) and smoking ( 3.13; p 0.05) as the principal risk factors. Further analysis showed that IIEF score correlated (r 0.44; p 0.001) with Gensini score ( 0.06; p 0.04), aspirin use ( 6.57; p 0.04), or clopidogrel therapy ( 7.34; p 0.07). No correlation was observed with any other drug therapy, including diuretics or blockers. • • • ED is a common symptom in men and is often attributed to the presence of diabetes or therapy with drugs used to treat cardiovascular risk, such as blockers or thiazide diuretics. It is not often recognized that ED shares the same determinants as atheroFrom the Departments of Cardiology and Chemical Pathology, St. Thomas’ Hospital, London, United Kingdom. Dr. Wierzbicki’s address is: Department of Chemical Pathology, St. Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, United Kingdom. E-mail: Anthony. Wierzbicki@kcl.ac.uk. Manuscript received May 21, 2002; revised manuscript received and accepted August 28, 2002. TABLE 1 Baseline Characteristics of Patients Who Underwent Angiography

Homocysteine and cardiovascular disease: a review of the evidence

Elevated homocysteine (HCY) levels can be caused by a number of factors, including folate and B-vitamin deficiency, pre-existing atherosclerotic disease, diabetes and various drugs. Epidemiological evidence, as well as data from retrospective and prospective studies, supports an association between elevated HCY levels and increased risk of cardiovascular disease (CVD). However, whether lowering HCY levels by administration of folate and vitamins B6 and B12 is associated with any significant decrease in vascular risk remains the subject of ongoing debate. Although the major studies that have reported to date show that vitamin supplementation was associated with a decrease in HCY levels, this failed to have any significant effect on cardiovascular risk. Furthermore, although some lipid-modifying treatments have been shown to increase HCY levels, there is no evidence that this attenuates or compromises the beneficial effects of such treatments on cardiovascular risk. Taken together, these data suggest that HCY is a marker, rather than a cause, of CVD and therefore do not provide support for routine screening for and treatment of elevated HCY to prevent CVD. Data from ongoing clinical trials are awaited to clarify this issue.

Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation

Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL) cholesterol and causes premature coronary heart disease. There are at least 20 million people with FH worldwide, but the majority remain undetected and current treatment is often suboptimal. To address this major gap in coronary prevention we present, from an international perspective, consensus-based guidance on the care of FH. The guidance was generated from seminars and workshops held at an international symposium. The recommendations focus on the detection, diagnosis, assessment and management of FH in adults and children, and set guidelines for clinical purposes. They also refer to best practice for cascade screening and risk notifying and testing families for FH, including use of genetic testing. Guidance on treatment is based on risk stratification, management of non-cholesterol risk factors, and safe and effective use of LDL lowering therapies. Recommendations are given on lipoprotein apheresis. The use of emerging therapies for FH is also foreshadowed. This international guidance acknowledges evidence gaps, but aims to make the best use of contemporary practice and technology to achieve the best outcomes for the care of FH. It should accordingly be employed to inform clinical judgement and be adjusted for country-specific and local health care needs and resources.

Familial hypercholesterolaemia: summary of NICE guidance.

The estimated prevalence of familial hypercholesterolaemia in the United Kingdom is 1 in 500. Heterozygous familial hypercholesterolaemia carries a high risk of premature coronary heart disease (>50% risk in men by the age of 50 years and >30% in women by 60 years), but the condition is underdiagnosed. This article summarises the most recent recommendations from the National Institute for Health and Clinical Excellence (NICE) on diagnosing and managing familial hypercholesterolaemia.1 NICE recommendations are based on systematic reviews of best available evidence. When minimal evidence is available, recommendations are based on the guideline development group’s opinion of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets. ### Diagnosis ### Management in primary care

The Agenda for Familial Hypercholesterolemia A Scientific Statement From the American Heart Association

Familial hypercholesterolemia (FH) is an autosomal-dominant genetic disease present in all racial and ethnic groups and has long been recognized as a cause of premature atherosclerotic coronary heart disease.1–3 Heterozygous FH has the highest prevalence of genetic defects that cause significant premature mortality (≈1:200 to 1:500 or higher in founder populations). The genetic basis of the disorder, impaired functioning of the low-density lipoprotein (LDL) receptor, was first recognized by Goldstein and Brown4 in their Nobel Prize–winning work. Studies of LDL receptor function have identified additional mechanisms for the pathogenesis of FH (defects in apolipoprotein [apo] B impairing binding with the LDL receptor and gain-of-function mutations in proprotein convertase subtulisin/kexin type 9 [PCSK9] that enhance LDL receptor degradation). FH leads to elevated LDL concentrations, with levels in heterozygous FH generally in untreated adults >190 mg/dL LDL cholesterol (LDL-C) and in untreated children or adolescents >160 mg/dL LDL-C. Long-term exposure to elevated plasma concentrations of LDL-C begins in utero, leading in heterozygotes to premature ischemic heart disease in mid adulthood and in homozygotes to ischemic heart disease in childhood or early adulthood. In those who meet clinical definitions of FH based on LDL-C levels and family history, genetic testing identifies mutations in most children and a large percentage of adults.5,6 Complementing these cell biology discoveries has been drug discovery that has linked enhancement of LDL receptor function to LDL-C lowering and successful prevention of ischemic heart disease, first with statins and now with newer drugs that affect LDL receptor function in other ways, including those that impair PCSK9 regulation of LDL receptor recycling.7 The natural history of FH, the natural history of genetic disorders that lead to lifelong low LDL-C, and the dramatic improvement in life expectancy created by effective cholesterol lowering provide the …

“European Panel on Low Density Lipoprotein (LDL) Subclasses”: A Statement on the Pathophysiology, Atherogenicity and Clinical Significance of LDL Subclasses

Aim of the present Consensus Statement is to provide a comprehensive and up to-date document on the pathophysiology, atherogenicity and clinical significance of low density liproproteins (LDL) subclasses. We sub-divided our statement in 2 sections. section I discusses the pathophysiology, atherogenicity and measurement issues, while section II is focused on the effects of drug and lifestyle modifications. Suggestions for future research in the field are highlighted at the end of section II. Each section includes Conclusions.

Statin-fibrate combination therapy for hyperlipidaemia: a review

SUMMARY Statins and fibrates are well-established treatments for hyperlipidaemias and the prevention of vascular events. However, fibrate + statin therapy has been restricted following early reports of rhabdomyolysis that mainly involved gemfibrozil, originally with lovastatin, and recently, with cerivastatin. Despite this limitation, several reports describing combination therapy have been published. This review considers these studies and the relevant indications and contraindications. Statin + fibrate therapy should be considered if monotherapy or adding other drugs (e.g. cholesterol absorption inhibitors, omega-3 fatty acids or nicotinic acid) did not achieve lipid targets or is impractical. Combination therapy should be hospital-based and reserved for high-risk patients with a mixed hyperlipidaemia characterised by low density lipoprotein cholesterol (LDL) > 2.6 mmol/l (100 mg/dl), high density lipoprotein cholesterol (HDL) < 1.0 mmol/l (40 mg/dl) and/or triglycerides > 5.6 mmol/l (500 mg/dl). These three ‘goals’ are individually mentioned in guidelines. Patients should have normal renal, liver and thyroid function tests and should not be receiving therapy with cyclosporine, protease inhibitors or drugs metabolised through cytochrome P450 (especially 3A4). Combination therapy is probably best conducted using drugs with short plasma half-lives; fibrates should be prescribed in the morning and statins at night to minimise peak dose interactions. Both drug classes should be progressively titrated from low doses. Regular (3-monthly) monitoring of liver function and creatine kinase is required. In conclusion, fibrate + statin therapy remains an option in high-risk patients. However, long-term studies involving safety monitoring and vascular endpoints are required to demonstrate the efficacy of this regimen.

Refsum's disease: a peroxisomal disorder affecting phytanic acid α-oxidation

Refsums disease (hereditary motor sensory neuropathy type IV, heredopathia atactica polyneuritiformis) is an autosomal recessive disorder the clinical features of which include retinitis pigmentosa, blindness, anosmia, deafness, sensory neuropathy, ataxia and accumulation of phytanic acid in plasma‐ and lipid‐containing tissues. The transport and biochemical pathways of phytanic acid metabolism have recently been defined with the cloning of two key enzymes, phytanoyl‐CoA 2‐hydroxylase (PAHX) and 2‐hydroxyphytanoyl‐CoA lyase, together with the confirmation of their localization in peroxisomes. PAHX, an iron(II) and 2‐oxoglutarate‐dependent oxygenase is located on chromosome 10p13. Mutant forms of PAHX have been shown to be responsible for some, but not all, cases of Refsums disease. Certain cases have been shown to be atypical mild variants of rhizomelic chondrodysplasia punctata type 1a. Other atypical cases with low‐plasma phytanic acid may be caused by α‐methylacyl‐CoA racemase deficiency. A sterol‐carrier protein‐2 (SCP‐2) knockout mouse model shares a similar clinical phenotype to Refsums disease, but no mutations in SCP‐2 have been described to‐date in man. This review describes the clinical, biochemical and metabolic features of Refsums disease and shows how the biochemistry of the α‐oxidation pathway may be linked to the regulation of metabolic pathways controlled by isoprenoid lipids, involving calcineurin or the peroxisomal proliferator activating α‐receptor.

Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4α mutations in a large European collection

Aims/hypothesisHeterozygous mutations in the gene of the transcription factor hepatocyte nuclear factor 4α (HNF-4α) are considered a rare cause of MODY with only 14 mutations reported to date. The description of the phenotype is limited to single families. We investigated the genetics and phenotype of HNF-4α mutations in a large European Caucasian collection.MethodsHNF-4α was sequenced in 48 MODY probands, selected for a phenotype of HNF-1α MODY but negative for HNF-1α mutations. Clinical characteristics and biochemistry were compared between 54 HNF-4α mutation carriers and 32 familial controls from ten newly detected or previously described families.ResultsMutations in HNF-4α were found in 14/48 (29%) probands negative for HNF-1α mutations. The mutations found included seven novel mutations: S34X, D206Y, E276D, L332P, I314F, L332insCTG and IVS5nt+1G>A. I314F is the first reported de novo HNF-4α mutation. The average age of diagnosis was 22.9 years with frequent clinical evidence of sensitivity to sulphonylureas. Beta cell function, but not insulin sensitivity, was reduced in diabetic mutation carriers compared to control subjects (homeostasis model assessment of beta cell function 29% p<0.001 vs controls). HNF-4α mutations were associated with lower apolipoprotein A2 (p=0.001), A1 (p=0.04) and total HDL-cholesterol (p=0.02) than in control subjects. However, in contrast to some previous reports, levels of triglycerides and apolipoprotein C3 were normal.Conclusions/interpretationHNF-4α mutations are common when no HNF-1α mutation is found in strictly defined MODY families. The HNF-4α clinical phenotype and beta cell dysfunction are similar to HNF-1α MODY and are associated with reduced apolipoprotein A2 levels. We suggest that sequencing of HNF-4α should be performed in patients with clinical characteristics of HNF-1α MODY in whom mutations in HNF-1α are not found.