Paul N. Durrington

European guidelines on cardiovascular disease prevention in clinical practice: executive summary

Guidelines and Expert Consensus Documents summarize and evaluate all currently available evidence on a particular issue with the aim to assist physicians in selecting the best management strategies for a typical patient, suffering from a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines are not substitutes for textbooks. The legal implications of medical guidelines have been discussed previously. A great number of Guidelines and Expert Consensus Documents have been issued in recent years by the European Society of Cardiology (ESC) as well as by other societies and organizations. Because of the impact on clinical practice, quality criteria for development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines and Expert Consensus Documents can be found on the ESC web site (http://www.escardio.org/knowledge/guidelines/rules). In brief, experts in the field are selected and undertake a comprehensive review of the published evidence for management and/or prevention of a given condition. A critical evaluation of diagnostic and therapeutic procedures is performed, including assessment of the risk–benefit ratio. Estimates of expected health outcomes for larger societies are included, where data exist. The level of evidence and the strength of recommendation of particular treatment options are weighed and graded according to predefined scales, as outlined in the tables below. The experts of the writing panels have provided disclosure statements of all relationships they may have which might be perceived as real or potential sources of conflicts of interest. These disclosure forms are kept on file at the European Heart House, headquarters of the ESC. Any changes in conflict of interest that arise during the writing period must be notified to the ESC. The Task Force report was entirely …

Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial

BACKGROUND Type 2 diabetes is associated with a substantially increased risk of cardiovascular disease, but the role of lipid-lowering therapy with statins for the primary prevention of cardiovascular disease in diabetes is inadequately defined. We aimed to assess the effectiveness of atorvastatin 10 mg daily for primary prevention of major cardiovascular events in patients with type 2 diabetes without high concentrations of LDL-cholesterol. METHODS 2838 patients aged 40-75 years in 132 centres in the UK and Ireland were randomised to placebo (n=1410) or atorvastatin 10 mg daily (n=1428). Study entrants had no documented previous history of cardiovascular disease, an LDL-cholesterol concentration of 4.14 mmol/L or lower, a fasting triglyceride amount of 6.78 mmol/L or less, and at least one of the following: retinopathy, albuminuria, current smoking, or hypertension. The primary endpoint was time to first occurrence of the following: acute coronary heart disease events, coronary revascularisation, or stroke. Analysis was by intention to treat. FINDINGS The trial was terminated 2 years earlier than expected because the prespecified early stopping rule for efficacy had been met. Median duration of follow-up was 3.9 years (IQR 3.0-4.7). 127 patients allocated placebo (2.46 per 100 person-years at risk) and 83 allocated atorvastatin (1.54 per 100 person-years at risk) had at least one major cardiovascular event (rate reduction 37% [95% CI -52 to -17], p=0.001). Treatment would be expected to prevent at least 37 major vascular events per 1000 such people treated for 4 years. Assessed separately, acute coronary heart disease events were reduced by 36% (-55 to -9), coronary revascularisations by 31% (-59 to 16), and rate of stroke by 48% (-69 to -11). Atorvastatin reduced the death rate by 27% (-48 to 1, p=0.059). No excess of adverse events was noted in the atorvastatin group. INTERPRETATION Atorvastatin 10 mg daily is safe and efficacious in reducing the risk of first cardiovascular disease events, including stroke, in patients with type 2 diabetes without high LDL-cholesterol. No justification is available for having a particular threshold level of LDL-cholesterol as the sole arbiter of which patients with type 2 diabetes should receive statins. The debate about whether all people with this disorder warrant statin treatment should now focus on whether any patients are at sufficiently low risk for this treatment to be withheld.

ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS)

Cardiovascular disease (CVD) due to atherosclerosis of the arterial vessel wall and to thrombosis is the foremost cause of premature mortality and of disability-adjusted life years (DALYs) in Europe, and is also increasingly common in developing countries.1 In the European Union, the economic cost of CVD represents annually E192 billion1 in direct and indirect healthcare costs. The main clinical entities are coronary artery disease (CAD), ischaemic stroke, and peripheral arterial disease (PAD). The causes of these CVDs are multifactorial. Some of these factors relate to lifestyles, such as tobacco smoking, lack of physical activity, and dietary habits, and are thus modifiable. Other risk factors are also modifiable, such as elevated blood pressure, type 2 diabetes, and dyslipidaemias, or non-modifiable, such as age and male gender. These guidelines deal with the management of dyslipidaemias as an essential and integral part of CVD prevention. Prevention and treatment of dyslipidaemias should always be considered within the broader framework of CVD prevention, which is addressed in guidelines of the Joint European Societies’ Task forces on CVD prevention in clinical practice.2 – 5 The latest version of these guidelines was published in 20075; an update will become available in 2012. These Joint ESC/European Atherosclerosis Society (EAS) guidelines on the management of dyslipidaemias are complementary to the guidelines on CVD prevention in clinical practice and address not only physicians [e.g. general practitioners (GPs) and cardiologists] interested in CVD prevention, but also specialists from lipid clinics or metabolic units who are dealing with dyslipidaemias that are more difficult to classify and treat.

European guidelines on cardiovascular disease prevention in clinical practice: full text. Fourth Joint Task Force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts).

Other experts who contributed to parts of the guidelines: Edmond Walma, Tony Fitzgerald, Marie Therese Cooney, Alexandra Dudina European Society of Cardiology (ESC) Committee for Practice Guidelines (CPG): Alec Vahanian (Chairperson), John Camm, Raffaele De Caterina, Veronica Dean, Kenneth Dickstein, Christian Funck-Brentano, Gerasimos Filippatos, Irene Hellemans, Steen Dalby Kristensen, Keith McGregor, Udo Sechtem, Sigmund Silber, Michal Tendera, Petr Widimsky, Jose Luis Zamorano Document reviewers: Irene Hellemans (CPG Review Co-ordinator), Attila Altiner, Enzo Bonora, Paul N. Durrington, Robert Fagard, Simona Giampaoli, Harry Hemingway, Jan Hakansson, Sverre Erik Kjeldsen, Mogens Lytken Larsen, Giuseppe Mancia, Athanasios J. Manolis, Kristina Orth-Gomer, Terje Pedersen, Mike Rayner, Lars Ryden, Mario Sammut, Neil Schneiderman, Anton F. Stalenhoef, Lale Tokgözoglu, Olov Wiklund, Antonis Zampelas

Paraoxonase prevents accumulation of lipoperoxides in low-density lipoprotein

Oxidative modification of low‐density lipoprotein (LDL) enhances its uptake by macrophages in tissue culture and in vivo may underly the formation of arterial fatty streaks, the progenitors of atheroma. We investigated the possible protection which high‐density lipoprotein (HDL) affords against LDL oxidation. The formation of lipoperoxides and thiobarbituric acid reactive substances when LDL was incubated with copper ions was significantly decreased by HDL. The enzyme, paraoxonase (E.C. 3.1.8.1), purified from human HDL, had a similar effect and thus may be the component of HDL responsible for decreasing the accumulation of lipid peroxidation products.

Protection of low-density lipoprotein against oxidative modification by high-density lipoprotein associated paraoxonase

We have investigated the Cu2+ induced generation of lipid peroxides in low density lipoprotein (LDL) incubated with high density lipoprotein (HDL) and with purified paraoxonase, an enzyme normally resident on HDL. HDL (1.5 mg) and paraoxonase (20 micrograms) inhibited lipid peroxide generation in LDL by 32% and 25%, respectively after 24 h of incubation (both P < 0.01). The decrease in LDL lipid peroxides both with HDL and with paraoxonase were concentration dependent. The degree of protection offered by HDL tended to relate to its paraoxonase activity (R = 0.47; P < 0.06). Neither purified paraoxonase nor HDL chelated Cu2+ sufficiently to account for the decrease in LDL oxidation. Purified paraoxonase did not affect LDL oxidation when it had been heat inactivated. Mass transfer of lipid peroxides from LDL to HDL did not explain the protection of LDL against oxidation: the total lipid peroxides accumulating during incubation was decreased both by HDL and by paraoxonase. These results suggest a direct role for HDL in preventing atherosclerosis probably by an enzymic process which prevents the accumulation of lipid peroxides on LDL. Paraoxonase is an example of an enzyme which might possibly be involved.

Paraoxonase and Atherosclerosis

There is considerable evidence that the antioxidant activity of high density lipoprotein (HDL) is largely due to the paraoxonase-1 (PON1) located on it. Experiments with transgenic PON1 knockout mice indicate the potential for PON1 to protect against atherogenesis. This protective effect of HDL against low density lipoprotein (LDL) lipid peroxidation is maintained longer than is the protective effect of antioxidant vitamins and could thus be more important. There is evidence that the genetic polymorphisms of PON1 least able to protect LDL against lipid peroxidation are overrepresented in coronary heart disease, particularly in association with diabetes. However, these polymorphisms explain only part of the variation in serum PON1 activity; thus, a more critical test of the hypothesis is likely to be whether low serum PON1 activity is associated with coronary heart disease. Preliminary case-control evidence suggests that this is indeed the case and, thus, that the quest for dietary and pharmacological means of modifying serum PON1 activity may allow the oxidant model of atherosclerosis to be tested in clinical trials.

Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic review.

Abstract Objective To review systematically the evidence for an effect of long chain and shorter chain omega 3 fatty acids on total mortality, cardiovascular events, and cancer. Data sources Electronic databases searched to February 2002; authors contacted and bibliographies of randomised controlled trials (RCTs) checked to locate studies. Review methods Review of RCTs of omega 3 intake for 3 6 months in adults (with or without risk factors for cardiovascular disease) with data on a relevant outcome. Cohort studies that estimated omega 3 intake and related this to clinical outcome during at least 6 months were also included. Application of inclusion criteria, data extraction, and quality assessments were performed independently in duplicate. Results Of 15 159 titles and abstracts assessed, 48 RCTs (36 913 participants) and 41 cohort studies were analysed. The trial results were inconsistent. The pooled estimate showed no strong evidence of reduced risk of total mortality (relative risk 0.87, 95% confidence interval 0.73 to 1.03) or combined cardiovascular events (0.95, 0.82 to 1.12) in participants taking additional omega 3 fats. The few studies at low risk of bias were more consistent, but they showed no effect of omega 3 on total mortality (0.98, 0.70 to 1.36) or cardiovascular events (1.09, 0.87 to 1.37). When data from the subgroup of studies of long chain omega 3 fats were analysed separately, total mortality (0.86, 0.70 to 1.04; 138 events) and cardiovascular events (0.93, 0.79 to 1.11) were not clearly reduced. Neither RCTs nor cohort studies suggested increased risk of cancer with a higher intake of omega 3 (trials: 1.07, 0.88 to 1.30; cohort studies: 1.02, 0.87 to 1.19), but clinically important harm could not be excluded. Conclusion Long chain and shorter chain omega 3 fats do not have a clear effect on total mortality, combined cardiovascular events, or cancer.

LMNA, encoding lamin A/C, is mutated in partial lipodystrophy

The lipodystrophies are a group of disorders characterized by the absence or reduction of subcutaneous adipose tissue. Partial lipodystrophy (PLD; MIM 151660) is an inherited condition in which a regional (trunk and limbs) loss of fat occurs during the peri-pubertal phase. Additionally, variable degrees of resistance to insulin action, together with a hyperlipidaemic state, may occur and simulate the metabolic features commonly associated with predisposition to atherosclerotic disease. The PLD locus has been mapped to chromosome 1q with no evidence of genetic heterogeneity. We, and others, have refined the location to a 5.3-cM interval between markers D1S305 and D1S1600 (refs 5 , 6). Through a positional cloning approach we have identified five different missense mutations in LMNA among ten kindreds and three individuals with PLD. The protein product of LMNA is lamin A/C, which is a component of the nuclear envelope. Heterozygous mutations in LMNA have recently been identified in kindreds with the variant form of muscular dystrophy (MD) known as autosomal dominant Emery-Dreifuss MD (EDMD–AD; ref. 7) and dilated cardiomyopathy and conduction-system disease (CMD1A). As LMNA is ubiquitously expressed, the finding of site-specific amino acid substitutions in PLD, EDMD–AD and CMD1A reveals distinct functional domains of the lamin A/C protein required for the maintenance and integrity of different cell types.

Serum paraoxonase activity in familial hypercholesterolaemia and insulin-dependent diabetes mellitus

The activity of serum paraoxonase, an enzyme located on high-density lipoprotein, has been investigated in familial hypercholesterolaemia (FH) and insulin dependent diabetes mellitus (IDDM). Increases in total serum cholesterol and apolipoprotein B were present in both FH and IDDM compared to healthy controls and in the patients with IDDM, serum triglycerides were also raised. The serum HDL-cholesterol concentrations in controls and patients with FH and IDDM did not differ significantly. Serum paraoxonase activity was significantly lower in both the FH and IDDM populations than in controls (P less than 0.001 and P less than 0.01, respectively). 72% of the FH population and 67% of the IDDM population were in the lower half of the frequency distribution for serum paraoxonase (activity of less than 112 U/l). It is likely that the common factor related to low paraoxonase activity is hyperlipidaemia. It is possible that paraoxonase has a physiological role in lipid metabolism and that decreases in its activity may accelerate atherogenesis.