Randomized placebo-controlled study of the effects of simvastatin on haemostatic variables, lipoproteins and free fatty acids

The Oxford Cholesterol Study is a randomized placebo-controlledtrial designed primarily to assess the effects of simvastatinon blood cholesterol levels and side-effects in preparationfor a large, long-term trial of the effects of cholesterol-loweringdrug therapy on mortality. At present there is only limitedevidence from randomized comparisons of the effects of HMG-CoAreductase inhibitors, such as simvastatin, on thrombogenic,as distinct from atherogenic, pathways in coronary heart disease.The present sub-study was carried out to assess the effectsof simvastatin on a range of haemostatic variables, as wellas on free fatty acids and on lipoprotein fractions not studiedin detail previously. At an average of about 2 years after starting study treatment,non-fasting blood samples were obtained from a sequential sampleof 162 participants who had been randomly allocated to receive40 mg (54 patients) or 20 mg (57 patients) daily simvastatinor matching placebo treatment (51 patients). Only patients whoreported taking their study treatment and who were not knownto be diabetic or to be taking some other lipid lowering treatmentwere to be included. The principal comparisons were to be ofthose allocated simvastatin (i.e. 20 and 40 mg doses combined)vs those allocated placebo. Among patients allocated simvastatin, marginally significantlower factor VII antigen levels (12·10%±6·08of standard; 2P<0·05) and non-significantly lowerfactor VII coagulant activity (8·24%±4·99of standard) and fibrinogen concentrations (0·10±0·08g.l^–1) were observed. In contrast, plasminogen activatorinhibitor activity was significantly higher (2·62±1·03IU; 2P<0·01) among patients allocated simvastatin.No significant differences were seen in the other haemostaticfactors studied (e.g. prothrombin fragment 1·2, factorXII and C$$$ inhibitor). Total free fatty acid concentrationwas marginally significantly reduced (2P=0·02) with simvastatin,but none of the reductions in individual free fatty acids wassignificant. Lipoprotein fractions were only measured amongpatients allocated 40 mg daily simvastatin or placebo. Comparedwith placebo, simvastatin produced significant decreases notonly in LDL cholesterol (1·74±0·15 mmol.1^–1;2P<0·0001) but also in VLDL cholesterol (0·28±0·08mmol.1^–1; 2P<0·001) and IDL cholesterol (0·17±0·03mmol.1^–1; 2P<0·0001). There were also lowertriglyceride levels associated with LDL (0·07±0·01mmol.1^–1; 2P<0·0001), IDL (0·03±0·01mmol.1^–1; 2P<0·01) and VLDL (0·27±0·14;2P=0·05). The effects of simvastatin on haemostatic variables appear tobe far less marked than its lipid effects. Given the associationsof haemostatic factors with coronary heart disease incidence,larger randomized comparisons of the HMG-CoA re1ductase inhibitors(and of the newer fibrates, which may produce greater effects)are needed to provide more reliable estimates of the extentto which they influence these variables.     

MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experience

Aims In observational studies, prolonged lower blood total cholesterollevels—down at least to 3mmol.l^–1—are associatedwith lower risks of coronary heart disease. Cholesterol-loweringtherapy may, therefore, be worthwhile for individuals at highrisk of coronary heart disease events irrespective of theirpresenting cholesterol levels. Observational studies also suggestthat increased dietary intake of antioxidant vitamins may beassociated with lower risks of coronary heart disease. The presentrandomized trial aims to assess reliably the effects on mortalityand major morbidity of cholesterol-lowering therapy and of antioxidantvitamin supplementation in a wide range of different categoriesof high-risk patients. Methods and Results Men and women aged 40 to 80 years were eligibleprovided they were considered to be at elevated risk of coronaryheart disease death because of past history of myocardial infarctionor other coronary heart disease, occlusive disease of non-coronaryarteries, diabetes mellitus or treated hypertension; had baselineblood total cholesterol of 3·5mmol.l^–1or greater;and no clear indications for, or contraindications to, eitherof the study treatments. Eligible patients who completed a pre-randomizationrun-in phase on active treatment were randomly allocated toreceive simvastatin (40mg daily) or matching placebo tabletsand, in a ‘2x2 factorial’ design, antioxidant vitamins(600mg vitamin E, 250mg vitamin C and 20mg beta-carotene daily)or matching placebo capsules. Follow-up visits after randomizationare scheduled at 4, 8 and 12 months, and then 6-monthly, forat least 5 years.Between July 1994 and May 1997, 15454 men and5082 women were randomized, with 9515 aged over 65 years atentry. Diagnostic criteria overlapped, with 8510 (41%) havinghad myocardial infarction (most of whom were either female,or elderly or with low blood cholesterol), 4869 (24%) some otherhistory of coronary heart disease, 3288 (16%) cerebrovasculardisease, 6748 (33%) peripheral vascular disease, 5963 (29%)diabetes mellitus (of whom 3985 had no history of coronary heartdisease) and 8455 (41%) treated hypertension. Baseline non-fastingtotal cholesterol levels were less than 5·5mmol.l^–1in7882 (38%) participants, and LDL (low density lipoprotein) cholesterolless than 3·0mmol.l^–1in 6888 (34%).During a meanfollow-up of 25 months (range: 13 to 47 months), no significantdifferences had been observed between the treatment groups inthe numbers of patients with muscle symptoms, other possibleside-effects leading to termination of study treatment, or elevatedliver and muscle enzymes. After 30 months of follow-up, 81%of randomized patients remained compliant with taking theirstudy simvastatin or placebo tablets, and allocation to simvastatinproduced average reductions in non-fasting blood total and LDLcholesterol of about 1·5–1·6mmol.l^–1and1·1–1·2mmol.l^–1respectively. Eighty-sevenper cent of patients remained compliant with taking their vitaminor placebo capsules, and allocation to the vitamin supplementproduced an average increase in plasma vitamin E levels of about24µmol.l^–1. Based on this initial follow-up period,the estimated annual rate of non-fatal myocardial infarctionor fatal coronary heart disease is 2·4%, annual strokerate is 1·3%, and annual all-cause mortality rate is2·2%. Conclusion The Heart Protection Study is large, it has includeda wide range of patients at high risk of vascular events, andthe treatment regimens being studied are well-tolerated andproduce substantial effects on blood lipid and vitamin levels.The study should, therefore, provide reliable evidence aboutthe effects of cholesterol-lowering therapy and of antioxidantvitamin supplements on all-cause or cause-specific mortalityand major morbidity in a range of different categories of individualsfor whom uncertainty remains about the balance of benefits andrisks of these treatments.     

Effects of simvastatin on plasma lipid, lipoprotein and apolipoprotein concentrations in hypercholesterolaemia

The effect of 24 weeks of treatment with simvastatin, a newHMG coenzyme A reductase inhibitor (dosages of 20 and40 mg day^–1)on serum lipid, lipoprotein and apolipoprotein A-I and B concentrationsas well as safety parameters and subjective side effects werestudied in 11 patients with familial (FH) and 10 patients withpolygenic hypercholesterolaemia (P-HC). The effects on plasmalipoprotein and apolipoprotein concentrations had already beenachieved after four weeks in both groups and then remained duringthe study. In FH, mean fasting plasma total cholesterol concentrationdecreased from 10·51 to 6·71 mmol l^–1 (36%),and in P-HC from 6·55 to 4·54 mmol l^–1 (31%)at 24 weeks (P<0·001). Mean plasma low density lipoprotein(LDL) cholesterol concentrations also decreased, in FH from8·87 to 5·05 mmol l^–1 (43%) and in P-HCfrom 4–97 to 3–12 mmol l^–1 (37%) at 24 weeks(P<0·001). Furthermore, apolipoprotein B concentrationsdecreased significantly from 2·21 to 1·57 g l^–1(29%)(P<0·001) in FH and from 1·53 to 1·09g l^–1 (29%) (P<0·01) in P-HC. Plasma high densitylipoprotein (HDL) cholesterol increased in both FH and P-HCduring treatment. Increases were seen in both the subfractionsHDL₂ and HDL₃. Simvastatin was well tolerated. No serious clinicalor laboratory adverse effects were observed. It is concludedthat 24 weeks of treatment with simvastatin in doses up to 40mg day^–1 effectively reduces plasma total and LDL cholesterolconcentrations without causing subjective or significant objectiveside effects. Thus, simvastatin may be of great interest infuture studies for prevention of coronary heart disease dueto hypercholesterolaemia.     

The effect of simvastatin on progression of coronary artery disease: The Multicenter Coronary Intervention Study (CIS)

BACKGROUND: In several angiographic trials, HMG-CoA reductase inhibitorshave shown a beneficial effect on the progression of coronaryartery disease. Using 20 mg simvastatin day^–1, a treatmentperiod of up to 4 years was necessary to show a significantreduction in coronary artery disease progression. The questionremains however, whether higher dosages of simvastatin wouldbe more advantageous in respect to the magnitude of the effectand the required time interval to demonstrate treatment efficacy. METHODS AND RESULTS: In the Coronary Intervention Study (CIS), a multicentre randomizeddouble-blind placebo-controlled study, the effects of lipid-loweringtherapy with simvastatin on progression of coronary artery diseasein 254 men with documented coronary artery disease and hypercholesterolaemiawere investigated. Following a period of lipid-lowering diet,treatment with 40 mg simvastatin or placebo was maintained foran average of 2·3 years. Two primary angiographic endpointswere chosen: the global change score (visual evaluation accordingto the method of Blankenhorn) and the per patient mean changeof minimum lumen diameter (evaluated by the CAAS I system). The mean simvastatin dose was 34·5 mg day^–1. Inthe placebo group, the serum lipids remained unchanged; in comparisonto the placebo group the simvastatin group showed a 35% LDL-cholesteroldecrease. Coronary angiography was repeated in 205 patients(81%) and 203 film pairs (80%) were evaluable by quantitativecoronary angiography. In the simvastatin and placebo groups,the mean global change scores were +0·20 and +0·58respectively, demonstrating a significantly slower progressionof coronary artery disease in the treatment group (P=0·02).The change in minimum lumen diameter assessed by computer-assistedquantitative evaluation with the CAAS I system was –0·02mm in the simvastatin group and –0·10 mm in theplacebo group (P=0·002). In the simvastatin group, therewas a significant correlation between the LDL cholesterol levelsachieved therapeutically and the per patient mean loss of minimumlumen diameter (r=0·29; P=0·003). During the studyperiod, there was no significant difference in the incidenceof serious cardiac events (15 of 129 patients in the simvastatingroup and 19 of 125 patients in the placebo group, ns). CONCLUSION: Treatment with 40 mg simvastatin day^–1 reduces serum cholesteroland slows the progression of coronary artery disease significantlywithin a short period of treatment time. In the treatment group,retardation of progression is inversely correlated to the LDL-cholesterollevels achieved.     

Cholesterol lowering after participation in the Scandinavian Simvastatin Survival Study (4S) in Finland

BACKGROUND: Patient compliance is crucial for the effectiveness of preventivemedication. The aim of the study was to investigate changesin serum cholesterol levels and the use of cholesterol loweringdrugs one year after the end of the Scandinavian SimvastatinSurvival Study (4S), a randomized secondary prevention studyof coronary heart disease with simvastatin and placebo. METHODS AND RESULTS: A questionnaire asking the current use of cholesterol loweringdrugs, most recent serum cholesterol value and attitudes towardscholesterol lowering was sent to 785 surviving 4S participantsin four 4S centres in Finland. The response rate was 94%. Thecurrent use of cholesterol lowering drugs and the reported meanserum cholesterol values were similar to the original simvastatinand placebo groups. In all, 74% (n=546) reported that they hadused cholesterol lowering drugs after the study, and 63% (n=467)were currently using them, mostly simvastatin (96%) with anaverage dose of 14 (SD 5) mg . day–¹ Cholesterol loweringwas considered to be ‘very important’ by 53% and‘important’ by 37% of the respondents. The mostfrequent reasons for discontinuation were ‘drug costs’(38%) and ‘normal cholesterol values’ (30%). Thereported mean serum cholesterol levels were 5·1 (SD 1·0)and 5·7 (SD 1·1) mmol –¹ in the currentcholesterol lowering drug users and non-users, respectively(P<0·0001). The in-trial treatment goal of serum cholesterol( 5·2 mmol –¹) was not met in 38% of the usersand in 68% of the non-users of cholesterol lowering drugs. CONCLUSION: One year post-trial the original simvastatin and placebo groupsof the 4S had become similar with regard to the use of cholesterollowering drugs and serum cholesterol levels. The adherence tomedication, however, still remained relatively high, but therewas a shift toward lower doses, and consequently toward higherpost-trial serum cholesterol levels.     

Serum cholesterol and long-term prognosis in middle-aged men with myocardial infarction and angina pectoris: A 16-year follow-up of the Primary Prevention Study in Gateborg, Sweden

OBJECTIVE: To compare the role of serum cholesterol in the long-term prognosisof men with a history of myocardial infarction, in men withclinical angina without myocardial infarction, and men withoutclinical coronary disease. METHODS: In the second screening of the Primary Prevention Study in Göteborgwhich comprised 7100 men aged 51 to 59 years at baseline in1974–1977, 314 men with clinical angina but no myocardialinfarction at baseline were identified and 195 men who had surviveda myocardial infarction for 0 to 19 years (median 3 years). RESULTS: Of the men without clinical coronary disease at baseline andcholesterol at or below 5·2 mmol .1^–1, 2·7per 1000 observation years died from coronary disease comparedto 8·5 per 1000 of the men with serum cholesterol of7·2 mmol .1^–1 or more. Corresponding figures formen with angina was 5·5 and 31·0 per 1000 observationyears, and for men with prior myocardial infarction 19·8and 58·3 respectively, per 1000. After adjustment forage, smoking, systolic blood pressure, body mass index and diabetesthe risk of coronary death in men with serum cholesterol above7·2 mmol .1^–1 compared to below 5·2 mmol.1^–1 was 2·42 (1·66–3·51) inhealthy men, 4·82 (1·44–16·09) inmen with angina, 2·70 (0·95–7·67)in survivors of myocardial infarction, and 4·07 (1·86–8·91)in the combined group of men with either angina or prior infarction.The strongest effect was seen during the first half of the follow-up,with an adjusted relative risk for high in relation to low serumcholesterol of 8·08 (1·95–33·55)in men with preexisting coronary disease. Non-coronary deathsvaried little by serum cholesterol or coronary disease statusat baseline. After 16 years, 76% of the healthy men with lowcholesterol and 65% of healthy men with cholesterol above 7·2mmol. 1^–1 were still alive. Of the men with prior myocardialinfarction, 50% in the group with low cholesterol were aliveafter 16 years, as compared to 21% of those with high cholesterol. CONCLUSION: The long-term absolute risk of death in men with coronary diseaseand elevated serum cholesterol is very high. Implementationof lipid-lowering strategies shown to be efficacious is importantin this high-risk group.     

Monotherapy of stable angina with nicardipine hydrochloride: double-blind, placebo-controlled, randomized study

The effect of nicardipine hydrochloride, a calcium-channel blockingagent, was studied in 46 patients with stable angina in a double-blind,placebo-controlled, randomized, repeated cross-over protocol,using a 30 or 40 mg dose of nicardipine or placebo three timesa day. Mean resting heart rate and blood pressure did not changesignificantly with 30 mg nicardipine; heart rate increased from81 ±10 to 88 ±13 beats min^–1, systolic bloodpressure decreased from 129±18 to 119±16mmHg,and diastolic blood pressure from 81 ±12 to 74±11mmHg (P < 0·01 for all three variables) with a 40mg dose. Using a treadmill exercise protocol, mean exerciseduration increased from 5·4±1·8 to 6·0±1·8min (P<0·01) with 30 mg nicardipine, and from 5·8+1·7to 616+1·9 min (P<0101) with 40 mg. Time to onsetof angina increased from 4·6+1·9 to 5·2±1·7min(P<0·05) with 30 mg and from 5·1 ± 1·8to 5·7+1·8 min (P = NS) with 40 mg. Mean anginalfrequency and sublingual nitroglycerin consumption were lowduring the cross-over placebo period and did not change significantlyduring therapy with nicardipine. Non-cardiac side-effects weremild and required the withdrawal of only one patient from thestudy. However, during nicardipine therapy four patients hadunstable angina and two developed a non-Q wave myocardial infarction.Of these patients, five were receiving a ß-adrenergicblocker that was discontinued prior to the study. It is concludedthat nicardipine had only a mild positive effect on exerciseduration. As observed with other dihydropyridines, nicardipinehas the potential to precipitate important ischaemic eventsin patients with stable angina, particularly when started afterdiscontinuing a ß-adrenergic blocking agent.     

Coronary artery thrombosis and thrombolysis in baboons: the effect of atenolol treatment on myocardial infarct size

The effect of the beta-blocker atenolol on experimental infarctsize was studied in a non-human primate model. In 12 baboonsthrombosis of the left anterior descending coronary artery (LAD)was induced and atenolol (0·1 to 0·2 mg . kg^–1intravenously, sufficient to lower the heart rate by 20%) wasadministered 10 mm after the onset of ischaemia in six animals,whereas the others received placebo. Thrombolysis was induced60 mm after the onset of ischaemia by intravenous injectionof rt PA (12 µg. kg^–1. min^–1) in all animals. Heart rate dropped signficantly after atenolol injection (128±9beats . min^–1 versus 163±15 beats . min^–1,P<0001) and was also lower than in the control group (128±9beats. min^–1 versus 158±22 beats.min^–1, p<0·05).Blood pressure remained unchanged after atenolol treatment.As compared to the control group, atenolol limited infarct size,expressed as a percentage of left ventricular mass (4·6±1·9%versus 7·9±1·3%, P<0·05 or asa percentage of the perfusion area (26±8% versus 43%8%,P<0·05).     

Intravenous digoxin in acute atrial fibrillation: Results of a randomized, placebo-controlled multicentre trial in 239 patients

AIMS: The DAAF Trial was designed to investigate whether digoxin,within 16 h of its use, increases the rate of conversion tosinus rhythm in patients with acute atrial fibrillation. METHODS AND RESULTS: In a randomized, double-blind multicentre trial the effectsof intravenous digoxin and placebo, (mean dose 0·88±0·35mg and 0·96±0·37 mg) were compared in 239patients with a mean age of 66·2±13·0 yearsand atrial fibrillation of, at most, 7 days' duration. The meanarrhythmia duration was 21·7±30·4 h andbaseline heart rate 122·0±23·0 beats. min^–1.At 16 h, 46% of the placebo group and 51% of the digoxin grouphad converted to sinus rhythm, (ns). Time to sinus rhythm wasshorter in the digoxin group, but the difference was not significant.Digoxin had a pronounced and rapid effect on heart rate, whichwas already significant at 2 h; 104·6±20·9beats. min^–1 vs 116·8±22·5 beats.min^–1 (P=0·0001). CONCLUSION: Acute intravenous treatment with digoxin does not increase therate of conversion to sinus rhythm, but has a fast acting andclinically significant effect on heart rate and should remainan alternative in haemodynamically stable patients     

The recognition and management of hyperlipidaemia in adults: A policy statement of the European

The control of coronary heart disease (CHD) depends primarilyon its prevention at an early stage. It is generally agreedthat this depends upon the elimination or treatment of the knownrisk factors for CHD. Among these, hyperlipidaemia occupiesa central position. The diagnosis and treatment of this conditionis the subject of this statement. Before initiating therapy for primary hyperlipidaemia the commoncauses of secondary yperlipidaemia are sought and dealt with,including diabetes, hypothyroidism, over-use of alcohol, renaland liver diseases and certain drugs. Next, an assessment ofall risk factors for CHD is carried out, i.e. family historyof CHD, smoking, hypertension, high density lipoprotein (HDL)cholesterol measurement, diabetes tnellitus and overweight.More intensive therapy is called for in patients with multiplerisk factors than in those with lone hyperlipidaemia, and alsoafter successful bypass operation or after coronary angioplasty.Evaluation of hyperlipidaemia in the patient's family is oftenappropriate. The diagnosis and follow-up of the hyperlipidaemicpatient depend on reliable and well-controlled laboratory support. The primary hyperlipidaemias include several distinct diseasesthat are characterized by elevated serum levels of cholesterolandj or triglyceride with or without abnormally low levels ofHDL cholesterol. From these measurements, low-density lipoprotein(LDL) cholesterol levels are calculated [except when triglyceridelevels are > 500 mg dl^–1 (5·6 mmol l^–1)].Elevated LDL levels are causally important in atherosclerosis,and occur in three disorders: familial hypercholesterolaemia,familial combined hyperlipidaemia and common hypercholesterolaemia.The finding of elevated serum triglyceride without marked hypercholesterolaemiamay occur in familial h vpertriglyceridaemia and sometimes infamilial combined hyperlipidaemia. Elevation of serum cholesterol and triglyceride can have severalgenetic bases, including remnant (type III) hyperlipidaemiaand familial combined hyperlipidaemia. The characteristic featureof remnant (type III) hyperlipidaemia (demonstrated by ultracentrifugationin a specialized laboratory) is the presence of cholesteroland triglyceride-rich very low density lipoproteins (VLDL),whereas combined (mixed) hyperlipidaemia is diagnosed when bothVLDL (of normal composition) and LDL levels are elevated. Investigation of other family members is necessary to make thediagnosis of familial combined hyperlipidaemia. It depends onthe identification of different lipoprotein profiles in affectedmembers of the same family. In two rare disorders, the chylomicronaemia syndrome and severeprimary familial hypertriglyceridaemia, gross elevation of triglycerideis found to levels above 1000 mg dl^–1(II mmol l^–1).Such patients are at risk of pancreatitis and should be promptlyand effectively treated. Therapy of hyperlipidaemia always starts with dietary counselling.The general principles of the lipid-lowering diet are: (I) weightreduction in overweight subjects [body mass index (weight/height2)> 27]; (2) a lipid-lowering diet providing 55% of caloriesfrom carbohydrates, 10–15% from protein andup to 30% fromfat comprising 10% each of saturated, monounsaturated and polyunsaturatedfatty acids, cholesterol <300 mg day^–1 and 35 g day^–1of fibre derived largely from legumes and other vegetables,and fruit. Further reduction of fat consumption to 20–25%of total energy and of cholesterol to <150mg day-1 may beattempted when patients respond inadequately to the standarddiet. The goal of treatment is to minimize the risk ofCHD and of pancreatitis.Where possible, a level of LDL cholesterol of 135 mg dl^–1(3·5 mmol l^–1) is the aim in hypercholesterolaemicpatients with multiple or severe risk factors and of 155 mgdl^–1 (4 mmol l^–1) in the absence of other risk factors.Some patients with hyperlipidaemia do not respond adequatelyto diet and correction of underlying causes; drug treatmentis then additionally required, but careful attention to dietis continued. Five treatment groups are defined: Group A consists of subjects with mild hypercholesterolaemia[serum cholesterol 200–250 mg dl^–1 (5·2–6·5mmol l^–1), serum triglyceride < 200 mg dl^–1 (2·3mmol l^–1) J. Diet alone is effective and drug therapyis rarely necessary. Group B subjects have serum cholesterol levels in the range250–300 mg dl^–1 (6·5–7·8 mmoll^–1). If the response to a thorough trial of diet is notsatisfactory, drug therapy should be considered, e.g. bile acidsequestrants at low dosage. Group C comprises subjects with hypertriglyceridaemia [serumcholesterol < 200 mg dl^–1 (5·2 mmol l^–1),plasma triglyceride 200–500mg dl^–1 (2·3–5·6mmoll^–1)]. Many of these patients also have low HDL-cholesterollevels. Management is primarily by control of underlying causes,particularly overweight and excessive intake of alcohol. A lipid-loweringdiet is prescribed. Drug therapy is usually withheld, but maybe considered when persisting high triglyceride levels are dueto familial combined hyperlipidaemia or other high-risk subgroups. Group D consists of patients with elevated serum levels of bothcholesterol and triglyceride [serum cholesterol 200–300mg dl^–1 (5·2–7·8 mmol l^–1) andserum triglyceride 200–500 mg dl^–1 (2·3–5·6mmol l^–1)]. Such patients may have familial combined hyperlipidaemia,the diagnosis of which depends on a family study (see text).Although the lipid elevation is often mild, this disorder isassociated with increased risk of CHD. Management is by controlof underlying causes, weight reduction, if necessary, and alipid-lowering diet. Drug treatment together with controlleddiet is necessary in a minority of patients. A drug combinationis sometimes necessary. Group E includes patients with severe hyperlipidaemia [serumcholesterolabove 300 mg dl^–1 (7·8 mmol l^–1)and/or serum triglyceride greater than 500 mg dl^–1 (5·6mmol l^–1)]. Patients with serum cholesterol levels >300 mg dl^–1 (7·8 mmol l^–1) and with normaltriglyceride commonly have familial hypercholesterolaemia andare at especially high risk of CHD. Therapy usually comprisesdiet and one or two drugs, e.g. bile acid sequestrants oftentogether with a fibrate, or cholesterol synthesis inhibitor,or nicotinic acid. For the chylomicronaemia syndrome there isno satisfactory drug therapy, and it is managed by a low fatdiet.     

Skeletal muscle lactate accumulation and creatine phosphate depletion during heavy exercise in congestive heart failure: Cause of limited exercise capacity?

OBJECTIVE: To study the mechanisms of limited exercise capacity and skeletalmuscle energy production in male patients with congestive heartfailure. DESIGN: Muscle biopsy study. PATIENTS: Skeletal muscle metabolic response to maximal bicycle exercisewas studied in 10 patients with chronic congestive heart failure(ejection fraction 0·22±0·05; peak oxygenconsumption, Vo₂ 15·1±4·9 ml. min^–1.kg^–1) and in nine healthy subjects (peak Vo₂ 33·5±6·7ml. min^–1. kg^–1). Activities of skeletal muscleenzymes were measured from the vastus lateralis muscle of 48patients (ejection fraction 0·24±0·06,peak Vo₂ 17·4±5·4 ml. min^–1. kg^–1)and 36 healthy subjects (peak Vo₂ 38·3±8·4ml. min^–1. kg^–1). RESULTS: Although blood lactate levels were lower in patients than inhealthy subjects (2·2±0·3 vs 5·2±0·6mmol. 1^–1; P<0·001) at peak exercise (96±11W for patients and 273±14 W for controls), skeletal musclelactate was similarly elevated (25·6±3·2vs 22·7±2·7 mmol.kg^–1) and creatinephosphate was equally depressed (P<0·02) to low levels(7·0±1·9 vs 6·7±0·9mmol.kg^–1). The muscle ATP decreased by 21% (P<0·05)and 8% (P<0·01) in the patients and controls, respectively.Activities of rate limiting enzymes of the citric acid cycle(alpha-ketoglutarate dehydrogenase) and oxidation of free fattyacids (carnitine palmitoyltransferase II) were 48% and 21% lowerthan in controls, but the mean phosphofructokinase activitywas unchanged in congestive heart failure. CONCLUSIONS: It seems that the main limiting factor of exercise performanceduring heavy exercise is the same in congestive heart failureand healthy subjects, a high rate of skeletal muscle lactateaccumulation and high-energy phosphate depletion. In congestiveheart failure, the low activity of aerobic enzymes is likelyto impair energy production and lead to lactate acidosis atlow workloads.     

Plasma lipoproteins and renal function during simvastatin treatment in diabetic nephropathy

Summary The aim of this study was to assess the effect of simvastatin on plasma lipoproteins and renal function in hypercholesterolaemic Type 1 (insulin-dependent) diabetic patients with diabetic nephropathy. Twenty-six hypercholesterolaemic (total cholesterol ≽ 5.5 mmol/l) Type 1 diabetic patients with nephropathy were enrolled in a double-blind randomized placebo-controlled study for 12 weeks. The active treatment group (n -14) received simvastatin (10–20 mg/day) for 12 weeks while the remaining 12 patients received treatment with placebo. The results during simvastatin treatment (baseline vs 12 weeks): total cholesterol 6.6 vs 4.8 mmol/1 (p < 0.01), LDL-cholesterol 4.25 vs 2.57 mmol/l (p < 0.01) and apolipoprotein B 1.37 vs 1.06 mmol/l (p < 0.01). HDL-cholesterol, and apolipoprotein A-I remained unchanged. Total cholesterol, LDL-cholesterol, HDL-cholesterol, apolipoprotein A–I, apolipoprotein B remained unchanged during placebo treatment. Albuminuria measured during the simvastatin and the placebo treatment (baseline vs 12 weeks) (the data are logarithmically transformed before analysis because of their positively skewed transformation; geometric mean (×/÷ antilog SE) is indicated) was 458 (×/÷ 1.58) vs 393 (×/÷ 1.61) and 481 (×/÷ 1.62) vs 368 (×/÷ 1.78 μg/min (NS). Glomerular filtration rate during simvastatin and placebo treatment (baseline vs 12 weeks) was 64 vs 63 and 72 vs 74 ml·min⁻¹·1.73 m⁻², respectively. Two patients receiving simvastatin treatment were withdrawn, one due to gastrointestinal side effects and one due to myalgia. In conclusion, our short-term study in Type 1 diabetic patients with diabetic nephropathy did not reveal any beneficial effect on albuminuria despite a striking lipid-lowering effect of simvastatin in diabetic nephropathy.     

Dipyridamole stress thallium-201 perfusion abnormalities in patients with hypertrophic cardiomyopathy. Relationship to clinical presentation and outcome

Aims Thallium-201 perfusion abnormalities are common in patientswith hypertrophic cardiomyopathy and may be associated withan adverse prognosis in the young. The aim of this study wasto prospectively determine the relationship between thallium-201defects during dipyridamole stress to clinical presentationand outcome in a large consecutive series of patients with hypertrophiccardiomyopathy. Methods/Results Thallium-201 single photon computed tomography was performedin 216 patients with hypertrophic cardiomyopathy during dipyridamolestress (0·5mg.kg^–1). Fixed perfusion defects occurredin 25%, and reversible defects in 22%. A combination of defectswas present in 7%. Fixed defects were associated with: a historyof syncope (17 of 46 with, vs 36 of 170 without syncope, P=0·03);larger left ventricular end-diastolic (46·9±7·4mmvs 43·3±6·4mm; P=0·001) and end-systolicdimension (30·2±8·4mm vs 24·5±5·9mm,P<0·0001); increased left atrial diameter (46·1±8·1mmvs 40·5±7·7mm, P<0·0001); lowerfractional shortening (35·9±10·4% vs 43·8±8·6%,P<0·0001); and lower maximal exercise oxygen consumption(24·2±8·1ml.min^–1.kg^–1vs 29·4±8·8ml.min^–1.kg^–1,P<0·0003). Reversible defects did not correlate withsymptomatic status, but were associated with: larger left atrialdimensions (44·5±8·1mm vs 41·0±8·0mm;P=0·009) and greater maximal left ventricular wall thickness(24·0±7·0mm vs 20·6±7·0mm,P=0·003). The mean follow up time was 41±21 months,range 0·6–124. There was no association betweenany thallium-201 abnormality and disease related death in youngor adult patients. Conclusion The present study shows that fixed thallium-201 perfusion defectsdetected during dipyridamole stress in patients with hypertrophiccardiomyopathy are associated with syncope, larger left ventricularcavity dimensions and reduced exercise capacity. Although theevent rate was relatively small, there was no evidence for anassociation between thallium-201 defects and survival.     

Renal function and insulin sensitivity during simvastatin treatment in Type 2 (non-insulin-dependent) diabetic patients with microalbuminuria

Summary The effect of simvastatin (10–20 mg/day) on kidney function, urinary albumin excretion rate and insulin sensitivity was evaluated in 18 Type 2 (non-insulin-dependent) diabetic patients with microalbuminuria and moderate hypercholesterolaemia (total cholesterol ≥5.5 mmol·l⁻¹). In a double-blind, randomized and placebo-controlled design treatment with simvastatin (n=8) for 36 weeks significantly reduced total cholesterol (6.7±0.3 vs 5.1 mmol·l⁻¹ (p<0.01)), LDL-cholesterol (4.4±0.3 vs 2.9±0.2 mmol·l⁻¹ (p<0.001)) and apolipoprotein B (1.05±0.04 vs 0.77±0.02 mmol·l⁻¹ (p<0.01)) levels as compared to placebo (n=10). Both glomerular filtration rate (mean±SEM) (simvastatin: 96.6±8.0 vs 96.0±5.7 ml·min⁻¹·1.73 m⁻², placebo: 97.1±6.7 vs 88.8±6.0 ml·min⁻¹·1.73 m⁻²) (NS) and urinary albumin excretion rate (geometric mean x/÷ antilog SEM) (simvastatin: 18.4x/÷1.3vs 16.2 x/÷1.2 μg·min⁻¹, placebo 33.1 x/÷ 1.3 vs 42.7 x/÷ 1.3 μg·min⁻¹)(NS) were unchanged during the study. A euglycaemic hyperinsulinaemic clamp was performed at baseline and after 18 weeks in seven simvastatin-and nine placebo-treated patients. Isotopically determined basal and insulin-stimulated glucose disposal was similarly reduced before and during therapy in both the simvastatin (2.0±0.1 vs 1.9±0.1 (NS) and 3.1±0.6 vs 3.1±0.7 mg·kg⁻¹·min⁻¹ (NS)) and the placebo group (1.9±0.1 vs 1.8±0.1 (NS) and 4.1±0.6 vs 3.8±0.2 mg·kg⁻¹·min⁻¹ (NS)). No different was observed in glucose storage or glucose and lipid oxidation before and after treatment. Further, the suppression of hepatic glucose production during hyperinsulinaemia was not influenced by simvastatin (−0.7±0.8 vs −0.7±0.5 mg·kg⁻¹·min⁻¹ (NS)). In conclusion, despite marked improvement in the dyslipidaemia simvastatin had no impact on kidney function or urinary albumin excretion rate and did not reduce insulin resistance in these microalbuminuric and moderately hypercholesterolaemic Type 2 diabetic patients.     

Cardiovascular risk factor changes in the Kilkenny Health Project: A community health promotion programme

The Kilkenny Health Project was a community research and demonstrationprogramme which aimed to reduce risk of cardiovascular diseasein a county in the south-east of Ireland with a total populationof approximately 70 000. The health promotion programme wascarried out in Kilkenny from 1985 to 1992. Outcome evaluationwas by means of population surveys of independent samples ofmen and women aged 35 to 64 years in Kilkenny (n approximately800) and in the reference county (n approximately 600) in 1985/1986and in 1990/1991. Survey methods for health behaviour questionnaires and riskfactor measurements were similar to those of the WHO MONICAProject. Mean systolic blood pressure (SBP) declined significantly(P<0·01) in men and women in both counties, from 144·0by 5·4 mmHg and from 143·2 by 5·4 mmHgin men and from 139·5 by 7·7 mmHg and from 136·5by 6·6 mmHg in women in the intervention and referencecounties. The prevalence of hypertension declined from 23·1%by 2·8% and from 26·1% by 6·0% in men inthe two counties. Prevalence declined from 24·1% by 6·2%(P<0·05) in women in the intervention county but wasunchanged, increasing by 0·5% from 17·5%, in womenin the reference county. Mean serum total cholesterol declined from 6·04 mmol.1^–1 by 0·09 mmol. 1^–1 and from 6·00by 0·44 mmol. 1^–1 (P<0·01) in men andfrom 6·01 by 0·36 (P<0·01) and from5·90 by 0·31 (P<0·01) in women in theintervention and reference counties, respectively. Cigarettesmoking prevalence declined from 27·7% by 0·7%and from 29·8% by 2·6% in men and from 30·3%by 5·5% and from 27·7% by 2·6% in womenin the two counties. Mean body mass index (BMI) increased from26·4 by 0·4 kg. ^m–2 and from 26·8by 1·0 kg. ^m–2 (P<0·01) in men and from25·5 by 0·4 and from 25·6 by 1·3kg. ^m–2 (P<0·01) in women in the interventionand reference counties. Overall, changes in risk factor levels were similar in the interventionand reference counties. There were sign reductions (P<0·01)in the 5-year risk of a coronary heart disease (CHD) event asestimated using the Dundee Risk Score in men and women in bothcounties. This was consistent with the decline in CHD mortalityat national level between the two surveys. The reasons why greaterchanges over time were not detected in the intervention comparedto the reference area are discussed.     

Dromotropic effects of oral theophylline in patients with atrial fibrillation and a slow ventricular response

Theophylline increases sinus rate, but as yet its use has notbeen investigated in patients with chronic atrio ventricularconduction disturbances. Resting electrocardiogram, 24-h Holterrecording and treadmill test were performed in 17 patients withchronic atrialfibrillation and a slow ventricular response notrelated to drugs (age: 75±8 years). Then slow-releasetheophylline was administered (700mg daily) and after 5 daysthese investigations were repeated with the same methods. Theophyllineincreased mean resting heart rate (51±6 versus 67±13beats.min^–1, P<0·01 mean 24-h heart rate (51±6versus 68±14 beats.min^–1, P<0·01 andminimal 24-h heart rate (32±6 versus 42±11 beats.min^–1,P<0·01 Cardiac pauses >2·5 s were presentin 13 patients during control recording; after theophyllinethey disappeared in 11 and markedly decreased in the remainingtwo. The longest R-R interval decreased in all patients (3218±943versus 2121±518ms, P<0·01). The daily numberof wide QRS complexes increased in 16 out of 17 patients (428±752versus 1146±1464 ms, P<0·01). Exercise heartrate, evaluated at the end offirsi andsecondstage, was higherafter theophylline than during control test (P<0·01). These data suggest that oral theophylline can represent a validtherapy in most patients with atrialfibrillation and a slowventricular response.     

Influence of biological factors on lipid and fibrinogen measurements in young men: An epidemiological study in 2009 recruits

Aims The aim of the present study was to detect significant relationshipsbetween lipid and fibrinogen measurements and several biologicalfactors in young men. Methods and results Medical history was obtained, and plasma lipids, lipoprotein(a) and fibrinogen levels were measured in 2009 male Greek armyrecruits (mean age 22·37±3·03 years) nottaking any drugs. Plasma levels were as follows: total cholesterol,171±34mg.dl^–1, low density lipoprotein (LDL) cholesterol,111±34mg.dl^–1, high density lipoprotein (HDL) cholesterol,45±10mg.dl¹, and triglycerides, 74±32mg.dl^–1.Lipo-protein (a) and fibrinogen were 18±13 and 278±67mg.dl^–1.The atherosclerotic index, calculated as the ratio of totalcholesterol/HDL, was 4±1. Analysis of multivariate modelsthat included potentially confounding factors revealed the following:body mass index, season of year during which blood examinationswere performed, alcohol consumption, and place of residencewere found to be significantly associated with plasma levelsof total cholesterol, LDL-cholesterol, fibrinogen and the athero-scleroticindex in the pooled population. Season and physical activitywere significantly associated with HDL-cholesterol, whereasseason and family history of acute myocardial infarction wereassociated with triglycerides levels. Body mass index, familyhistory of myocardial infarction and physical activity wereassociated with lipoprotein (a). Conclusion Body mass index, season, alcohol consumption and place of residenceare markers of plasma lipid profile and fibrinogen in youngmen. A family history of acute myocardial infarction and physicalactivity are related to lipoprotein (a).The European Societyof Cardiology     

Discontinuous transdermal nitroglycerin as treatment for stable angina in the elderly: A double-blind multicentre study

A transdermal nitroglycerin (TNG) patch (10mg . 24 h^–1),using a daily overnight 8-h free interval, was assessed by meansof a multicentre trial in 96 elderly patients with stable angina(age 65 years). The main entry requirement was a reproducibleexercise-induced ST depression (1 mm) appearing at a load of60 to 90 W, during an incremental bicycle ergometer test (10W. min^–1).During the study only one other antianginaldrug andsublingual TNG tablets were allowed. The protocol consisted of a run-in period (mean 10 days), followedby a double-blind, randomized, parallel, placebo- controlled28-day phase and a single-blind active treatment phase of thesame duration. The exercise test parameters, the number of spontaneousanginal attacks and any unwanted effects were evaluated at theend of every study phase. In the double-blind phase, no ergometric values changed withplacebo while transdermal TNG significantly improved total workloadand double product by 36·4% and 7·7% at the maximalworkload respectively and by 49·8% and 13·5% atthe time to onset of 1 mm ST depression respectively and reducedST depression (-58·8%) at the equivalent baseline workload.Anginal attacks decreased by 61·5% and 30·8% withTNG patch and placebo respectively. A similar trend was seenat the end of the single-blind active treatment period in patientswho had received placebo in the double-blind phase. Nine patients failed to complete the study; six for unwantedeffects (four in the active group and two in the placebo group)and three for other reasons. Mild headache or local skin irritationwere the complaints in 23% and 44% of patients in the activeand placebo groups respectively. The results of this trial,specifically designed for elderly patients with angina, suggestthat transdermal TNG patch provide safe, effective antianginaltherapy in this age group.     

Skeletal muscle function at low work level as a model for daily activities in patients with chronic heart failure

AIM: Metabolic exercise abnormalities have been reported in chronicheart failure patients. This study sought to evaluate whetherthese abnormalities affected daily activity. METHODS AND RESULTS: In 16 patients with moderate-to-severe chronic heart failureand in eight controls we measured femoral flow (thermodilution)and metabolism (glucose, lactate, free fatty acids, blood gasvalues) at rest and during a constant load of 20 W, which maymimic a daily activity. At rest, chronic heart failure patientshad a leg flow similar to controls, but showed a higher legoxygen consumption (4·6±0· vs 2·6±0·4ml. min^–1; P>0·05), a higher arteriovenous oxygendifference (7·2±0·5 vs 5·4±0·7ml . d1^–1; P>0·05), and a lower femoral veinpH (7·37±5·–03 vs 7·42±0·01;P=0·01). At 20 W, chronic heart failure patients hada leg flow similar to controls, but showed increased lactaterelease (from resting 11·7±33 to 142+125 µg. min^–1 P>0·0001 vs controls, from resting 5·7±15·4to 50±149 µg . min^–1 ns), higher arterialconcentration of free fatty acids (781±69 vs 481±85µmol . 1^–1; P>0·01), lower femoral veinHCO₃ (24·1+2·6 vs 26·3±1·7mmol .1^–1;P>0·05) and base excess (–2·3+2·3vs –0·24±1·7 mmol . 1^–1 P=0·01 CONCLUSION: In chronic heart failure patients, the important cellular metabolicalterations already present at rest partially affect daily activities,owing to a further decrease in the efficiency of muscle metabolicprocesses, and may preclude tolerance of heavier activities.Such alterations appear, at least in part, independent of peripheralhaemodynamic responses to exercise.     

Growth hormone (GH) replacement decreases serum total and LDL-cholesterol in hypopituitary patients on maintenance HMG CoA reductase inhibitor (statin) therapy

Objective Adult onset GH deficiency (GHD) is characterized by abnormalities of serum lipoprotein profiles and GH replacement results in favourable alterations in serum total and low density lipoprotein (LDL)‐cholesterol. Preliminary evidence has indicated that the effect of GH replacement in this respect may be additive to that of HMG CoA reductase inhibitor (statin) therapy. We have examined this possibility during prospective follow‐up of adult onset hypopituitary patients enrolled in KIMS (Pfizer International Metabolic Database), a pharmacoepidemiological study of GH replacement in adult hypopituitary patients. Design Lipoprotein profiles were measured centrally at baseline and after 12 months GH replacement therapy. Patients Sixty‐one hypopituitary patients (30 male, 31 female) on maintenance statin therapy (mean 2·5 ± 2·7 SD years before GH) (statin group – SG) and 1247 (608 male, 639 female) patients not on hypolipidaemic therapy (nonstatin group – NSG) were studied. All patients were naïve or had not received GH replacement during the 6 months prior to study. Patients who developed diabetes mellitus during the first year of GH therapy or in the subsequent year and those with childhood onset GHD were excluded from this analysis. An established diagnosis of diabetes mellitus was present in 18% SG and 4·4% NSG at baseline. Measurements Serum concentrations of total, high density lipoprotein (HDL)‐cholesterol, triglycerides and IGF‐I were measured centrally in all patients and LDL‐cholesterol was estimated using Friedewald's formula. Results The relative frequency of various statin use was simvastatin 52% (15·8 ± 8·1 mg, mean ± SD), atorvastatin 30% (14·4 ± 7·8 mg), pravastatin 9·8% (31·6 mg ± 13·9 mg), lovastatin 6·6% (17·5 ± 5 mg) and fluvastatin 1·6% (40 mg). Baseline serum total and LDL‐cholesterol (mean ± SD) were 5·2 ± 1·4 and 3·1 ± 1·3 mmol/l in SG and 5·8 ± 1·2 and 3·7 ± 1·0 mmol/l in NSG, respectively (P < 0·0001, SG vs. NSG). After 12 months GH replacement (SG: 0·32 ± 0·17 mg/day; NSG: 0·38 ± 0·1 mg/day) serum total and LDL‐cholesterol decreased by a mean (±SD) of 0·48 (± 1·25) mmol/l (P < 0·0004) and 0·53 (± 1·08) mmol/l (P < 0·0001) in SG and by 0·30 (± 0·89) mmol/l (P < 0·0001) and 0·28 (± 0·80) mmol/l (P < 0·0001) in NSG, respectively. There were no significant changes in HDL‐cholesterol or triglycerides in either group (SG vs. NSG: NS). A relationship between LDL‐cholesterol at baseline and the decrease in LDL‐cholesterol after 12 months GH was evident in both groups (SG: R = –0·54, P < 0·001; NSG: R = –0·4, P < 0·001) and a similar relationship for cholesterol was observed. Conclusions These data indicate that GH replacement exerts additional beneficial effects on lipoprotein profiles in patients on maintenance statin therapy, confirming that the effects of these interventions are complementary rather than exclusive.