M. J. West

Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels

BACKGROUND In patients with coronary heart disease and a broad range of cholesterol levels, cholesterol-lowering therapy reduces the risk of coronary events, but the effects on mortality from coronary heart disease and overall mortality have remained uncertain. METHODS In a double-blind, randomized trial, we compared the effects of pravastatin (40 mg daily) with those of a placebo over a mean follow-up period of 6.1 years in 9014 patients who were 31 to 75 years of age. The patients had a history of myocardial infarction or hospitalization for unstable angina and initial plasma total cholesterol levels of 155 to 271 mg per deciliter. Both groups received advice on following a cholesterol-lowering diet. The primary study outcome was mortality from coronary heart disease. RESULTS Death from coronary heart disease occurred in 8.3 percent of the patients in the placebo group and 6.4 percent of those in the pravastatin group, a relative reduction in risk of 24 percent (95 percent confidence interval, 12 to 35 percent; P<0.001). Overall mortality was 14.1 percent in the placebo group and 11.0 percent in the pravastatin group (relative reduction in risk, 22 percent; 95 percent confidence interval, 13 to 31 percent; P<0.001). The incidence of all cardiovascular outcomes was consistently lower among patients assigned to receive pravastatin; these outcomes included myocardial infarction (reduction in risk, 29 percent; P<0.001), death from coronary heart disease or nonfatal myocardial infarction (a 24 percent reduction in risk, P<0.001), stroke (a 19 percent reduction in risk, P=0.048), and coronary revascularization (a 20 percent reduction in risk, P<0.001). The effects of treatment were similar for all predefined subgroups. There were no clinically significant adverse effects of treatment with pravastatin. CONCLUSIONS Pravastatin therapy reduced mortality from coronary heart disease and overall mortality, as compared with the rates in the placebo group, as well as the incidence of all prespecified cardiovascular events in patients with a history of myocardial infarction or unstable angina who had a broad range of initial cholesterol levels.

Effect of Pravastatin on Cardiovascular Events in People With Chronic Kidney Disease

Background—Limited data describe the cardiovascular benefit of HMG-CoA reductase inhibitors (statins) in people with moderate chronic kidney disease (CKD). The objective of this analysis was to determine whether pravastatin reduced the incidence of cardiovascular events in people with or at high risk for coronary disease and with concomitant moderate CKD. Methods and Results—We analyzed data from the Pravastatin Pooling Project (PPP), a subject-level database combining results from 3 randomized trials of pravastatin (40 mg daily) versus placebo. Of 19 700 subjects, 4491 (22.8%) had moderate CKD, defined by an estimated glomerular filtration rate of 30 to 59.99 mL/min per 1.73 m2 body surface area. The primary outcome was time to myocardial infarction, coronary death, or percutaneous/surgical coronary revascularization. Moderate CKD was independently associated with an increased risk of the primary outcome (adjusted HR 1.26, 95% CI 1.07 to 1.49) compared with those with normal renal function. Among the 4491 subjects with moderate CKD, pravastatin significantly reduced the incidence of the primary outcome (HR 0.77, 95% CI 0.68 to 0.86), similar to the effect of pravastatin on the primary outcome in subjects with normal kidney function (HR 0.78, 95% CI 0.65 to 0.94). Pravastatin also appeared to reduce the total mortality rate in those with moderate CKD (adjusted HR 0.86, 95% CI 0.74 to 1.00, P=0.045). Conclusions—Pravastatin reduces cardiovascular event rates in people with or at risk for coronary disease and concomitant moderate CKD, many of whom have serum creatinine levels within the normal range. Given the high risk associated with CKD, the absolute benefit that resulted from use of pravastatin was greater than in those with normal renal function.

Pravastatin Therapy and the Risk of Stroke

Background Several epidemiologic studies have concluded that there is no relation between total cholesterol levels and the risk of stroke. In some studies that classified strokes according to cause, there was an association between increasing cholesterol levels and the risk of ischemic stroke and a possible association between low cholesterol levels and the risk of hemorrhagic stroke. Recent reviews of trials of 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors have suggested that these agents may reduce the risk of stroke. Methods In a double-blind trial (the Long-Term Intervention with Pravastatin in Ischaemic Disease study), we compared the effects of pravastatin on mortality due to coronary heart disease (the primary end point) with the effects of placebo among 9014 patients with a history of myocardial infarction or unstable angina and a total cholesterol level of 155 to 271 mg per deciliter (4.0 to 7.0 mmol per liter). Our goal in the present study was to assess effects on stroke from any c...

Abnormal Extracellular Matrix Protein Transport Associated With Increased Apoptosis of Vascular Smooth Muscle Cells in Marfan Syndrome and Bicuspid Aortic Valve Thoracic Aortic Aneurysm

Background—Marfan syndrome (MS) is a genetic disorder caused by a mutation in the fibrillin gene FBN1. Bicuspid aortic valve (BAV) is a congenital heart malformation of unknown cause. Both conditions are associated with ascending aortic aneurysm and premature death. This study examined the relationship among the secretion of extracellular matrix proteins fibrillin, fibronectin, tenascin, and vascular smooth muscle cell (VSMC) apoptosis. The role of matrix metalloproteinase (MMP)-2 in VSMC apoptosis was studied in MS aneurysm. Methods and Results—Aneurysm tissue was obtained from patients undergoing surgery (MS: 4 M, 1 F, age 27–45 years; BAV: 3 M, 2 F, age 28–65 years). Normal aorta from subjects with nonaneurysm disease was also collected (4 M, 1 F, age 23–93 years). MS and BAV aneurysm histology showed areas of cystic medial necrosis (CMN) without inflammatory infiltrate. Immunohistochemical study of cultured MS and BAV VSMC showed intracellular accumulation and reduction of extracellular distribution of fibrillin, fibronectin, and tenascin. Western blot showed no increase in expression of fibrillin, fibronectin, or tenascin in MS or BAV VSMC and increased expression of MMP-2 in MS VSMCs.There was 4-fold increase in loss of cultured VSMC incubated in serum-free medium for 24 hours in both MS (27±8%) and BAV (32±14%) compared with control (7±5%). Conclusions—In MS and BAV there is alteration in both the amount and quality of secreted proteins and an increased degree of VSMC apoptosis. Up-regulation of MMP-2 might play a role in VSMC apoptosis in MS VSMC. The findings suggest the presence of a fundamental cellular abnormality in BAV thoracic aorta, possibly of genetic origin.

‘Steady-state’ properties of the baroreceptor-heart rate reflex in essential hypertension in man

SUMMARY 1. Rises and falls in mean arterial (MAP) and pulse (PP) pressures from the resting value were evoked by intravenous injections of phenylephrine and glyceryl trinitrate, and were related to the reflexly evoked changes in heart period (HP; pulse interval).

A multicenter, double-blind, one-year study comparing safety and efficacy of atorvastatin versus simvastatin in patients witb hypercholesterolemia☆

We directly compared the safety and efficacy of atorvastatin and simvastatin in hypercholesterolemic patients. This 1-year, randomized, double-blind study was performed at 9 community- and university-based research hospitals in Australia. One-hundred seventy-seven patients between the ages of 18 and 80 years with baseline low-density-lipoprotein (LDL) cholesterol ≤4.14 and ≤7.76 mmol/L (160 and 300 mg/dl, respectively) and triglycerides ≤4.52 mmol/L (400 mg/dl) received once-daily dosing with atorvastatin (Lipitor) 10 mg or simvastatin (Zocor) 10 mg. At week 16, the dose of medication was titrated to atorvastatin 20 mg or simvastatin 20 mg if patients did not meet LDL cholesterol target of ≤ 3.36 mmol/L (130 mg/dl). Efficacy was reported as percent change from baseline in LDL cholesterol, total cholesterol, very low density lipoprotein cholesterol, total triglycerides, high-density lipoprotein cholesterol, apolipoproteins Al and B, and lipoprotein(a). Atorvastatin caused significantly greater reductions from baseline than did simvastatin for LDL cholesterol, total cholesterol, very low density lipoprotein cholesterol, triglycerides, and apolipoprotein B (p <0.05). No patient in either treatment group had clinically important elevations in creatine phosphokinase, alanine amino-transaminase, or aspartate aminotransaminase. No serious adverse events were considered associated with treatment. With atorvastatin 10 mg, 46% of the patients achieved LDL cholesterol target goal by week 16, whereas only 27% of the simvastatin patients achieved the target goal at the 10-mg dose. This cholesterol-lowering profile affords utility in many patient types.

Effect of Pravastatin on Rate of Kidney Function Loss in People With or at Risk for Coronary Disease

Background—Limited data suggest that HMG-CoA reductase inhibitors (statins) reduce rates of kidney function loss. We performed this analysis to determine whether pravastatin reduced the rate of kidney function loss over ≈5 years in people with or at high risk for coronary disease. Methods and Results—This was a post hoc subgroup analysis of data from 3 randomized double-blind controlled trials comparing pravastatin 40 mg/d and placebo in subjects with a previous acute coronary syndrome or who were at high cardiovascular risk. The primary outcome was the rate of change in estimated glomerular filtration rate (GFR; in mL/min per 1.73 m2/y). The Modified Diet and Renal Disease Study (MDRD) and Cockcroft-Gault equations were used to estimate GFR. We studied 18 569 participants, 3402 (18.3%) of whom had moderate chronic kidney disease as defined by an estimated GFR of 30 to 59.9 mL/min per 1.73 m2 body surface area. In subjects with moderate chronic kidney disease at baseline, pravastatin reduced the adjusted rate of kidney function loss by ≈34%, although the absolute reduction in the rate of loss was small (0.22 mL/min per 1.73 m2/y by MDRD-GFR; 95% CI, 0.07 to 0.37). Pravastatin did not reduce the frequency of ≥25% decreases in kidney function in this group when MDRD-GFR was used to estimate GFR (relative risk [RR], 0.84; 95% CI, 0.66 to 1.06). When all 18 569 subjects were considered, pravastatin reduced the adjusted rate of kidney function loss by 8% (0.08 mL/min per 1.73 m2/y by MDRD-GFR; 95% CI, 0.01 to 0.15) and the risk of acute renal failure (RR, 0.60; 95% CI, 0.41 to 0.86) but did not significantly reduce the frequency of a ≥25% decline in kidney function by MDRD-GFR (RR, 0.94; 95% CI, 0.88 to 1.01). Conclusions—Pravastatin modestly reduced the rate of kidney function loss in people with or at risk for cardiovascular disease. However, the primary indication for the use of statins in people with or at risk for coronary events remains the reduction in mortality that results from their use.

Brachial Blood Pressure But Not Carotid Arterial Waveforms Predict Cardiovascular Events in Elderly Female Hypertensives

Central arterial waveforms and related indices of large artery properties can be determined with relative ease. This would make them an attractive adjunct in the risk stratification for cardiovascular disease. Although they have been associated with some classical risk factors and the presence of coronary disease, their prospective value in predicting cardiovascular outcomes is unknown. The present study determined the relative predictive value for cardiovascular disease–free survival of large artery properties as compared with noninvasive brachial blood pressure alone in a population of elderly female hypertensive subjects. We measured systemic arterial compliance, central systolic pressure, and carotid augmentation index in a subset of female participants in the Second Australian National Blood Pressure Study (untreated blood pressure 169/88±12/8 mm Hg). There were a total of 53 defined events during a median of 4.1 years of follow-up in 484 women with complete measurements. Although baseline blood pressures at the brachial artery predicted cardiovascular disease–free survival (hazard ratio [HR], 2.3; 95% CI, 1.3 to 4.1 for pulse pressure ≥81 versus <81 mm Hg; P=0.01), no such relation was found for carotid augmentation index (HR, 0.80; 95% CI, 0.44 to 1.44; P value not significant) or systemic arterial compliance (HR, 1.25; 95% CI, 0.72 to 2.16; P value not significant). Blood pressure, but not noninvasively measured central arterial waveforms, predict outcome in the older female hypertensive patient. Thus, blood pressure measurement alone is superior to measurement of arterial waveforms in predicting outcome in this group.

Increases in plasma neuropeptide Y concentrations during sympathetic activation in man.

Neuropeptide Y (NPY) coexists with noradrenaline in postganglionic sympathetic neurons. In order to test the hypothesis that NPY may be released along with catecholamines by activation of the sympathoadrenal system we measured plasma NPY-like immunoreactivity (NPY-LI) concentrations during cold pressor test, head up tilt and bicycle exercise in healthy volunteers. All 3 manoeuvres resulted in elevation of blood pressure, heart rate and plasma noradrenaline and adrenaline concentrations. These were accompanied by increases in plasma NPY-LI concentrations on cold pressor test and exercise, but not with head up tilt. The increases in both NPY-LI and catecholamines were greatest with exercise. These findings suggest that NPY is released at the same time as noradrenaline when sympathetic noradrenergic nerves are activated.

Central Nervous System Control of Baroreceptor Reflexes in the Rabbit

Aortic and inferior vena caval balloons were used to alter mean arterial blood pressure, pulse pressure (PP), and right atrial pressure (RAP) in unanesthetized rabbits and to reflexly evoke changes in heart period (pulse interval). Curves relating mean arterial blood pressure to heart period were compared in different groups of rabbits at similar ΔPP and ΔRAP. Median blood pressure (BP50), average gain (G), and heart period range (maximum to minimum heart period) were calculated from the S-shaped curves. The reflex was evoked from arterial baroreceptors and probably from cardiac and pulmonary baroreceptors. Curves relating mean arterial blood pressure and heart period differed with regard to BP50 and G in sham-operated, thalamic, and pontine rabbits, indicating that suprabulbar centers normally play a role in the reflex. Curves from sham-operated and pontine rabbits treated with atropine also differed, suggesting suprabulbar control of sympathetic effectors. In intact rabbits, forebrain and diencephalic centers caused vagal and sympathetic effectors to respond over the same arterial blood pressure range, but, in pontine rabbits, the effectors responded over dissimilar ranges. In intact rabbits, changes in mean arterial blood pressure evoked reciprocal and nearly equal changes in vagal and sympathetic effectors, but, in pontine rabbits, a given pressure change altered heart period predominantly through one effector. In sham-operated rabbits, vagal effects on heart period were lower by a constant amount at every level of mean arterial blood pressure than they were in pontine rabbits, suggesting that suprabulbar centers exerted a tonic inhibitory effect on vagal motoneurons not involved in the reflex.