Carl J. Vaughan

Statins do more than just lower cholesterol

Clinical trials have demonstrated that inhibitors of 3hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (statins) greatly reduce cardiovascular-related morbidity and mortality in patients with and without coronary artery disease. 1,2 These drugs were designed to inhibit the rate-limiting enzyme of cholesterol synthesis in the liver, thereby decreasing hepatic production of lowdensity lipoprotein (LDL), and upregulating expression of hepatic LDL receptors, thus lowering concentrations of circulating LDL. With lower plasma LDL concentrations, plaque development should be retarded or should regress because of lipid loss, which would render the plaque less occlusive and less likely to disrupt or cause thrombosis. The use of simvastatin in the Scandinavian (4S) secondary intervention study 1 and the use of pravastatin in the West of Scotland Coronary Prevention Study (WOSCOPS) primary intervention trial 2 supported the hypothesis that drugs that lower plasma cholesterol concentration are of benefit to patients with coronary artery disease. However, the clinical benefit of the drugs used in these studies is manifest early in the course of lipidlowering therapy before plaque regression could occur. Quantitative angiographic assessments of the impact of statin therapy on coronary atherosclerosis have demonstrated that improvement in arterial topographical morphology occurs slowly and only to a small extent. 3 In the Multicentre Anti-Atheroma Study (MAAS), 3

Mutations in the protein kinase A R1α regulatory subunit cause familial cardiac myxomas and Carney complex

Cardiac myxomas are benign mesenchymal tumors that can present as components of the human autosomal dominant disorder Carney complex. Syndromic cardiac myxomas are associated with spotty pigmentation of the skin and endocrinopathy. Our linkage analysis mapped a Carney complex gene defect to chromosome 17q24. We now demonstrate that the PRKAR1alpha gene encoding the R1alpha regulatory subunit of cAMP-dependent protein kinase A (PKA) maps to this chromosome 17q24 locus. Furthermore, we show that PRKAR1alpha frameshift mutations in three unrelated families result in haploinsufficiency of R1alpha and cause Carney complex. We did not detect any truncated R1alpha protein encoded by mutant PRKAR1alpha. Although cardiac tumorigenesis may require a second somatic mutation, DNA and protein analyses of an atrial myxoma resected from a Carney complex patient with a PRKAR1alpha deletion revealed that the myxoma cells retain both the wild-type and the mutant PRKAR1alpha alleles and that wild-type R1alpha protein is stably expressed. However, in this atrial myxoma, we did observe a reversal of the ratio of R1alpha to R2beta regulatory subunit protein, which may contribute to tumorigenesis. Further investigation will elucidate the cell-specific effects of PRKAR1alpha haploinsufficiency on PKA activity and the role of PKA in cardiac growth and differentiation.

Familial Thoracic Aortic Aneurysms and Dissections Genetic Heterogeneity With a Major Locus Mapping to 5q13-14

Background—Aneurysms and dissections affecting the ascending aorta are associated primarily with degeneration of the aortic media, called medial necrosis. Families identified with dominant inheritance of thoracic aortic aneurysms and dissections (TAA/dissections) indicate that single gene mutations can cause medial necrosis in the absence of an associated syndrome. Methods and Results—Fifteen families were identified with multiple members with TAAs/dissections. DNA from affected members from 2 of the families was used for a genome-wide search for the location of the defective gene by use of random polymorphic markers. The data were analyzed by the affected-pedigree-member method of linkage analysis. This analysis revealed 3 chromosomal loci with multiple markers demonstrating evidence of linkage to the phenotype. Linkage analysis using further markers in these regions and DNA from 15 families confirmed linkage of some of the families to 5q13-14. Genetic heterogeneity for the condition was confirmed by a heterogeneity test. Data from 9 families with the highest conditional probability of being linked to 5q were used to calculate the pairwise and multipoint logarithm of the odds (LOD) scores, with a maximum LOD of 4.74, with no recombination being obtained for the marker D5S2029. In 6 families, the phenotype was not linked to the 5q locus. Conclusions—A major locus for familial TAAs and dissections maps to 5q13-14, with the majority (9 of 15) of the families identified demonstrating evidence of linkage to this locus. The condition is genetically heterogeneous, with 6 families not demonstrating evidence of linkage to any loci previously associated with aneurysm formation.

Update on Statins: 2003

Received March 31, 2004; revision received May 28, 2004; accepted June 3, 2004. The number of significant developments in the years since the first version of this review has made necessary an update about the evolving role of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, or statins, in the management and prevention of cardiovascular disease.1 Two contrasting events have dominated the statin field in the last 3 years. First, the withdrawal of cerivastatin in 2001 reignited the issue of statin safety. Second, the efficacy and safety of statins in both the primary and secondary prevention of cardiovascular disease in diverse patient populations have helped shape the most recent set of guidelines from the National Cholesterol Education Program (NCEP).2 The NCEP’s Third Adult Treatment Panel (ATP III) forms the basis for contemporary lipid management. However, very recent trials suggest that even lower LDL cholesterol (LDL-C) targets may be indicated in high-risk patients. Improved understanding of the metabolism, safety, and clinical effects of this class of drugs has placed the statins at the forefront of drug strategies to treat dyslipidemia. HMG-CoA reductase is the rate-limiting enzyme for cholesterol formation in the liver and other tissues. By inhibiting HMG-CoA reductase, statins reduce the hepatocyte cholesterol content, stimulate expression of LDL receptors, and ultimately enhance removal of LDL-C from the circulation. X-ray crystallographic studies have determined the structures of the catalytic portions of HMG-CoA reductase in complex with statins.3 These studies show that the HMG-like moiety of statins occupies the HMG binding site of the reductase enzyme, thus sterically inhibiting the substrate from binding. Additional structural differences among the statins have been elucidated through such crystallographic studies that may account for some differences in the potency of statins. However, atorvastatin, fluvastatin, and rosuvastatin exhibit additional binding via their fluorophenyl groups and the HMG-CoA …

Identification of a Chromosome 11q23.2-q24 Locus for Familial Aortic Aneurysm Disease, a Genetically Heterogeneous Disorder

Background—Aortic aneurysms cause significant mortality, and >20% relate to hereditary disorders. Familial aortic aneurysm (FAA) has been described in such conditions as the Marfan and Ehlers-Danlos type IV syndromes, due to defects in the fibrillin-1 and type III procollagen genes, respectively. Other gene defects that cause isolated aneurysms, however, have not thus far been described. Methods and Results—We studied 3 families affected by FAA. No family met the diagnostic criteria for either Marfan or Ehlers-Danlos syndrome. Echocardiography defined involvement of both the thoracic and abdominal aorta. In family ANA, candidate gene analysis excluded linkage to loci associated with aneurysm formation, including fibrillin-1, fibrillin-2, and type III procollagen, and chromosome 3p24.2-p25. Genome-wide linkage analysis identified a 2.3-cM FAA locus (FAA1) on chromosome 11q23.3-q24 with a maximum multipoint logarithm of the odds score of 4.4. In family ANB, FAA was linked to fibrillin-1. In family ANF, however, FAA was not linked to any locus previously associated with aneurysm formation, including fibrillin-1 and FAA1. Conclusions—FAA disease is genetically heterogeneous. We have identified a novel FAA locus at chromosome 11q23.3-q24, a critical step toward elucidating 1 gene defect responsible for aortic dilatation. Future characterization of the FAA1 gene will enhance our ability to achieve presymptomatic diagnosis of aortic aneurysms and will define molecular mechanisms to target therapeutics.

Medical causes of seizures

Seizures are commonly encountered in patients who do not have epilepsy. Factors that may provoke such seizures include organ failure, electrolyte imbalance, medication and medication withdrawal, and hypersensitive encephalopathy. There is usually one underlying cause, which may be reversible in some patients. A full assessment should be done to rule out primary neurological disease. Treatment of seizures in medically ill patients is aimed at correction of the underlying cause with appropriate short-term anticonvulsant medication. Phenytoin is ineffective in the management of seizures secondary to alcohol withdrawal, and in those due to theophylline or isoniazid toxicity. Control of blood pressure is important in patients with renal failure and seizures. Non-convulsive status epilepticus should be considered in any patient with confusion or coma of unclear cause, and electroencephalography should be done at the earliest opportunity. Most ill patients with secondary seizures do not have epilepsy, and this should be explained to patients and their families. Only those patients with recurrent seizures and uncorrectable predisposing factors need long-term treatment with anticonvulsant medication.

Vascular Effects of Statins in Stroke

BACKGROUND Recent clinical trials and meta-analyses of beta-hydroxy-beta-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have demonstrated a reduction in ischemic stroke in patients with a history of coronary artery disease both with and without elevations of serum cholesterol. This review summarizes clinical trials of these compounds and their recent impact on stroke and explores the underlying vascular mechanisms of their actions. SUMMARY OF REVIEW Use of statins in patients with vascular disease has been shown to lower the incidence of stroke by approximately 30%. Statins exhibit a number of antiatherosclerotic and antithrombotic properties that likely underlie the recently observed reductions in cerebrovascular disease. Statins reduce inflammatory, proliferative, and thrombogenic processes in plaque, making it less likely to rupture. Additionally, they reverse the endothelial dysfunction and platelet activation accompanying hypercholesterolemia and may reduce the tendency to thrombosis. CONCLUSIONS Hypercholesterolemia has reemerged as a risk factor for ischemic stroke. Statins protect against thromboembolic stroke through multiple beneficial effects within the vascular milieu. Further data are awaited to support the growing importance of cholesterol as a risk factor for ischemic stroke and the benefits of statin therapy in patients with cerebrovascular disease.

Prevention of stroke and dementia with statins: effects beyond lipid lowering

Stroke is a major cause of mortality and morbidity. The epidemiologic association between elevated serum cholesterol and stroke risk is controversial. However, recent secondary prevention studies with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have demonstrated a significant reduction in ischemic stroke without an increase in hemorrhagic stroke. Statins probably reduce stroke by a variety of mechanisms, including modulation of precerebral atherothrombosis in the aorta and the carotid artery, thus preventing plaque disruption and artery-to-artery thromboembolism. Statins also improve endothelial homeostasis by increasing the bioavailability of nitric oxide, which orchestrates the paracrine antiatherosclerotic functions of the endothelium. Studies in experimental models of ischemic stroke show that statin therapy reduces brain infarct size and improves neurologic outcome by directly upregulating brain endothelial nitric oxide synthase. Putative anti-inflammatory actions of statins may also contribute to neuroprotection and stroke prevention. Although the clinical benefit of statins largely depends on lowering low-density lipoprotein cholesterol, accumulating data indicate that many of the pleiotropic effects of statins are attributable to the cellular consequences of depletion of intermediates in the cholesterol biosynthetic pathway (isoprenoids). These molecules play fundamental roles in cell growth, signal transduction, and mitogenesis. In addition to reducing stroke risk, emerging data suggest that statins may reduce dementia. Further studies are needed to fully address the role of statins in the prevention of stroke in patients without established vascular disease and the role of cholesterol modulation in the treatment of dementia.

Erythropoietin-associated hypertensive posterior leukoencephalopathy

Human recombinant erythropoietin is used to treat chronic anemia in patients with end-stage renal failure. Erythropoietin causes hypertension, and hypertensive encephalopathy has been associated with its use. We describe six dialysis-dependent, chronic renal failure patients who developed hypertension, headache, and seizures while on erythropoietin. Four of the six patients had posterior white matter changes on neuroimaging. The encephalopathy was managed by prompt antihypertensive and anticonvulsant treatment and by discontinuation of erythropoietin. Hypertensive posterior leukoencephalopathy is associated with erythropoietin use.

Statin therapy and stroke prevention.

Hypercholesterolemia has not traditionally been considered an important risk factor in the pathogenesis of stroke. However, recent studies show that statin therapy significantly reduces ischemic stroke for patients with established coronary artery disease. Statin therapy may reduce stroke through amelioration of precerebral atherosclerosis in the carotid artery and the aorta. Anti-atherosclerotic, anti-inflammatory, and antithrombotic actions of statins occur within the blood and in plaque. Statins may also protect against cerebral ischemia through beneficial modulation of the brain endothelial nitric oxide system. Ongoing studies are exploring the role of statin therapy in the primary prevention of stroke and in the prevention of cognitive decline and multi-infarct cerebrovascular disease.