Biomedical subjects

Wilma Petersen

Publications and source records attributed to Wilma Petersen.

3 recordsLinked to original sources

PubMed2005

Compromised LCAT function is associated with increased atherosclerosis.

BACKGROUND: Prospective epidemiological studies have shown that low plasma levels of HDL cholesterol (HDL-C) are associated with an increased risk for cardiovascular disease (CVD). Despite nearly 40 years of research, however, it is unclear whether this also holds true for individuals with severely reduced levels of HDL-C due to mutations in the lecithin:cholesterol acyltransferase (LCAT) gene. Better insight into CVD risk in these individuals may provide clues toward the potential of LCAT as a pharmaceutical target to raise HDL-C levels. METHODS AND RESULTS: Lipids, lipoproteins, high-sensitivity C-reactive protein (CRP), and carotid artery intima-media thickness (IMT) were assessed in 47 heterozygotes for LCAT gene mutations and 58 family controls. Compared with controls, heterozygotes presented with a mean 36% decrease in HDL-C levels (P<0.0001), a 23% increase in triglyceride levels (P<0.0001), and a 2.1-fold increase in CRP levels (P<0.0001). Mean carotid IMT was significantly increased in heterozygotes compared with family controls (0.623+/-0.13 versus 0.591+/-0.08 mm). After adjustment for age, gender, and alcohol use, this difference proved statistically significant (P<0.0015). CONCLUSIONS: The data show that heterozygosity for LCAT gene defects is associated with low HDL-C levels and elevated concentration of triglycerides and CRP in plasma. This phenotype underlies increased IMT in carriers versus controls, which suggests that LCAT protects against atherosclerosis. This in turn indicates that targeting LCAT to raise HDL-C may reduce CVD risk.

Adult↗

PubMed2005

Gene therapy for lipoprotein lipase deficiency: working toward clinical application.

Lipoprotein lipase (LPL) deficiency causes hypertriglyceridemia and recurrent, potentially life-threatening pancreatitis. There currently is no adequate treatment for this disease. Previously, we showed that intramuscular administration of an adeno-associated virus serotype 1 (AAV1) vector encoding the human LPL(S447X) variant cDNA (AAV1-LPL(S447X)) normalized the dyslipidemia of LPL-/- mice for more than 1 year. In preparation for a clinical trial, we evaluated the safety and biodistribution of AAV1-LPL(S447X) in wild-type mice and fully characterized six LPL-deficient patients. Toxicological analysis in mice showed that intramuscular administration was well tolerated. Acute inflammatory response markers were transiently increased, and anti- AAV1 antibodies were generated. Histological analyses indicated a dose-dependent reversible spleen hyperplasia, and myositis at the injection sites. Biodistribution data showed short-term vector leakage from injection sites into the circulation, followed by liver-mediated clearance. Persistence of vector DNA was limited to the injected muscle and draining lymph nodes, and spread to reproductive organs was limited. Characterization of LPL-deficient patients showed that all patients presented with hypertriglyceridemia and recurrent pancreatitis. LPL catalytic activity was absent, but LPL protein levels were 20-100% of normal. Myoblasts derived from skeletal muscle biopsies of these patients were efficiently transduced by AAV1-LPL(S447X) and secreted active LPL. These data support the initiation of a clinical trial in LPL-deficient patients, for which regulatory approval has been granted.

Animals↗

PubMed2004

A novel apoA-I mutation (L178P) leads to endothelial dysfunction, increased arterial wall thickness, and premature coronary artery disease.

OBJECTIVES: We investigated the consequences of an apolipoprotein A-I (apoA-I) gene defect with regard to lipid metabolism, endothelial function, arterial wall thickness, and coronary artery disease (CAD) risk. BACKGROUND: Due to limited numbers of carriers of the apoA-I defects, data on the consequences of such defects have remained inconclusive. METHODS: Lipids and lipoproteins were measured in 54 apoA-I (L178P) carriers and 147 nonaffected siblings. Flow-mediated dilation (FMD) was assessed in 29 carriers and 45 noncarriers, and carotid intima-media thickness (IMT) could be determined in 33 heterozygotes and 40 controls. Moreover, CAD risk was evaluated for all apoA-I mutation carriers. RESULTS: Heterozygotes exhibited lower plasma levels of apoA-I (-50%; p < 0.0001) and high-density lipoprotein cholesterol (-63%; p < 0.0001). In addition, carriers had impaired FMD (p = 0.012) and increased carotid IMT (p < 0.001), whereas multivariate analysis revealed that heterozygotes had a striking 24-fold increase in CAD risk (p = 0.003). CONCLUSIONS: Heterozygosity for a novel apoA-I mutation underlies a detrimental lipoprotein profile that is associated with endothelial dysfunction, accelerated carotid arterial wall thickening, and severely enhanced CAD risk. Importantly, the extent of atherosclerosis in these subjects was similar to the burden of premature arterial wall abnormalities seen in patients with familial hypercholesterolemia. These data illustrate the pivotal role in humans of apoA-I in the protection against CAD.

Adult↗