Apolipoprotein E genotypes and response of plasma lipids and progression-regression of coronary atherosclerosis to lipid-lowering drug therapy.

OBJECTIVES: We sought to examine the association of apolipoprotein (apo) E genotypes with baseline plasma lipid levels and severity of coronary artery disease (CAD), as well as the response to treatment with fluvastatin in the Lipoprotein and Coronary Atherosclerosis Study (LCAS). BACKGROUND: Apo E genotypes have been associated with plasma lipid levels and CAD. However, the influence of apo E genotypes on the response of plasma lipids and CAD progression or regression to statin treatment in patients with mildly to moderately elevated cholesterol remains unknown. METHODS: Apo E genotypes were determined by polymerase chain reaction and restriction mapping. Plasma lipids were measured at baseline and 12 weeks after therapy with fluvastatin or placebo in 320 subjects. In 287 subjects, quantitative coronary angiography was performed at baseline and after 2.5 years of treatment. RESULTS: Subjects with the 3/3 genotype had greater reductions in total cholesterol (20.4% vs. 15.4%, p = 0.01) and low density lipoprotein (LDL) cholesterol (28.8% vs. 22.7%, p = 0.03) than did the subjects with the 3/4 or 4/4 genotype. In contrast, subjects with the 2/3 genotype (n = 10) had a greater increase in high density lipoprotein cholesterol (19.1%) than did the subjects with the 3/3 genotype (4.3%, p = 0.002) and those with the 3/4 or 4/4 genotype (7.0%, p = 0.02). Subjects with the 3/4 or 4/4 genotype had an increased frequency of previous angioplasty, but other measures of baseline CAD severity and baseline lipids did not differ significantly among the genotypes, nor did CAD progression or clinical events. CONCLUSIONS: Although subjects with the epsilon4 allele had less reduction in LDL cholesterol with fluvastatin, they had similar benefit in terms of CAD progression.

Shocks as predictors of survival in patients with implantable cardioverter-defibrillators.

OBJECTIVES: The objective of the study was to determine whether the occurrence of shocks for ventricular tachyarrhythmias during therapy with implantable cardioverter-defibrillators (ICD) is predictive of shortened survival. BACKGROUND: Ventricular tachyarrhythmias eliciting shocks are often associated with depressed ventricular function, making assessment of shocks as an independent risk factor difficult. METHODS: Consecutive patients (n = 421) with a mean follow-up of 756+/-523 days were classified into those who had received no shock (n = 262) or either one of two shock types, defined as single (n = 111) or multiple shocks (n = 48) per arrhythmia episode. Endpoints were all-cause and cardiac deaths. A survival analysis using a stepwise proportional hazards model evaluated the influence of two primary variables, shock type and left ventricular ejection fraction (LVEF <35% or >35%). Covariates analyzed were age, gender, NYHA Class, coronary artery disease, myocardial infarction, coronary revascularization, defibrillation threshold and tachyarrhythmia inducibility. RESULTS: The most complete model retained LVEF (p = 0.005) and age (p = 0.023) for the comparison of any shock versus no shock (p = 0.031). The occurrence of any versus no shock, or of multiple versus single shocks significantly decreased survival at four years, and these differences persisted after adjustment for LVEF. In the LVEF subgroups <35% and <25%, occurrence of multiple versus no shock more than doubled the risk of death. Compared with the most favorable group LVEF > or =35% and no shock, risk in the group multiple shocks and LVEF <35% was increased 16-fold. CONCLUSIONS: In defibrillator recipients, shocks act as potent predictors of survival independent of several other risk factors, particularly ejection fraction.

Influence of low HDL on progression of coronary artery disease and response to fluvastatin therapy.

BACKGROUND--Patients with coronary artery disease (CAD) commonly have low HDL cholesterol (HDL-C) and mildly elevated LDL cholesterol (LDL-C), leading to uncertainty as to whether the appropriate goal of therapy should be lowering LDL-C or raising HDL-C. METHODS AND RESULTS--Patients in the Lipoprotein and Coronary Atherosclerosis Study (LCAS) had mildly to moderately elevated LDL-C; many also had low HDL-C, providing an opportunity to compare angiographic progression and the benefits of the HMG-CoA reductase inhibitor fluvastatin in patients with low versus patients with higher HDL-C. Of the 339 patients with biochemical and angiographic data, 68 had baseline HDL-C <0.91 mmol/L (35 mg/dL), mean 0.82+/-0.06 mmol/L (31. 7+/-2.2 mg/dL), versus 1.23+/-0.29 mmol/L (47.4+/-11.2 mg/dL) in patients with baseline HDL-C >/=0.91 mmol/L. Among patients on placebo, those with low HDL-C had significantly more angiographic progression than those with higher HDL-C. Fluvastatin significantly reduced progression among low-HDL-C patients: 0.065+/-0.036 mm versus 0.274+/-0.045 mm in placebo patients (P=0.0004); respective minimum lumen diameter decreases among higher-HDL-C patients were 0. 036+/-0.021 mm and 0.083+/-0.019 mm (P=0.09). The treatment effect of fluvastatin on minimum lumen diameter change was significantly greater among low-HDL-C patients than among higher-HDL-C patients (P=0.01); among low-HDL-C patients, fluvastatin patients had improved event-free survival compared with placebo patients. CONCLUSIONS--Although the predominant lipid-modifying effect of fluvastatin is to decrease LDL-C, patients with low HDL-C received the greatest angiographic and clinical benefit.

Body weight gain is correlated with serum cholesterol at 8 weeks of age in pigs selected for four generations for low or high serum cholesterol.

We determined the relationship of BW at birth, weaning (4 wk of age), and 8 wk of age to serum total cholesterol (C), high-density lipoprotein-cholesterol (HDL-C), and triglycerides (TG) at 8 wk of age in pigs, from the fourth generation that had been selected for low (10 litters, 75 pigs, LC) or high (10 litters, 63 pigs, HC) C at 8 wk of age. Mean C concentration at 8 wk of age was 81 +/- 30 mg/dL for LC groups and 136 +/- 19 mg/dL for HC groups. Serum C, HDL-C, and TG concentrations were not correlated with birth weight, suggesting that the physiological factors that may cause reduced weight gain in older animals are not operative in newborn pigs. All three constituents were correlated (P < .05) with BW at weaning and at 8 wk. However, only 4% of the variation in weight at weaning and 7% at 8 wk could be explained by a relationship with serum TG. There was a positive correlation between C and BW at 8 wk (r = .46, P < .05), which was apparent within the subgroups of LC and HC females and LC males (r = .46, .48, .68, respectively); the correlation was low (r = .26) in HC males.

Growth failure in children with inflammatory bowel disease: a prospective study.

BACKGROUND: Growth failure frequently complicates the clinical course of inflammatory bowel disease (IBD) in children. This study was designed to investigate the role of disease activity versus steroid therapy on growth faltering in this disorder. METHODS: We studied growth failure and its relationship to disease activity and steroid therapy in 69 children who have IBD by prospectively monitoring height for a maximum of 3 years. Disease activity and steroid use were recorded at entry into the study. RESULTS: The prevalence of growth failure was 24%, 23%, and 39% by height velocity, Z score, and height-for-age criteria, respectively; deficits were equally prevalent regardless of the stage of pubertal development. A delay in linear growth persisted throughout puberty and was not reversed after surgery. Patients who had Crohn's disease were twice as likely to have growth abnormalities than patients who had ulcerative colitis. We detected significant negative associations between linear growth and disease activity but not steroid therapy. CONCLUSIONS: In a unique group of children, growth failure is an early, "prepatterned" manifestation of IBD. The inflammatory process, rather than steroid use, has a predominant influence on the development of growth faltering.