Achilles tendon thickness and ischemic heart disease in familial hypercholesterolemia

Achilles tendon thickness (ATT) of 112 patients with familial hypercholesterolemia (FH) with and without ischemic heart disease (IHD) was measured radiographically and was compared with that of normal subjects. The mean and SD of serum cholesterol in the heterozygotes (107 cases), the homozygotes (5 cases) and the normal subjects (36 cases) were 347 ± 63, 589 ± 69 and 187 ± 30 mg/dl, respectively. The mean and SEM of ATT in the heterozygotes, the homozygotes and the normal subjects were 12.5 ± 0.4 mm, 18.6 ± 6.6 mm, and 6.3 ± 0.2 mm, respectively. Cutaneous xanthomas were observed in 34 out of 112 patients (30.4%). Increased ATT was observed in 95 (84.8%). IHD was diagnosed in 39 (34.8%). The ATT of FH with IHD was significantly thicker than that of FH without IHD (p < 0.05) and that of normal subjects (p < 0.001). Thus, the increased ATT evaluated by x-ray was the earliest clinical sign of FH and the measurement of ATT seems to be a useful adjunctive procedure for detecting familial hypercholesterolemic patients and predicting IHD in them.     

Genetic factors of risk of ischemic heart disease development in patients with familial hypercholesterolemia

Ischemic heart disease (IHD) develops in patients with familial hypercholesterolemia (FHC) 15-20 years earlier than in general population. However age of onset of the disease, its clinical manifestations are variable and not completely determined by cholesterol level and class of low density lipoprotein receptor mutations. AIM: To elucidate associations of some auxiliary genetic factors -- such as C151565T, C677T, R353Q polymorphisms of glycoprotein IIIa (GPIIIa), methylenetetrahydrofolate reductase (MTHFR) and coagulation factor VII genes, respectively, -- with the presence of IHD in patients with FHC. MATERIAL: Patients with clinical diagnosis of heterozygous FHC (n=198) with (n=106) and without (n=92) IHD. RESULTS: Patients with compared with those without IHD had similar frequency of T-allele of MTHFR gene (p=0.519), more often had T-allele of GPIIIa gene (23 and 12.5%, respectively, p=0.009), and less often -- Q-allele of factor VII gene (13 and 21%, respectively, p=0.048). Multifactorial analysis showed that risk of IHD was higher in patients with TT compared with CC genotype of the GPIIIa gene (OR 1.53, 95%CI 1.12-2.3), and lower in patients with RQ and QQ compared with RR genotype of factor VII gene (OR 0.41, 95%CI 0.19-0.75). CONCLUSION: In patients with FHC polymorphisms in factor VII and GPIIIa genes but not C677T polymorphism of MTHFR gene were associated with the presence of IHD.     

Plasma high-density lipoproteins and ischemic heart disease: studies in a large kindred with familial hypercholesterolemia.

The expression of ischemic heart disease was studied in a large kindred with familial hypercholesterolemia. Tendon xanthomas, multiple generation transmission, and the appearance of bimodality in the distributions of total and low-density lipoprotein cholesterol were found. The segregation ratio was 0.9 in females and 0.43 in males, a difference first apparent during adolescence. The upper quartile of total and low-density lipoprotein cholesterol contained all but two cases of ischemic disease, whereas the lower quartile of high-density lipoprotein cholesterol contained one half of the cases. The ratio of high- to low-density lipoprotein cholesterol (range, 0.06 to 1.6) was less than or equal to 0.20 in each patient with ischemic disease. The association of a low level of high-density lipoprotein cholesterol with ischemic disease persisted after adjustment for differences in other lipids and lipoproteins. A low level of high-density lipoprotein cholesterol, as well as a high level of low-density lipoprotein cholesterol, may influence the development of ischemic heart disease in this disorder.     

Haplotype of the angiotensinogen gene is associated with coronary heart disease in familial hypercholesterolemia

OBJECTIVE: Familial hypercholesterolemia is characterized by high plasma low-density lipoprotein cholesterol levels and premature coronary heart disease. Despite the monogenetic origin of familial hypercholesterolemia, the incidence of coronary heart disease varies considerably among patients, which is only partly explained by classical risk factors. Hypertension is an important risk factor for coronary heart disease that is associated with angiotensinogen levels. Therefore, we analyzed the angiotensinogen gene as a modifier gene for coronary heart disease risk in patients with familial hypercholesterolemia. METHODS: In a cohort of 1785 familial hypercholesterolemia patients, we reconstructed five frequent haplotypes of the angiotensinogen gene, based on four polymorphisms. The five haplotypes cover approximately 98% of the genetic diversity accounted for by these four polymorphisms. The associations between the haplotypes and coronary heart disease were analyzed with the haplo.stats program, adjusted for age, sex and smoking. RESULTS: Patients homozygous for the C allele of the 4072 T>C polymorphism had a 34% increased coronary heart disease risk (P = 0.017) compared to patients homozygous for the T allele. Haplotype H3, consisting of the minor allele of the 4072T>C polymorphism and the major alleles of the other polymorphisms, had a frequency of 15% and was associated with a 45% increased coronary heart disease risk (P = 0.006) compared to the wild-type haplotype H1. CONCLUSIONS: We conclude that genetic variation in the angiotensinogen gene contributes to coronary heart disease risk in patients with familial hypercholesterolemia.     

Development of coronary heart disease in familial hypercholesterolemia

We studied the development of coronary artery disease in 10 homozygous and 692 heterozygous patients with familial hypercholesterolemia. Seventy-five (22%) male heterozygotes and 35 (10%) female heterozygotes were affected by myocardial infarction, which was first noted in men in the 3rd decade of life and in women in the 4th decade of life. Thirty-eight (70%) out of the deceased 54 heterozygous patients died of coronary heart disease. The mean age at death was significantly less in male heterozygotes (54 years) than in female heterozygotes (69 years). Five homozygous and 105 male and 56 female heterozygous patients received coronary angiographic evaluation. The regression equations between age (X) and coronary stenosis index (Y) obtained by assigning score (0 to 5) to each of 15 coronary artery segments were Y = 1.57X - 20.43 (r = 0.956, p less than 0.05) in the homozygotes, Y = 0.52X - 9.11 (r = 0.438, p less than 0.001) in the male heterozygotes, and Y = 0.47X - 12.54 (r = 0.343, p less than 0.01) in the female heterozygotes. From these data, we can assume that coronary artery stenosis detectable by angiography will occur after 17 and 25 years of age in male and female heterozygotes, respectively, and the treatment of heterozygotes with lipid-lowering drugs can be delayed until late adolescence.     

Fluvastatin attenuates nitrate tolerance in patients with ischemic heart disease complicating hypercholesterolemia

Background: Long-term administration of nitrates results in the development of tolerance. Nitrate tolerance is considered to occur in association with oxidative stress, although its underlying mechanisms are multi-factorial. Fluvastatin, a newly developed statin, is considered to have not only a cholesterol-lowering effect but also anti-oxidative properties. Methods: In this study, the effect of fluvastatin on nitrate tolerance was investigated in 12 dyslipidemic patients (nine men and three women, aged 63.5±6.7 years), who were complicated with ischemic heart disease and had received organic nitrates for a long period. Results: Four months after fluvastatin therapy, symptoms of angina were significantly reduced. Consumption of sublingual nitrates over 2 weeks significantly decreased (14.4±11.2 to 2.3±2.5 tablets, P<0.01). In exercise stress testing, exercise duration was significantly prolonged (275±73 to 360±86 s, P<0.01) and the blood pressure-heart rate products significantly increased (16 368±2246 to 18 381±1772, P<0.01). Both the percent change in forearm blood flow with reactive hyperemia (232±83 to 282±104%, P<0.05) and that after sublingual nitroglycerine (2.5±4.7 to 5.8±4.7%, P<0.05) were increased. Although the levels of total cholesterol, triglyceride, HDL-cholesterol, and LDL-cholesterol were unchanged, the serum anti-Ox-LDL titer (16.7±6.3 to 13.4±5.4 AcU/ml, P<0.05) and 8-OHdG level (1.11±0.34 to 0.73±0.34 ng/ml, P<0.05) decreased. Conclusions: Fluvastatin attenuated nitrate tolerance in dyslipidemic patients complicated with ischemic heart disease who had been receiving organic nitrates over long period. The anti-oxidative effect of fluvastatin may attenuate nitrate tolerance.     

Pathology of chronic rheumatic heart disease with particular reference to tricuspid value involvement.

This study is based on a retrospective analysis of 144 autopsied cases of rheumatic heart disease. Majority of cases (79%) were chronic and 21% were acute in nature. The mortality was high and was maximum below the age of 30 years. The males predominated over females. A high incidence of organic tricuspid valve involvement was observed (45.8%). Tricuspid stenosis was observed in 3 cases. Latter was associated with aortic and mitral valve involvement. Mitral stenosis was severe in all the three cases. Criteria, both gross and microscopic for the involvement of the tricuspid valve have been described. Involvement of mitral valve either singly or in combination with the other valves, emerged to be the commonest. Changes observed in the lungs in these cases have been dealth with briefly. Pulmonary vascular changes were usually severe, particularly in the juvenile age group.     

Apolipoprotein E genotype is not associated with cardiovascular disease in heterozygous subjects with familial hypercholesterolemia

Background

Familial hypercholesterolemia (FH) is a genetic disorder characterized by high low-density lipoprotein cholesterol levels and premature cardiovascular disease (CVD). There are important differences in the presence of CVD among heterozygous subjects with FH. Some of this variability can be explained by genetic factors, and the apolipoprotein (apo) E genotype has been proposed as a useful marker.

Methods

We analyzed the apo E genotype in 706 non-related subjects who were heterozygous for FH from Spain. CVD was present in 198 subjects (28%), 132 men (41%) and 66 women (17%).

Results

Apo E allele frequencies for the ε3, ε4, and ε2 alleles were 0.89, 0.09, and 0.02 respectively. Age, body mass index, smoking status, high blood pressure, diabetes mellitus, presence of tendon xanthomas, total cholesterol level, triglyceride levels, high-density lipoprotein cholesterol level, low-density lipoprotein cholesterol level, and Lp(a) did not differ among genotypes. The incidence of CVD and the age of onset of CVD did not differ among genotypes either. In the multivariant analysis, apo E genotype did not contribute significantly to CVD.

Conclusions

Heterozygous men with FH have a very high risk of coronary disease in a Mediterranean country, and the apo E genotype in this large group of adults with FH is not associated either with CVD or lipid values, in contrast with the established effect in the general population.     

Long-term efficacy of low-density lipoprotein apheresis on coronary heart disease in familial hypercholesterolemia

Familial hypercholesterolemia (FH) is characterized by severe hypercholesterolemia and premature coronary heart disease (CHD). The lower the plasma cholesterol level, the more likely it is that CHD can be prevented or retarded; aggressive cholesterol-lowering therapies may be indicated for FH patients with CHD. This study describes the long-term (6 years) safety and efficacy of intensive cholesterol-lowering therapies with low-density lipoprotein (LDL) apheresis in heterozygous FH patients with CHD. One hundred thirty heterozygous FH patients with CHD documented by coronary angiography had been treated by cholesterol-lowering drug therapy alone (n = 87) or LDL apheresis combined with cholesterol-lowering drugs (n = 43). Serum lipid levels and outcomes in each treatment group were compared after approximately 6 years. Both treatment groups had significant reductions in serum cholesterol, LDL cholesterol, and high density lipoprotein cholesterol levels. LDL apheresis significantly reduced LDL cholesterol levels from 7.42 ± 1.73 to 3.13 ± 0.80 mmol/L (58%) compared with group taking drug therapy, from 6.03 ± 1.32 to 4.32 ± 1.53 mmol/L (28%). With Kaplan-Meier analyses of the coronary events including nonfatal myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, and death from CHD, the rate of total coronary events was 72% lower in the LDL-apheresis group (10%) than in drug therapy group (36%) (p = 0.0088). It is concluded that LDL-apheresis is effective as treatment of CHD in FH heterozygotes, and may become the therapy of choice in severe types of FH.     

Plasma Lp(a) values in familial hypercholesterolemia and its relation to coronary heart disease

BACKGROUND AND AIM: To analyze plasma Lp(a) levels and examine different risk factors and coronary heart disease (CHD) in a sample of genetically diagnosed familial hypercholesterolemia (FH) patients. METHODS AND RESULTS: Ninety heterozygous FH patients and 41 non-FH relatives were enrolled in a study to evaluate their plasma and lipoprotein cholesterol, as well as their triglyceride and Lp(a) levels. We found no differences in plasma Lp(a) levels and log transformed values between 90 FH subjects and their 41 unaffected relatives (22.3 mg/dl +/- 19.4 vs 17.7 mg/dl +/- 21.3 and 1.12 +/- 0.5 vs 0.96 +/- 0.54) nor between null allele and defective allele FH subjects (log Lp (a) levels 2.013 +/- 0.282 vs 1.959 +/- 0.151). FH CHD+ were significantly older, and had higher mean systolic and diastolic blood pressure and higher mean plasma triglyceride levels than FH CHD-. No differences in mean and log transformed Lp(a) plasma concentrations were found. CONCLUSIONS: Plasma Lp(a) levels are not related to LDL receptor status and class mutations, nor to the presence of CHD in FH patients.