The History of the WHHL Rabbit, an Animal Model of Familial Hypercholesterolemia (I) - Contribution to the Elucidation of the Pathophysiology of Human Hypercholesterolemia and Coronary Heart Disease.

Animal models that closely resemble both human disease findings and their onset mechanism have contributed to the advancement of biomedical science. The Watanabe heritable hyperlipidemic (WHHL) rabbit and its advanced strains (the coronary atherosclerosis-prone and the myocardial infarction-prone WHHL rabbits) developed at Kobe University (Kobe, Japan), an animal model of human familial hypercholesterolemia, have greatly contributed to the elucidation of the pathophysiology of human lipoprotein metabolism, hypercholesterolemia, atherosclerosis, and coronary heart disease, as described below. 1) The main part of human lipoprotein metabolism has been elucidated, and the low-density lipoprotein (LDL) receptor pathway hypothesis derived from studies using fibroblasts was proven in vivo. 2) Oxidized LDL accumulates in the arterial wall, monocyte adhesion molecules are expressed on arterial endothelial cells, and monocyte-derived macrophages infiltrate the arterial intima, resulting in the formation and progression of atherosclerosis. 3) Coronary lesions differ from aortic lesions in lesion composition. 4) Factors involved in the development of atherosclerosis differ between the coronary arteries and aorta. 5) The rupture of coronary lesions requires secondary mechanical forces, such as spasm, in addition to vulnerable plaques. 6) Specific lipid molecules in the blood have been identified as markers of the progression of coronary lesions. At the end of the breeding of the WHHL rabbit family at Kobe University, this review summarizes the history of the development of the WHHL rabbit family and their contribution to biomedical science.

Discovery of the cellular and molecular basis of cholesterol control.

The cellular control of cholesterol metabolism mediated by lipoproteins was first appreciated in pioneering work published in a 1974 PNAS Classic by Michael Brown and Joseph Goldstein. We know from this paper that the LDL binds to a cell surface receptor and dampens the activity of a key enzyme in cholesterol biosynthesis and that a receptor deficiency is responsible for a major genetic cause of hypercholesterolemia and premature atherosclerosis.

The lower the better: target values after LDL-Apheresis and semi-selective LDL-elimination therapies.

Prior to 1980 the drug therapy of hereditary hypercholesterolaemia was, as compared to nowadays standards, rather limited. There was virtually no effective therapy for homozygous patients, though plasma exchange introduced in France and Britain, demonstrated the use-fullness of the introduction of apheresis techniques. Parallel to the improvement of cholesterol lowering drug therapy for heterozygous patients, apheresis was developed as therapeutic affinity chromatography since 1980 at the university of Cologne for both homozygous and therapy refractory heterozygous patients. This development was named LDL-Apheresis based on the specificity for the removal of Apoprotein B bound cholesterol, the capacity due to the development of a repetitive cycling technique and the economy determined from the reuse of affinity chromatography columns for each single patient. The capacity of the system allowed for the introduction of new standards of post-treatment values such as 100mg/dl total cholesterol or alternatively 50mg/dl LDL-cholesterol and if cholesterol lowering drugs can also applied for a limited extent the rebound can be also slowed down. After 33 years of experience with seven homozygotes and 32 heterozygotes without treatment alternative, we found that in addition to the improvement of the quality of live the extension of live expectancy are the real proof of a therapeutic success as compared to other diagnostic procedures. The average live expectancy of our seven homozygous patients is 45.6 years; our oldest heterozygous patient is 81 years. There are no comparable long term data at present available neither from studies using drugs nor from subsequently developed apheresis techniques which also removed LDL-cholesterol together with plasma constituents not participating in the development of atherosclerosis. Also two homozygous patients giving birth to four children without complication support our concept of aggressive cholesterol lowering therapy being without major side effects (3-4% minor undesired reactions).

Familial hypercholesterolemia: epidemiology, Neolithic origins and modern geographic distribution.

The elucidation of the molecular basis of familial hypercholesterolemia (FH) by Brown and Goldstein about three decades ago provided the most convincing evidence for a causative relationship between a high plasma level of low-density lipoprotein (LDL) cholesterol and the conditions of atherosclerosis and premature atherosclerotic cardiovascular disease. Today, with a prevalence of about one in 500 individuals, FH remains the most common monogenic disorder of lipoprotein metabolism, and is mainly due to mutations in the LDL receptor (LDLR) gene that lead to the plasma accumulation of cholesterol ester-laden LDL particles. Another form of autosomal dominant hypercholesterolemia, familial defective apolipoprotein B-100, a genocopy of FH caused by defects in the APOB gene that lead to decreased clearance of LDL, is now established as a significant cause of coronary heart disease. Yet another form, due to mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, has been recently identified that similarly causes decreased clearance of LDL by novel mechanisms also involving the hepatic LDLR endocytotic pathway. Recent advances in molecular genotyping technology have yielded a staggering amount of detail about human genetic diversity at the single nucleotide level in both private and public databases including the International HapMap Consortium. This, as well as the availability of ancient human DNA from burial sites and the development of new statistical methods, now provide an unprecedented capacity to study human demography and the ability to examine the genealogical ties between ancient and modern people. The aim of this article is to review the epidemiology of FH, and to attempt to draw inferences from our knowledge at a DNA level of inherited hypercholesterolemia of contemporary people that may contribute to the understanding of human population history and adaptation that resulted in the massive demographic expansion following the adoption of agriculture in the Neolithic period.

Familial hypercholesterolaemia in South Africans: tracking findings and developments over time - with reference to : prevalence of hypercholesterolaemia in young Afrikaners with myocardial infarction. Ischaemic heart disease risk factors.

This review discusses the 1987 article by Wyndham, Seftel, Pilcher and Baker on familial hypercholesterolaemia (FH) and myocardial infarction (MI) in young Afrikaners, in terms of the significance at the time of publication, as well as the relevance of their findings versus current observations on hypercholesterolaemia in South Africa. Risk factors for coronary heart disease (CHD) were investigated in this study, with specific reference to familial hypercholesterolaemia. The significance of Wyndham's article is evaluated with regard to the contributions on hypercholesterolaemia by other South African researchers that preceded this publication. The clinical diagnostic criteria that were applied to identify possible FH at the time of publication are compared with currently employed criteria and guidelines. This review also acknowledges and honours other clinicians and researchers who, like Wyndham et al., have made significant contributions to the diagnosis and treatment of FH in South Africans.

Brief history of low-density lipoprotein apheresis.

Low-density lipoprotein (LDL) apheresis is a technology used to remove LDL from hypercholesterolemic patients. The technique includes both specific and non-specific removal of LDL such as exchange of the whole plasma and selective adorption of LDL. The therapy is mainly used for homozygotes and in severe cases of heterozygotes of familial hypercholesterolemia (FH) (LDL receptor deficiency). Since HMG-CoA reductase inhibitors, statins, were introduced in late 1980s, the number of patients who required LDL apheresis decreased, in particular for the heterozygous FH patients with more recent powerful statins. Modern LDL apheresis technology is very sophisticated and perhaps expensive, while the number of the patients is very limited. Several companies developed the instruments for this procedure, but found the market is limited. Nevertheless, these companies are expected to remain in the market for an ethical reasons, as the patients using their LDL apheresis machines are entirely dependent on them for their life.

[Müller-Harbitz disease--familial hypercholesterolemia]. / Müller-Harbitz' sykdom--familiaer hyperkolesterolemi.

The first patients with xanthomatosis and cardiovascular disease were described in end of the 18th century. From 1925 to 1938, the Norwegian pathologist Francis Harbitz (1867-1950) published several reports on sudden death and xanthomatosis. Harbitz called attention to certain peculiarities of the xanthomatosis. Microscopically he found that the so-called foam cells are more marked and more characteristic than in senile arteriosclerosis. Carl Müller's (1886-1983) attention was directed to this form of cardiovascular disease by the publications of Harbitz. Based on his own studies of 17 families in Oslo over a short period from 1936, he published his final report in 1939. He described hereditary heart disease due to xanthomatosis and hypercholesterolaemia to be fairly common. It was demonstrated to be a dominant trait in the families. Hypercholesterolaemia was present, most marked in connection with xanthoma tuberosus, but there was no definitive relationship between hypercholesterolaemia and xanthomatous deposits in the skin. The occurrence of heart disease in families should direct attention to this disorder. Carl Müller postulated that causal and prophylactic treatment might prove to be of value, but more than 50 years passed before this was possible in the disorder that is now called familial hypercholesterolaemia.

Familial hypercholesterolemia in the Finnish north Karelia. A molecular, clinical, and genealogical study.

A specific mutation termed FH-North Karelia [FH-NK] accounts for almost 90% of familial hypercholesterolemia [FH] cases in the Finnish North Karelia, with a population of about 180,000. Extensive search for its presence in the entire North Karelia province revealed 340 carriers of this mutation. Other mutations of the LDL receptor [LDLR] gene accounted for 67 cases of heterozygous FH. This gives a minimum FH prevalence of 1 in 441 inhabitants in North Karelia, with the highest density of patients in the Polvijärvi commune (1 in 143 inhabitants). Old parish records, confirmation records, and tax records were used to track a common ancestor for most of the present-day North Karelian FH-NK patients in the village of Puso, located within an area where the FH prevalence today is the highest. DNA analysis indicated that 2% of the subjects aged 1 to 25 years would have been diagnosed as false-negative and 7% as false-positive FH patients on the basis of LDL cholesterol [LDL-C] determinations alone. Common genetic variations of apolipoprotein E [apoE], XbaI, polymorphism of apolipoprotein B [apoB], and PvuII polymorphism of the intact LDLR allele contributed little to serum lipid variation in established carriers of the FH-NK allele, although apoE2/4 genotype and the presence of the PvuII restriction site tended to be associated with relatively low LDL-C levels. Coronary heart disease (CHD) was present in 65 (30%) out of the 179 FH gene carriers aged > or = 25 years, and 19 individuals had a previous history of acute myocardial infarction (AMI). The average age (mean +/- SD) at onset of CHD was 42 +/- 7 years for males and 48 +/- 11 years for females (P < .05). In stepwise logistic regression analysis carried out in carriers of the FH-NK allele, age, gender, smoking, and apoE allele E2 all emerged as independent determinants of risk of CHD or AMI. It may be concluded that the relatively high prevalence of FH patients in North Karelia province provides a unique founder population in which genetic and nongenetic factors modifying the course of FH can be effectively investigated.

A large deletion in the LDL receptor gene--the cause of familial hypercholesterolemia in three Italian families: a study that dates back to the 17th century (FH-Pavia).

In the LDL-receptor gene, a large rearrangement causing hypercholesterolemia was detected in three apparently unrelated families living in northern Italy. In all probands, binding, internalization, and degradation of 125I-LDL measured in skin fibroblasts were found to be 40%-50% of control values, indicative of heterozygous familial hypercholesterolemia (FH). Southern blot analysis revealed that the probands were heterozygous for a large (25-kb) deletion of the LDL-receptor gene eliminating exons 2-12. The affected subjects possessed two LDL-receptor mRNA species: one of normal size (5.3 kb) and one of smaller size (3.5 kb). In the latter mRNA, the coding sequence of exon 1 is joined to the coding sequence of exon 13, causing a change in the reading frame and thereby giving rise to a premature stop codon. The receptor protein deduced from the sequence of the defective mRNA is a short polypeptide of 29 amino acids, devoid of any function. Tracing these three families back to the 17th century, we found both their common ancestor and the possible origin of the mutation, in a region which is called "Lomellina" and which is located in southwest Lombardy, near the old city of Pavia. Therefore we named the mutation "FH-Pavia."