Khalid Al-Waili

The HDL proteome in acute coronary syndromes shifts to an inflammatory profile

Inflammation is a major factor underlying acute coronary syndromes (ACS). HDL particles may be remodeled, becoming functionally defective, under the inflammatory conditions seen in ACS. Shotgun proteomics was used to monitor changes in the HDL proteome between male age-matched control, stable CAD, and ACS subjects (n=10/group). HDL was isolated by ultracentrifugation and separated by 1D-gel followed by LC-MS/MS. We identified 67 HDL-associated proteins, 20 of which validated recently identified proteins including vitronectin and complement C4B, and 5 of which were novel. Using gene ontology analysis, we found that the HDL-proteome consisted of proteins involved in cholesterol homeostasis (~50%), with significant contributions by proteins involved in lipid binding, antioxidant, acute-phase response, immune response, and endopeptidase/protease inhibition. Importantly, levels of apoA-IV were significantly reduced in ACS patients, whereas levels of serum amyloid A (SAA) and complement C3 (C3) were significantly increased (spectral counting; t-test p≤0.05), as confirmed by immunoblot or ELISA. Despite differences in protein composition, ABCA1, ABCG1, and SR-BI mediated cholesterol efflux assays did not indicate that HDL from ACS patients is functionally deficient as compared to controls, when corrected for apoA-I mass. Our results support that the HDL proteome differs between control, CAD and ACS patients. Increased abundance of SAA, C3, and other inflammatory proteins in HDL from ACS patients suggests that HDL reflects a shift to an inflammatory profile which, in turn, might alter the protective effects of HDL on the atherosclerotic plaque. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).

High-density lipoproteins and cardiovascular disease: 2010 update

High-density lipoprotein-cholesterol (HDL-C) is a continuous inverse cardiovascular risk factor. The mechanisms by which HDLs protect against atherosclerosis are multiple. The major effect is thought to be reverse cholesterol transport, the mechanism by which excess cellular cholesterol is returned to the liver for excretion in the bile. HDLs also have pleiotropic roles: they decrease inflammation, prevent low-density lipoprotein oxidation, vascular endothelial cell apoptosis and thrombosis, and improve vascular endothelial function. Recent studies suggest that nascent HDL particles are metabolized rapidly and that their components (Apo AI, cholesterol and phospholipids) are rapidly exchanged within lipoprotein classes. There are many causes of HDL-C deficiency. Using Mendelian randomization, several groups have concluded that many genetic forms of HDL deficiency do not increase cardiovascular risk. This raises the controversial issue of the causality of low HDL-C as a cardiovascular risk factor, rather than a marker of cardiovascular health. This is reflected in the importance of lifestyle in determining HDL-C levels. The treatment of low HDL-C remains controversial, in part because the only currently available effective medication, niacin, is relatively poorly tolerated and outcomes studies on cardiovascular disease prevention are still pending.

Aortic calcifications in familial hypercholesterolemia: Potential role of the low-density lipoprotein receptor gene

BACKGROUND We have previously reported premature, extensive aortic calcifications in patients with homozygous familial hypercholesterolemia (hmzFH) due to mutations in the low-density lipoprotein receptor gene (LDL-R). The objective of this study was to measure the degree of aortic calcification in heterozygous FH (htzFH) compared to both hmzFH and controls. We hypothesized that the LDL-R gene may contribute to aortic calcifications in a gene-dosage effect. METHOD Patients with htzFH due to the French Canadian mutation (Delta15 kb del. null allele) were selected. All patients underwent computed tomographic scan to measure vascular calcification. We used 22 hmzFH patients from our previous study and patients undergoing computed tomographic virtual colonoscopy as controls. RESULTS Mean age for htzFH was 50 +/- 15 years; initial cholesterol level before treatment was 10.45 +/- 1.73 mmol/L. Major cardiovascular events occurred in 9 of 17 patients. A strong correlation between age and calcium score was found (r = 0.72, P = .0016). There was a strong correlation between the cholesterol-year score (an index of lifelong cholesterol burden) and the aortic calcium score (r = 0.62, P = .0105). Aortic calcifications in htzFH subjects occurred later than in hmzFH patients, but much earlier than in controls, suggesting a gene-dosage effect of LDL-R mutations and aortic calcium deposition. CONCLUSION Aortic calcification was observed in patients with htzFH but presented at a later time and were less extensive than in hmzFH (34 vs 14 years, respectively). Because aortic calcifications may be partly independent of serum cholesterol levels in patients with familial hypercholesterolemia, implications for screening and the timing of treatment initiation may need reassessment.

Approach to the diagnosis and management of lipoprotein disorders.

Purpose of reviewDisorders of lipoprotein metabolism are frequently encountered in clinical practice. Although the severe genetic hyperlipidemias are relatively infrequent, prompt recognition and treatment can prevent complications, such as atherosclerosis and pancreatitis. The secondary dyslipidemias, due to medication or other metabolic disorders (hypothyroidism, renal or hepatic diseases), must be identified and treated. With the growing epidemic of obesity, dyslipidemias are a component of the metabolic syndrome. Recent findingsThe stratification of cardiovascular risk now includes family history and biomarkers of inflammation, especially high-sensitivity C-reactive protein, which enables sound clinical decision making. Lifelong hypercholesterolemia is strongly associated with increasing risk of atherosclerosis and coronary heart disease death, but the decision to treat pharmacologically depends on the absolute cardiovascular risk over the next 10 years. Clinical trial data support intensive treatment of patients at high cardiovascular risk or for the secondary prevention of recurrent coronary heart disease. The recently published JUPITER trial shows that patients with an elevated C-reactive protein benefit from treatment with a statin (rosuvastatin 20 mg) for primary prevention. SummaryThe current guidelines for the prevention of coronary artery disease will continue to focus on the determination of global risk, with intensive treatment aimed at the high-risk group. Family history and high-sensitivity C-reactive protein provide additional risk stratification.

Comparison of Treatment of Severe High-Density Lipoprotein Cholesterol Deficiency in Men With Daily Atorvastatin (20 mg) Versus Fenofibrate (200 mg) Versus Extended-Release Niacin (2 g)

To determine whether available lipid-modifying medication can increase high-density lipoprotein (HDL) cholesterol in well-defined genetic or familial HDL-deficiency states, we studied 19 men with HDL deficiency (HDL cholesterol <5th percentile for age and gender) 55 +/- 10 years of age. Concomitant risk factors included diabetes (n = 3) and hypertension (n = 7) and 8 patients had coronary artery disease. Molecular analysis revealed that 4 patients had a mutation in the ABCA1 gene. Patients were assigned to sequentially receive atorvastatin 20 mg/day, fenofibrate 200 mg/day, and extended-release niacin 2 g/day for 8 weeks, with a 4-week washout period between each treatment. Patients in whom a statin was required, according to current treatment guidelines, were kept on atorvastatin throughout the study. Baseline HDL cholesterol level was 0.63 +/- 0.12 mmol/L (24 +/- 5 mg/dl), triglycerides 2.01 +/- 0.98 mmol/L (180 +/- 86 mg/dl), and low-density lipoprotein (LDL) cholesterol 2.29 +/- 0.95 mmol/L (94 +/- 39 mg/dl). Mean percent changes in HDL cholesterol on atorvastatin, fenofibrate, and niacin were -6% (p = NS), +6% (p = NS), and +22% (p <0.05), respectively. Furthermore, niacin significantly increased the large alpha-1 apolipoprotein A-I-containing HDL subspecies (12 to 17 nm). In conclusion, niacin was the only effective drug to increase HDL cholesterol. The absolute increase in HDL cholesterol, approximately 0.10 mmol/L (3.9 mg/dl), is of uncertain clinical significance. Biomarkers of HDL-mediated cellular cholesterol efflux were not changed by niacin therapy. Atorvastatin or fenofibrate had little effect on HDL cholesterol; atorvastatin decreased the total cholesterol/HDL cholesterol ratio by 26%. Fenofibrate did not change HDL cholesterol levels and caused an increase in LDL cholesterol. Aggressive LDL cholesterol lowering may be the strategy of choice in such patients.

Familial hypercholesterolemia mutations in the Middle Eastern and North African region: A need for a national registry

BACKGROUND Familial hypercholesterolemia (FH) is a well-understood Mendelian disorder that increases the risk of cardiovascular disease (CVD), a leading cause of mortality in Middle Eastern and North African (MENA) countries. OBJECTIVE Review the reporting status of FH mutations across MENA and propose a systemic and strategic method for building a MENA FH registry. METHODS Systematic literature search for statistics pertaining to CVD and comparison of number of FH mutations reported in MENA countries and countries with established FH registries. RESULTS Only 57 mutations were reported in 17 MENA countries, whereas more than 500 mutations reported in 3 Western countries. Mortality rates due to CVD were significantly higher in MENA countries compared with Western countries. CONCLUSIONS The relatively low reporting of FH mutations in the consanguineous MENA communities with higher prevalence of CVD indicates poor awareness of CVD genetic risk and warrants a registry to prevent premature CVD due to FH. This registry will help in identifying novel and reported FH mutations, all of which will have clinical and research benefits in MENA countries.

Calcium Homeostasis and Skeletal Integrity in Individuals with Familial Hypercholesterolemia and Aortic Calcification

BACKGROUND Familial hypercholesterolemia (FH) due to mutations in the low-density lipoprotein receptor (LDLR) gene exhibit severe, premature aortic calcification in a gene-dosage, age-dependent fashion. We sought to determine potential associations with mineral and skeletal indices. METHODS We obtained computed tomography (CT) scan aortic calcium scores (AoCSs) in 19 (age 49 [SD 14] years) FH patients heterozygous for the 15-kb deletion at the LDLR gene and examined associations with various indices of mineral and skeletal homeostasis. RESULTS We found that mean bone mineral density (BMD) at the femoral neck in these patients did not differ from age-, sex-, and province-matched mean BMD, and we observed no association of AoCS with any marker of bone resorption. However, there were negative correlations between AoCS and serum concentrations of osteocalcin, a marker of bone formation (r = -0.64, P = 0.0034), urinary calcium (r = -0.59, P = 0.0085), and estimated glomerular filtration rate (r = -0.67, P = 0.0019). CONCLUSIONS We found that LDLR-deficient FH was not associated with obvious bone loss or a major disturbance in calcium homeostasis. The lack of LDLR, however, may modify osteoblast function or extracellular calcium distribution, manifesting as lower bone formation, and reduced calcium excretion, resulting in increased deposition in calcifying vascular tissue.

Dyslipidaemia in the Middle East: Current status and a call for action.

The increase in the cardiovascular disease (CVD)-associated mortality rate in the Middle East (ME) is among the highest in the world. The aim of this article is to review the current prevalence of dyslipidaemia and known gaps in its management in the ME region, and to propose initiatives to address the burden of dyslipidaemia. Published literature on the epidemiology of dyslipidaemia in the ME region was presented and discussed at an expert meeting that provided the basis of this review article. The high prevalence of metabolic syndrome, diabetes, familial hypercholesterolaemia (FH) and consanguineous marriages, in the ME region, results in a pattern of dyslipidaemia (low high-density lipoprotein cholesterol and high triglycerides) that is different from many other regions of the world. Early prevention and control of dyslipidaemia is of paramount importance to reduce the risk of developing CVD. Education of the public and healthcare professionals and developing preventive programs, FH registries and regional guidelines on dyslipidaemia are the keys to dyslipidaemia management in the ME region.

First Case Report of Familial Hypercholesterolemia in an Omani Family Due to Novel Mutation in the Low-Density Lipoprotein Receptor Gene

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder. Mutations have been found in at least 3 genes: the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9). We report the first case of FH in an Omani family due to a novel mutation in the LDLR gene. A 9-year-old female was referred to our lipid clinic with eye xanthelasmata and thickening of both Achilles tendons. Evaluation of the lipid profile showed the off treatment total cholesterol of 896 mg/dL (23.2 mmol/L), low-density lipoprotein cholesterol (LDL-C) of 853 mg/dL (22.1 mmol/L), APOB of 4.5 g/L, triglyceride of 71 mg/dL (0.8 mmol/L), and high-density lipoprotein cholesterol of 0.74 mmol/L. Genetic analysis of the LDLR gene showed a homozygous frameshift deletion mutation (272delG) at exon 3. The female patient was treated with a combination of rosuvastatin/ezetimibe and LDL apheresis.

Identification and Treatment of Patients with Homozygous Familial Hypercholesterolaemia: Information and Recommendations from a Middle East Advisory Panel

We present clinical practice guidelines for the diagnosis and treatment of homozygous familial hypercholesterolaemia (HoFH) in the Middle East region. While guidelines are broadly applicable in Europe, in the Middle East we experience a range of confounding factors that complicate disease management to a point whereby the European guidance cannot be applied without significant modification. Specifically, for disease prevalence, the Middle East region has an established epidemic of diabetes and metabolic syndrome that can complicate treatment and mask a clinical diagnosis of HoFH. We have also a high incidence of consanguineous marriages, which increase the risk of transmission of recessive and homozygous genetic disorders. This risk is further augmented in autosomal dominant disorders such as familial 
hypercholesterolaemia (FH), in which a range of defective genes can be transmitted, all of which contribute to the phenotypic expression of the disease. In terms of treatment, we do not have access to lipoprotein apheresis on the same scale as in Europe, and there remains a significant reliance on statins, ezetimibe and the older plasma exchange methods. Additionally, we do not have widespread access to anti-apolipoprotein B therapies and microsomal transfer protein inhibitors. In order to adapt existing global guidance documents on HoFH to the Middle East region, we convened a panel of experts from Oman, Saudi Arabia, UAE, Iran and Bahrain to draft a regional guidance document for HoFH. We also included selected experts from outside the region. This panel statement will form the foundation of a detailed appraisal of the current FH management in the Middle Eastern population and thereby provide a suitable set of guidelines tailored for the region.