Molecular diagnosis of familial hypercholesterolemia: an important tool for cardiovascular risk stratification.

UNLABELLED: Familial hypercholesterolemia (FH) is associated with an increased risk of premature coronary heart disease. Molecular identification of these patients can reduce the burden of mortality from cardiovascular disorders simply by the correct identification of the disease early in life, followed by counseling and appropriate lifestyle modifications, and therapeutic measures when required. Recent studies show that, in Portugal, this disease is severely under-diagnosed. After more than 10 years of research through the Portuguese FH Study, it is now possible to translate the original research results into clinical application. AIMS: The main aims of the present work were to determine whether clinical characterization is sufficient to identify these individuals at high risk of developing CHD and to evaluate the clinical applicability of molecular diagnosis for FH. METHODS: All patients described in this study were recruited for the Portuguese FH Study. The diagnostic criteria used to select the index patients were adapted from the Simon Broome Heart Research Trust. To analyze the usefulness of the molecular diagnosis, graphs of total and LDL cholesterol values by age were constructed for 622 possible FH patients. The lipid profile of patients genetically identified as having FH, before and under medication, were analyzed to assess whether these patients were receiving appropriate treatment. The data are shown separately for children and adults and for female and male propositi (index cases and hypercholesterolemic relatives), both with and without a detectable mutation in the LDLR gene. RESULTS: The Portuguese FH Study has already genetically identified 404 individuals (171 index patients and 233 relatives) among more than one thousand individuals sent for study. A total of 78 different mutations in the LDLR gene were found in 171 index patients, 2 different mutations were found in the apoB gene of 4 patients and 2 patients had a unique PCSK9 mutation. Statistical analysis revealed that there are significant differences between total cholesterol (p < 0.001) and apoB (p = 0.026) values in the group of children (male and female) with and without a mutation in LDLR. For female children LDL values were also significantly different (p < 0.001) between subgroups but for male children this difference did not reach statistical significance. In adult women there is a statistically significant difference for total cholesterol (p = 0.049), LDL cholesterol (p = 0.031) and apoB (p = 0.003) values in the subgroups with and without a LDLR mutation. In adult males there is a statistical difference for total cholesterol (p = 0.002). LDL cholesterol (p = 0.003) and apoB (p = 0.0023) in subgroups with and without an LDLR mutation. Nevertheless there was considerable dispersion of values and individually it is not possible to distinguish between patients with and without a mutation in the LDLR gene, based only on lipid profile. CONCLUSIONS: By analysis of the clinical data of 696 possible FH patients, the present report shows evidence that clinical characterization is not sufficient to distinguish between patients with genetic or environmental dyslipidemia, and so molecular diagnosis is useful in clinical practice, allowing correct identification of FH patients and their relatives, and the early implementation of therapeutic measures to reduce the elevated cardiovascular risk of these patients. In general, molecular diagnosis of FH is feasible and could be obtained in 1-2 months if the technology is available. In Portugal the test will be offered to the population by our Institute at a cost of about 500 euros, like many other genetic tests or exams such as nuclear magnetic resonance.

[Adipsin system--acylation-stimulation protein (ASP) and hyperapo-B]. / Sistema da adipsina--proteína estimuladora da acilação (ASP) e hiperapoB.

Acylation Stimulating Protein (ASP) is a small basic protein which was isolated from the human plasma and which has been shown to be the most potent stimulant yet discovered of triglyceride synthesis. The initial observation were made in vitro, but there is now in vivo evidence that the adipsina-ASP system has an important regulatory role in triglyceride clearance from plasma. Studies in normals have shown that the higher the fasting and the peak ASP plasma levels are after an oral fat load, the faster the triglyceride clearance from plasma. Moreover, decreased function of the adipsina-ASP system appears to lead to increased delivery of free fatty acids and triglyceride-rich chylomicron remnants to the liver with a consequent increase in the rate of secretion of B100 lipoprotein particles. That is to say, defective function of this system is one of the causes of hyperapoB which in turn is one of the commonest dyslipoproteinemias associated with premature coronary artery disease.

[Supraventricular tachycardia complicated by acute myocardial ischemia induced by atropine injection. Report of a clinical case]. / Taquidisritmia supraventricular complicada por isquemia aguda do miocárdio desencadeada pela injecção de atropina. A propósito de um caso clínico.

The authors report a case of supraventricular tachyarrhythmia complicated by severe myocardial ischemia after IV injection of Atropine in a 37 years old woman, without known coronary artery disease. She had an ECG with sinusal bradycardia (40/min) and she was on the waiting list for to be submitted to surgical intervention on the lumbar spine.