Analysis of HDL-microRNA panel in heterozygous familial hypercholesterolemia subjects with LDL receptor null or defective mutation.

In the last years increasing attention has been given to the connection between genotype/phenotype and cardiovascular events in subjects with familial hypercholesterolemia (FH). MicroRNAs (miRs) bound to high-density lipoprotein (HDL) may contribute to better discriminate the cardiovascular risk of FH subjects. Our aim was to evaluate the HDL-miR panel in heterozygous FH (HeFH) patients with an LDLR null or defective mutation and its association with pulse wave velocity (PWV). We evaluated lipid panel, HDL-miR panel and PWV in 32 LDLR null mutation (LDLR-null group) and 35 LDLR defective variant (LDLR-defective group) HeFH patients. HDL-miR-486 and HDL-miR-92a levels were more expressed in the LDLR-null group than the LDLR-defective group. When we further stratified the study population into three groups according to both the LDLR genotype and history of ASCVD (LDLR-null/not-ASCVD, LDLR-defective/not-ASCVD and LDLR/ASCVD groups), both the LDLR/ASCVD and the LDLR-null/not-ASCVD groups had a higher expression of HDL-miR-486 and HDL-miR-92a than the LDLR-defective/not-ASCVD group. Finally, HDL-miR-486 and HDL-miR-92a were independently associated with PWV. In conclusion, the LDLR-null group exhibited HDL-miR-486 and HDL-miR-92a levels more expressed than the LDLR-defective group. Further studies are needed to evaluate these HDL-miRs as predictive biomarkers of cardiovascular events in FH.

Sural nerve biopsy and functional studies support the pathogenic role of a novel MPZ mutation.

Our patient is a 65-year-old woman presenting with bilateral pes cavus, pronounced distal muscle wasting, weakness and areflexia. Electrophysiological findings included diffuse unrecordable motor and sensory responses. While the CMT phenotype was evident, the lack of family history and the severe, but unspecific electrophysiological impairment, was a challenge for genetic diagnosis. A sural nerve biopsy was performed, showing a severe loss of myelinated fibers with residual axons surrounded by myelin outfoldings. Whereas myelin outfoldings are a pathological hallmark of autosomal recessive CMT4B1 and CMT4B2, due to mutations in myotubularin-related 2 (MTMR2) and 13 (MTMR13) genes respectively, they may also occur in nerve biopsies from CMT1B patients. By direct sequencing, a novel heterozygous transversion c.410G>T in MPZ gene was demonstrated, producing an amino acid change from glycine to valine in position 108 (p.G108V). In HeLa cells the fusion P0G108V-EGFP was normally trafficked to the cell membrane, but with decreased P0 adhesion function, compared with wild-type P0, thus supporting a pathogenic role of the new variant. In conclusion this case highlights the relevance, in selected cases, of sural nerve biopsy to orient the genetic/molecular tests, while in vitro analyses may strengthen the pathogenic role of novel mutations.

Management of patients with persistent chest pain and ST-segment elevation during 5-fluorouracil treatment: report about two cases.

5-Fluorouracil, a widely used drug in cancer treatment, is known to have cardiotoxic effects: chest pain with ECG changes, arrhythmias, arterial hypertension or hypotension, myocardial infarction, cardiogenic shock and sudden death have been described in the literature. Coronary artery vasospasm is the pathogenetic mechanism hypothesized in most cases, but mechanisms other than myocardial ischemia had been advocated in some patients. The approach to the patient with persistent chest pain, despite therapy and persistent ST-segment elevation mimicking an acute myocardial infarction, has not been well addressed, and the appropriate diagnostic and therapeutic pathways have not yet been defined. We present our experience regarding 2 patients treated with 5-fluorouracil and referred to our coronary care unit because of prolonged chest pain (in one case with clinical evidence of hemodynamic impairment) and persistent ST-segment elevation, in whom an acute myocardial infarction was suspected. One patient was treated with systemic fibrinolysis, and coronary angiography was performed 6 days later; the other was submitted to urgent coronary angiography shortly after admission. In both cases the ECG and echocardiographic abnormalities were transient and normalized within a few days, the serum markers of myocardial necrosis were persistently in the normal range and the coronary artery trees were normal. The diagnostic and therapeutic approach to patients with this unusual clinical presentation is also discussed.