What Do We Know So Far About Ventricular Arrhythmias and Sudden Cardiac Death Prediction in the Mitral Valve Prolapse Population? Could Biomarkers Help Us Predict Their Occurrence?

PURPOSE OF THE REVIEW: To summarize currently available data on the topic of mitral valve prolapse (MVP) and its correlation to the occurrence of atrial and ventricular arrhythmias. To assess the prognostic value of several diagnostic methods such as transthoracic echocardiography, transesophageal echocardiography, cardiac magnetic resonance, cardiac computed tomography, electrocardiography, and electrophysiology concerning arrhythmic episodes. To explore intra and extracellular biochemistry of the cardiovascular system and its biomarkers as diagnostic tools to predict rhythm disturbances in the MVP population. RECENT FINDINGS: MVP is a common and mainly benign valvular disorder. It affects 2-3% of the general population. MVP is a heterogeneous and highly variable phenomenon with three structural phenotypes: myxomatous degeneration, fibroelastic deficiency, and forme fruste. Exercise intolerance, supraventricular tachycardia, and chest discomfort are the symptoms that are often paired with psychosomatic components. Though MVP is thought to be benign, the association between isolated MVP without mitral regurgitation (MR) or left ventricle dysfunction, with ventricular arrhythmia (VA) and sudden cardiac death (SCD) has been observed. The incidence of SCD in the MVP population is around 0.6% per year, which is 6 times higher than the occurrence of SCD in the general population. Often asymptomatic MVP population poses a challenge to screen for VA and prevent SCD. Therefore, it is crucial to carefully assess the risk of VA and SCD in patients with MVP with the use of various tools such as diagnostic imaging and biochemical and genetic screening.

Pharmacokinetic analysis of anti-hemophilic factor in the obese patient.

Standard dosing for individuals with hemophilia A is based on body weight such that 50 IU kg(-1) is defined as a 100% dose, or one attaining 1.00 IU mL(-1) factor VIII (FVIII) clotting activity. No guidelines exist, however, for individuals with hemophilia who are obese, body mass index (BMI) ≥ 30, who may actually be 'over'-treated based on higher in vivo recovery based on higher weight. Alternative treatment guidelines are needed for such patients. To determine FVIII pharmacokinetics we retrospectively collected data during ideal-body-weight dosing from six obese (BMI ≥ 30) hemophilia A patients cared for at the Hemophilia Center of Western PA, for prophylaxis or surgery. The pharmacokinetic data from six subjects undergoing ideal-body-weight dosing with recombinant FVIII indicate peak levels and half-life comparable to standard 50 IU kg(-1) dosing. The mean peak FVIII:C was 1.00 IU dL(-1) and the mean FVIII:C half-life was 10.14 h. IBW-dosing resulted in an average 48.9% reduction in factor use per patient over a 3-month period, for an annualized savings of $133,000 per patient. Ideal-body-weight dosing of recombinant FVIII in obese patients with hemophilia A results in comparable pharmacokinetics, including peak and half-life, with comparable hemostatic efficacy for prophylaxis and surgical treatment, at a significant reduction in factor use and cost. Future studies are needed to confirm these findings in individuals with other congenital bleeding disorders and in children.

Comparative pharmacokinetics of acetylsalicylic acid and sodium salicylate in chickens and turkeys.

1. Pharmacokinetics of acetylsalicylic acid (ASA) and sodium salicylate (SS) were assessed following single intravenous (i.v.) and oral administration at doses of 50 mg/kg body weight to chickens and turkeys. Plasma drug concentrations were determined using high-performance liquid chromatography with ultraviolet detection and pharmacokinetic variables were calculated using a non-compartmental model. 2. The mean residence time (MRT) of salicylate (SA) after i.v. administration of SS was 6.08 ± 0.59 and 3.32 ± 0.27 h and after oral administration was 6.95 ± 0.72 and 4.55 ± 0.71 h in chickens and turkeys, respectively. The elimination half-life (T 1/2 e) was shorter in turkeys compared with chickens. The value of body clearance (ClB) was higher in turkeys than in chickens, but the apparent volume of distribution (V ss) was similarly low in both species. The bioavailability of SS was complete and the maximal plasma concentration of SA (C max) after oral administration was 96.93 ± 8.06 and 91.76 ± 9.64 µg/ml, respectively, in chickens and turkeys. 3. The MRT of ASA after iv administration was 0.24 ± 0.08 and 0.24 ± 0.02 h and after oral administration was 0.78 ± 0.25 and 0.59 ± 0.13 h, respectively, in chickens and turkeys. In both species, T 1/2 e was very short, ClB and V ss were similar and markedly higher than those of salicylate. The bioavailability of unchanged ASA was low and C max after oral administration was 6.9 ± 3.6 µg/ml in chickens and 8.6 ± 1.3 µg/ml in turkeys.

Pharmacokinetics of florfenicol, thiamphenicol, and chloramphenicol in turkeys.

The pharmacokinetics of florfenicol (FF), thiamphenicol (TP) and chloramphenicol (CP) after single intravenous (i.v.) or oral (p.o.) administration was studied in an independent cross-over study in broiler turkeys. All the fenicol antibiotics were administered at a dose of 30 mg/kg b.w. and their concentrations in plasma samples were assayed using the same validated high-performance liquid chromatography method. Pharmacokinetic parameters were calculated by a noncompartmental method. The kinetic profiles of the compounds were compared with the results of the structure-activity relationship. According to the proposed mathematical description, no differences in plasma clearance values for the studied antibiotics were observed. The mean residence time values of FF, TF, and CP after i.v. injection were 3.37+/-0.63, 2.43+/-0.29, and 2.12+/-0.21 h, respectively. The mean values of Varea for FF (1.39+/-0.31 L/kg) and TP (1.31+/-0.19 L/kg) were similar, but significantly different from that of CP (1.04+/-0.12 L/kg). The bioavailabilities of FF, TP, and CP after oral administration were 82%, 69%, and 45%, respectively. Differences in the bioavailability values of the compared fenicol antibiotics correspond to the ratio of the apolar/polar surface areas of their particles.

S-nitrosothiols do not induce oxidative stress, contrary to other nitric oxide donors, in cultures of vascular endothelial or smooth muscle cells.

Nitric oxide (NO) has been described to exert various anti-atherogenic actions. However, NO, in some cases, has been shown to stimulate the oxidation of low-density lipoprotein (LDL), which constitute an important triggering event in atherosclerosis. Thus, some NO donors, despite their advantages, might also induce oxidative stress. Therefore, the purpose of this study is to examine the effect of three different NO donors on LDL oxidation, in acellular system as well as in cultures of normal endothelial cells or smooth muscle cells, which constitute the two major cellular components of the arterial wall. Sodium nitroprusside oxidized strongly LDL in medium alone as well as in endothelial or smooth muscle cell cultures. Sydnonimine-1 (SIN-1) oxidized LDL already in the absence of cells and enhanced clearly the LDL oxidation in the cultures. S-nitroso-N-acetylpenicillamine was unable to oxidize LDL in synthetic medium alone as well as in the presence of cells, showing that the amount of superoxide and other reactive oxygen species released by these cells did not suffice, contrary to those liberated by macrophages, to combine to NO providing oxidant activity.

Smooth muscle cells influence monocyte response to LDL as well as their adhesion and transmigration in a coculture model of the arterial wall.

We investigated the possible interference of smooth muscle cells with monocyte response to LDL as well as with their adhesion and transmigration in a coculture of porcine endothelial and smooth muscle cells. Lysophosphatidylcholine (LPC), a component of oxidized LDL (oxLDL), stimulated the adhesion of THP-1 cells to endothelial cells both in mono- and in coculture with smooth muscle cells. When THP-1 cells were incubated with endothelial cells in the presence of copper oxLDL, their adhesion was increased, but only in coculture. The addition of sodium nitroprusside (SNP) together with oxLDL markedly increased the adhesion of THP-1 cells in coculture. Close proximity between endothelial and smooth muscle cells was necessary to observe that effect. Furthermore, this increase in adhesion of THP-1 cells can, at least in part, be attributed to the augmented production of monocyte chemoattractant protein-1 (MCP-1) observed in coculture under the influence of oxLDL and SNP. The passage of THP-1 cells through the coculture was stimulated by MCP-1 and LPC. These results show that physical contacts or close proximity between endothelial and smooth muscle cells play a key role in the adhesion of monocytes and their infiltration into the intima in response to oxLDL.

On the ozonization of cholesterol 3-acyl esters in protic media.

The structures of cholesterol 3 beta-acyl ester ozonides formed by reaction with ozone in participating alcoholic solvents are established by proton and carbon-13 spectra as a 3 beta-acyloxy-7 alpha-alkoxy-(5R,7R)-5 alpha-B-homo-6-oxacholestane-5-hydroperoxides (7a, 7b), and that of the dimeric cholesterol ozonide formed in nonparticipating solvents with cholesterol acting as alcohol is established as 7 alpha-cholest-5'-en-3'-yloxy-3 beta-hydroxy-(5R,7R)-5 alpha-B-homo-6-oxacholestane-5-hydroperoxide (7c).