Matrix metalloproteinases and atrial remodeling in patients with mitral valve disease and atrial fibrillation

BACKGROUND: Atrial fibrillation (AF) is associated with extracellular matrix remodeling involving atrial fibrosis and atrial dilatation. Angiotensin II mediated pathways and matrix metalloproteinases (MMPs) have been implicated in these processes. Our aim was to study atrial structural remodeling and the expression of the angiotensin receptor subtypes and MMPs and their inhibitors (TIMPs) in patients with mitral valve disease with and without AF. METHODS AND RESULTS: Biopsies from right and left atrial appendages (RA and LA) were taken from patients undergoing CABG (n=9, all in sinus rhythm (SR)) or mitral valve surgery (MVS; n=19; 9 with permanent AF and 10 in SR). Patients with MVS and AF had significantly larger atria (versus MVS and SR: p=0.02; versus CABG: p<0.01). The MVS patients had significantly more fibrosis than the control CABG group. Fibrosis was increased in both the AF and SR MVS groups in the LA, but only in the MVS-AF group in the RA. These AF patients had significantly more tricuspid regurgitation than SR patients. MMP-1 was down-regulated in LA of MVS patients (p=0.02) independent of the underlying rhythm (SR or AF; p=0.95). In RA biopsies, MMP-1 was down-regulated only in the MVS and AF group. MMP-9 was down-regulated in the MVS patients compared to CABG both in the RA and LA, and without a difference between the SR and AF groups. Protein expression of AT-1, AT-2, MMP-2, TIMP-1, -2 and -4, TNF-alpha, and TNF-alpha-converting enzyme did not differ significantly between the 3 groups. CONCLUSIONS: Concordant changes between MMP-expression and fibrosis during mitral valve disease, both in LA and RA, suggest involvement of MMPs in structural atrial remodeling. AF itself did not contribute to altered fibrosis or MMP-expression in the LA. The association between AF and RA changes may be precipitated by greater hemodynamic load due to tricuspid regurgitation in these patients.     

Complete recovery in plasma of enzymes lost from the heart after permanent coronary artery occlusion in the dog

Plasma activities of creatine kinase (CK) and alpha-hydroxybutyrate dehydrogenase (HBD) were measured after permanent coronary artery occlusion in the dog. Cumulative release of enzymes in plasma was calculated from these data by using a previously validated two-compartment model for circulating enzymes. Regional myocardial ischemia was measured by injection of radiolabeled microspheres. After 48 hours, the dogs were killed, and a detailed map of left ventricular enzyme activity was obtained from 108 tissue samples. Cumulative release into plasma of CK and HBD was 96 +/- 20% and 112 +/- 26%, respectively, of the total activities depleted from the heart (mean +/- SD, n = 11). The scatter in these values is inherent to the calculations, and it is concluded that both enzymes are recovered completely in plasma and, thus, can be used as quantitative markers of injury. Discrepancies between this result and earlier reports on the recovery of CK are only partly apparent and can be explained partly by underestimation of the elimination rate of CK from plasma, irregardless of tissue edema and incomplete extraction of enzyme activity from tissue.     

Pericardial effusion and right-sided pneumothorax resulting from an atrial active-fixation lead.

We report on a patient in whom an active-fixation pre-shaped atrial lead caused perforation of the right atrial wall, pericardium and pleura, resulting in pericardial effusion and right-sided pneumothorax. Chest X-ray did not demonstrate protrusion of the atrial lead outside the cardiac silhouette but computed tomography visualized the tip of the helix of the atrial screw-in electrode outside the contours of the right atrial appendage touching the right upper lobe of the lung. The lead was repositioned with resolution of pericardial effusion and pneumothorax. Due to their proximity to the right lung, high anterolaterally positioned atrial screw-in leads carry a small but definite risk for right-sided pneumothorax.     

Durability of serologic response after lamivudine treatment of chronic hepatitis B

Forty subjects with chronic hepatitis B and hepatitis B e antigen (HBeAg) seroconversion following lamivudine therapy in previous trials were monitored after treatment to assess the durability of serologic responses. Patient follow-up began a median of 4.3 months after completion of therapy in previous trials. At months 2, 4, 6, 9, and 12 of year 1, and every 6 months thereafter, we tested for HBeAg and hepatitis B surface antigen (HBsAg), hepatitis B virus (HBV) DNA, and alanine aminotransferase (ALT). After a median (range) of 36.6 (4.8-45.6) months of follow-up monitoring, HBeAg seroconversion was demonstrated at the last visit by 77% (30 of 39) of patients. In a post hoc analysis of a slightly different population of all 65 patients with HBeAg seroconversion in previous trials, the 3-year durability of HBeAg seroconversion measured from the time immediately after discontinuing lamivudine therapy was 64%. Nine (9 of 40, 23%) patients were HBsAg negative at the last assessment. Seventy-four percent (17 of 23) of patients with baseline undetectable HBV DNA and normal ALT maintained these responses at the last visit. Eight patients (8 of 40, 20%) initiated retreatment for reappearance of HBV markers, and 7 showed biochemical and/or virologic improvement (including regained HBeAg seroconversion in 2). No safety issues of concern emerged. In conclusion, most HBeAg responses achieved during lamivudine therapy were durable, and most responders experienced prolonged clinical benefit after HBeAg seroconversion and subsequent discontinuation of lamivudine. Lamivudine retreatment for reappearance of hepatitis B markers can achieve resumption of viral suppression.     

Estimation of circulatory parameters in patients with acute myocardial infarction. Significance for calculation of enzymatic infarct size

Estimation of infarct size from enzyme activities in plasma or serum presupposes known values of circulatory parameters such as the extravascular distribution volume Ve and the permeability constant P for the transport of enzyme between intravascular volume Vi and Ve. In man, parameter values are used that are extrapolated either from values found in the dog or from turnover studies of non-myocardial proteins. Large systematic errors can be introduced in this way, as demonstrated in this study. It is shown that by simultaneous determination of two different enzymes in the same patient, estimates of circulatory parameters are obtained. The method is applied to creatine kinase (CK) and alpha-hydroxybutyrate dehydrogenase (HBDH) plasma activities in 36 patients with acute myocardial infarction (AMI). The following results are obtained: 1. Exchange of enzyme between Vi and Ve is much slower and clearance of CK is much faster than presently assumed in the literature. 2. Release of CK and HBDH into the circulation is proportional to the amounts of these enzymes present in the myocardium. This finding is supported by data on early enzyme release. 3. Quantitation of HBDH release needs a two-compartment model, while for CK a one-compartment model can be used in good approximation. 4. Release of CK and HBDH after AMI continues up to 96 hours. 5. Using obtained parameter values, a simulated model demonstrates that estimation of clearance rates of CK from exponential fits on plasma levels results in large errors. This may explain recent conflicting results in validation of enzymatic estimates of infarct size.     

Management and treatment of hepatitis C virus in patients with HIV and hepatitis C virus coinfection: A practical guide for health care professionals

Concomitant HIV and hepatitis C virus (HCV) is a common yet complex coinfection. The present document is a practical guide for treating HCV infection in people coinfected with HIV. Effective antiretroviral therapies have prolonged survival rates for HIV-infected people over the past decade, which have made latent complications of HCV major causes of morbidity and mortality in these patients. Advances in the treatment of HCV (eg, combined pegylated interferon and ribavirin) offer the possibility of eradicating HCV infection in coinfected persons. The treatment of HCV must be considered in all cases. Intensive management of the adverse effects of HCV treatment is one of the factors for the success of these therapies. HCV eradication is predicted to decrease the mortality associated with coinfection and reduce the toxicity of HIV treatment.     

Endocardial mapping and high frequency catheter ablation of ventricular tachycardia after myocardial infarction

Recurrent ventricular tachycardia in the setting of remote myocardial infarction are frequently resistant to antiarrhythmic drug treatment. Endocardial mapping and ablation is feasible in case of hemodynamically tolerable and reproducibly inducible forms. Identification of critical components of the reentrant circuit is mainly guided by entrainment mapping and the analysis of the post-pacing interval. The emergence of multiple types of ventricular tachycardia is a common limitation of the procedure. Ventricular tachycardia can be acutely abolished by radiofrequency current ablation in 60-70% of cases when only single forms are present. This success rate is substantially lower in case of multiple tachycardia morphologies. The incidence of tachycardia recurrences varies from 20-30%. The overall mortality during follow-up is increased due to progressive heart failure and the occurrence of rapid ventricular tachyarrhythmias. Catheter ablation has been shown to be a useful tool for the treatment of clusters of ventricular tachycardia following implantation of a cardioverter-defibrillator. Furthermore, this method can be life-saving in the setting of incessant forms. Currently, catheter ablation represents an adjunctive treatment to antiarrhythmic drugs and the implantation of a cardioverter-defibrillator. Improvement of mapping and ablation technologies may help to further increase the efficacy of this treatment strategy in the near future.     

Hydrochloric acid

The effect of a single instillation of acid and pepsin on the cell proliferation in the distal esophageal mucosa was investigated in four dogs. The doses of acid and pepsin used were lower than those provoking acute esophagitis and erosions. Usingin vitro labeling with [³H]thymidine and autoradiography, the epithelial mitotic and DNA synthesis indices were determined at 0, 4, 8, 12, 16, 20, and 24 hr after instillation of saline, of acid alone, or of acid with pepsin. Instillation of acid alone was followed, 16 hr later, by an increase (P<0.01) in DNA synthetic activity in the proliferative area. A mitotic peak (P<0.01) started from the 20th hour. After instillation of acid with pepsin in the same animals, a similar sequence of kinetic phenomena was observed, suggesting that the concentration of pepsin used did not potentiate the stimulating effect of acid on the cell proliferation in this epithelium. Our data indicate that hydrochloric acid stimulates the proliferative activity in the normal esophageal epithelium.This work was supported in part by a grant for cancer research from the Algemene Spaar-en Lijfrentekas and by the Fonds voor Geneeskundig Wetenschappelijk Onderzoek.     

Homocysteine and venous thrombosis: outline of a vitamin intervention trial

In the past years several case-control studies established the association of an elevated plasma homocysteine concentration and the risk of venous thromboembolism. It is still unclear if elevated homocysteine concentrations can cause venous thrombosis. The VITRO (VItamins and ThROmbosis) trial is the first multicenter, randomized, double-blind and placebo-controlled study to evaluate the effect of homocysteine-lowering therapy by means of 5 mg folic acid, 0.4 mg vitamin B12 and 50 mg vitamin B6. The study is a secondary prevention trial in 600 patients who suffered from a first episode of idiopathic deep vein thrombosis (DVT) or pulmonary embolism (PE), or both. There will be 300 hyperhomocysteinemic and 300 normohomocysteinemic patients included, all with an objectivated venous thrombosis. The end point is recurrence of venous thrombosis.