Intimal hyperplasia and coronary flow reserve after heart transplantation: association with big endothelin-1

BACKGROUND: Endothelin, a peptide with strong vasoconstrictive and mitogenic properties, has been found to increase after cardiac transplantation. We therefore assessed the association between its precursor peptide, big endothelin-1, and intimal hyperplasia and coronary flow reserve after heart transplantation. METHODS: Thirty-five patients without hemodynamically significant coronary artery disease after heart transplantation were investigated: Average peak flow velocity in the left anterior descending artery (LAD) was assessed by intracoronary Doppler at baseline as well as after injection of adenosine; coronary flow reserve was calculated as a ratio of both and was corrected for patient age and baseline average peak flow velocity. Lumen, intima + media and total vessel area were measured by intracoronary ultrasound. The plasma concentration of big endothelin-1 in venous blood was determined by radioimmunoassay. RESULTS: Patients with elevated big endothelin-1 levels (>2 fmol/ml) tended to have a decreased corrected coronary flow reserve (2.60 +/- 0.9 vs 3.21 +/- 1.0, p = 0.078). They also had a significantly larger intima + media area (5.82 +/- 2.9 vs 2.37 +/- 2.9 mm(2), p = 0.004) and total vessel area (18.36 +/- 5.8 vs 12.81 +/- 4.8 mm(2), p = 0.012) than those with normal plasma concentrations. CONCLUSIONS: Our study suggests an association between elevated big endothelin-1 plasma levels and the development of intimal hyperplasia and reduction of coronary flow reserve after cardiac transplantation.     

Modelling Germline Mosaicism and Different New Mutation Rates Simultaneously for Appropriate Risk Calculations in Families with Duchenne Muscular Dystrophy

For several genetic diseases two biological phenomena have been recognised as important: germline mosaicism; and different new mutation rates in males and females depending on mutation type. Both principles have been investigated separately and their influence on risk estimation in families has been exemplified in the literature. The aim of this paper is to present a general model that includes mosaicism and different new mutation rates. Mosaicism is introduced by defining additional alleles at the disease locus in combination with adapted segregation rules. Taking Duchenne muscular dystrophy as an example, we derive the conditions which have to be fulfilled for a population in mutation selection equilibrium. Our approach describes the model at the population level and not in individual subjects. This has the advantage of being able to use well known algorithms for the calculation of likelihoods in pedigrees, and to include additional diagnostic information such as marker genotypes and carrier deletion test results. We demonstrate the impact of the new model on a typical pedigree. In families where the patient is not available, the distinction between point mutations and deletions is important, since often molecular diagnostic tests for females can only screen for deletions. Negative deletion test results can now be included in the risk calculations.     

Pregnancy and uncomplicated vaginal delivery only 13 months after cardiac transplantation (case report)

Summary Background Pregnancy is prossible in female patients who underwent cardiac transplantation but is associated with unpredictable risks. Methods A 23-year old female patient underwent cardiac transplantation because of dilatative cardiomyopathy. Results Against our advice, she became pregnant 4 months after transplantation. Following an uneventful pregnancy, spontaneous vaginal delivery occurred 13 months after transplantation. The patient gave birth to a healthy new-born in good physical condition. Thereafter, the patient refused to attend any further routine follow-up control. 9 months after delivery, the patient was admitted to hospital in severe cardiac shock. Biopsy showed a serious, acute rejection which was treated with a course of methylprednisolone. Clinically, the patient recovered within 1 week, but died from acute myocardial infarction 1 day after discharge from hospital. Conclusions Only women without a history of rejection episodes, with good kidney function, good graft function, and high compliance should be counselled to become pregnant.      

Role of amiodarone on the systemic inflammatory response induced by cardiac surgery: proinflammatory actions

PURPOSE: Amiodarone (AMIO), a widely used anti-arrhythmic drug, has been shown to reduce the incidence of atrial fibrillation after cardiac surgery and also to exert immunomodulatory actions in vitro and proinflammatory effects in vivo. The present study investigated the immunomodulatory properties of AMIO in the inflammatory response induced by cardiac surgery with cardiopulmonary bypass (CPB). METHODS: In this double-blind, placebo-controlled trial, 20 patients undergoing elective coronary artery bypass graft were randomized to receive placebo or AMIO 600 mg day(-1) orally for seven days before surgery and 45 mg hr(-1) intravenously for 48 hr postoperatively. Plasma levels of the proinflammatory markers C-reactive protein (CRP), fibrinogen (FBG), tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1, and the antiinflammatory marker IL-10, were compared before and after surgery. RESULTS: Ninety-six hours after start of surgery, plasma levels of FBG had more than doubled (2.2 +/- 0.5-fold increase, P < 0.0001). Overall, FBG formation was significantly increased in the AMIO group (P = 0.048). Monocyte chemoattractant protein 1 secretion transiently increased four hours after start of surgery (6.6 +/- 4.5-fold increase) but rapidly declined thereafter, (P < 0.0001). There was a trend toward higher MCP-1 plasma concentrations in the AMIO group (P = 0.13). The plasma levels of CRP, TNF-alpha, IL-6 and Il-10 changed significantly over time, but were not altered by AMIO treatment. CONCLUSION: In the inflammatory response induced by cardiac surgery with CPB, our data suggest that AMIO treatment is associated with a selective trend toward proinflammatory actions.     

Leukocyte count and risk of major coronary heart disease events.

The association between leukocyte count and subsequent risk of major coronary heart disease events was examined using data from three prospective cohort studies--two from the United States and one from Great Britain. A total of 28,181 middle-aged men were followed for 6-12 years. A total of 1,768 men had a nonfatal myocardial infarction or died of coronary heart disease. In all three cohorts, there was a positive, statistically significant relation between baseline leukocyte count and risk of subsequent major coronary heart disease events after adjustment for age, serum total cholesterol, diastolic blood pressure, and number of cigarettes smoked per day (relative odds = 1.32 (p less than 0.0001), 1.15 (p = 0.0001), and 1.14 (p = 0.003), corresponding to a 2,000/mm3 difference in leukocyte count). The associations persisted when all nonsmokers (former smokers plus never smokers) and never smokers alone were considered and when those with evidence of preexisting coronary heart disease at baseline were excluded. Leukocyte count appears to be an indicator of a person's future risk of major coronary heart disease events.     

Occurrence of quinolone resistance in Staphylococcus aureus from nosocomial infection.

Among 63 Staphylococcus aureus isolates (one isolate per one patient) counted from infections (from August to November 1991) in hospital T., eight exhibited resistance to fluoroquinolones. Seven of these quinolone-resistant isolates were multiply- and methicillin-resistant S. aureus (QR-MRSA). The results of phage-, plasmid- and genotyping (pulsed field electrophoresis) revealed that six different strain-clones of these MRSA were spread in the hospital. In vitro spontaneous mutants resistant to fluoroquinolones are 10-100-fold more frequent in MRSA than in other S. aureus when selected on isosensitest-agar containing 1 microgram/ml of ciprofloxacin. However, the same mutant frequencies were found in strain 8325-4 with and without the mecA-determinant. The resistance phenotype was stable over 30 generations of subculture in nutrient broth as well in natural quinolone resistant MRSA as in mutants of other types of S. aureus selected in vitro. The phenotypic association of quinolone resistance and MRSA is rather likely due to a higher frequency of spontaneous resistant mutants which are present in natural populations of MRSA. Data of chemotherapy prior to the isolation of S. aureus show that three of seven patients from whom QR-MRSA were isolated were treated with a quinolone. In eight cases of infections with non-MRSA and quinolone treatment the isolated S. aureus strains were in vitro sensitive to quinolones.