Sex differences in characteristics and outcome in acute coronary syndrome patients in the Netherlands.

BACKGROUND: Sex differences in acute coronary syndrome (ACS) have been reported, but little is known about the situation in the Netherlands. METHODS: This registry is a merge of available data on ACS patients in the electronic data capture systems of 11 centres with 24/7 interventional cardiology services. We included patients >18 years undergoing a cardiac catheterisation between 2010-2012. We evaluated sex differences in clinical and procedural characteristics and 1­year mortality. RESULTS: A total of 29,265 ACS patients (8,720 women and 20,545 men) were registered. Women were on average 4.5 years older (68.5 vs 63.0 years, p < 0.001) and had a higher prevalence of hypertension (62.7 vs 49.8%, p < 0.001) and insulin-dependent diabetes mellitus (9.6 vs 6.8%, p < 0.001) than men. Women less often presented with ST-elevation myocardial infarction (43.7% vs 47.6%, p < 0.001) and appeared to have less extensive coronary artery disease than men. Women less often underwent coronary angiography by radial access (52.5 vs 55.9%, p < 0.001). One-year mortality was higher in women than in men (7.3% and 5.6%, p < 0.001). More specific, the relationship between sex and mortality was age-dependent and showed higher mortality in women ≤71 years, but lower mortality in older women compared with men (p-interaction <0.001). CONCLUSION: We found differences in clinical and procedural characteristics and outcome between women and men admitted for ACS, which are in line with other Western countries. The limitations of our registry, based on existing local databases, can be overcome by the use of the prospective Netherlands Heart Registry that is currently in development.

Optimization of single-cell gel electrophoresis (SCGE) for quantitative analysis of neuronal DNA damage.

Neuronal death can be induced by DNA-damaging agents and occurs by apoptosis involving a specific signal-transduction pathway. However, to our knowledge, methods for the quantitative determination of DNA damage in individual neurons have not yet been described. Here we optimize the single-cell gel electrophoresis (SCGE) or "comet"-assay to measure DNA damage within individual neurons growing in dissociated cell culture. In addition, we have written a macro for the NIH Image program to determine the tail moment of individual comets. We have calibrated this method using gamma-irradiated (0-16 Gy) cerebral cortical neurons from the rat central nervous system. Neuronal DNA damage (in the form of DNA strand breaks) occurs in a linear, dose-dependent manner, which can be quantitatively determined in vitro using the SCGE assay. These data demonstrate that the SCGE assay is an effective method to measure DNA damage in individual neurons and may be highly useful for the study of neuronal DNA damage formation, repair and apoptosis.

Efficacy and safety of low- and high-dose sotalol versus propranolol in the prevention of supraventricular tachyarrhythmias early after coronary artery bypass operations.

Supraventricular tachyarrhythmias are reported in up to 40% of patients early after coronary artery bypass graft operations. In a randomized study, we compared the efficacy and safety of the class III antiarrhythmic beta-blocking drug sotalol versus propranolol at low and high doses in the prevention of supraventricular tachyarrhythmias in 429 consecutive patients after coronary artery bypass graft operations. Patients with severely depressed left ventricular function and other contraindications for beta-blockers were excluded. From the fourth hour up to the sixth day after coronary artery bypass, 74 patients received low-dose sotalol (40 mg every 8 hours), 66 patients low-dose propranolol (10 mg every 6 hours), 133 patients high-dose sotalol (80 mg every 8 hours), and 156 patients high-dose propranolol (20 mg every 6 hours). Baseline characteristics were comparable in all groups. Supraventricular tachyarrhythmia was observed in 10 of 72 (13.9%) who received low-dose sotalol, 12 of 64 (18.8%) who received low-dose propranolol, 13 of 119 (10.9%) who received high-dose sotalol, and 19 of 139 (13.7%) who received high-dose propranolol (not significant). Drug-related adverse effects necessitating discontinuation of the drug occurred in four receiving low doses (2.9%) and in 31 receiving high doses (10.7%) (p less than 0.02). In conclusion, no medication was found to be superior, although supraventricular tachyarrhythmias tended to be less prevalent in patients treated with sotalol than in those treated with propranolol. Moreover, significantly fewer adverse effects were noted in both low-dose groups. Therefore, low-dose beta-blocking treatment, especially low-dose sotalol, seems preferable.

Aminoglycoside-mediated suppression of nonsense mutations in late infantile neuronal ceroid lipofuscinosis.

The ability of aminoglycoside antibiotics to promote readthrough of eukaryotic stop codons has attracted interest in these drugs as potential therapeutic agents in human disorders caused by nonsense mutations. One disease for which such a therapeutic strategy may be viable is classical late infantile neuronal ceroid lipofuscinosis (LINCL), a fatal childhood neurodegenerative disorder with currently no effective treatment. Premature stop codon mutations in the gene CLN2 encoding the lysosomal tripeptidyl-peptidase 1 (TPP-I) are associated with disease in approximately half of children diagnosed with LINCL. The aim of this study was to examine the ability of the aminoglycoside gentamicin to restore TPP-I activity in LINCL cell lines. In one patient-derived cell line that was compound heterozygous for a commonly seen nonsense mutation, Arg208Stop and a different rare nonsense mutation, approximately 7% of normal levels of TPP-I were maximally restored with gentamicin treatment. In other cell lines from patients that were compound heterozygous for Arg208Stop and a splice junction mutation, approximately 0.5% of maximal activity was restored. These results suggest that pharmacological suppression of nonsense mutations by aminoglycosides or functionally similar pharmaceuticals may have therapeutic potential in LINCL.

Congenital ovine neuronal ceroid lipofuscinosis--a cathepsin D deficiency with increased levels of the inactive enzyme.

We recently showed that a form of neuronal ceroid lipofuscinosis (NCL) in white Swedish landrace sheep is caused by a missense mutation in the cathepsin D gene resulting in complete inactivation of the enzyme. Despite the lack of cathepsin D activity, the brains of the cathepsin D deficient sheep showed strongly increased staining for cathepsin D in immunohistochemistry. By Western blotting, a 5-10 fold increase in the level of cathepsin D was confirmed. These results indicate that the missense mutation in congenital NCL sheep results in the synthesis of an inactive yet stable cathepsin D.

Percutaneous recanalization of chronic total coronary occlusions: experience with the direct argon laser assisted angioplasty system (LASTAC).

The present study reports initial experience with the argon laser LASTAC system in patients with chronic coronary artery occlusion not amenable to recanalization with conventional systems. The LASTAC system conducts focused argon laser light through an optical fiber of 200 microns which is inserted through a multiple-lumen balloon catheter. The balloon serves the purpose of coaxially positioning the optical fiber. The balloon catheter is advanced by means of a guidewire to about 2 mm proximal to the occlusive lesion. After advancing the optical fiber, in three times 10 to 20 Joules are applied. Thereafter, the optical fiber is withdrawn, the balloon deflated, the catheter system repositioned and the sequence repeated. The integrity of the system with respect to temperature increase, energy loss and contact with tissue is monitored with lens fluorescence. In 29 patients with angina pectoris and documented ischemia, 30 complete occlusions were treated. In 18 (60%), there was successful recanalization with conventional balloon dilation thereafter. The total success rate for the right coronary artery was 55%, for the circumflex artery 71% and for the left anterior descending artery 67%. With regard to complications, in one patient there was nontransmural myocardial infarction, in seven there were asymptomatic dissections, one patient required defibrillation. The value of the LASTAC system for recanalization of chronically occluded coronary arteries has not yet been fully delineated. However, the success rate of 60% in previously treatment-refractory patients as well as the fact that no perforations were incurred, is encouraging. Further assessment will require analysis of long-term results as well as comparison of other methods.

Predictability and prognosis of PTCA-induced coronary artery aneurysms.

The natural history of coronary aneurysms, defined as local dilatations exceeding the diameter of the normal adjacent vessel segments by at least 1.5 times, is not significantly different from the natural history of nonaneurysmal coronary disease. However, little is known about the prognosis of percutaneous transluminal coronary angioplasty (PCTA)-induced coronary aneurysms. Therefore, we investigated the occurrence and the medium long-term prognosis of such aneurysms in 728 patients who, after successful PTCA, underwent repeat coronary angiography at mean 4.5 months post-PTCA. A coronary aneurysm at the site of PTCA ws noted in 3.9% of patients (n = 28). Of the potentially predictive factors analyzed, only a coronary dissection at the time of PTCA had statistically significant influence. The long-term prognosis of PTCA-induced coronary aneurysms was excellent. One patient underwent (unrelated) cardiac surgery, all other 27 patients remained eventfree. We conclude that the same benign nature of coronary aneurysmal disease holds true for those aneurysms that develop after PTCA.

A mutation in the ovine cathepsin D gene causes a congenital lysosomal storage disease with profound neurodegeneration.

The neuronal ceroid lipofuscinoses (NCLs) constitute a group of neurodegenerative storage diseases characterized by progressive psychomotor retardation, blindness and premature death. Pathologically, there is accumulation of autofluorescent material in lysosome-derived organelles in a variety of cell types, but neurons in the central nervous system appear to be selectively affected and undergo progressive death. In this report we show that a novel form of NCL, congenital ovine NCL, is caused by a deficiency in the lysosomal aspartyl proteinase cathepsin D. A single nucleotide mutation in the cathepsin D gene results in conversion of an active site aspartate to asparagine, leading to production of an enzymatically inactive but stable protein. This results in severe cerebrocortical atrophy and early death, providing strong evidence for an important role of cathepsin D in neuronal development and/or homeostasis.

Mutational analysis of the defective protease in classic late-infantile neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal storage disorder.

The late-infantile form of neuronal ceroid lipofuscinosis (LINCL) is a progressive and ultimately fatal neurodegenerative disease of childhood. The defective gene in this hereditary disorder, CLN2, encodes a recently identified lysosomal pepstatin-insensitive acid protease. To better understand the molecular pathology of LINCL, we conducted a genetic survey of CLN2 in 74 LINCL families. In 14 patients, CLN2 protease activities were normal and no mutations were identified, suggesting other forms of NCL. Both pathogenic alleles were identified in 57 of the other 60 LINCL families studied. In total, 24 mutations were associated with LINCL, comprising six splice-junction mutations, 11 missense mutations, 3 nonsense mutations, 3 small deletions, and 1 single-nucleotide insertion. Two mutations were particularly common: an intronic G-->C transversion in the invariant AG of a 3' splice junction, found in 38 of 115 alleles, and a C-->T transition in 32 of 115 alleles, which prematurely terminates translation at amino acid 208 of 563. An Arg-->His substitution was identified, which was associated with a late age at onset and protracted clinical phenotype, in a number of other patients originally diagnosed with juvenile NCL.