Desmoplakin cardiomyopathy-an inherited cardiomyopathy presenting with recurrent episodes of acute myocardial injury.

We present two female patients with recurrent episodes of myocardial injury, consisting of acute chest pain and elevated cardiac markers without coronary artery disease. Cardiovascular magnetic resonance imaging identified extensive late gadolinium enhancement suggestive of an inherited cardiomyopathy. Genetic testing showed heterozygous pathogenic variants in the desmoplakin (DSP) gene, the gene coding for the desmoplakin protein, a structural protein found in the cardiac desmosome. Pathogenic variants in the DSP gene are associated with dilated and arrhythmogenic cardiomyopathy. DSP cardiomyopathies may cause recurring myocardial injury mimicking an acute coronary syndrome or myocarditis. Cardiac magnetic resonance imaging is key in its diagnosis due to its specifying imaging features. Genetic testing is essential for the evaluation and confirmation of the diagnosis.

von Willebrand factor plasma levels, genetic variations and coronary heart disease in an older population.

BACKGROUND: High von Willebrand factor (VWF) levels are associated with an increased risk of coronary heart disease (CHD). However, it remains unclear whether VWF is causally related to the occurrence of CHD or primarily mirrors endothelial dysfunction, which predisposes to atherosclerosis and subsequent CHD. OBJECTIVES: Because VWF is largely determined by genetic factors, we investigated whether VWF antigen levels (VWF:Ag) and the risk of CHD are affected by common variations in the VWF gene. METHODS: We included 7002 participants (≥ 55 years) from the large prospective population-based Rotterdam Study in the discovery cohort. The extension cohort of the Rotterdam Study, consisting of 3011 participants, was used as a replication cohort. We determined VWF:Ag levels and genotype data of 38 single-nucleotide polymorphisms (SNPs) in VWF. Subsequently, hazard ratios for CHD were calculated and genetic analyses were performed to assess the relationship between SNPs, VWF:Ag levels and CHD risk. RESULTS: We identified and replicated three SNPs that were associated with VWF:Ag: rs216321 (ß = 0.10 [95% confidence interval, CI, 0.06;0.13]) (Ala852Gln), rs1063856 (ß = 0.05 [95% CI 0.03;0.07]) (Thr789Ala) and rs2283333 (ß = 0.09 [95% CI 0.05;0.21]) (intron 15). However, genetic polymorphisms in the VWF gene were not associated with the risk of CHD. CONCLUSIONS: In this study we have shown that genetic variations in VWF strongly affect VWF plasma levels, but are not associated with the risk of CHD. Our findings therefore do not support a strong causal relationship between VWF and CHD in elderly individuals of ≥ 55 years, but suggest that VWF is primarily a marker of CHD.

Genetic determinants of von Willebrand factor levels and activity in relation to the risk of cardiovascular disease: a review.

It is well established that high plasma von Willebrand factor (VWF) levels are associated with an increased risk of arterial thrombosis, including myocardial infarction and ischemic stroke. As plasma VWF levels are, to a large extent, genetically determined, numerous association studies have been performed to assess the effect of genetic variability in the VWF gene (VWF) on VWF antigen and activity levels, and on the risk of arterial thrombosis. Genetic variations in other regulators of VWF, including the ABO blood group, ADAMTS-13, thrombospondin-1 and the recently identified SNARE protein genes, have also been investigated. In this article, we review the current literature as exploring the associations between genetic variations and the risk of arterial thrombosis may help elucidate the role of VWF in the pathogenesis of arterial thrombosis. However, as studies frequently differ in design, population and endpoint, and are often underpowered, it remains unclear whether VWF is causally related to the occurrence of arterial thrombosis or primarily mirrors endothelial dysfunction, which predisposes to atherosclerosis and subsequent arterial thrombosis. Nevertheless, current studies provide interesting results that do not exclude the possibility of VWF as causal mediator and justify further research into the relationship between VWF and arterial thrombosis. Large prospective studies are required to further establish the role of VWF in the occurrence of arterial thrombosis.