Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Diagnostic Task Force Criteria Impact of New Task Force Criteria

Background-Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) Diagnostic Task Force Criteria (TFC) proposed in 1994 are highly specific but lack sensitivity. A new international task force modified criteria to improve diagnostic yield. A comparison of diagnosis by 1994 TFC versus newly proposed criteria in 3 patient groups was conducted. Methods and Results-In new TFC, scoring by major and minor criteria is maintained. Structural abnormalities are quantified and TFC highly specific for ARVD/C upgraded to major. Furthermore, new criteria are added: terminal activation duration of QRS ≥55 ms, ventricular tachycardia with left bundle-branch block morphology and superior axis, and genetic criteria. Three groups were studied: (1) 105 patients with proven ARVD/C according to 1994 TFC, (2) 89 of their family members, and (3) 39 patients with probable ARVD/C (ie, 3 points by 1994 TFC). All were screened for pathogenic mutations in desmosomal genes. Three ARVD/C patients did not meet the new sharpened criteria on structural abnormalities and thereby did not fulfill new TFC. In 62 of 105 patients with proven ARVD/C, mutations were found: 58 in the gene encoding Plakophilin2 (PKP2), 3 in Desmoglein2, 3 in Desmocollin2, and 1 in Desmoplakin. Three patients had bigenic involvement. Ten additional relatives (11%) fulfilled new TFC: 9 (90%) were female, and all carried PKP2 mutations. No rel

The arrhythmogenic cardiomyopathy phenotype associated with PKP2 c.1211dup variant

BackgroundThe arrhythmogenic cardiomyopathy (ACM) phenotype, with life-threatening ventricular arrhythmias and heart failure, varies according to genetic aetiology. We aimed to characterise the phenotype associated with the variant c.1211dup (p.Val406Serfs*4) in the plakophilin-2 gene (PKP2) and compare it with previously reported Dutch PKP2 founder variants.MethodsClinical data were collected retrospectively from medical records of 106 PKP2 c.1211dup heterozygous carriers. Using data from the Netherlands ACM Registry, c.1211dup was compared with 3 other truncating PKP2 variants (c.235C > T (p.Arg79*), c.397C > T (p.Gln133*) and c.2489+1G > A (p.?)).ResultsOf the 106 carriers, 47 (44%) were diagnosed with ACM, at a mean age of 41 years. By the end of follow-up, 29 (27%) had experienced sustained ventricular arrhythmias and 12 (11%) had developed heart failure, with male carriers showing significantly higher risks than females on these endpoints (p < 0.05). Based on available cardiac magnetic resonance imaging and echocardiographic data, 46% of the carriers showed either right ventricular dilatation and/or dysfunction, whereas a substantial minority (37%) had some form of left ventricular involvement. Both geographical distribution of carriers and haplotype analysis suggested PKP2 c.1211dup to be a founder variant originating from the South-Western coast of the Netherlands. Finally, a Cox proportional hazards model suggested significant differences in ventricular arrhythmia-free survival between 4 PKP2 founder variants, including c.1211dup.ConclusionsThe PKP2 c.1211dup variant is a Dutch founder variant associated with a typical right-dominant ACM phenotype, but also left ventricular involvement, and a possibly more severe phenotype than other Dutch PKP2 founder variants.Cardiolog

Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy

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Loss-of-function ABCC8 mutations in pulmonary arterial hypertension

Background: In pulmonary arterial hypertension (PAH), pathological changes in pulmonary arterioles progressively raise pulmonary artery pressure and increase pulmonary vascular resistance, leading to right heart failure and high mortality rates. Recently, the first potassium channelopathy in PAH, because of mutations in KCNK3, was identified as a genetic cause and pharmacological target. Methods: Exome sequencing was performed to identify novel genes in a cohort of 99 pediatric and 134 adult-onset group I PAH patients. Novel rare variants in the gene identified were independently identified in a cohort of 680 adult-onset patients. Variants were expressed in COS cells and function assessed by patch-clamp and rubidium flux analysis. Results: We identified a de novo novel heterozygous predicted deleterious missense variant c.G2873A (p.R958H) in ABCC8 in a child with idiopathic PAH. We then evaluated all individuals in the original and a second cohort for rare or novel variants in ABCC8 and identified 11 additional heterozygous predicted damaging ABCC8 variants. ABCC8 encodes SUR1 (sulfonylurea receptor 1)—a regulatory subunit of the ATP-sensitive potassium channel. We observed loss of ATP-sensitive potassium channel function for all ABCC8 variants evaluated and pharmacological rescue of all channel currents in vitro by the SUR1 activator, diazoxide. Conclusions: Novel and rare missense variants in ABCC8 are associated with PAH. Identified ABCC8 mutations decreased ATP-sensitive potassium channel function, which was pharmacologically recovered

Imaging for salivary gland sparing radiotherapy

One of the major side effects of radiotherapy in the head-and-neck area is a reduced saliva production due to the high radiation-sensitivity of the salivary glands. The reduced salivary flow induces difficulties in swallowing, eating, speaking, and often induces dental caries. This thesis addresses the aspects of the radiotherapy treatment of HN cancer patients and the radiation-induced complications of the largest salivary glands, the parotid and submandibular glands. The topics follow the same path as a patient during treatment: from imaging, through radiotherapy planning and the daily treatment, to unfortunately in some cases, radiation-induced xerostomia. Magnetic resonance imaging (MRI) strategies to visualize both the tumour and the salivary glands were explored. The feasibility of perfusion MRI to assess the blood perfusion characteristics of the head-and-neck tumours was investigated. Compared to healthy tissue, the blood perfusion within the tumour was significantly increased. Perfusion MRI was shown to be a promising tool in tumour characterisation and to guide the radiotherapy treatment. As for the salivary glands, MR sialography was used to obtain high-resolution images, which show the outline of the gland as a medium-intense signal with high-intense ducts inside. The MRI images were superior to CT in defining the outline of the submandibular gland, resulting in a significant increase in defined volume and by that a more accurate sparing of the gland. Improvements in the radiotherapy treatment were obtained by adapting the dose distribution to reduce the dose to the salivary glands. An advanced intensity-modulated radiotherapy (IMRT) technique was used, resulting in a decrease in mean dose to the submandibular gland of 12 Gy. This amount of reduction will reduce the chance of complication of 85% to 50%. Another improvement in the treatment was accomplished by optimizing the immobilization of the patients during treatment. Patients are treated in daily fractions and differences in patient positioning results in uncertainties in tumour position within the patient. To reduce this uncertainty, patients were immobilized with a special head support and a thermoplastic mask. Improvements in this head support reduced the movement during treatment, resulting in better treatment accuracies. Finally, the chance of developing a complication given a certain dose distribution to the parotid gland was investigated to further improve clinical decision making. To accomplish accurate modelling on a large dataset, a combined dataset of the University Medical Center Utrecht and the University of Michigan Hospital was used. The mean dose was found to be the best prediction dose parameter and a mean dose of 40 Gy to the parotid gland resulted in a 50% chance of a complication. The improvements in the radiotherapy treatment of head-and-neck cancer patients described in this thesis will make an important difference in preventing radiation-induced xerostomia and improve the quality of life of these patients. This will reduce the occurrence of submandibular gland complications from the 80% we see nowadays to 50% or les