Mutated desmoglein-2 proteins are incorporated into desmosomes and exhibit dominant-negative effects in arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary cardiac condition associated with ventricular arrhythmias, heart failure, and sudden death. The most frequent ARVC genes encode desmosomal proteins of which mutations in desmoglein-2 (DSG2), account for 10%-20% of cases. This study aimed to investigate how DSG2 mutations contribute to the pathogenesis of ARVC. Initial mutation analysis of DSG2 in 71 probands identified the first family reported with recessively inherited ARVC due to a missense mutation. In addition, three recognized DSG2 mutations were identified in 12 families. These results and further mutation analyses of four additional desmosomal genes indicated that ARVC caused by DSG2 mutations is often transmitted by recessive or digenic inheritance. Because desmosomal proteins are also expressed in skin tissue, keratinocytes served as a cell model to investigate DSG2 protein expression by Western blotting, 2D-PAGE, and liquid chromatography-mass spectrometry. The results showed that heterozygous mutation carriers expressed both mutated and wild-type DSG2 proteins. These findings were consistent with the results obtained by immunohistochemistry of endomyocardial biopsies and epidermal tissue of mutation carriers, which indicated a normal cellular distribution of DSG2. The results suggested a dominant-negative effect of the mutated DSG2 proteins because they were incorporated into the desmosomes.

Artery-related differences in atherosclerosis expression: implications for atherogenesis and dynamics in intima-media thickness.

BACKGROUND AND PURPOSE: Information about the expression of atherosclerosis in different arteries is important. The impact of cardiovascular risk factors is artery-related, and the assessment of arterial structure and function in peripheral arteries are increasingly used as surrogate markers for coronary atherosclerosis and the risk of developing heart attack. METHODS: In an autopsy study, we analyzed the coronary, carotid and superficial femoral arteries from 100 individuals (70 men; 20 to 82 years of age) of which 27 died from coronary atherosclerosis. Microscopic sections (n=4756) were analyzed blindly using a modification of the histological classification endorsed by the American Heart Association (AHA). RESULTS: We found distinct artery-dependent patterns of atherosclerosis with a high prevalence of foam cell lesions and lipid core plaques in the carotid arteries. The femoral arteries were least affected by atherosclerosis, foam cell lesions were rare, and the development of advanced atherosclerosis was strongly age-dependent and dominated by fibrous plaques. Plaques were most common in the left anterior descending coronary artery and the carotid bifurcation. In coronary (versus noncoronary) death, lipid core plaques were more prevalent in all arteries. CONCLUSIONS: The initiation, speed of development, and phenotypic expression of atherosclerotic plaques are artery-related. Foam cell lesions are frequent in the carotid arteries, probably explaining the dynamics in carotid intima-media thickness. Atherosclerosis develops slowly in femoral arteries, and severe atherosclerosis is dominated by fibrous plaques. The higher prevalence of lipid core plaques in all arteries in coronary death indicates a systemically more vulnerable expression of atherosclerosis in these individuals.

Large eccrine angiomatous hamartoma: a novel clinical presentation of disease.

BACKGROUND: Eccrine angiomatous hamartoma is a rare benign cutaneous malformation with a diverse clinical appearance, therefore likely to be misdiagnosed and underreported. MAIN OBSERVATIONS: A 44-year-old man presented with a congenital erythematous hyperhidrotic plaque on the left upper back measuring 18 x 25 cm. No pain or tenderness nor hypertrichosis were observed. Histopathology was consistent with the mucinous variant of eccrine angiomatous hamartoma. Intralesional injection of botulinum toxin type A greatly reduced localized sweating, improving patient quality of life. CONCLUSIONS: This article describes a novel clinical presentation of eccrine angiomatous hamartoma: large, erythematous, and slightly indurated plaque localized on the upper back. It emphasizes the role of histopathology in the diagnostic process and botulinum toxin as a viable treatment option.

Truncating plakophilin-2 mutations in arrhythmogenic cardiomyopathy are associated with protein haploinsufficiency in both myocardium and epidermis.

BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is a hereditary cardiac condition associated with ventricular arrhythmias, heart failure, and sudden death. The disease is most often caused by mutations in the desmosomal gene for plakophilin-2 (PKP2), which is expressed in both myocardial and epidermal tissue. This study aimed to investigate protein expression in myocardial tissue of patients with AC carrying PKP2 mutations and elucidate whether keratinocytes of the same individuals exhibited a similar pattern of protein expression. METHODS AND RESULTS: Direct sequencing of 5 AC genes in 71 unrelated patients with AC identified 10 different PKP2 mutations in 12 index patients. One patient, heterozygous for a PKP2 nonsense mutation, developed severe heart failure and underwent cardiac transplantation. Western blotting and immunohistochemistry of the explanted heart showed a significant decrease in PKP2 protein expression without detectable amounts of truncated PKP2 protein. Cultured keratinocytes of the patient showed a similar reduction in PKP2 protein expression. Nine additional PKP2 mutations were investigated in both cultured keratinocytes and endomyocardial biopsies from affected individuals. It was evident that PKP2 mutations introducing a premature termination codon in the reading frame were associated with PKP2 transcript and protein levels reduced to ≈50%, whereas a missense variant did not seem to affect the amount of PKP2 protein. CONCLUSIONS: The results of this study showed that truncating PKP2 mutations in AC are associated with low expression of the mutant allele and that the myocardial protein expression of PKP2 is mirrored in keratinocytes. These findings indicate that PKP2 haploinsufficiency contributes to pathogenesis in AC.

Pregnancy associated plasma protein-A (PAPP-A) is not a marker of the vulnerable atherosclerotic plaque.

OBJECTIVE: To investigate if pregnancy associated plasma protein-A (PAPP-A) was present in the vulnerable plaque, and if not, to find alternative hypothesis for the release of PAPP-A. DESIGN AND METHODS: Vulnerable plaques and control tissues were examined by immunohistochemistry. Volunteers and patients with non-atherosclerotic disease were examined for release of PAPP-A during ischemia and medical treatment. Non-atherosclerotic tissue samples were examined after incubation with heparins. RESULTS: We were not able to detect PAPP-A in vulnerable plaques. Patients and volunteers experiencing ischemic events without atherosclerotic lesions only had elevated PAPP-A when treated with heparin. When tissue from normal artery wall was incubated with heparin, PAPP-A was eluted. This was not the case for non-arterial tissue samples. CONCLUSION: Elevation of PAPP-A in patients with acute coronary syndromes seems to be caused by heparin induced release of PAPP-A from the arterial wall and not due to excretion from vulnerable plaques.

Imaging atherosclerotic plaques by cardiac computed tomography in vitro: impact of contrast type and acquisition protocol.

OBJECTIVE: Noninvasive contrast-enhanced coronary computed tomography (CT) angiography enables distinction between calcified and noncalcified atherosclerotic plaques. However, separation of noncalcified plaques into rupture prone lipid-rich and stable fibrous subtypes is challenging because CT density of the plaque, characterized by Hounsfield Units (HU), varies with intraluminal contrast density and acquisition protocol. This study aims at testing the influence of intraluminal contrast densities and kV-settings on coronary plaque density values in vitro. MATERIALS AND METHODS: We scanned 16 coronary arteries with 3 different contrast solutions (no contrast, 1:70, and 1:23 Iomeron, 350 mgI/mL) and 3 different kV-settings (80, 120, and 140 kV). The arteries were sectioned into 5-mm segments. Every segment was evaluated with CT and histopathology for suitability of analysis, presence, and subtype of plaque. RESULTS: Sixty-four segments were analyzed and classified with CT. Agreement between plaques classified with CT angiography in vitro and histopathology was poor-to-moderate, with no kappa-values above 0.21. The kV-settings affected the CT density in all plaque types. The CT density decreased 0.25 (0.07) HU, P=0.013 in noncalcified plaques, and 5.5 (0.7) HU, P<0.0001, in calcified plaques for every kV increase. CT densities in noncalcified plaques changed when the contrast concentration was changed. From no to high contrast concentration resulted in a 21.7 (8.3) HU increase, P=0.041, and from low to high contrast concentration resulted in a 21.5 (6) HU increase, P=0.011, causing several plaques to change in subtype from lipid-rich (low contrast concentration) to fibrotic (high contrast concentration). CONCLUSION: Agreement between CT angiography in vitro and histopathology for classification of coronary plaque subtype is poor to moderate. However, no specific combination seems superior to the most commonly used protocols for distinction between lipid-rich and fibrotic plaque subtypes in current clinical practice.

[Overlooked Wolff-Parkinson-White syndrome]. / Overset Wolff-Parkinson-White-syndrom.

An autopsy in a 28-year-old man did not explain the cause of sudden unexpected death. However, a history of episodes with tachycardia and dizziness and a reassessed previous electrocardiogram exhibiting ventricular pre-excitation was consistent with Wolff-Parkinson-White (WPW) syndrome. In this patient we believe that the occurrence of atrial fibrillation caused sudden cardiac death from ventricular fibrillation due to a short refractory period of an accessory atrioventricular pathway and a very rapid ventricular rate in atrial fibrillation.

Fatal giant cell myocarditis in a patient with multiple autoimmune disorders.

A case of circulatory collapse due to severe heart failure is reported in a 52-year old male with autoimmune disorders in the form of type-1 diabetes, Graves' disease and total alopecia.Upon admission, the patient had severe heart failure with a cardiac index of 0.9 l/min/m(2), a mixed venous saturation of 29% and left ventricular ejection fraction of 5%. The condition was refractory to treatment with inotropic agents and required mechanical cardiopulmonary support. Endomyocardial biopsies revealed extensive giant cell myocarditis (GCM). Immunosuppressant treatment did not alter the condition and urgent orthotopic heart transplantation was performed.Histopathological examination of the explanted heart confirmed the diagnosis and showed widespread vascular deposition of complement C4d suggesting a pathogenic role for the innate immune system in GCM.At 1-year follow-up the patient was in New York Heart Association (NYHA) class I, had episodes of sustained ventricular tachycardia but showed no evidence of GCM recurrence in endomyocardial biopsies.

Plaque in superficial femoral arteries indicates generalized atherosclerosis and vulnerability to coronary death: an autopsy study.

OBJECTIVES: Risk factors for atherosclerosis have limited ability to identify persons at high risk of coronary heart disease. Assessment of subclinical atherosclerosis in peripheral arteries might improve this limitation. We studied the relationship between atherosclerotic plaques in peripheral arteries, coronary plaques, and coronary death. METHODS: Predefined segments from the left anterior descending coronary artery, the right coronary artery, bilateral carotid, and superficial femoral arteries (SFA) were obtained from 100 autopsies (20-82 years, 30 females, 27 coronary deaths). Based on microscopic examination of 4756 sections, the extension of atherosclerosis (plaque burden) and the largest plaque area in each segment were quantified. RESULTS: Plaque burden in all arteries increased with age and was larger in coronary death (P < .05). SFA plaques occurred later than coronary and carotid plaques. When SFA plaque had developed, coronary plaque was also present. SFA plaque (odds ratio, 95% confidence interval: 7.07 [2.40-20.81]), but not carotid plaque, was significantly associated with coronary death, also after age and gender adjustment (21.25 [5.02-89.97]). The area under the receiver operating characteristic curves for the identification of coronary death individuals was 0.72 (95% confidence interval: 0.62-0.83) for coronary plaque, and 0.80 (0.72-0.89) for SFA plaque (age and gender adjusted). CONCLUSIONS: Atherosclerosis develops slower in SFA compared with coronary and carotid arteries. In persons with plaque in the SFA, plaque is always present in the coronary arteries. In younger persons, the presence of SFA plaque indicates a generalized susceptibility to atherosclerosis and vulnerability to coronary death.