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Objective: (1) Evaluate feasibility and acceptability of a mindfulness-based group in adolescent girls at-risk for type 2 diabetes (T2D) with depressive symptoms, and (2) compare efficacy of a mindfulness-based versus cognitive-behavioral group for decreasing depressive symptoms and improving insulin resistance., Design and Setting: Parallel-group, randomized controlled pilot trial conducted at a university., Participants: Thirty-three girls 12-17y with overweight/obesity, family history of diabetes, and elevated depressive symptoms were randomized to a six-week mindfulness-based (n=17) or cognitive-behavioral program (n=16)., Interventions: Both interventions included six, one-hour weekly group sessions. The mindfulness-based program included guided mindfulness awareness practices. The cognitive-behavioral program involved cognitive restructuring and behavioral activation., Main Outcome Measures: Adolescents were evaluated at baseline, post-intervention, and six-months. Feasibility/acceptability were measured by attendance and program ratings. Depressive symptoms were assessed by validated survey. Insulin resistance was determined from fasting insulin and glucose, and dual energy x-ray absorptiometry was used to assess body composition., Results: Most adolescents attended ≥80% sessions (mindfulness: 92% versus cognitive-behavioral: 87%, p=1.00). Acceptability ratings were strong. At post-treatment and six-months, adolescents in the mindfulness condition had greater decreases in depressive symptoms than adolescents in the cognitive-behavioral condition (ps<.05). Compared to the cognitive-behavioral condition, adolescents in the mindfulness-based intervention also had greater decreases in insulin resistance and fasting insulin at post-treatment, adjusting for fat mass and other covariates (ps<.05)., Conclusions: A mindfulness-based intervention shows feasibility and acceptability in girls at-risk for T2D with depressive symptoms. Compared to a cognitive-behavioral program, after the intervention, adolescents who received mindfulness showed greater reductions in depressive symptoms and better insulin resistance. ClinicalTrials.gov identifier: NCT02218138 clinicaltrials.gov., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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., (© 2014 American Heart Association, Inc.)

Mutations in the gene for desmoplakin (DSP) may cause arrhythmogenic right ventricular cardiomyopathy (ARVC) and Carvajal syndrome (CS). Desmoplakin is part of all desmosomes, which are abundantly expressed in both myocardial and epidermal tissue and serve as intercellular mechanical junctions. This study aimed to investigate protein expression in myocardial and epidermal tissue of ARVC and CS patients carrying DSP mutations in order to elucidate potential molecular disease mechanisms. Genetic investigations identified three ARVC patients carrying different heterozygous DSP mutations in addition to a homozygous DSP mutation in a CS patient. The protein expression of DSP in mutation carriers was evaluated in biopsies from myocardial and epidermal tissue by immunohistochemistry. Keratinocyte cultures were established from skin biopsies of mutation carriers and characterized by reverse transcriptase polymerase chain reaction, western blotting, and protein mass spectrometry. The results showed that the mutation carriers had abnormal DSP expression in both myocardial and epidermal tissue. The investigations revealed that the disease mechanisms varied accordingly to the specific types of DSP mutation identified and included haploinsufficiency, dominant-negative effects, or a combination hereof. Furthermore, the results suggest that the keratinocytes cultured from patients are a valuable and easily accessible resource to elucidate the effects of desmosomal gene mutations in humans., (© 2012 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2013 Wiley Periodicals, Inc.)

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.

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., (Copyright © 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

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.

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.

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.

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.

Results: Sudden unexpected death in epilepsy (SUDEP) gains more and more acknowledgment across the various interdisciplinary fields. Accordingly, we performed in a prospective setting a case-control study of all SUDEP cases in a well-defined part of Denmark (Northern Jutland), between January 1998 and September 2000. We attempted to look into the cardiopathologic mechanism behind this phenomenon by assessing the degree of myocardial fibrosis in SUDEP patients versus controls. The histologic evaluation was possible in 65% of the cases (15/23) whose death was attributed to SUDEP and in 71% (15/21) of controls. Forty percent of the SUDEP cases (6/15) presented several foci of fibrotic changes in the deep and subendocardial myocardium in contrast to 1 control (6.6%, P = 0.03). None of the subjects from the SUDEP group showed fibrotic changes in their conduction system as compared with 1 control (6.6%). The quantitative evaluation of fibrosis demonstrated a trend toward more fibrosis in the deep and subendocardial myocardium of the SUDEP cases. Forty percent of cases in the SUDEP group were men (6/15), characteristically young at time of death (mean age 38 years) and with a late epilepsy onset (mean age 21 years). Antemortem, 73% of the SUDEP patients (11/15) had experienced infrequent seizures (self-reported). We conclude that the SUDEP cases displayed significant fibrosis of the myocardium when this was assessed by qualitative means. This fibrosis may be the consequence of myocardial ischemia as a direct result of repetitive epileptic seizures, which, associated with the ictal sympathetic storm, may lead to lethal arrhythmias.

Using magnetic resonance imaging the effects of temperature, formalin fixation, and decalcification on the size and morphology of atherosclerotic arteries were evaluated. Ten ex vivo carotid arteries were scanned fresh at body and room temperature and formalin-fixed and decalcified at room temperature. Different spin-echo pulse sequences were used and absolute T2 values calculated. During processing for histopathology, the contrast between the arterial layers increased. From body to room temperature there were significant increases in size (4%-7%), T2 of media (60--> 68 msec), and fibrous plaque component (95--> 110 msec). Formalin fixation caused significant increases in size (2%-3%) and media T2 (68--> 74 msec). Decalcification caused significant shrinkage (2%-5%) and decrease in T2 of media (74--> 53 msec) and fibrous plaque component (118--> 76 msec). Thus temperature and preparation have profound effects on contrast, size, and T2 of atherosclerotic arteries. Ex vivo experiments should be performed on fresh specimens at body temperature. J. Magn. Reson. Imaging 1999;10:876-885., (Copyright 1999 Wiley-Liss, Inc.)

Without thrombosis, coronary atherosclerosis is generally benign. It is plaque disruption, or fissuring, and subsequent thrombosis that make coronary atherosclerosis dangerous. Small ruptures often remain clinically silent, whereas more extensive plaque rupture may cause the development of unstable angina, myocardial infarction, and sudden death. The risk of plaque disruption depends more on plaque type (composition) than on plaque size and stenosis severity. Both plaque vulnerability (intrinsic disease) and rupture triggers (extrinsic forces) are important for plaque disruption. The resultant thrombotic response, which affects the clinical presentation and outcome, is partly determined by the reactivity of the circulating platelets and the balance between the coagulation and fibrinolytic systems. To prevent and treat life-threatening coronary thrombosis, the medical community should seek new ways to identify and treat dangerous, vulnerable plaques and to optimize antithrombotic treatment.

The most important mechanism responsible for the sudden and unpredictable onset of acute coronary syndromes is coronary plaque rupture with thrombosis and vasospasm superimposed. The risk of plaque rupture depends on plaque type (composition) rather than plaque size (volume); most ruptures occur in plaques containing a soft, lipid-rich core that is covered by a thin and inflamed cap of fibrous tissue. Compared with intact caps, the ruptured ones usually are thinner and contain less collagen (responsible for tensile strength), fewer smooth muscle cells (smc; collagen synthesizing cells), and many more macrophages (collagen degrading cells). Therefore, major determinants of plaque vulnerability and rupture are progressive lipid accumulation (core formation) and cap weakening due to ongoing inflammation with collagen degradation (macrophage-related) and impaired healing and repair (smc-related). These intrinsic plaque changes predispose plaques to rupture whereas extrinsic forces imposed on plaques, such as biomechanical and haemodynamic stresses, may determine the actual time of rupture by precipitating or 'triggering' it. Luckily, recent research in patients with coronary artery disease indicates that both plaque vulnerability and rupture triggers may be modified beneficially by treatment.