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Many unrelated patients with the disorder for mutation in human desmosomal cadherin desmocollin-2 (DSC2) are investigated. The results have identified DSC2 mutations as a cause of arrhythmogenic right ventricular cardiomyopathy (ARVC) in humans and have shown that physiologic levels of DSC2 are crucial for normal cardiac desmosome formation, early cardiac morphogenesis and cardiac function.

The R6740 mutation of the MYH8 gene encoding perinatal myosin heavy chain causes a variant form of the carney complex associated with distal arthrogryposis, which includes typical spotty pigmentation of the skin, familial cardiac and cutaneous myxoma, and endocrinopathy. Novel roles for perinatal myosin in both the development of skeletal muscle and cardiac tumorigenesis are demonstrated.

A 27-year-old woman who began having episodes of fainting was found to have a heart tumor called a cardiac myxoma. She also had a history of Cushing's disease and freckles. She was diagnosed with a medical syndrome called Carney complex.

A mutation in the gene for the gamma2 regulatory subunit of AMP-activated protein kinase has been linked to a heart arrhythmia called Wolff-Parkinson-White syndrome. The arrhythmia is caused by an abnormal electrical pathway between the upper and lower parts of the heart.

Purpose: To evaluate the safety and potential efficacy of LLF580, a genetically engineered variant of human fibroblast growth factor-21, for triglyceride lowering, weight loss, and hepatic fat reduction. Methods: A multicenter, double-blind, parallel design trial in obese, mildly hypertriglyceridemic adults randomized (1:1) to LLF580 300 mg or placebo subcutaneously every 4 weeks for 3 doses. Results: Of 64 randomized study participants, 61 (mean ± SD: age 45 ± 11 years, 49% male, 80/15/5% Caucasian/African American/other, body mass index 36.1 ± 3.8 kg/m2) received LLF580 (n = 30) or placebo (n = 31) at 7 research sites in the United States. LLF580 lowered serum triglycerides by 54% (least square mean placebo adjusted change from baseline), total cholesterol 7%, low-density lipoprotein cholesterol 12%, and increased high-density lipoprotein cholesterol 36% compared with placebo (all P < 0.001) over 12 weeks. Substantial reduction of liver fat of 52% over placebo (P < 0.001) was also demonstrated in the setting of improved liver function tests including alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, the composite enhanced liver fibrosis score, and N-terminal type III collagen propeptide (all P < 0.05). Insulin and C-peptide levels and insulin resistance by homeostatic model assessment for insulin resistance were all lower, and adiponectin higher with LLF580 treatment compared with placebo, whereas fasting glucose and glycated hemoglobin were unchanged. Reductions in biomarkers of bone formation without differences in markers of bone resorption were observed. LLF580 was generally safe and well tolerated, except for higher incidence of generally mild to moderate gastrointestinal adverse effects. Conclusions: In obese, mildly hypertriglyceridemic adults, LLF580 was generally safe and demonstrated beneficial effects on serum lipids, liver fat, and biomarkers of liver injury, suggesting it may be effective for treatment of select metabolic disorders including hypertriglyceridemia and nonalcoholic fatty liver disease. Assessments of longer term safety and efficacy are warranted. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and insulin resistance. The dual sodium‐glucose co‐transporter 1/2 inhibitor (SGLT1/2i) licogliflozin (LIK066) ameliorates hyperinsulinism in patients with diabetes and obesity. This study examines the effect of licogliflozin on androgens in women with PCOS. In a multicentre, randomized, placebo‐controlled, double‐blind, 2‐week trial, patients with PCOS received licogliflozin 50 mg or placebo three times a day (TID). Changes in free testosterone (FT), other androgens and variables of insulin resistance were analysed. Concentration of FT did not change (TRLIK066:TRPCB [FT]: 0.88; 90% CI: 0.70‐1.11; P =.353). Licogliflozin reduced androstendione (A4) by 19% (TRLIK066:TRPCB [A4]: 0.81; 90% CI: 0.68‐0.99; P =.089) and dehydroepiandrosteron sulphate (DHEAS) by 24% (TRLIK066:TRPCB [DHEAS]: 0.76; 90% CI: 0.65‐0.89; P =.008). Hyperinsulinaemia was reduced by 70% by licogliflozin (highest insulin concentration [MAXI]; TRLIK066:TRPCB [MAXI]: 0·26; 90% CI:0.20‐0.34; P <.001 and area under the curve insulin [AUCI]; TRLIK066:TRPCB [AUCI]: 0.32; 90% CI: 0.25‐0.41; P <.001). Diarrhoea and nausea occurred as common adverse events. Dual inhibition of SGLT1/2 ameliorates hyperinsulinaemia and hyperandrogenaemia in women with PCOS. Licogliflozin may represent a promising novel treatment option for PCOS. [ABSTRACT FROM AUTHOR]

Holt-Oram syndrome may be caused by mutations in a gene on chromosome 12q2. Holt-Oram syndrome is an inherited disorder characterized by skeletal deformities and heart defects. Researchers performed clinical and genetic-linkage studies on two large, unrelated families with the syndrome. In Family A, 26 of 49 members were affected and 18 surviving members were evaluated. All affected members of Family A had skeletal abnormalities and cardiovascular disease. Eleven had heart conduction diseases. In Family B, 18 of 31 affected members were still alive for examination. All affected family members had skeletal abnormalities and had severe skeletal deformities more frequently than affected members of Family A. In contrast, Family B had less severe and less frequent cardiovascular disease than Family A and only one member had a heart conduction disease. Genetic analysis revealed a linkage of the syndrome to mutations on chromosome 12.

Radiofrequency catheter ablation treatment may be effective for treating Wolff-Parkinson-White syndrome even if the patient has no symptoms, according to a study published in 2003. Other studies have shown that these patients have a low risk of sudden death from a severe arrhythmia. So many doctors decided not to treat them. This study shows that this decision may need to be reconsidered.

Extensive atherosclerotic plaque burden in the lower extremities often leads to symptomatic peripheral artery disease (PAD) including impaired walking performance and claudication. Interleukin-1β (IL-1β) may play an important pro-inflammatory role in the pathogenesis of this disease. Interruption of IL-1β signaling was hypothesized to decrease plaque progression in the leg macrovasculature and improve the mobility of patients with PAD with intermittent claudication. Thirty-eight patients (mean age 65 years; 71% male) with symptomatic PAD (confirmed by ankle–brachial index) were randomized 1:1 to receive canakinumab (150 mg subcutaneously) or placebo monthly for up to 12 months. The mean vessel wall area (by 3.0 T black-blood magnetic resonance imaging (MRI)) of the superficial femoral artery (SFA) was used to measure plaque volume. Mobility was assessed using the 6-minute walk test. Canakinumab was safe and well tolerated. Markers of systemic inflammation (interleukin-6 and high-sensitivity C-reactive protein) fell as early as 1 month after treatment. MRI (32 patients at 3 months; 21 patients at 12 months) showed no evidence of plaque progression in the SFA in either placebo-treated or canakinumab-treated patients. Although an exploratory endpoint, placebo-adjusted maximum and pain-free walking distance (58 m) improved as early as 3 months after treatment with canakinumab when compared with placebo. Although canakinumab did not alter plaque progression in the SFA, there is an early signal that it may improve maximum and pain-free walking distance in patients with symptomatic PAD. Larger studies aimed at this endpoint will be required to definitively demonstrate this. ClinicalTrials.gov Identifier: NCT01731990 [ABSTRACT FROM AUTHOR]

Author(s): Cathy J. Hatcher [1]; Craig T. Basson [1] T-box transcription factors comprise an ancient gene family [1] that contributes to the embryonic development of many organ systems. Heritable abnormalities [...]

Author(s): Craig T. Basson [1] The Shape of the Heart by Pierre J. Vinken Elsevier Science, 206 pp, $20.00 The scalloped-shaped "Valentine's" heart is a ubiquitous icon in Western culture. [...]

Mouse strains C57BL/6 (B6) and MRL were studied by whole mouse genome chip microarray analyses of RNA isolated from amputation sites at different times pre- and postamputation at the midsecond phalange of the middle digit. Many keratin genes were highly differentially expressed. All keratin genes were placed into three temporal response classes determined by injury/preinjury ratios. One class, containing only Krt6and Krt16,were uniquely expressed relative to the other two classes and exhibited different temporal responses in MRL vs. B6. Immunohistochemical staining for Krt6 and Krt16 in tissue sections, including normal digit, flank skin, and small intestine, and from normal and injured ear pinna tissue exhibited staining differences in B6 (low) and MRL (high) that were consistent with the microarray results. Krt10 staining showed no injury-induced differences, consistent with microarray expression. We analyzed Krt6 and Krt16gene association networks and observed in uninjured tissue several genes with higher expression levels in MRL, but not B6, that were associated with the keratinocyte activated state: Krt6, Krt16, S100a8, S100a9,and Il1b; these data suggest that keratinocytes in the MRL strain, but not in B6, are in an activated state prior to wounding. These expression levels decreased in MRL at all times postwounding but rose in the B6, peaking at day 3. Other keratins significantly expressed in the normal basal keratinocyte state showed no significant strain differences. These data suggest that normal MRL skin is in a keratinocyte activated state, which may provide it with superior responses to wounding. [ABSTRACT FROM AUTHOR]

The article presents a study which determined the mutation frequency in MYH11, ACTA2, TGΒRI, and TGFΒRII in a population of individuals with genetically mediated thoracic aortic aneurysm (TAA). Nine percent of patients had mutation in one of the genes analyzed while three percents had mutations in ACTA2. Analyses showed that the TGFΒ2;IIb activating mutations alter receptor function on TGFΒ2 signaling.

The article focuses on the contributions of several key transcription factors to specification, patterning, maturation, as well as the function of the cardiac conduction system. It further analyzes the molecular programs that are involved in the following process that should lead to improve diagnosis and therapy of conduction system disease. Moreover, it discusses the risk factors of the cardiovascular disease.

Secreted Frizzled-related proteins (sFRPs) have emerged as key regulators of a wide range of developmental and disease processes. Most of the known functions of mammalian sFRPs have been attributed to their ability to antagonize Wnt signalling. Recently however, Xenopus laevis and zebrafish sFRP, Sizzled, was shown to function as an antagonist of Chordin processing by Tolloid-like metalloproteinases. This has led to the proposal that sFRPs may function as evolutionarily conserved antagonists of chordinase activities of this class of proteinases. In contrast to this proposal, we show here that the mammalian sFRP, sFRP2, does not affect Chordin processing, but instead, can serve as a direct enhancer of procollagen C proteinase activity of Tolloid-like metalloproteinases. We also show that the level of fibrosis, in which procollagen processing by Tolloid-like proteinases has a rate-limiting role, is markedly reduced in Sfrp2-null mice subjected to myocardial infarction. Importantly, this reduced level of fibrosis is accompanied by significantly improved cardiac function. This study thus uncovers a function for sFRP2 and a potential therapeutic application for sFRP2 antagonism in controlling fibrosis in the infarcted heart. [ABSTRACT FROM AUTHOR]

Carney complex is a genetic condition in which affected individuals develop benign tumours in various tissues, including the heart. Most individuals with Carney complex have a mutation in the PRKAR1A gene, which encodes the regulatory R1α subunit of protein kinase A — a significant component of the cyclic-AMP signalling pathway. Genetically engineered mutant Prkar1a mouse models show an increased propensity to develop tumours, and have established a role for R1α in initiating tumour formation and, potentially, in maintaining cell proliferation. Ongoing investigations are exploring the intersection of R1α-dependent cell signalling with other gene products such as perinatal myosin, mutation of which can also cause cardiac myxomas. [ABSTRACT FROM AUTHOR]

Some forms of hypertrophic cardiomyopathy (HCM) are caused by mutations in cardiac sarcomeric genes, but environmental factors are believed to influence the hypertrophic response. A highly variable but potentially significant environmental factor is diet. Since soy-rich diets have been speculated to confer protection against cardiovascular disease, Stauffer et al. have explored the influence of a soy diet on cardiac growth and function in a transgenic mouse model of HCM. They report that mice fed a soy diet exhibited significantly worse HCM than mice fed a soy-free (milk protein) diet. This study provides the first evidence of an environmental modifier--diet--on the hypertrophic phenotype and has implications for the way in which disease phenotypes are assessed in genetically altered murine models of disease. [ABSTRACT FROM AUTHOR]

Congenital heart disease is the most common form of human birth defects, yet much remains to be learned about its underlying causes. Here we report that mice lacking functional ADAM19 (mnemonic for a disintegrin and metalloprotease 19) exhibit severe defects in cardiac morphogenesis, including a ventricular septal defect (VSD), abnormal formation of the aortic and pulmonic valves, leading to valvular stenosis, and abnormalities of the cardiac vasculature. During mouse development, ADAM19 is highly expressed in the conotruncus and the endocardial cushion, structures that give rise to the affected heart valves and the membranous ventricular septum. ADAM19 is also highly expressed in osteoblast-like cells in the bone, yet it does not appear to be essential for bone growth and skeletal development. Most adam19[sup -/-] animals die perinatally, likely as a result of their cardiac defects. These findings raise the possibility that mutations in ADAM19 may contribute to human congenital heart valve and septal defects. [ABSTRACT FROM AUTHOR]

PRKAG2 Gene in Sporadic WPW Syndrome. Introduction: Mutations in the PRKAG2 gene that encodes the gamma2 regulatory subunit of AMP-activated protein kinase have been shown to cause autosomal dominant Wolff-Parkinson-White (WPW) syndrome associated with hypertrophic cardiomyopathy. Prior studies focused on familial WPW syndrome associated with other heart disease such as hypertrophic cardiomyopathy. However, such disease accounts for only a small fraction of WPW cases, and the contribution of PRKAG2 mutations to sporadic isolated WPW syndrome is unknown. Methods and Results: Subjects presented for clinical electrophysiologic evaluation of suspected WPW syndrome. WPW syndrome was diagnosed by ECG findings and/or by clinically indicated electrophysiologic study prior to enrollment. Echocardiography excluded hypertrophic cardiomyopathy. Denaturing high-performance liquid chromatography and automated sequencing were used to search for PRKAG2 mutations. Twenty-six patients without a family history of WPW syndrome were studied. No subject had cardiac hypertrophy, and only one patient had associated congenital heart disease. Accessory pathways were detected at diverse locations within the heart. Two polymorphisms in PRKAG2 were detected. [inv6+36insA] occurred in intron 6 in 4 WPW patients and [inv10+10delT] in intron 10 in 1 WPW patient. Both occurred in normal unrelated chromosomes. No PRKAG2 mutations were detected. Conclusion: This study shows that, unlike familial WPW syndrome, constitutional mutation of PRKAG2 is not commonly associated with sporadic WPW syndrome. Although polymorphisms within the PRKAG2 introns were identified, there is no evidence that these polymorphisms predispose to accessory pathway formation because their frequency is similarly high in both WPW patients and normal individuals. Further studies are warranted to identify the molecular basis of common sporadic WPW syndrome.(J Cardiovasc Electrophysiol, Vol. 14, pp. 263-268, March 2003). [ABSTRACT FROM AUTHOR]

[Figure: see text]. [ABSTRACT FROM AUTHOR]