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The G protein-coupled receptor 30 (GPR30) has been claimed as an estrogen receptor. However, the literature reports controversial findings and the physiological function of GPR30 is not fully understood yet. Consistent with studies assigning a role of GPR30 in the cardiovascular and metabolic systems, GPR30 expression has been reported in small arterial vessels, pancreas and chief gastric cells of the stomach. Therefore, we hypothesized a role of GPR30 in the onset and progression of cardiovascular and metabolic diseases. In order to test our hypothesis, we investigated the effects of a high-fat diet on the metabolic and cardiovascular profiles of Gpr30-deficient mice (GPR30-lacZ mice). We found that GPR30-lacZ female, rather than male, mice had significant lower levels of HDL along with an increase in fat liver accumulation as compared to control mice. However, two indicators of cardiac performance assessed by echocardiography, ejection fraction and fractional shortening were both decreased in an age-dependent manner only in Gpr30-lacZ male mice. Collectively our results point to a potential role of Gpr30 in preserving lipid metabolism and cardiac function in a sex- and age-dependent fashion. (C) 2014 Elsevier B.V. All rights reserved.

Targeted gene ablation technology has uncovered biological mechanisms that have led to important therapeutics in humans. In a study by Zhou et al., ablation of the 1alpha-hydroxylase gene led to hypertension, cardiac hypertrophy, and systolic dysfunction, and this cardiac phenotype was rescued with exogenous 1,25-dihydroxyvitamin D administration.

© 2013 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L. Todos os direitos reservados., Sarcomeric hypertrophic cardiomyopathy (HCM) is the most common genetic cause of unexplained left ventricular hypertrophy and has no specific treatment. Anderson-Fabry disease (AFD) is rare and usually multisystemic, but occasionally expresses clinically as a predominantly cardiac phenotype mimicking HCM. We describe an illustrative case of a patient followed regularly for 25 years with a diagnosis of familial HCM and no identified sarcomeric mutations. Next-generation sequencing analysis identified a novel pathogenic mutation in the GLA gene, leading to a diagnosis of previously unknown multisystemic AFD, with consequent implications for the patient's treatment and prognosis and familial screening., A miocardiopatia hipertrófica sarcomérica é a causa genética mais comum da hipertrofia ventricular esquerda inexplicada e não tem tratamento específico. A doença de Anderson-Fabry é rara, geralmente multissistémica mas, ocasionalmente, pode expressar-se clinicamente com um fenótipo predominantemente cardíaco, imitando miocardiopatia hipertrófica. Os autores descrevem o caso ilustrativo de uma doente seguida regularmente durante 25 anos com o diagnóstico de miocardiopatia hipertrófica familiar, sem mutação sarcomérica identificada. A utilização da análise de sequenciação de nova geração identificou uma mutação patogénica nova no gene GLA, aclarando o diagnóstico oculto de doença de Anderson-Fabry multissistémica, com as consequentes implicações terapêuticas, prognósticas e na investigação familiar.

Development of cardiac hypertrophy after thyroxin (T4) treatment is well recognized. Recently, we observed that T4-induced cardiac hypertrophy is associated with increased cardiac Rac1 expression and activity. Whether this Rac1 increase has a role in inducing this cardiac phenotype is, however, still unknown. Here, we showed that T4 treatment (500 µg/kg/d) for 2 weeks resulted in increased myocardial Rac1 activity with subsequent hypertension, cardiac hypertrophy, and left ventricular systolic dysfunction in vivo. Isolated right ventricular papillary muscles of T4-treated mice maintained their peak isometric active developed tension but exhibited significant decreases in their corresponding time to peak and in relaxation times. Positive inotropic responses to increasing pacing rate and β-adrenergic stimulation were also depressed in these muscles. Pravastatin (10 mg/kg/d), a Rac1 inhibitor, significantly decreased myocardial Rac1 activity, hypertension, and cardiomyocyte size in T4-treated mice but could not attenuate gross heart weight or functional cardiac changes in these mice. Our data showed that T4 could activate different signaling pathways with distinct cardiovascular outcomes. We also provide the first mechanistic evidence for the partial involvement of Rac1 activation in T4-induced cardiomyocyte hypertrophy and reveal a putative role for Rac1 in the development of T4-induced hypertension.

Cardiovascular diseases are a major cause of mortality in industrialized countries. Patients who survive after an acute myocardial infarction (AMI) are prone to ventricular remodelling, resulting from loss of myocardial tissue, and to progressive chronic heart failure (CHF). Heart has just a minimal potential of repair and regeneration, thus the use of new strategies of treatment involving stem-cell transplantation and/or endogenous stem cell mobilization is expected as a promising alternative to standard therapy. Stem cells are undifferentiated cells with self-renewal and differentiation potential. Among stem cells, embryonic (ESCs) are considered as the best for cardiac regeneration (Nir et al., 2003); on the other hand several issues, including ethical questions, immunorejection and teratoma formation, limit their practical use. To overcome these restrictions, research interest is focusing on adult stem cells, indentified in different tissues and resulted able to differentiate towards the cardiac phenotype. Stem cells obtained from bone marrow, contain a subpopulation of hematopoietic stem cells (HSCs) (Goodell et al., 1997), a component of mesenchymal stem cells (MSCs) (Pittenger and Martin, 2004) and multipotent progenitor cells (MAPCs) (Jiang et al., 2002). MSCs derived from bone-marrow show some potential of differentiation into beating cardiomyocytes in vitro (Makino et al., 1999; Hakuno et al., 2002; Fukuda, 2001; Toma et al., 2002). Somatic stem cells also include endothelial progenitor cells (EPCs), obtained from peripheral circulation (Badorff et al., 2003), and cells arisen from umbilical cord (USSCs). USSCs showed capacity of differentiation towards the cardiac phenotype and to promote angiogenesis (Badorff et al., 2003; Kogler et al., 2004). Resident stem cells, located in cardiac niches, showed a differentiation potential towards cardiomyocites (Bollini et al., 2010]. In the last decade another group of somatic stem cells, derived from adipose tissue (ADSCs) was studied, most of all for their easy way of extraction, relative abundance and differentiative capacity towards different lineages. This chapter will focus on this last family of somatic stem cells. We will describe the features of ADSCs, how to isolate them from lipoaspirates, their cell surface markers and their differentiative potential. We will also report of ADSCs ability to differentiate into cardiomyocytes. Finally we will outline the epigenetic signature of ADSCs, to define if epigenetic modifications could influence their commitment towards a specific phenotype.

Aims Hereditary transthyretin (TTR)-related amyloidosis (ATTR) is mainly considered a neurologic disease. We assessed the phenotypic and genotypic spectra of ATTR in a Caucasian area and evaluated the prevalence, genetic background, and disease profile of cases with an exclusively cardiac phenotype, highlighting possible hints for the differential diagnosis with hypertrophic cardiomyopathy (HCM) and senile systemic amyloidosis (SSA). Methods and results In this Italian multicentre study, 186 patients with ATTR were characterized at presentation. Thirty patients with SSA and 30 age–gender-matched HCM patients were used for comparison. Phenotype was classified as exclusively cardiac ( n = 31, 17%), exclusively neurologic ( n = 46, 25%), and mixed cardiac/neurologic ( n = 109, 58%). Among the eight different mutations responsible for an exclusively cardiac phenotype, Ile68Leu was the most frequent. Five patients with an exclusively cardiac phenotype developed mild abnormalities at neurological examination, but no symptoms during a 36-month follow-up (range: 14–50). Exclusively cardiac phenotype was characterized by male gender, age >65 years, heart failure symptoms, symmetric left ventricular (LV) ‘hypertrophy’, and moderately depressed LV ejection fraction. This profile was similar to SSA, but relatively distinct from HCM. Compared with patients with a mixed phenotype, patients with an exclusively cardiac phenotype showed a more pronounced cardiac involvement on both echocardiogram and electrocardiogram (ECG). Conclusion A clinically relevant subset of Caucasian ATTR patients present with an exclusively cardiac phenotype, mimicking HCM or SSA. Echocardiographic and ECG findings are useful to differentiate ATTR from HCM but not from SSA. The role of liver transplantation in these patients should be reconsidered.

More and more journals relegate scientific data into Supplementary Information, which are often not seen by the scientific community. The amount of this ‘dead' data is often impressive, and papers may contain up to 30 Supplementary Figures of really high quality. Here we propose a solution by publishing them as a ‘Companion' paper. Conventional journals, such as Cell Death & Differentiation, operate within the constraints of a page budget, generally agreed on an annual basis between the Editor-in-Chief and the Publishers, although the limitations are not so tight with journals that are completely web-based, such as Cell Death & Disease. For conventional journals, therefore, this means that if the page budget is set at, say, 1000, then 200 papers of 5 pages can be published in one volume, but only 100 papers if their average length is 10 pages. It is obviously advantageous for the journal and for the scientific community, it serves, to publish more rather than fewer papers, and it is for this reason that there has developed greater reliance on including data that is not central to the message of the paper as Supplementary Information online. Indeed, of the 129 original papers published to date in Volume 18 (2011) of Cell Death & Differentiation, 108 (83.7%) included Supplementary Information of some sort. One problem in publishing Supplementary Information is whether readers, and indeed Editors and referees, bother to access it even though it is just another click on the webpage. Anecdotally, at the journal clubs we attend, group members will have downloaded the PDF of the main text, but not the Supplementary Information. Often, of course, Supplementary Information is just that; it supplements and even complements the data in the main text. There are times, however, when the Supplementary Information is sufficiently comprehensive to add another dimension to the story and would really justify the publication as a separate paper. A good example of the latter situation is the paper by Cesca et al.1 Here, the authors have investigated the role of kinase D interacting substrate of 220 kDa (Kidins 220; also known as ankyrin repeat-rich membrane spanning, ARMS), a membrane-bound scaffold protein for the neurotrophin receptor Trk and p75NTR signalling. To do this, they generated Kidins 220-/- mice and, obviously, a large amount of the data describes the generation of the mice and their characterisation. They demonstrate that the knockout mice die at a late embryonic stage with defects in the central nervous system (CNS) due to apoptosis of neurons. Moreover, primary neurons show reduced responsiveness to BDNF as assessed by the lower complexity of neurite outgrowth and by electrophysiological abnormalities. Kidins 220 was also shown to constitutively interact with VEGFR2. In the original submission, data was also included, as Supplementary Information, showing that the CNS abnormalities were accompanied by defects in the peripheral nervous system (PNS) and in the heart. In the PNS, as in the CNS, cell death occurs by apoptosis, and the cardiac phenotype includes defects in the outflow tract and in the ventricular wall. Finally, neuronal specific deletion of Kidins 220 allows live births, but the animals die early in postnatal life with profound CNS abnormalities. Because of the wealth of novel information they contain, these Supplementary Information have now been reformatted as an independent companion manuscript.2 Clearly, in this case, the original Supplementary Information require a full exposure to the scientific community as a self-standing publication,2 without detracting from the main paper.1 Could this be the solution to the exploding requests by editors and reviewers to add Supplementary Information to the majority of papers, and thus make more visible data which is often of considerable interest in its own right?

This report describes an infant presenting with deletion 22q11.2 in combination with left ventricular noncompaction and a coronary artery fistula. These two cardiac findings have rarely been reported in association with each other and have never been reported together in combination with deletion 22q11.2. The reported case demonstrates the expanding cardiac phenotype of individuals with deletion 22q11.2, suggesting that it may be appropriate to offer studies for the detection of deletion 22q11.2 to individuals with a wide range of structural cardiac defects.

The interplay between Na/Ca exchanger (NCX) and Na/K-ATPase (NKA) is essential in regulating cardiac [Na]i, [Ca]i and contractility. The membrane targeting and stability of both NCX and NKA require direct interaction with cytoskeletal protein ankyrin B (AnkB). Humans with AnkB loss-of-function mutations and AnkB heterozygous mice (AnkB+/-) display a complex cardiac phenotype that includes ventricular arrhythmias and sudden death. Cardiac myocytes from AnkB+/- mice show reduced NCX and NKA expression at the T-tubules, larger cellular and SR Ca load and increased frequency of delayed afterdepolarizations (DADs). How the coordinated loss of NCX and NKA affects SR Ca release and [Na]i is poorly understood. We measured Ca sparks and waves in myocytes from AnkB+/- and wild-type (WT) mice with and without 1 μM isoproterenol. Under control conditions, Ca transients, SR Ca load and Ca sparks frequency (CaSpF), even normalized to SR Ca content, were higher in AnkB+/- mice at all frequencies. With isoproterenol, Ca transient amplitude and SR Ca content were similar in myocytes from WT and AnkB+/- mice, but CaSpF was still elevated in AnkB+/- mice. Ca waves occurred preponderantly in AnkB+/- mice. In some cases, Ca waves and sparks evolved into synchronous after-Ca transients that are indicative of DADs. This data suggest that SR Ca release is enhanced in AnkB+/- mice. We measured [Na]i to determine whether the increased CaSpF in AnkB+/- mice is due to higher [Na]i, which may elevate diastolic Ca. [Na]i was slightly, but not significantly, lower in AnkB+/- vs. WT mice (11.4±1.1 vs. 13.2±1.7 mM in WT). Isoproterenol lowered [Na]i by a comparable amount in both AnkB+/- and WT mice (to 8.1±0.9 mM and 11.1±1.5 mM). Thus, altered [Na]i does not explain the increased Ca sparks frequency in AnkB+/- mice.

Our aim was to assess the differential effect of waist circumference on left-ventricular (LV) structural and functional alterations, in hypertensive males and females. One thousand seven hundred and eighty nine consecutive, nondiabetic, essential hypertensives (aged 55.8 +/- 13.5 years, 966 females), included in the 3H Study, an ongoing registry of hypertension-related-target-organ damage, were classified to obese and nonobese groups according to Adult Treatment Panel III criteria. All participants underwent complete echocardiographic study including LV diastolic function evaluation by means of conventional and tissue Doppler imaging (TDI) methods, averaging early and late diastolic mitral annular peak velocities (Em, Am, Em/Am) from four separate sites of measurement. Hypertensive obese women compared with nonobese exhibited significantly greater LV mass index and prevalence of LV hypertrophy (by 5.5 g/m(2), P = 0.003, and 8.8%, P = 0.005, respectively), while such differences were not present among men. Obese women compared to nonobese ones were accompanied by lower transmitral E/A (by 0.08, P0.001), TDI-derived Em/Am (by 0.12, P0.001), and higher E/Em ratio (by 0.8, P = 0.016). In contrast, hypertensive obese men compared to nonobese ones exhibited lower E and Em (by 0.04 m/s and 0.6 cm/s, both P0.05). A significant interaction between sex and abdominal obesity was observed only regarding TDI-derived Am and Em/Am. Furthermore, waist circumference was a predictor of E/A (beta = -0.097, P = 0.002) and Em/Am (beta = -0.116, P = 0.001), independently of body size, in females but not in males. The adverse effect of abdominal obesity on LV alterations is more pronounced among female hypertensives, suggesting that routine measurement of waist circumference provides additional information on cardiac phenotype especially in women.

Cardiovascular disease is the leading cause of death and disability in the developed world. To design novel therapeutic strategies to treat and prevent this disease, better understanding of cardiac cell function is necessary. In addition to (and, indeed, in combination with) genetics, physiology and molecular biology, proteomics plays a critical role in our understanding of cardiovascular systems at multiple scales. The purpose of this review is to examine recent developments in the field of myocardial injury and protection, examining how proteomics has informed investigations into organelles, signaling complexes, and cardiac phenotype.

Mice are increasingly used in cardiovascular research, and echocardiography is ideally suited to evaluate their cardiac phenotype. This review describes the current use of mice echocardiography and focuses on some of its applications in both basic and clinical science.

Mice allow biologists to study various genes playing a role in cardiac function and pathophysiological situations. Echocardiography is a non-invasive tool for assessing cardiac phenotype. Because of load dependence of conventional parameters (left ventricular shortening fraction, left ventricular ejection fraction and mitral pulsed Doppler), we have to perform Doppler tissular velocity imaging and strain imaging for the characterization of cardiomyopathies mice models.

Background Classification and analysis of congenital heart defects (CHD) in etiologic studies is particularly challenging because of diversity of cardiac phenotypes and underlying developmental mechanisms. We describe an approach to classification for risk assessment of CHD based on developmental and epidemiologic considerations, and apply it to data from the National Birth Defect Prevention Study (NBDPS). Methods The classification system incorporated the three dimensions of cardiac phenotype, cardiac complexity, and extracardiac anomalies. The system was designed to facilitate the assessment of simple isolated defects and common associations. A team with cardiologic expertise applied the system to a large sample from the NBDPS. Results Of the 4,703 cases of CHDs in the NBDPS with birth years 1997 through 2002, 63.6% were simple, isolated cases. Specific associations of CHDs represented the majority of the remainder. The mapping strategy generated relatively large samples for most cardiac phenotypes and provided enough detail to isolate important subgroups of CHDs that may differ by etiology or mechanism. Conclusions Classification of CHDs that considers cardiac and extracardiac phenotypes is practically feasible, and yields manageable groups of well-characterized phenotypes. Although best suited for large studies, this approach to classification and analysis can be a flexible and powerful tool in many types of etiologic studies of heart defects.

Precise and noninvasive characterization of the development of the cardiac phenotype in murine models of heart failure has been widely demanded in modern cardiovascular research. High-resolution cardiovascular magnetic resonance (CMR) has been proven to be a powerful tool for the accurate and reproducible assessment of LV and RV parameters in healthy mice. Whereas changes in LV parameters in models of heart failure have been thoroughly evaluated, RV dysfunction has not. Purpose of this study was to characterize a model of isolated RV failure induced by pulmonal banding by in vivo CMR at 7T. RV parameters differed significantly from those of normal mice in terms of RV end-diastolic volume (EDV: 85 +/- 14 microL vs. control 36 +/- 3 microL, p < 0.0001), RV end-systolic volume (ESV: 121 +/- 10 microL vs. control 84 +/- 4 microL, p < 0.005) and RV ejection fraction (EF: 31 +/- 6 % vs. control 57 +/- 2 %, p < 0.001). With regard to EDV, ESV, SV and EF LV parameters, there were no significant differences between pulmonary banded and control mice indicating overt isolated RV failure.

Patients with a functionally univentricular circulation represent a challenge for both surgeons and cardiologists. In this introductory paper, we aim to describe the variability in cardiac phenotype amongst these patients, and to review how function might relate to anatomy.

To the Editor: In a recent issue of Circulation , Hoorntje et al1 presented data on a family with a duplication in exon 4 of HERG. A consanguineous marriage resulted in 2 homozygous offspring: one died before birth and the other had a severe cardiac phenotype characterized by arrhythmias and conduction defects. The importance of these findings regarding the role of HERG in the heart is clear. The authors conclude that these homozygous individuals will lack functional IKr and that HERG likely plays no critical roles in other organs. Various laboratories have reported the existence of alternate HERG isoforms.2 3 One …

In this paper, a bioreactor for cell cultures is presented. Main features of the bioreactor are the possibility of applying controlled movements of the substrate during the culture of cells, reproducing the typical cardio movements and stresses.

In 1995, Mark Keating and colleagues identified two genes responsible for congenital long QT syndrome, a cause of sudden cardiac death. Perturbations in the ion channels that orchestrate the beating heart were central to the disorder. This revelation provided a molecular model for the study of ventricular arrhythmias and enabled further dissection of the genetic defects underlying subtleties in the cardiac phenotype. Soon, these discoveries will be further translated to clinical medicine, with the expected release of one of the first comprehensive clinical genetic tests in cardiology.