Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function

BACKGROUND: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function. RESULTS: The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue. CONCLUSION: The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies. FUNDING: For detailed information per study, see Acknowledgments.This work was supported by a grant from the US National Heart, Lung, and Blood Institute (N01-HL-25195; R01HL 093328 to RSV), a MAIFOR grant from the University Medical Center Mainz, Germany (to PSW), the Center for Translational Vascular Biology (CTVB) of the Johannes Gutenberg-University of Mainz, and the Federal Ministry of Research and Education, Germany (BMBF 01EO1003 to PSW). This work was also supported by the research project Greifswald Approach to Individualized Medicine (GANI_MED). GANI_MED was funded by the Federal Ministry of Education and Research and the Ministry of Cultural Affairs of the Federal State of Mecklenburg, West Pomerania (contract 03IS2061A). We thank all study participants, and the colleagues and coworkers from all cohorts and sites who were involved in the generation of data or in the analysis. We especially thank Andrew Johnson (FHS) for generation of the gene annotation database used for analysis. We thank the German Center for Cardiovascular Research (DZHK e.V.) for supporting the analysis and publication of this project. RSV is a member of the Scientific Advisory Board of the DZHK. Data on CAD and MI were contributed by CARDIoGRAMplusC4D investigators. See Supplemental Acknowledgments for consortium details. PSW, JFF, AS, AT, TZ, RSV, and MD had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis

Population Characteristics of Central Stonerollers in Iowa Streams

The central stoneroller (Campostoma anomalum) is a herbivore that can have substantial effects on algal communities, nutrient dynamics, and energy flow in streams. Despite its importance in lotic ecosystems, little is known about its population dynamics in streams of the Great Plains. Our objective was to describe age structure, age-specific mortality, and growth rates of central stonerollers in three Iowa streams. We sampled fish from 41 reaches during June-August 2007. We sampled 466 central stonerollers, of which we aged 192. Fish varied in length from 32 to 130 mm and in age from age 0 to 4 years. Over 75% of the central stonerollers were age 2 or younger. Total annual mortality varied from 53.5 to 65.5% across the 3 streams and averaged 64.4% for all streams. Age-specific mortality was approximately 35% between ages I and 2, but increased to approximately 50% and above for older ages. Central stonerollers grew approximately 75 mm during their first year and approximately 10-20 mm per year in subsequent years. Size structure, age structure, mortality, and growth were similar to other central stoneroller populations in the Great Plains. Our results provide important insight for the management and conservation of streams, and provide a foundation for future research on factors influencing small-bodied, nongame fishes in stream ecosystems

Population Characteristics of Central Stonerollers in Iowa Streams

The central stoneroller (Campostoma anomalum) is a herbivore that can have substantial effects on algal communities, nutrient dynamics, and energy flow in streams. Despite its importance in lotic ecosystems, little is known about its population dynamics in streams of the Great Plains. Our objective was to describe age structure, age-specific mortality, and growth rates of central stonerollers in three Iowa streams. We sampled fish from 41 reaches during June-August 2007. We sampled 466 central stonerollers, of which we aged 192. Fish varied in length from 32 to 130 mm and in age from age 0 to 4 years. Over 75% of the central stonerollers were age 2 or younger. Total annual mortality varied from 53.5 to 65.5% across the 3 streams and averaged 64.4% for all streams. Age-specific mortality was approximately 35% between ages I and 2, but increased to approximately 50% and above for older ages. Central stonerollers grew approximately 75 mm during their first year and approximately 10-20 mm per year in subsequent years. Size structure, age structure, mortality, and growth were similar to other central stoneroller populations in the Great Plains. Our results provide important insight for the management and conservation of streams, and provide a foundation for future research on factors influencing small-bodied, nongame fishes in stream ecosystems

Synthesis of aircraft noise operations

This paper provides an overview of the aircraft noise synthesis techniques that were developed within the European FP7 project COSMA (Community Orientated Solutions to Minimize Aircraft Noise Annoyance). The main ambition of COSMA is to develop engineering criteria for aircraft design and operations in order to reduce the annoyance within airport communities due to aircraft exterior noise. As a basis for this activity, a powerful aircraft flyover noise synthesis tool was developed, allowing psychometric studies and the analysis of community noise annoyance in relation to aircraft design and flight procedures. The sound synthesis tool integrates dedicated interfaces for on-line interactive sound quality analysis and for simulating complex airport noise scenarios based on aircraft source and noise propagation models. The main tool features are described and an example case study is presented, illustrating the noise modeling and audio synthesis. Next to that, an overview is given of the different airport noise scenarios that were synthesized in the COSMA project, considering standard and optimized procedures, existing aircraft and target sounds, as well as first examples of design optimizations, innovative concepts and low noise technologies

Vocalizations in juvenile anurans: common spadefoot toads (Pelobates fuscus) regularly emit calls before sexual maturity

Acoustic communication is prominent in adult anuran amphibians, in reproductive, territorial and defensive contexts. In contrast, reports on vocalizations of juvenile anurans are rare and anecdotal, and their function unstudied. We here provide conclusive evidence for vocalizations in juvenile spadefoot toads (Pelobates fuscus) in very early terrestrial stages. While the aquatic tadpoles did not emit sounds, first vocalizations of metamorphs were heard as early as in stages 42-43, and calls were regularly emitted from stage 44 on, often from specimens still bearing extensive tail stubs. Three main types of calls could be distinguished, of which one consists of a series of short notes, one of a typically single longer and pulsed note, and one of a single tonal note. In experimental setups, the number of calls per froglet increased with density of individuals and after feeding, while on the contrary calls were not elicited by playback. The function of these juvenile calls remains un-clarified, but they might reflect a general arousal in the context of feeding. Further evidence is necessary to test whether such feeding calls could confer a signal to conspecifics and thus might represent intraspecific acoustic communication in these immature terrestrial amphibians

Early remodeling of perinuclear Ca2+ stores and nucleoplasmic Ca2+ signaling during the development of hypertrophy and heart failure.

BackgroundA hallmark of heart failure is impaired cytoplasmic Ca(2+) handling of cardiomyocytes. It remains unknown whether specific alterations in nuclear Ca(2+) handling via altered excitation-transcription coupling contribute to the development and progression of heart failure.Methods and resultsUsing tissue and isolated cardiomyocytes from nonfailing and failing human hearts, as well as mouse and rabbit models of hypertrophy and heart failure, we provide compelling evidence for structural and functional changes of the nuclear envelope and nuclear Ca(2+) handling in cardiomyocytes as remodeling progresses. Increased nuclear size and less frequent intrusions of the nuclear envelope into the nuclear lumen indicated altered nuclear structure that could have functional consequences. In the (peri)nuclear compartment, there was also reduced expression of Ca(2+) pumps and ryanodine receptors, increased expression of inositol-1,4,5-trisphosphate receptors, and differential orientation among these Ca(2+) transporters. These changes were associated with altered nucleoplasmic Ca(2+) handling in cardiomyocytes from hypertrophied and failing hearts, reflected as increased diastolic Ca(2+) levels with diminished and prolonged nuclear Ca(2+) transients and slowed intranuclear Ca(2+) diffusion. Altered nucleoplasmic Ca(2+) levels were translated to higher activation of nuclear Ca(2+)/calmodulin-dependent protein kinase II and nuclear export of histone deacetylases. Importantly, the nuclear Ca(2+) alterations occurred early during hypertrophy and preceded the cytoplasmic Ca(2+) changes that are typical of heart failure.ConclusionsDuring cardiac remodeling, early changes of cardiomyocyte nuclei cause altered nuclear Ca(2+) signaling implicated in hypertrophic gene program activation. Normalization of nuclear Ca(2+) regulation may therefore be a novel therapeutic approach to prevent adverse cardiac remodeling

Early Remodeling of Perinuclear Ca2+ Stores and Nucleoplasmic Ca2+ Signaling During the Development of Hypertrophy and Heart Failure

Background—A hallmark of heart failure is impaired cytoplasmic Ca2+ handling of cardiomyocytes. It remains unknown whether specific alterations in nuclear Ca2+ handling via altered excitation-transcription coupling contribute to the development and progression of heart failure. Methods and Results—Using tissue and isolated cardiomyocytes from nonfailing and failing human hearts, as well as mouse and rabbit models of hypertrophy and heart failure, we provide compelling evidence for structural and functional changes of the nuclear envelope and nuclear Ca2+ handling in cardiomyocytes as remodeling progresses. Increased nuclear size and less frequent intrusions of the nuclear envelope into the nuclear lumen indicated altered nuclear structure that could have functional consequences. In the (peri)nuclear compartment, there was also reduced expression of Ca2+ pumps and ryanodine receptors, increased expression of inositol-1,4,5-trisphosphate receptors, and differential orientation among these Ca2+ transporters. These changes were associated with altered nucleoplasmic Ca2+ handling in cardiomyocytes from hypertrophied and failing hearts, reflected as increased diastolic Ca2+ levels with diminished and prolonged nuclear Ca2+ transients and slowed intranuclear Ca2+ diffusion. Altered nucleoplasmic Ca2+ levels were translated to higher activation of nuclear Ca2+/calmodulin-dependent protein kinase II and nuclear export of histone deacetylases. Importantly, the nuclear Ca2+ alterations occurred early during hypertrophy and preceded the cytoplasmic Ca2+ changes that are typical of heart failure. Conclusions-During cardiac remodeling, early changes of cardiomyocyte nuclei cause altered nuclear Ca2+ signaling implicated in hypertrophic gene program activation. Normalization of nuclear Ca2+ regulation may therefore be a novel therapeutic approach to prevent adverse cardiac remodeling