Roles of the creatine kinase system and myoglobin in maintaining energetic state in the working heart

<p>Abstract</p> <p>Background</p> <p>The heart is capable of maintaining contractile function despite a transient decrease in blood flow and increase in cardiac ATP demand during systole. This study analyzes a previously developed model of cardiac energetics and oxygen transport to understand the roles of the creatine kinase system and myoglobin in maintaining the ATP hydrolysis potential during beat-to-beat transient changes in blood flow and ATP hydrolysis rate.</p> <p>Results</p> <p>The theoretical investigation demonstrates that elimination of myoglobin only slightly increases the predicted range of oscillation of cardiac oxygenation level during beat-to-beat transients in blood flow and ATP utilization. In silico elimination of myoglobin has almost no impact on the cytoplasmic ATP hydrolysis potential (Δ<it>G</it>_ATPase). In contrast, disabling the creatine kinase system results in considerable oscillations of cytoplasmic ADP and ATP levels and seriously deteriorates the stability of Δ<it>G</it>_ATPasein the beating heart.</p> <p>Conclusion</p> <p>The CK system stabilizes Δ<it>G</it>_ATPaseby both buffering ATP and ADP concentrations and enhancing the feedback signal of inorganic phosphate in regulating mitochondrial oxidative phosphorylation.</p

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

The expansion field: The value of H_0

Any calibration of the present value of the Hubble constant requires recession velocities and distances of galaxies. While the conversion of observed velocities into true recession velocities has only a small effect on the result, the derivation of unbiased distances which rest on a solid zero point and cover a useful range of about 4-30 Mpc is crucial. A list of 279 such galaxy distances within v<2000 km/s is given which are derived from the tip of the red-giant branch (TRGB), from Cepheids, and from supernovae of type Ia (SNe Ia). Their random errors are not more than 0.15 mag as shown by intercomparison. They trace a linear expansion field within narrow margins from v=250 to at least 2000 km/s. Additional 62 distant SNe Ia confirm the linearity to at least 20,000 km/s. The dispersion about the Hubble line is dominated by random peculiar velocities, amounting locally to <100 km/s but increasing outwards. Due to the linearity of the expansion field the Hubble constant H_0 can be found at any distance >4.5 Mpc. RR Lyr star-calibrated TRGB distances of 78 galaxies above this limit give H_0=63.0+/-1.6 at an effective distance of 6 Mpc. They compensate the effect of peculiar motions by their large number. Support for this result comes from 28 independently calibrated Cepheids that give H_0=63.4+/-1.7 at 15 Mpc. This agrees also with the large-scale value of H_0=61.2+/-0.5 from the distant, Cepheid-calibrated SNe Ia. A mean value of H_0=62.3+/-1.3 is adopted. Because the value depends on two independent zero points of the distance scale its systematic error is estimated to be 6%. Typical errors of H_0 come from the use of a universal, yet unjustified P-L relation of Cepheids, the neglect of selection bias in magnitude-limited samples, or they are inherent to the adopted models.Comment: 44 pages, 4 figures, 6 tables, accepted for publication in the Astronony and Astrophysics Review 15

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

Patterns of Stress Testing and Diagnostic Catheterization After Coronary Stenting in 250 350 Medicare Beneficiaries

BACKGROUND: Patterns of non-invasive stress test (ST) and invasive coronary angiography (CA) utilization after percutaneous coronary intervention (PCI) are not well described in older populations. METHODS AND RESULTS: We linked National Cardiovascular Data Registry® CathPCI Registry® data with longitudinal Medicare claims data for 250,350 patients undergoing PCI from 2005 to 2007 and described subsequent testing and outcomes. Between 60 days post-PCI and end of follow-up (median 24 months), 49% (n=122,894) received stress testing first, 10% (n=25,512) underwent invasive CA first, and 41% (n=101,944) had no testing (NT). A number of clinical risk factors at time of index PCI were associated with decreased likelihood of downstream testing (ST or CA, p<0.05 for all), including older age (HR 0.784 per 10 year increase), male sex (HR 0.946), heart failure (HR 0.925), diabetes (HR 0.954), smoking (HR 0.804), and renal failure (HR 0.880). Fifteen percent of patients with ST first proceeded to subsequent CA within 90 days of testing (n=18,472/101,884); of these, 48% (n=8831) underwent revascularization within 90 days, compared to 53% (n=13,316) of CA first patients (p<0.0001). CONCLUSIONS: In this descriptive analysis, stress testing and invasive CA were common in older patients after PCI. Paradoxically, patients with higher-risk features at baseline were less likely to undergo post-PCI testing. The revascularization yield was low on patients referred for ST after PCI, with only 9% undergoing revascularization within 90 days