Complexity in genetic cardiomyopathies and new approaches for mechanism-based precision medicine

Genetic cardiomyopathies have been studied for decades, and it has become increasingly clear that these progressive diseases are more complex than originally thought. These complexities can be seen both in the molecular etiologies of these disorders and in the clinical phenotypes observed in patients. While these disorders can be caused by mutations in cardiac genes, including ones encoding sarcomeric proteins, the disease presentation varies depending on the patient mutation, where mutations even within the same gene can cause divergent phenotypes. Moreover, it is challenging to connect the mutation-induced molecular insult that drives the disease pathogenesis with the various compensatory and maladaptive pathways that are activated during the course of the subsequent progressive, pathogenic cardiac remodeling. These inherent complexities have frustrated our ability to understand and develop broadly effective treatments for these disorders. It has been proposed that it might be possible to improve patient outcomes by adopting a precision medicine approach. Here, we lay out a practical framework for such an approach, where patient subpopulations are binned based on common underlying biophysical mechanisms that drive the molecular disease pathogenesis, and we propose that this function-based approach will enable the development of targeted therapeutics that ameliorate these effects. We highlight several mutations to illustrate the need for mechanistic molecular experiments that span organizational and temporal scales, and we describe recent advances in the development of novel therapeutics based on functional targets. Finally, we describe many of the outstanding questions for the field and how fundamental mechanistic studies, informed by our more nuanced understanding of the clinical disorders, will play a central role in realizing the potential of precision medicine for genetic cardiomyopathies

One-Particle Measurement of the Antiproton Magnetic Moment

\DeclareRobustCommand{\pbar}{\HepAntiParticle{p}{}{}\xspace} \DeclareRobustCommand{\p}{\HepParticle{p}{}{}\xspace} \DeclareRobustCommand{\mup}{$\mu_{p}${}{}\xspace} \DeclareRobustCommand{\mupbar}{\mu_{\pbar}{}{}\xspace} \DeclareRobustCommand{\muN}{$\mu_N${}{}\xspace For the first time a single trapped \pbar is used to measure the \pbar magnetic moment {\bm\mu}_{\pbar}. The moment {\bm\mu}_{\pbar} = \mu_{\pbar} {\bm S}/(\hbar/2) is given in terms of its spin ${\bm S}$ and the nuclear magneton (\muN) by \mu_{\pbar}/\mu_N = -2.792\,845 \pm 0.000\,012. The 4.4 parts per million (ppm) uncertainty is 680 times smaller than previously realized. Comparing to the proton moment measured using the same method and trap electrodes gives \mu_{\pbar}/\mu_p = -1.000\,000 \pm 0.000\,005 to 5 ppm, for a proton moment ${\bm{\mu}}_{p} = \mu_{p} {\bm S}/(\hbar/2)$, consistent with the prediction of the CPT theorem.Comment: 4 pages, 4 figures. arXiv admin note: substantial text overlap with arXiv:1201.303

Two-neutron transfer reaction mechanisms in 12^{12}C(6^6He,4^{4}He)14^{14}C using a realistic three-body 6^{6}He model

The reaction mechanisms of the two-neutron transfer reaction $^{12}$C($^6$He,$^4$He) have been studied at 30 MeV at the TRIUMF ISAC-II facility using the SHARC charged-particle detector array. Optical potential parameters have been extracted from the analysis of the elastic scattering angular distribution. The new potential has been applied to the study of the transfer angular distribution to the 2$^+_2$ 8.32 MeV state in $^{14}$C, using a realistic 3-body $^6$He model and advanced shell model calculations for the carbon structure, allowing to calculate the relative contributions of the simultaneous and sequential two-neutron transfer. The reaction model provides a good description of the 30 MeV data set and shows that the simultaneous process is the dominant transfer mechanism. Sensitivity tests of optical potential parameters show that the final results can be considerably affected by the choice of optical potentials. A reanalysis of data measured previously at 18 MeV however, is not as well described by the same reaction model, suggesting that one needs to include higher order effects in the reaction mechanism.Comment: 9 pages, 9 figure

Prevalence of diabetic and impact on cardiovascular events and mortality in patients with chronic coronary syndromes, across multiple geographical regions and ethnicities

Background: In contrast with the setting of acute myocardial infarction, there are limited data regarding the impact of diabetes mellitus on clinical outcomes in contemporary cohorts of patients with chronic coronary syndromes. We aimed to investigate the prevalence and prognostic impact of diabetes according to geographical regions and ethnicity. Methods: CLARIFY is an observational registry of patients with chronic coronary syndromes, enrolled across 45 countries in Europe, Asia, America, Middle East, Australia and Africa in 2009-2010, and followed-up yearly for 5 years. Chronic coronary syndromes were defined by ≥1 of the following criteria: prior myocardial infarction, evidence of coronary stenosis >50%, proven symptomatic myocardial ischemia, or prior revascularisation procedure. Results: Among 32,694patients, 9502 (29%) had diabetes, with a regional prevalence ranging from below 20% in Northern Europe to approximately 60% in the Gulf countries. In a multivariable-adjusted Cox proportional hazards model, diabetes was associated with increased risks for the primary outcome(cardiovascular death, myocardial infarction or stroke)with an adjusted hazard ratio of1.28(95% CI 1.18-1.39) and for all secondary outcomes (all-cause and cardiovascular mortality, myocardial infarction, stroke, heart failure and coronary revascularization). Differences on outcomes according to geography and ethnicity were modest. Conclusion: In patients with chronic coronary syndromes, diabetes is independently associated with mortality and cardiovascular events, including heart failure, which is not accounted by demographics, prior medical history, left ventricular ejection fraction, or use of secondary prevention medication. This is observed across multiple geographic regions and ethnicities, despite marked disparities in the prevalence of diabetes

Effects of organic additives on the formation of solids from hypersaline geothermal brine

Studies are underway to identify compounds that will, at cost-effective concentrations, inhibit scale and solids formation when added to the brine at the high-temperature (approximately 200{sup 0}C) front end of the plant. The study reported here constitutes a preliminary, bench-test screening of 49 substances, the most promising of which will be examined later in on-line pilot plant studies. A variety of substances were tested, including both simple and polymeric alcohols, ethers, aldehydes, carboxylic acids, amines, amides, cellulose derivatives, and classes of materials such as detergents, surfactants, and coupling agents. An inorganic phosphate, KH{sub 2}PO{sub 4}, and a chelating agent EDTA, also were tested. In the present work the additives were mixed with hypersaline brine that had been acidified to pH 4.0 +- 0.3 and flashed to 1 atm, approximately 100{sup 0}C, in the LLL Geothermal Field Test Apparatus near Niland, California. The rate of disappearance of dissolved silica from the treated brine was compared with the rate for untreated brine as a measure of the effectiveness of the additive. (JGB