Implementation Research to Address the United States Health Disadvantage: Report of a National Heart, Lung, and Blood Institute Workshop.

Four decades ago, U.S. life expectancy was within the same range as other high-income peer countries.

Refining Current Scientific Priorities and Identifying New Scientific Gaps in HIV-Related Heart, Lung, Blood, and Sleep Research.

The National Heart, Lung, and Blood Institute (NHLBI) AIDS Program's goal is to provide direction and support for research and training programs in areas of HIV-related heart, lung, blood, and sleep (HLBS) diseases. To better define NHLBI current HIV-related scientific priorities and with the goal of identifying new scientific priorities and gaps in HIV-related HLBS research, a wide group of investigators gathered for a scientific NHLBI HIV Working Group on December 14-15, 2015, in Bethesda, MD. The core objectives of the Working Group included discussions on: (1) HIV-related HLBS comorbidities in the antiretroviral era; (2) HIV cure; (3) HIV prevention; and (4) mechanisms to implement new scientific discoveries in an efficient and timely manner so as to have the most impact on people living with HIV.

Reducing Health Inequities in the U.S.: Recommendations From the NHLBI's Health Inequities Think Tank Meeting.

The National, Heart, Lung, and Blood Institute convened a Think Tank meeting to obtain insight and recommendations regarding the objectives and design of the next generation of research aimed at reducing health inequities in the United States. The panel recommended several specific actions, including: 1) embrace broad and inclusive research themes; 2) develop research platforms that optimize the ability to conduct informative and innovative research, and promote systems science approaches; 3) develop networks of collaborators and stakeholders, and launch transformative studies that can serve as benchmarks; 4) optimize the use of new data sources, platforms, and natural experiments; and 5) develop unique transdisciplinary training programs to build research capacity. Confronting health inequities will require engaging multiple disciplines and sectors (including communities), using systems science, and intervening through combinations of individual, family, provider, health system, and community-targeted approaches.

Perspectives from NHLBI Global Health Think Tank Meeting for Late Stage (T4) Translation Research.

Almost three-quarters (74%) of all the noncommunicable disease burden is found within low- and middle-income countries. In September 2014, the National Heart, Lung, and Blood Institute held a Global Health Think Tank meeting to obtain expert advice and recommendations for addressing compelling scientific questions for late stage (T4) research-research that studies implementation strategies for proven effective interventions-to inform and guide the National Heart, Lung, and Blood Institute's global health research and training efforts. Major themes emerged in two broad categories: 1) developing research capacity; and 2) efficiently defining compelling scientific questions within the local context.

Developmental expression of a functional TASK-1 2P domain K+ channel in embryonic chick heart.

Background: Background K+ channels are the principal determinants of the resting membrane potential (RMP) in cardiac myocytes and thus, influence the magnitude and time course of the action potential (AP).

Methods: RT-PCR and in situ hybridization are used to study the distribution of TASK-1 and whole-cell patch clamp technique is employed to determine the functional expression of TASK-1 in embryonic chick heart.

Results: Chicken TASK-1 was expressed in the early tubular heart, then substantially decreased in the ventricles by embryonic day 5 (ED5), but remained relatively high in ED5 and ED11 atria.

Temperature-sensitive TREK currents contribute to setting the resting membrane potential in embryonic atrial myocytes.

TREK channels belong to the superfamily of two-pore-domain K(+) channels and are activated by membrane stretch, arachidonic acid, volatile anaesthetics and heat. TREK-1 is highly expressed in the atrium of the adult heart. In this study, we investigated the role of TREK-1 and TREK-2 channels in regulating the resting membrane potential (RMP) of isolated chicken embryonic cardiac myocytes.

Investigating nanoscale cellular dynamics with cross-sectional spectral domain phase microscopy.

We report on cross-sectional imaging of dynamic biological specimens using a spectral domain phase microscopy (SDPM) system capable of operating at a line rate of 19 kHz. This system combines the time-sensitive capabilities of SDPM with the multi-point acquisition features of related phase-sensitive techniques. The presented phase portraits and B-scan phase images of spontaneously beating embryonic cardiomyocytes and cytoplasmic flow in A.

Changes in regulation of sodium/calcium exchanger of avian ventricular heart cells during embryonic development.

It has been suggested that the sodium/calcium exchanger NCX1 may have a more important physiological role in embryonic and neonatal hearts than in adult hearts. However, in chick heart sarcolemmal vesicles, sodium-dependent calcium transport is reported to be small and, moreover, to be 3-12 times smaller in hearts at embryonic day (ED) 4-5 than at ED18, the opposite of what would be expected of a transporter that is more important in early development. To better assess the role of NCX1 in calcium regulation in the chick embryonic heart, we measured the activity of NCX1 in chick embryonic hearts as extracellular calcium-activated exchanger current (I(NCX)) under controlled ionic conditions.

Cardiac arterial pole alignment is sensitive to FGF8 signaling in the pharynx.

Morphogenesis of the cardiac arterial pole is dependent on addition of myocardium and smooth muscle from the secondary heart field and septation by cardiac neural crest cells. Cardiac neural crest ablation results in persistent truncus arteriosus and failure of addition of myocardium from the secondary heart field leading to malalignment of the arterial pole with the ventricles. Previously, we have shown that elevated FGF signaling after neural crest ablation causes depressed Ca2+ transients in the primary heart tube.

Expression of a two-pore domain K+ channel (TASK-1) in developing avian and mouse ventricular conduction systems.

In this study, we report the identification and amino acid sequence of a novel two-pore domain potassium channel (TASK-1) in chicken. This protein, cTASK-1, is highly similar to mouse and human TASK-1 particularly within the pore regions. We describe the expression profile of both chicken and mouse TASK-1 in the embryonic heart as the ventricular conduction system develops.

Spectral-domain phase microscopy.

Broadband interferometry is an attractive technique for the detection of cellular motions because it provides depth-resolved phase information via coherence gating. We present a phase-sensitive technique called spectral-domain phase microscopy (SDPM). SDPM is a functional extension of spectral-domain optical coherence tomography that allows for the detection of nanometer-scale motions in living cells.

A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis.

Focal and segmental glomerulosclerosis (FSGS) is a kidney disorder of unknown etiology, and up to 20% of patients on dialysis have been diagnosed with it. Here we show that a large family with hereditary FSGS carries a missense mutation in the TRPC6 gene on chromosome 11q, encoding the ion-channel protein transient receptor potential cation channel 6 (TRPC6). The proline-to-glutamine substitution at position 112, which occurs in a highly conserved region of the protein, enhances TRPC6-mediated calcium signals in response to agonists such as angiotensin II and appears to alter the intracellular distribution of TRPC6 protein.

Effects of eugenol, an essential oil, on the mechanical and electrical activities of cardiac muscle.

Eugenol (EUG) acts as a calcium antagonist but effects on the contractile proteins could also occur. We investigated inotropic effects of EUG in rat left ventricular papillary muscles, measuring isometric force, time variables, and post rest potentiation and EUG actions on the effects of Ca2+ (0.62 to 2.

L-type Ca2+ channel function in the avian embryonic heart after cardiac neural crest ablation.

In avian and mammalian embryos, surgical ablation or severely reduced migration of the cardiac neural crest leads to a failure of outflow tract septation known as persistent truncus arteriosus (PTA) and leads to embryo lethality due partly to impaired excitation-contraction coupling stemming primarily from a reduction in the L-type Ca(2+) current (I(Ca),(L)). Decreased I(Ca,L) occurs without a corresponding reduction in the alpha(1)-subunit of the Ca(2+) channel. We hypothesize that decreased I(Ca),(L) is due to reduced function at the single channel level.

Transitions in ventricular activation revealed by two-dimensional optical mapping.

While cardiac function in the mature heart is dependent on a properly functioning His-Purkinje system, the early embryonic tubular heart efficiently pumps blood without a distinct specialized conduction system. Although His-Purkinje system precursors have been identified using immunohistological techniques in the looped heart, little is known whether these precursors function electrically. To address this question, we used high-resolution optical mapping and fluorescent dyes with two CCD cameras to describe the motion-corrected activation patterns of 76 embryonic chick hearts from tubular stages (stage 10) to mature septated hearts (stage 35).

Calcium buffering and excitation-contraction coupling in developing avian myocardium.

This report provides a detailed analysis of developmental changes in cytoplasmic free calcium (Ca(2+)) buffering and excitation-contraction coupling in embryonic chick ventricular myocytes. The peak magnitude of field-stimulated Ca(2+) transients declined by 41% between embryonic day (ED) 5 and 15, with most of the decline occurring between ED5 and 11. This was due primarily to a decrease in Ca(2+) currents.

Myocardial volume and organization are changed by failure of addition of secondary heart field myocardium to the cardiac outflow tract.

Cardiac neural crest ablation results in primary myocardial dysfunction and failure of the secondary heart field to add the definitive myocardium to the cardiac outflow tract. The current study was undertaken to understand the changes in myocardial characteristics in the heart tube, including volume, proliferation, and cell size when the myocardium from the secondary heart field fails to be added to the primary heart tube. We used magnetic resonance and confocal microscopy to determine that the volume of myocardium in the looped heart was dramatically reduced and the compact layer of myocardium was thinner after neural crest ablation, especially in the outflow tract and ventricular regions.

T-type Ca2+ current contribution to Ca2+-induced Ca2+ release in developing myocardium.

In normal adult-ventricular myocardium, Ca2+-induced Ca2+ release (CICR) from the sarcoplasmic reticulum (SR) is activated via Ca2+ entry through L-type Ca2+ channels. However, embryonic-ventricular myocytes have a prominent T-type Ca2+ current (ICa,T). In this study, the contribution of ICa,T to CICR was determined in chick-ventricular development.

Localization, macromolecular associations, and function of the small heat shock-related protein HSP20 in rat heart.

Background: The small heat shock proteins HSP20, HSP25, alphaB-crystallin, and myotonic dystrophy kinase binding protein (MKBP) may regulate dynamic changes in the cytoskeleton. For example, the phosphorylation of HSP20 has been associated with relaxation of vascular smooth muscle. This study examined the function of HSP20 in heart muscle.

Role of sodium-calcium exchanger (Ncx1) in embryonic heart development: a transgenic rescue?

Na(+)/Ca(2+) exchanger (Ncx-1) is highly expressed in cardiomyocytes, is thought to be required to maintain a low intracellular Ca(2+) concentration, and may play a role in excitation-contraction coupling. Significantly, targeted deletion of Ncx-1 results in Ncx1-null embryos that do not have a spontaneously beating heart and die in utero. Ultrastructural analysis revealed gross anomalies in the Ncx1-null contractile apparatus, but physiologic analysis showed normal field-stimulated Ca(2+) transients, suggesting that Ncx-1 function may not be critical for Ca(2+) extrusion from the cytosol as previously thought.