Grand Challenges at the Interface of Engineering and Medicine.

Over the past two decades Biomedical Engineering has emerged as a major discipline that bridges societal needs of human health care with the development of novel technologies. Every medical institution is now equipped at varying degrees of sophistication with the ability to monitor human health in both non-invasive and invasive modes. The multiple scales at which human physiology can be interrogated provide a profound perspective on health and disease.

Na microdomains and sparks: Role in cardiac excitation-contraction coupling and arrhythmias in ankyrin-B deficiency.

Cardiac sodium (Na) potassium ATPase (NaK) pumps, neuronal sodium channels (I), and sodium calcium (Ca) exchangers (NCX1) may co-localize to form a Na microdomain. It remains controversial as to whether neuronal I contributes to local Na accumulation, resulting in reversal of nearby NCX1 and influx of Ca into the cell. Therefore, there has been great interest in the possible roles of a Na microdomain in cardiac Ca-induced Ca release (CICR).

A Loss of Epigenetic Control Can Promote Cell Death through Reversing the Balance of Pathways in a Signaling Network.

Epigenetic control of regulatory networks is only partially understood. Expression of Insulin-like growth factor-II (IGF2) is controlled by genomic imprinting, mediated by silencing of the maternal allele. Loss of imprinting of IGF2 (LOI) is linked to intestinal and colorectal cancers, causally in murine models and epidemiologically in humans.

Mechanisms of the cyclic nucleotide cross-talk signaling network in cardiac L-type calcium channel regulation.

Regulation of L-type Calcium (Ca) Channel (LCC) gating is critical to shaping the cardiac action potential (AP) and triggering the initiation of excitation-contraction (EC) coupling in cardiac myocytes. The cyclic nucleotide (cN) cross-talk signaling network, which encompasses the β-adrenergic and the Nitric Oxide (NO)/cGMP/Protein Kinase G (PKG) pathways and their interaction (cross-talk) through distinctively-regulated phosphodiesterase isoenzymes (PDEs), regulates LCC current via Protein Kinase A- (PKA) and PKG-mediated phosphorylation. Due to the tightly-coupled and intertwined biochemical reactions involved, it remains to be clarified how LCC gating is regulated by the signaling network from receptor to end target.

Modeling Na-Ca exchange in the heart: Allosteric activation, spatial localization, sparks and excitation-contraction coupling.

The cardiac sodium (Na)/calcium (Ca) exchanger (NCX1) is an electrogenic membrane transporter that regulates Ca homeostasis in cardiomyocytes, serving mainly to extrude Ca during diastole. The direction of Ca transport reverses at membrane potentials near that of the action potential plateau, generating an influx of Ca into the cell. Therefore, there has been great interest in the possible roles of NCX1 in cardiac Ca-induced Ca release (CICR).

Roles of phosphodiesterases in the regulation of the cardiac cyclic nucleotide cross-talk signaling network.

The balanced signaling between the two cyclic nucleotides (cNs) cAMP and cGMP plays a critical role in regulating cardiac contractility. Their degradation is controlled by distinctly regulated phosphodiesterase isoenzymes (PDEs), which in turn are also regulated by these cNs. As a result, PDEs facilitate communication between the β-adrenergic and Nitric Oxide (NO)/cGMP/Protein Kinase G (PKG) signaling pathways, which regulate the synthesis of cAMP and cGMP respectively.

Modeling calcium regulation of contraction, energetics, signaling, and transcription in the cardiac myocyte.

Calcium (Ca(2+)) plays many important regulatory roles in cardiac muscle cells. In the initial phase of the action potential, influx of Ca(2+) through sarcolemmal voltage-gated L-type Ca(2+) channels (LCCs) acts as a feed-forward signal that triggers a large release of Ca(2+) from the junctional sarcoplasmic reticulum (SR). This Ca(2+) drives heart muscle contraction and pumping of blood in a process known as excitation-contraction coupling (ECC).

Interaction between phosphodiesterases in the regulation of the cardiac β-adrenergic pathway.

In cardiac myocytes, the second messenger cAMP is synthesized within the β-adrenergic signaling pathway upon sympathetic activation. It activates Protein Kinase A (PKA) mediated phosphorylation of multiple target proteins that are functionally critical to cardiac contractility. The dynamics of cAMP are also controlled indirectly by cGMP-mediated regulation of phosphodiesterase isoenzymes (PDEs).

An integrated mitochondrial ROS production and scavenging model: implications for heart failure.

It has been observed experimentally that cells from failing hearts exhibit elevated levels of reactive oxygen species (ROS) upon increases in energetic workload. One proposed mechanism for this behavior is mitochondrial Ca(2+) mismanagement that leads to depletion of ROS scavengers. Here, we present a computational model to test this hypothesis.

Toward an integrative computational model of the Guinea pig cardiac myocyte.

The local control theory of excitation-contraction (EC) coupling asserts that regulation of calcium (Ca(2+)) release occurs at the nanodomain level, where openings of single L-type Ca(2+) channels (LCCs) trigger openings of small clusters of ryanodine receptors (RyRs) co-localized within the dyad. A consequence of local control is that the whole-cell Ca(2+) transient is a smooth continuous function of influx of Ca(2+) through LCCs. While this so-called graded release property has been known for some time, its functional importance to the integrated behavior of the cardiac ventricular myocyte has not been fully appreciated.

Protein geometry and placement in the cardiac dyad influence macroscopic properties of calcium-induced calcium release.

In cardiac ventricular myocytes, events crucial to excitation-contraction coupling take place in spatially restricted microdomains known as dyads. The movement and dynamics of calcium (Ca2+) ions in the dyad have often been described by assigning continuously valued Ca2+ concentrations to one or more dyadic compartments. However, even at its peak, the estimated number of free Ca2+ ions present in a single dyad is small (approximately 10-100 ions).

Voltage noise influences action potential duration in cardiac myocytes.

Stochastic gating of ion channels introduces noise to membrane currents in cardiac muscle cells (myocytes). Since membrane currents drive membrane potential, noise thereby influences action potential duration (APD) in myocytes. To assess the influence of noise on APD, membrane potential is in this study formulated as a stochastic process known as a diffusion process, which describes both the current-voltage relationship and voltage noise.

Multiscale modeling of calcium signaling in the cardiac dyad.

Calcium (Ca(2+))-induced Ca(2+)-release (CICR) takes place in spatially restricted microdomains known as dyads. The length scale over which CICR occurs is on the order of nanometers and relevant time scales range from micro- to milliseconds. Quantitative understanding of CICR therefore requires development of models that are applicable over a range of spatio-temporal scales.

Transcriptomic profiling of the canine tachycardia-induced heart failure model: global comparison to human and murine heart failure.

Alterations of cardiac gene expression are central to ventricular dysfunction in human heart failure (HF). The canine tachycardia pacing-induced HF model is known to reproduce the main hemodynamic, echocardiographic and electrophysiological changes observed in human HF. In this study, we use this HF model to compare gene expression profiles in the left and right ventricles (LV, RV) of normal and end-stage failing canine hearts and compare the transcription profiles to those in human and murine models of HF.

Measuring and mapping cardiac fiber and laminar architecture using diffusion tensor MR imaging.

The ventricular myocardium is known to exhibit a complex spatial organization, with fiber orientation varying as a function of transmural location. It is now well established that diffusion tensor magnetic resonance imaging (DTMRI) may be used to measure this fiber orientation at high spatial resolution. Cardiac fibers are also known to be organized in sheets with surface orientation varying throughout the ventricles.

Using models of the myocyte for functional interpretation of cardiac proteomic data.

There has been significant progress towards the development of highly integrative computational models of the cardiac myocyte over the past decade. Models now incorporate descriptions of voltage-gated ionic currents and membrane transporters, mechanisms of calcium-induced calcium release and intracellular calcium cycling, mitochondrial ATP production and its coupling to energy-requiring membrane transport processes and mechanisms of force generation. There is an extensive literature documenting both the reconstructive and predictive abilities of these models and there is no question that an interplay between quantitative modelling and experimental investigation has become a central component of modern cardiovascular research.

The role of stochastic and modal gating of cardiac L-type Ca2+ channels on early after-depolarizations.

Certain signaling events that promote L-type Ca2+ channel (LCC) phosphorylation, such as beta-adrenergic stimulation or an increased expression of Ca(2+)/calmodulin-dependent protein kinase II, promote mode 2 gating of LCCs. Experimental data suggest the hypothesis that these events increase the likelihood of early after-depolarizations (EADs). We test this hypothesis using an ionic model of the canine ventricular myocyte incorporating stochastic gating of LCCs and ryanodine-sensitive calcium release channels.

A computational model of the human left-ventricular epicardial myocyte.

A computational model of the human left-ventricular epicardial myocyte is presented. Models of each of the major ionic currents present in these cells are formulated and validated using experimental data obtained from studies of recombinant human ion channels and/or whole-cell recording from single myocytes isolated from human left-ventricular subepicardium. Continuous-time Markov chain models for the gating of the fast Na(+) current, transient outward current, rapid component of the delayed rectifier current, and the L-type calcium current are modified to represent human data at physiological temperature.