J. Yasha Kresh

Internal thoracic artery for coronary artery grafting in octogenarians

BACKGROUND Use of the left internal thoracic artery as a bypass graft has been shown to result in better long-term patency and improved survival. In elderly patients, the internal thoracic artery has been used less often for coronary artery bypass grafts because of the belief that greater morbidity and mortality are associated with this procedure. This study was undertaken to test this premise in the octogenarian population. METHODS Over an 8-year period, 474 consecutive patients 80 years of age and greater had coronary artery bypass grafting. The left internal thoracic artery was used in 188 patients (39.7%) (group 1) and saphenous vein grafts only (group 2), in 286 (60.3%). The mean age was 82.6 years (range, 80 to 95 years). There were 312 men (65.8%) and 162 women (34.2%). RESULTS Use of the internal thoracic artery as a graft has risen steadily each year, as has the number of patients who are octogenarians. The hospital mortality rate was 7.8%. Patients in group 1 had a mortality rate of 9.0% and patients in group 2, a mortality rate of 7.0%. The mortality rate among survivors at 1 year was 6.7%. Long-term survival was significantly greater in group 1. CONCLUSIONS On the basis of this study, we conclude that the internal thoracic artery is the bypass graft of choice, especially in regard to long-term mortality, and should not be denied to this high-risk group.

Complex systems science in biomedicine

Integrative Systems View of Life: Perspectives from General Systems Thinking.- Complex Systems Science: The Basics.- Methods and Techniques of Complex Systems Science: An Overview.- Nonlinear Dynamical Systems.- Biological Scaling and Physiological Time: Biomedical Applications.- The Architecture of Biological Networks.- Robustness in Biological Systems: A Provisional Taxonomy.- Complex Adaptive Biosystems: A Multi-Scaled Approach.- Noise in Gene Regulatory Networks.- Modeling RNA Folding.- Protein Networks.- Electronic Cell Environments: Combining Gene, Protein, and Metabolic Networks.- Tensegrity, Dynamic Networks, and Complex Systems Biology: Emergence in Structural and Information Networks Within Living Cells.- Spatiotemporal Dynamics of Eukaryotic Gradient Sensing.- Patterning by EGF Receptor: Models from Drosophila Development.- Developmental Biology: Branching Morphogenesis.- Modeling Cardiac Function.- Cardiac Oscillations and Arrhythmia Analysis.- How Distributed Feedbacks from Multiple Sensors Can Improve System Performance: Immunology and Multiple-Organ Regulation.- Microsimulation of Inducible Reorganization in Immunity.- The Complexity of the Immune System: Scaling Laws.- Neurobiology and Complex Biosystem Modeling.- Modeling Spontaneous Episodic Activity in Developing Neuronal Networks.- Clinical Neuro-Cybernetics: Motor Learning in Neuronal Systems.- Modeling Cancer as A Complex Adaptive System: Genetic Instability and Evolution.- Spatial Dynamics in Cancer.- Modeling Tumors as Complex Biosystems: An Agent-Based Approach.- The Complexity of Dynamic Host Networks.- Physiologic Failure: Multiple Organ Dysfunction Syndrome.- Aging as a Process of Complexity Loss.- Enabling Technologies.- Biomedical Microfluidics and Electrokinetics.- Gene Selection Strategies in Microarray Expression Data: Applications to Case-Control Studies.- Application of Biomolecular Computing to Medical Science: A Biomolecular Database System for Storage, Processing, and Retrieval of Genetic Information and Material.- Tissue Engineering: Multiscaled Representation of Tissue Architecture and Function.- Imaging the Neural Systems for Motivated Behavior and Their Dysfunction in Neuropsychiatric Illness.- A Neuromorphic System.- A Biologically Inspired Approach Toward Autonomous Real-World Robots.- Virtual Reality, Intraoperative Navigation, and Telepresence Surgery.

Augmentation of integrin-mediated mechanotransduction by hyaluronic acid

Changes in tissue and organ stiffness occur during development and are frequently symptoms of disease. Many cell types respond to the stiffness of substrates and neighboring cells in vitro and most cell types increase adherent area on stiffer substrates that are coated with ligands for integrins or cadherins. In vivo cells engage their extracellular matrix (ECM) by multiple mechanosensitive adhesion complexes and other surface receptors that potentially modify the mechanical signals transduced at the cell/ECM interface. Here we show that hyaluronic acid (also called hyaluronan or HA), a soft polymeric glycosaminoglycan matrix component prominent in embryonic tissue and upregulated during multiple pathologic states, augments or overrides mechanical signaling by some classes of integrins to produce a cellular phenotype otherwise observed only on very rigid substrates. The spread morphology of cells on soft HA-fibronectin coated substrates, characterized by formation of large actin bundles resembling stress fibers and large focal adhesions resembles that of cells on rigid substrates, but is activated by different signals and does not require or cause activation of the transcriptional regulator YAP. The fact that HA production is tightly regulated during development and injury and frequently upregulated in cancers characterized by uncontrolled growth and cell movement suggests that the interaction of signaling between HA receptors and specific integrins might be an important element in mechanical control of development and homeostasis.

Using heart rate variability to stratify risk of obstetric patients undergoing spinal anesthesia.

In this study, we evaluated whether point correlation dimension (PD2), a measure of heart rate variability, can predict hypotension accompanying spinal anesthesia for cesarean delivery. After the administration of spinal anesthesia with bupivacaine, hypotension was defined as systolic blood pressure ≤75% of baseline within 20 min of intrathecal injection. Using the median prespinal PD2 (3.90) to form 2 groups, LO and HI, all 11 hypotensive patients were in the LO group, and all 11 patients without hypotension were in the HI group. Baseline heart rate in the LO group was 95 bpm (10.2 sd), versus 81 bpm (9.6 sd) in the HI group. PD2 shows promise as a predictor of hypotension in pregnant women receiving spinal anesthesia.

Cardiac myocyte remodeling mediated by N-cadherin-dependent mechanosensing.

Cell-to-cell adhesions are crucial in maintaining the structural and functional integrity of cardiac cells. Little is known about the mechanosensitivity and mechanotransduction of cell-to-cell interactions. Most studies of cardiac mechanotransduction and myofibrillogenesis have focused on cell-extracellular matrix (ECM)-specific interactions. This study assesses the direct role of intercellular adhesion, specifically that of N-cadherin-mediated mechanotransduction, on the morphology and internal organization of neonatal ventricular cardiac myocytes. The results show that cadherin-mediated cell attachments are capable of eliciting a cytoskeletal network response similar to that of integrin-mediated force response and transmission, affecting myofibrillar organization, myocyte shape, and cortical stiffness. Traction forces mediated by N-cadherin were shown to be comparable to those sustained by ECM. The directional changes in predicted traction forces as a function of imposed loads (gel stiffness) provide the added evidence that N-cadherin is a mechanoresponsive adhesion receptor. Strikingly, the mechanical sensitivity response (gain) in terms of the measured cell-spread area as a function of imposed load (adhesive substrate rigidity) was consistently higher for N-cadherin-coated surfaces compared with ECM protein-coated surfaces. In addition, the cytoskeletal architecture of myocytes on an N-cadherin adhesive microenvironment was characteristically different from that on an ECM environment, suggesting that the two mechanotransductive cell adhesion systems may play both independent and complementary roles in myocyte cytoskeletal spatial organization. These results indicate that cell-to-cell-mediated force perception and transmission are involved in the organization and development of cardiac structure and function.

Reprogramming cardiomyocyte mechanosensing by crosstalk between integrins and hyaluronic acid receptors

The elastic modulus of bioengineered materials has a strong influence on the phenotype of many cells including cardiomyocytes. On polyacrylamide (PAA) gels that are laminated with ligands for integrins, cardiac myocytes develop well organized sarcomeres only when cultured on substrates with elastic moduli in the range 10 kPa-30 kPa, near those of the healthy tissue. On stiffer substrates (>60 kPa) approximating the damaged heart, myocytes form stress fiber-like filament bundles but lack organized sarcomeres or an elongated shape. On soft (<1 kPa) PAA gels myocytes exhibit disorganized actin networks and sarcomeres. However, when the polyacrylamide matrix is replaced by hyaluronic acid (HA) as the gel network to which integrin ligands are attached, robust development of functional neonatal rat ventricular myocytes occurs on gels with elastic moduli of 200 Pa, a stiffness far below that of the neonatal heart and on which myocytes would be amorphous and dysfunctional when cultured on polyacrylamide-based gels. The HA matrix by itself is not adhesive for myocytes, and the myocyte phenotype depends on the type of integrin ligand that is incorporated within the HA gel, with fibronectin, gelatin, or fibrinogen being more effective than collagen I. These results show that HA alters the integrin-dependent stiffness response of cells in vitro and suggests that expression of HA within the extracellular matrix (ECM) in vivo might similarly alter the response of cells that bind the ECM through integrins. The integration of HA with integrin-specific ECM signaling proteins provides a rationale for engineering a new class of soft hybrid hydrogels that can be used in therapeutic strategies to reverse the remodeling of the injured myocardium.

Intercellular and extracellular mechanotransduction in cardiac myocytes

Adult cardiomyocytes are terminally differentiated with minimal replicative capacity. Therefore, long-term preservation or enhancement of cardiac function depends on structural adaptation. Myocytes interact with the extracellular matrix, fibroblasts, and vascular cells and with each other (end to end; side to side). We review the current understanding of the mechanical determinants and environmental sensing systems that modulate and regulate myocyte molecular machinery and its structural organization. We feature the design and application of engineered cellular microenvironments to demonstrate the ability of cardiac cells to remodel their cytoskeletal organization and shape, including sarcomere/myofibrillar architectural topography. Cell shape-dependent functions result from complex mechanical interactions between the cytoskeleton architecture and external conditions, be they cell–cell or cell–extracellular matrix (ECM) adhesion contact-mediated. This mechanobiological perspective forms the basis for viewing the cardiomyocyte as a mechanostructural anisotropic continuum, exhibiting constant mechanosensory-driven self-regulated adjustment of the cytoskeleton through tight interplay between its force generation activity and concurrent cytoarchitectural remodeling. The unifying framework guiding this perspective is the observation that these emerging events and properties are initiated by and respond to cytoskeletal reorganization, regulated by cell–cell and cell–ECM adhesion and its corresponding (mutually interactive) signaling machinery. It is important for future studies to elucidate how cross talk between these mechanical signals is coordinated to control myocyte structure and function. Ultimately, understanding how the highly interactive mechanical signaling can give rise to phenotypic changes is critical for targeting the underlying pathways that contribute to cardiac remodeling associated with various forms of dilated and hypertrophic myopathies, myocardial infarction, heart failure, and reverse remodeling.

A Novel Approach to Robotic Cardiac Surgery Using Haptics and Vision

Cardiovascular disease is one of the leading causes of death in the United States and also a major disease nationwide. Over 700,000 coronary artery bypass graft (CABG) procedures are performed annually all around the world, of which 350,000 are performed in the United States. The use of mechanical stabilizers to isolate and immobilize the surface region of the heart is not without its limitations such as hemodynamic deterioration, and arrythmia induction requiring inotropic support. Consequently, the use of mechanical stabilizers leads to a poor immobilization of the surgical field in spite of significant forces of traction and retraction used with these devices. The primary goal of this research is to develop effective haptic (sense of touch) and visual servoing methods with the long-term goal of eliminating the need for mechanical stabilizers and extracorporeal support for CABG procedures. We present in this paper the results from our initial work in the area of tracking a deformable membrane using vision and providing haptic feedback to the user, based on the visual information through the vision hardware and the material properties of the membrane. In our first experiment, we track the deformation of a rubber membrane in real-time through stereovision while providing haptic feedback to the user interacting with the reconstructed membrane through the PHANToM haptic device. In the second experiment, we verify the ability of our vision system to track a point on a surface undergoing a complex 3D motion.

Left ventricular volume regulation in heart failure with preserved ejection fraction

Ejection Fraction (EF) has attained the recognition as indicator of global ventricular performance. Remarkably, precise historical origins promoting the apparent importance of EF are scant. During early utilization EF has been declared a gold standard for the evaluation of the heart as a pump. In contrast, during the last two decades, clinicians have developed a measure of doubt in the universal applicability of EF. This reluctance lead to the introduction of a new and prevalent syndrome in which heart failure (HF) is diagnosed as having a preserved EF (pEF). We examine the existing criticism regarding EF, and describe a novel avenue to characterize ventricular function within the unifying framework of cardiac input–output volume regulation. This approach relates end‐systolic volume (ESV) to end‐diastolic volume (EDV), and derives for a subgroup matching pEF criteria a distinct pattern in the ESV–EDV domain. In patients with pEF (n = 34), a clear difference (P < 0.0004) in the slope of the regression line for ESV versus EDV was demonstrated compared to control patients with EF < 50% (n = 29). These findings are confirmed by analysis of data presented in two independent publications. The volume regulation approach proposed employs primary end‐point determinants (such as ESV and EDV) rather than derived quantities (e.g., the ratio EF or its differential parameter, that is, stroke volume) and confirms a distinct advantage over the classical Starling curve. Application of the ESV‐EDV‐construct provides the basis and clarifies why some patients present as HFpEF, while others have reduced EF.

Application of chaos theory to a model biological system: Evidence of self-organization in the intrinsic cardiac nervous system

The neural organization that determines the specific beat-to-beat pattern of cardiac behavior is expected to be demonstrated in the independent regulation of the RR intervals (chronotropy) and the corresponding QT subintervals (inotropy), as the former defines the rate of contraction and the latter has a linear negative correlation with the peak pressure inside the contracting ventricular muscles. The neurons of the isolated cardiac nervous system, many of which are located in the fat-pads of the heart, exhibit the same types of mechanical and chemical receptors and the same types of cholinergic and noradrenergic effectors as those found in the neural superstructure. In the surgically isolated and perfused rabbit heart we studied the responses of the QT and RR intervals evoked by block of coronary blood flow. We found that if we separated each RR cycle into QT and RR-QT components, then the dynamics of variation for each subinterval series often had the same fractional number of degrees of freedom (i.e., chaotic dimensions), a finding which suggests they are both regulated by the same underlying system. The ischemia/anoxia evoked transient dimensional increases and separations between the two subinterval series that, after the temporary divergence, reconverged to having the same lower value. The dimensional fluctuations occurred repeatedly and preceded or coincided with alterations in the magnitude and sign of the slope of QT vs RR-QT. We interpret the dimensional fluctuations of the two subinterval series as correlates of adaptation-dependent self-organization and reorganization in the underlying intrinsic cardiac nervous system during accumulating ischemia/anoxia. Such attempts at functional reorganization in this simple neurocardiac system may explain the transient dimensional changes in the RR intervals that precedes by 24 hrs the occurrences of fatal ventricular fibrillation in high-risk cardiac patients.