Chronic heart failure results from a variety of insults to the cardiac tissues.

In early disease ventricular contractility is largely maintained by adrenergic stimulation. As disease progresses compensatory mechanisms cease to provide benefit, fibrosis and dilation occur and function deteriorates. Left ventricular assist devices allow the left ventricle to repair and recover. We demonstrated a number of these repair outcomes, such as restored membrane integrity, improved calcium handling, and better mechanical indices. One major problem associated with heart failure is the ability of the myocytes to control calcium concentrations, indicating the vital role of adrenoreceptors. However, these receptors are down regulated and desensitized, possibly as a a protective mechanism against ionic overload, but our findings have indicated a) that the receptors are up-regulated during unloading, and regain normal numbers and sensitivity; b) that both alpha and beta adrenoreceptors are involved in recovery; and c) there is a mechanism in place to bring about a homogeneous distribution of the adrenoreceptors.

Our future studies will investigate changes in receptor subtypes to delineate specific receptors and their involvement and relocalization in this recovery process. We also wish to take our formulated data and correlate these changes with patient outcome, type of LVAD used, and pre-LVAD treatment (use of beta-blockers and/or intra aortic balloon for example). The ultimate aim is to use the types and numbers of receptors at the time of LVAD implantation to dictate something of a predictive factor as to probable outcome and the best treatment protocols. If this can be achieved, and we have had some success with ‘blind’ predictions of prior LVAD recipients, then there is every chance that another weapon can be added to the arsenal for treating heart failure, and deciding the likelihood of progression to organ transplantation with appropriate drug regimens, continued use of LVAD support, or an immediate need for transplant surgery.

heartfailureCardiac Muscle

Brian Poindexter, Roger Bick, Green shows cardiac actin

 

 

purkinjefibresSub-endocardial purkinje fibers

Brian Poindexter, Roger Bick, Sub-endocardial purkinje fibers of human myocardium. Red probe identifies dystrophin.

 

dedifferentiating-myocyteDe-differentiating myocyte

Brian Poindexter, David Sheikh-Hamad, Michael Stephen, Roger Bick, Dedifferentiating, binucleate (white) cultured adult cardiomyocyte. Red demonstrates perinuclear stanniocalcin-1 synthesis.

 

cardiac-dystrophinCardiac dystrophin

Roger Bick, OH Frazier (Texas Heart Institute), Brian Poindexter, Disrupted, cardiac dystrophin (green) surrounding myofibrils (red) from a core sample of a heart failure patient.

 

alpha-exp-paper-figure-3bα adrenoreceptors

Pippa Evans, Brian Poindexter, OH Frazier, Roger Bick, Red alpha-adrenoreceptors on green myofibrils of a core sample prior to LVAD implantation. Reference – Schnee, PM et al, J Heart Lung Transpl. 27(7):710-717, 2008.

 

alpha-imp-paper-figure3aα adrenoreceptors

Pippa Evans, Brian Poindexter, OH Frazier, Roger Bick, Red alpha-adrenoreceptors on green myofibrils of a core sample prior to LVAD implantation. Reference – Schnee, PM et al, J Heart Lung Transpl. 27(7):710-717, 2008.

 

beating-myocytesBeating myocytes

Brian Poindexter, Roger Bick, High nuclear calcium (white) seen in cultured neonatal cardiomyocytes.

 

binucleate-cardiomyocyteBinucleated cardiomyocyte

Michael Stephen (UT-Cardiology), Roger Bick, Johan Moolman (Univ. of Stellenbosch), David Sheikh-Hamad (BCM), Brian Poindexter, 3D model of multiple stacked images of a cardiac myocytes showing the binucleate (white) form, synthesized proteins (red) and blue cardiac actin.

 

calcium-channel-proteins-3DCa channel proteins (3D)

Brian Poindexter, Roger Bick, L-type calcium channel proteins (red) in the nuclear envelope of a cardiomyocyte.

 

calcium-heart-cellCa in heart cell

Brain Poindexter, Roger Bick, Fluo 3 probed calcium in beating heart adult rodent heart cells.
Reference – Poindexter BJ et al, Cell Calcium; 30(6):373-82, 2001.

 

cardiac-muscle-cellCardiomyocytes

Roger Bick, Brian Poindexter, Textured rendition of a cultured, binucleate cardiomyocyte

 

 

cardiac-muscleIICardiomyocytes

Roger Bick, OH Frazier, Brian Poindexter, Pippa Schnee, Beta-adrenoreceptors (yellow) distributed along cardiac myosin (red) prior to cardiac unloading by LVAD. Reference – Schnee, PM et al, Medscape General Medicine, http://www.medscape.com/viewarticle/530973_print, 8(2):45, 2006.

 

cardiac-muscleIIICardiomyocytes

Roger Bick, OH Frazier, Brian Poindexter, Pippa Schnee, Alpha-adrenoreceptors (yellow) distributed along cardiac actin (green) prior to cardiac unloading by LVAD. Reference -Schnee, PM et al, Medscape General Medicine, http://www.medscape.com/viewarticle/530973_print, 8(2):45, 2006.

 

cardiac-muscleIVCardiomyocytes

Roger Bick, OH Frazier, Brian Poindexter, Pippa Schnee, Alpha-adrenoreceptors (red) distributed along cardiac actin (green) prior to cardiac unloading by LVAD and acquired images are stacked to give a 3D rendition. Reference – Schnee, PM et al, Medscape General Medicine, http://www.medscape.com/viewarticle/530973_print, 8(2):45, 2006.

 

CKIPaarR1Perinuclear adrenoreceptors

Brian Poindexter, Roger Bick, Perinuclear distribution model of alpha-adrenoreceptors (red) before cardiac unloading via LVAD.

 

contractile-sequenceContractile sequence

Brian Poindexter, L. Max Buja, Roger Bick, Adult cardiomyocyte acquisitions of real time fluorescence calcium transients. Reference – Poindexter BJ et al, Cell Calcium; 30(6):373-82, 2001.

 

damaged-myocardiumDamaged myocardium

Roger Bick, Brian Poindexter, O.H. Frazier (THI)
Myofibrils in disarray exhibiting a great deal of discontinuity and fraying. Sample from a heart failure patient prior to insertion of an LVAD. Reference: Bick RJ et al, J. Heart and Lung Transpl; 24:454-461, 2005.

 

H1As503Post-LVAD myocardium

Roger Bick, Pippa Schnee, Brian Poindexter, O.H. Frazier, Cardiac myofibrils showing compact form, visible intercalated discs and copious beta-adrenoreceptors, following unloading with LVAD. Reference: Bick RJ et al, J. Cardiac Surg; 20:1-5, 2005.

 

H4Bs202β receptors post-LVAD

Roger Bick, Alina Grigore, O.H. Frazier, L. Max Buja, Brian Poindexter, Up-regulation of beta adrenoreceptors (yellow) in straight, continuous, compact myofibrils following ventricular unloading with LVAD. Reference: Bick RJ et al, J. Cardiac Surg; 20:1-5, 2005.

 

microvessel-myocardiumMicrovessel in myocardium

Brian Poindexter, Roger Bick, Localization of small blood vessels (blue/lilac) coursing between contractile proteins (green) before ventricular unloading. Red shows position of alpha-adrenergic receptors. Reference: Grigore A et al, J. Heart and Lung Transplantation; 24(5):609-613, 2005.

 

neonatal-myocyteNeonatal myocyte

 

 

 

nucleus-receptorsNucleus receptors

3D model constructed from stacked image acquisitions to show the nucleus blue, cardiac myosin (green) and beta-adrenergic receptors (red) prior to ventricular unloading. Reference: Bick RJ et al, J. Cardiac Surg; 20:1-5, 2005.

 

myocyteMyocyte

Brian Poindexter, Barry Van Winkle, Roger Bick

Funky, Catherine wheel neonatal myocyte, showing nucleus, adrenoreceptors, and cardiac myosin. Reference: Bick RJ et al, Cell Adhes. Comm; 6:301-310, 1998.

 

smooth-muscle-actinSmooth muscle actin

Barry Van Winkle, Roger Bick and Brian Poindexter, Smooth muscle actin (red) seen in this cultured, dedifferentiating adult cardiomyocyte. Reference: Bick RJ et al, Cell Adhes. Comm; 6:301-310, 1998.