Basic research studies in the division are supported by five federally funded R01 grants with additional awards and private funding. A variety of chronic HF and hypertrophy models are routinely used in these investigations, including the canine tachycardia pacing-induced dilated cardiomyopathy model, infarct models (murine rat, rabbit or canine), pressure overload models (mouse, rat and rabbit) and transgenic mouse models. In addition, seminal findings in the animal models are confirmed in human failing cardiac muscle obtained in collaboration with UW heart transplant surgeon, Robert B. Love.
Calcineurin signaling in cardiac hypertrophy - Cardiac hypertrophy is an adaptive mechanism by the heart to various stimuli including exercise, hypertension, sarcomeric mutations, myocardial infarctions, and growth factor overstimulation. The hypertrophic response is frequently followed by dilation and heart failure. Many of these hypertrophic stimuli appear to involve calcium and calcineurin signaling. Recent experiments by Kaji and investigators in his lab have revealed that two murine models of hypertrophy, thyroxin overstimulation and myosin binding protein C deletion, both involve calcineurin signaling. Current work focuses on defining the molecules involved in this signaling cascade.
Electrical remodeling in the failing heart - Investigations led by Jonathan Makielski have revealed a persistent inward Na+ current which contributes to the prolonged action potential in failing myocytes. The proarrhythmic effect of this current can contribute to the high risk of sudden death in patients with HF. Studies are continuing to characterize this current and its regulation. Complementary investigations on the L-type Ca2+ channel lead by Timothy J. Kamp and Roberto Coronado (Physiology) demonstrate that this channel is half as abundant in failing myocytes from the canine tachycardia pacing model. In addition, currents through these channels decay more slowly, contributing to the prolonged action potential noted in HF. This loss of L-type Ca2+ channels contributes to the abnormalities of excitation-contraction coupling and contractile dysfunction.
Embryonic stem cell-derived cardiomyocytes - Pioneering studies by James A. Thomson (Primate Research Center) have produced pluripotent embryonic stem cells from rhesus monkeys as well as humans. Timothy J. Kamp, in collaboration with Thomson, is characterizing embryonic stem cell-derived cardiomyocytes. This unique cell system provides opportunities for important research. The cardiomyocytes also represent a promising future therapeutic approach to replace diseased heart myocytes.
Myocardial energy metabolism and exercise intolerance in heart disease - The Saupe laboratory's current research has two main components. The first is the study of myocardial energy metabolism; how it changes with normal aging, exercise training, and diseases such as heart failure, diabetic cardiomyopathy and ischemic heart disease. The overall goal of this research is to improve understanding of the biochemistry of myocardial metabolism, allowing therapeutic manipulation of myocardial metabolism. We are particularly interested in investigating the mechanism(s) by which increasing the amount of glucose and insulin provided to the ischemic heart is cardioportective. We also focus on an important enzyme in maintenance of cardiac energy stores, AMP-activated protein kinase. In additions, other research investigates the causes of exercise intolerance in heart disease. These studies investigate the molecular and biochemical mechanisms of exercise intolerance in animal models of heart failure of varying etiologies. Upon determining contributing causes to exercise intolerance, the major goal is to develop targeted pharmacological and non-pharmacological interventions that may improve exercise tolerance. The experimental models we use are primarily rat models of acute and chronic heart failure, as well as young and old transgenic and wild type mice.
Myofibrillar function in heart failure - Matthew R. Wolff and Richard L. Moss (Physiology) have demonstrated that myofilaments from failing canine and human hearts exhibit increased Ca2+ sensitivity due to decreased basal phosphorylation. These results provide an explanation for some of the contractile dysfunction observed in failing myocytes. The dynamic nature of these alterations in myofibrillar function during the cardiac cycle is under continued investigation.
Neurohormonal regulation of excitation-contraction coupling in heart failure - A variety of studies examining the molecular mechanisms of beta-adrenergic dysregulation of various proteins involved in excitation-contraction coupling including the L-type Ca2+ channel, the Ca2+ release channel of the sarcoplasmic reticulum, and myofilament proteins are being investigated by Timothy J. Kamp, Matthew R. Wolff, Johannes Hell (Pharmacology), Richard L. Moss and Hector Valdivia (Physiology). This work has demonstrated altered phosphorylation status of these proteins and is dissecting the molecular details underlying these changes.
Sleep disordered breathing in heart failure - Jerome A. Dempsey (Preventive Medicine) and Matthew R. Wolff collaborate in investigating the role of sleep disordered breathing in the progression of HF in the canine tachycardia pacing dilated cardiomyopathy model and in patients with advanced HF. Therapies to prevent the transient hypoxemia associated with this disordered breathing are showing promise.
Transverse tubular system remodeling in heart failure - Efforts led by Timothy J. Kamp, Roberto Coronado (Physiology), Matthew R. Wolff, Robert A. Haworth (Surgery), and Hector Valdivia recently revealed that the transverse tubular system in failing canine ventricular myocytes is dramatically decreased. Since the T-tubules are where excitation-contraction coupling is normally initiated, remodeling of this system plays a critical role in producing the contractile dysfunction in failing muscle. Further studies are underway characterizing the alterations in the proteins involved in excitation-contraction coupling and Ca2+ cycling as a result of T-tubule loss.