Heart failure (HF) is a major and increasingly common cardiovascular syndrome, and is the end result of many cardiovascular disorders. Moreover, the syndrome is one of the most common reasons for new or recurrent hospitalizations among persons over 65 years of age. To fight with this problem, one of the best ways is to identify the high risk group subject to HF by new risk stratification biomarkers far before the happening of diseases. By elucidating the relationship between biomarkers and pathogenesis in HF, the novel strategies that involve suitable medicine and rehabilitation will be developed to prevent early hemodynamic dysfunction and thrombotic events, further retarding the progression of HF.
HF is associated with neurohumoral changes as the body attempts to reverse the effect of reduced cardiac output and organ perfusion. The sympathetic and renin–angiotensin–aldosterone systems are activated in an attempt to increase myocardial contractility, heart rate and vasoconstriction, and expand extracellular fluid volume. Persistent neurohumoral excitation, however, actually results in deterioration of myocardial function with inflammatory response, end-organ damage, and skeletal muscle derangement, which lead to worsened exercise capacity. According to previous investigations, the biomarkers of HF may include various influence factors that involved inflammation, oxidative stress, extracellular matrix remodeling, neurohormones, and mycardiocyte stress/injury. To our knowledge, an integrated strategy for the analytic multimarkers in HF progression has not yet been established. This proposal will integrate the research sources in CGU oxidative stress/damage and metabolomic core laboratories to establish an excellent research platform for analyzing HF multimarkers including oxidative stress profiles, metabolomics, and mycardiocyte stress/injury.
Cardiac dysfunction is generally considered to be a critical influencing factor for the abnormal exercise response observed in HF population. However, clinical investigations have indicated weak correlation between resting ventricular function and exercise tolerance as well as failure of inotropic and vasodilatory agents to improve exercise capacity, implying that cardiac dysfunction is not the only factor contributing to progressive exercise intolerance in patients with HF, impaired pulmonary and skeletal muscle function are also thought to have a role. Recently, abnormal cerebral metabolism has been diagnosed using magnetic resonance spectroscopy in patients with advanced HF, which abnormality is chiefly attributable to cerebral hypo-perfusion. This proposal will be the first to integrate the novel bioreactance-based measurement with near-infrared spectroscopy and automatic gas analysis to identify the roles of ventilatory and cardiac-cerebral-muscle hemodynamic responses to exercise on functional impairments in patients with HF. Additionally, hemorheology, atherothrombosis, and angiogenesis modulated by erythrocyte, monocyte, and endothelial progenitor cells in patients with HF will be also determined in this investigation.
The importance of oxidative stress is increasingly emerging, with respect to a pathophysiological mechanism of the myocardium remodeling responsible for HF progression. However, the molecular mechanisms in HF progression are complex and not fully defined. Therefore, this proposal will focus on the dissection of molecular mechanisms concerning involvement of ROS in HF. Increased understanding of signal transduction mechanisms underlying oxidative stress/inflammation gene regulations will create opportunities for the development of therapeutic strategies beneficial for HF.
In the etiology of HF, coronary artery disease is frequently encountered, associated with severe or end-stage of coronary artery obstruction. In the population of aging, available conduit vessels are often not enough for a complete re-vascularization when bypass surgery is performed. Thus, it is important in the future to bio-engineer an artificial vessel, especially from an autologous source and non-invasively. Vascular progenitor cells contain a few different cell types, at least smooth muscle progenitor cells (SMPCs) and endothelial progenitor cells (EPCs). These progenitor cells have unlimited potentials in both risk stratification and tissue engineering. In this project, we will use updated technologies to find out potential gene targets for separating SMPCs from EPCs. To use these targets to identify SMPCs, development of antibodies appropriate for flow cytometer use is mandatory to positively select SMPCs from other contaminated or mixed cell populations. Finally, combined with the magnet system, we will test whether our work can separate pure SMPCs from other cell populations and specifically head for vascular conduit engineering.
Decreased exercise capacity negatively affects an individual’s ability to adequately perform activities required for normal daily life and, therefore, their independence and quality of life. Physical training can have beneficial effects on neurohumoral, inflammatory, metabolic and central hemodynamic responses, as well as on endothelial, skeletal muscle and cardiovascular function, leading to improvement in functional capacity and quality of life. However, which exercise intensity yields maximal beneficial adaptations is controversial. Aerobic interval training has been shown to rescue impaired cardiomyocyte contractility, attenuate myocardial hypertrophy, and reduce myocardial expression of atrial natriuretic peptide in animal model of post-infarction heart failure. However, underlying mechanisms of the exercise-improved regulations of cardiac hemodynamics and risk factors in patients with HF remain unclear. This proposal will further clarify how various regimens of cardiac rehabilitation affect cardiovascular hemorheological characterics and atherothrombosis/angiogenesis-related variables in patients with HF.
In light of the above discussion, this proposal will integrate six research programs that include from bio/functional markers to clinical therapeutics in HF. By elucidating the relationship between biomarkers/physiological markers and HF pathogenesis, this proposal attempts to provide some novel strategies for developing suitable medicine/rehabilitation regimens that prevent early hemodyamic dysfunction and thrombotic events, further retarding the progression of HF. The six research programs in this proposal list as follows:
(1) To establish the research platform of multi-biomarkers for analyzing oxidative stress profiles, metabolomics, and mycardiocyte stress/injury in HF progression.
(2) To establish the research platform of systemic physiological markers for evaluating central/peripheral hemorheological characterics and atherothrombosis/ angiogenesis-related variables in HF progression.
(3) To dissect molecular mechanisms concerning involvement of oxidative stress/inflammation inHF progression for creating opportunities for the development of therapeutic strategies beneficial for HF.
(4) To develop the animal models in HF for employing novel developments of tissue engineering and cardiac rehabilitation.
(5) To develop a novel technology of vascular conduit engineering for constructing an artificial vessel from an autologous source and non-invasively.
To design the “safe and effective” cardiac rehabilitation for promoting aerobic fitness and minimizing the hemodynamic limitations and vascular thrombotic events.
【Falculty Honors】The assessment for activity restriction in patient with heart disease by using cardiodynamics, brain/skeletal muscle blood system and oxygen utilization has won "Symbol of National Quality" and "Healthcare Quality Improvement Campaign" gold award of Joint Commission of Taiwan (JCT).
【Patent】Smart Bike and Operation Method Thereof; Taiwan Patent Number: I458521 (Issued: 2012/10/19)