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Departments of Physiology, Nutritional Sciences,
and Molecular and Cellular Biology

konhilas portraitLaboratory of John Konhilas


Sex differences in the development of cardiac disease

Sex/gender differences exist in human cardiac disease resulting from many disease etoilogies including hypertension, myocardial infarction, and cardiomyopathies (HCM). The hearts of women with these disorders maintain, at least, adequate cardiac function whereas men typically demonstrate increased chamber dilation and wall thinning, all signs of progressively deteriorating cardiac disease. We know that a number of environmental, cellular, and genetic factors contribute to sex differences in gene expression and cell signaling from previous publications during my pre- and post-doctoral studies. Evidence from my current lab indicates that the observed sex difference may result from the inability of male hearts to match the increased energetic demand as a result of cardiac disease compared to females. We have examined the impact of sex/gender on cardiac adaptation to both pathological (disease) and physiological (exercise) stimuli and factors that modify this adaptation. Adenosine monophosphate-activated kinase (AMPK) may be a central regulator of this sex difference because of its established role in (1) sensing changes in cellular energy state, (2) regulating mediators of energy producing pathways, and, (3) directly modifying contractile proteins by phosphorylation. This latter function of AMPK becomes of critical importance because AMPK can directly sense the energetic state of the heart and, at the same time, modify the contractile properties of the heart, which is an important determinant of cardiac disease.

Impact of gut microbiota on acute and chronic cardiac injury

Our lab has a long-standing interest in the ability of environmental factors, like diet, to impact cardiac disease. Advances in sequencing and bioinformatic technologies have allowed unprecedented characterization of the gut microbiome. As a result, there is a growing appreciation that our microbial environment plays an integral role in the maintenance of health and the pathogenesis of disease. The bidirectional communication between gut microbiota and immune system places the gut at the center of balancing innate and adaptive immune cell populations and, consequently, inflammatory responses. Acute Coronary Syndrome (ACS) typically produced by myocardial ischemia/infarction (MI) often results from coronary heart disease (atherosclerosis). Concurrently, the last 15-20 years of research has established a mechanistic link between inflammation in every aspect of ACS produced by MI often resulting from atherosclerosis. Taken together, the emerging clinical focus on inflammation coupled with direct evidence that harmful gut microbiota (bacteria) directly instigate inflammation implicates a potential preventative and/or therapeutic niche for beneficial gut microbiota as repressors of inflammation and, accordingly, ACS.

Optimizing the treatment for CVD-induced cognitive impairment

Coronary revascularization by coronary bypass graft (CABG) surgery remains among the most common interventional procedures in the United States. Recent trends demonstrate that many patients referred for CABG surgery harbor multiple comorbid conditions putting them at greater risk for congestive heart failure (CHF). On the other hand, as treatment strategies for cardiovascular disease (CVD) improve, more and more CVD patients are living longer only to develop CHF at a later time. The cumulative effect is that CHF has been steadily on the rise, increasing to 5-6 million Americans. Unfortunately, many prognostic models overlook the impact of CABG- and CHF-induced cognitive impairment on the clinical trajectory. Following CABG surgery, cognitive impairment is reported in 50-75% of patients at discharge, 20-50% at 6 weeks and up to 40% at five years {Epstein, 2011 #6608}. Similarly, recent studies have demonstrated that 30-80% of patients with CHF have some level of cognitive impairment. Simple tasks that involve reasoning or decision making such as remembering to take medications become labored and inconsistent. Further, post-CABG or CHF patients with cognitive impairment have hospital readmission rates ranging from 40 to 50% within 6 months, partly due to non-compliance with medical therapy. While the loss of cognitive function that occurs in CVD and following CABG surgery is recognized clinically, there are no therapies or strategies to prevent or even treat CVD- or CABG-induced cognitive impairment. We have developed novel therapeutics to reverse and prevent CVD-induced cognitive impairment.

Optimizing the repair and remodeling of the heart in Pre-clinical Models of Acute and Chronic Cardiac Injury

Over the last decade, strategies to utilize exogenously-delivered stem cells to regenerate damaged myocardium, such as following a heart attack, have transformational potential for cardiovascular therapeutics. However, despite promising preclinical trials, consistently low stem cell engraftment rates have limited treatment efficacy in clinical trials to date. New stem cell sources and/or approaches are required to facilitate stem cell therapy as a viable therapeutic intervention. My laboratory has embarked on very timely studies that for the first time test how combining the use of emerging novel cell sources (adipose-derived stem cells combined with its stromal vascular fraction) and human amniotic allografts to facilitate stem cell homing, engraftment, and differentiation for the regeneration of the myocardium. These studies are being conducted with Dr. Zain Khalpey, M.D., Ph.D., who is a member of the Department of Surgery allowing my laboratory to build direct translational relevance through simultaneous human and rodent studies and may lead to the immediate implementation of new clinical treatment options. Although these studies are natural extensions of on-going research and techniques in my laboratory, the introduction of alternative cell sources to the experimental setting represents a significant conceptual shift in our current laboratory focus.

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