Reflex Regulation of Cardio-Renal Physiology in Heart Failure
In a broad sense, my laboratory focuses on reflex regulation of the autonomic nervous system and cardiorespiratory function in health and disease. My recent work has explored the contribution of aberrant cardiovascular reflex function (specifically the carotid body chemoreflex, CBC) to autonomic dysregulation and disordered breathing patterns in heart failure with reduced ejection fraction (HFREF). Currently, we are focused on determining the role of hyperactive CBC function in renal injury, declines in renal function, and increases in sodium and water retention in HFREF.
Significant declines in renal function in the setting of HFREF are commonly referred to as the ‘Cardio-Renal syndrome’ (CRS). This general term refers to a positive feedback loop between the heart and kidneys in which dysfunction in one organ precipitates or exacerbates dysfunction in the other. A significant proportion of patients with HFREF (30-40%) develop co-morbid renal dysfunction, or type II CRS. CRS has become an area of intense interest due to the complexity of therapeutic management and associated morbidity and mortality.
Identifying the key determinants of type II CRS is complicated by the fact that some HFREF patients also experience obstructive and central apneas during sleep. Sleep apnea is independently associated with enhanced CBC function and sympathetic activation, and sleep apnea severity is positively correlated with markers of renal damage. Thus, intermittent hypoxemia associated with sleep apnea may contribute to development of CRS in HFREF patients. To further explore this association, my lab is examining the interaction of intermittent hypoxemia and HFREF, to determine if this hypoxemia further exacerbates the effects of enhanced CBC sensitivity on HFREF and renal dysfunction.
To address these questions, surgical, genetic, and pharmacological interventions are employed in my laboratory to determine how enhanced neural stimulation of the kidney, reduced kidney perfusion, and hypoxemia may injure kidney tissue and bring about the development of fibrosis and subsequent renal dysfunction (see schematic). Conventional CHF therapy is of limited utility in patients with type II CRS, and renal dysfunction is a prominent independent risk factor for all-cause mortality in HFREF patients. Thus, these studies represent an important step toward understanding the pathophysiology and progression of type II CRS in HFREF. These studies are currently supported by a grant from the National Institute of Health (1 R15 HL-138600-01).
The projects described above provide an excellent opportunity for graduate and undergraduate students to engage in a robust program of physiology research that requires developing expertise in cardiovascular, renal, and autonomic function. The nature of this project makes it well suited to the biomedical sciences research initiative at Des Moines University and we invite inquiries from qualified undergraduate, graduate, and professional students who are interested in gaining research experience. Interested students should email a letter of introduction and a resume/c.v. to Dr. Marcus (firstname.lastname@example.org).
Marcus NJ, Del Rio R, Ding Y, Schultz HD. KLF2 mediates enhanced chemoreflex sensitivity, disordered breathing and autonomic dysregulation in heart failure. J Physiol. 2017 Sep 6. [Epub ahead of print]
Marcus NJ. Aberrant reflex mechanisms contributing to reno-vascular hypertension: a pain in the neck? J Physiol. 2016 Nov 1;594(21):6075-6076.
Marcus NJ, Pügge C, Mediratta JK, Schiller AM, Del Rio R, Zucker IH, Schultz HD. Exercise Training Attenuates Chemoreflex-Mediated Reductions of Renal Blood Flow in Heart Failure. Am J Physiol Heart Circ Physiol. 2015 Jul 15;309(2):H259-66.
Marcus NJ, Del Rio R, Schultz HD. Central Role of Carotid Body Chemoreceptors in Disordered Breathing and Cardiorenal Dysfunction in Chronic Heart Failure. Front Physiol. 2014 Nov 24; 5:438.
Marcus NJ, Del Rio R, Schultz EP, Xia X-H, Schultz HD, Carotid Body Denervation Improves Autonomic and Cardiac Function and Attenuates Disordered Breathing Patterns in Congestive Heart Failure. J Physiol. 2014; 592(pt 2):391-408.
*Haack KKV, *Marcus NJ, *Del Rio R, Zucker IH, and HD Schultz. Simvastatin Treatment Attenuates Increased Respiratory Variability and Apnea/Hypopnea Index in Rats with Chronic Heart Failure. Hypertension 2014; 63(5):1041-9.
Del Rio R, Marcus NJ, Schultz HD. Carotid Chemoreceptor Ablation Improves Survival in Heart Failure, Rescuing Autonomic Control of Cardiorespiratory Function. JACC. 2013 62(25): 2013;