Genito-Thyroid Index : A Global Systems Approach to the Neutrophil-to-Lymphocyte Ratio According to the Theory of Endobiogeny Applied to Ambulatory Patients with Chronic Heart Failure

Background: Chronic heart failure (CHF) is an inflammatory disorder. Elevated Neutrophil-to-Lymphocyte ratio (NLR) is associated with inflammation and increased morbidity and mortality in various disorders including CHF. NLR is a non-specific, quantitative biomarker assessment. It does not allow for a personalized approach to treatment. A global systems approach to biomarker assessment is quantitative and qualitative, contextualizing basic data into larger sets of meaning. Such a system may provide greater meaning to the NLR, increasing its clinical utility in CHF. Endobiogeny is a global systems theory. It claims to be able to model complex physiology through biomarkers, offering context-rich interpretations of data for meaningful clinical applicability. In Endobiogeny, NLR is referred to as the Genito-Thyroid index (GT). Aim: The NLR has never been studied in ambulatory CHF patients. The first aim of this study was to determine if NLR is elevated for ambulatory CHF patients versus controls. The second was to determine if the endobiogenic interpretation of the NLR as the GT index is consistent with current pathophysiologic models. Methods: A retrospective observational case-controlled study was performed in 93 patients with New York Heart Association class II-III heart failure patients and 104 individuals with no cardiovascular pathology as a control group. Two biomarkers, percent neutrophils and percent lymphocytes, were entered into the Biology of Functions modeling software, from which a direct index was produced to model an aspect of the heart failure terrain. All calculations were performed using SPSS Inc. (version 22.0) and analyzed by univariate or multivariate analysis of covariance. Results: NLR or, GT index (normal 1.5-2.5) was elevated in CHF patients vs. control (2.81 vs 2.01, p<0.001). Conclusions: NLR, or, GT index, when elevated reflects a hyperimmune response to an aggression. CHF is associated with elevated immune activity. Ambulatory CHF patients show signs of a hyperimmune response even when clinically stable. The endobiogenic explanation of the NLR is consistent with current pathophysiological models of CHF. Future studies should explore if a certain cutoff value of the GT index is predictive of future deterioration in CHF patients. Future studies should evaluate other endobiogenic indexes for their clinical relevance in CHF. Central Bringing Excellence in Open Access   Hedayats et al. (2017) Email: 2/6 J Cardiol Clin Res 5(1): 1091 (2017) ABBREVIATIONS CHF: Chronic Heart Failure; NLR: Neutrophil-to-Lymphocyte Ratio; GT: Genito-Thyroid; BOF: Biology of Functions INTRODUCTION The neutrophil-to-lymphocyte ratio (NLR) has been widely studied. Elevated NLR is believed to reflect a systemic inflammatory terrain, and correlated with increased morbidity and mortality. It is inexpensive and often performed but remains infrequently used in clinical practice due to lack of specificity. If there were a way to reinterpret the NLR as a more precise expression of physiologic activity, it may have a greater value in clinical practice. Biomarkers are evaluated independent of each other, infrequently contextualized to the etiologic or compensatory mechanisms within the patient. Direct ratios are an attempt to contextualize two or more pieces of data in a qualitative way: one level of activity relative to another. The NRL is one example: %Neutrophils ÷ %Lymphocytes. Other examples include hematocrit (red blood cells/hemoglobin) and the blood urea nitrogen/creatinine ratio. This approach contextualizes two or more levels of function but doesn’t address etiological or teleological concerns such as “what caused it to appear? ” and, “what is the clinical implication? ”. Systems theory seeks to answer these questions by introducing the concept of upstream regulators and downstream output. In a case such as the NLR, the neutrophils and lymphocytes are downstream output from bone marrow. The question then becomes: “What are the upstream factors that influenced the production or mobilization of these factors? ” and, “If NLR reflects systemic inflammation, what are the factors that augment or diminish this tendency? ” Answering these questions would open a new level of understanding of cause and effect and beyond mechanisms of action for all biomarkers, including the NLR. Endobiogeny is a global systems theory rooted in clinical practice. It claims to assess human physiology in a manner that contextualizes upstream and downstream events. The theory of endobiogeny considers the neuroendocrine system as the manager of metabolism, thus, the manager of the global terrain [1]. Biomarkers are considered the downstream metabolic output of tissues that were regulated upstream by neuroendocrine factors. From the theory of endobiogeny, a series of direct and indirect ratios of biomarkers have been developed called the Biology of Functions (BoF), [2] discussed in detail elsewhere [2]. In the BoF, the NLR is referred to as the Genito-thyroid ratio (GT) for reasons discussed below. For the remainder of the article, the NLR will be referred to in both ways: NLR (GT). We hypothesized that in ambulatory patients with chronic heart failure (CHF), NLR (GT) would be elevated versus control subjects, reflecting the inflammatory terrain of CHF patients. A secondary hypothesis was that the theory of Endobiogeny could contextualize the NLR (GT) values in CHF patients based on currently accepted notions of the CHF terrain. METHODS Study Participants A retrospective observational case-controlled study was performed. The study sample consisted of 93 patients diagnosed with New York Heart Association (NYHA) classes II through III heart failure and 104 individuals with no cardiovascular pathology as a control group. Patients were recruited from the San Diego Veterans Affairs Medical Center Cardiology Clinic and the University of California, San Diego (UCSD) Medical Center Advanced Heart Failure Program as part of a larger study on the effects of depression on cellular adhesion and inflammation in HF. We included the non-CHF control sample from the local community via advertisements (e.g., newspapers, flyers, brochures, and websites) and word of mouth referrals. Inclusion criteria for all study participants were age between 30 and 85 years. Additional inclusion criteria for CHF patients included symptoms of CHF for at least 3 months that had been optimally treated with beta blockers, diuretics, and Angiotensinconverting enzyme (ACE) inhibitors. Left ventricular ejection fraction (LVEF) was assessed by echocardiography as part of the patient’s routine medical evaluation. Exclusion criteria included recent myocardial infarction (1 month), recent stroke or significant cerebral neurological impairment, severe chronic obstructive pulmonary disease, and psychiatric illness other than depression and co-morbid anxiety. Subjects were instructed to abstain from taking aspirin for 24 hours prior to the testing session. The investigation conformed to the principles outlined in the Declaration of Helsinki. The University of California, San Diego Institutional Review Board, approved the study. All subjects gave informed written consent. Biochemical Analyses Blood was drawn into ethylendiaminetetra acetic acid (EDTA)-coated vacutainer tubes (BD Biosciences, San Jose, California) for complete blood count with differential and platelets, which was determined at the Clinical Laboratory at the UCSD Medical Center. Statistical Analyses All calculations were performed using SPSS Inc. (version22.0) software package (SPSS, Chicago, Illinois). Data are presented as mean ± SEM or ± SD. Results were considered statistically significant at the p ≤ . 05 level and tests were either univariate or multivariate analysis of covariance (ANCOVA). In both groups, normal distribution of data was verified prior to statistical analyses using the Kolmogorov-Smirnov test. We calculated mean arterial pressure (MAP) from resting BP readings (1/3 systolic BP + 2/3 diastolic BP) and body mass index (BMI) was calculated by the formula weight in kg/ (height in m2).