Proposed mechanisms of relative bradycardia

Medical Hypotheses 119 (2018) 63–67 Contents lists available at ScienceDirect Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy Proposed mechanisms of relative bradycardia a b c d d d Fan Ye , David Winchester , Carolyn Stalvey , Michael Jansen , Arthur Lee , Matheen Khuddus , ⁎ Joseph Mazzae, Steven Yalef, T a Graduate Medical Education, University of Central Florida College of Medicine, 6850 Lake Nona Blvd, Orlando, FL 32827, United States Department of Cardiology, University of Florida, College of Medicine, Gainesville, FL 32610, United States Department of General Internal Medicine, University of Florida, College of Medicine, Gainesville, FL 32610, United States d The Cardiac and Vascular Institute, Gainesville, 4645 NW 8th Ave., Gainesville, FL 32605, United States e Marshfield Clinic Research Foundation, 1000 North Oak Avenue, Marshfield, WI 54449, United States f Department of Internal Medicine, University of Central Florida College of Medicine, 6850 Lake Nona Blvd, Orlando, FL 32827, United States b c A B S T R A C T Relative bradycardia is the term used to describe the mechanism where there is dissociation between pulse and temperature. This finding is important to recognize since it may provide further insights into the potential underlying causes of disease. There is no known proposed mechanism to explain this phenomenon. We hypothesize that relative bradycardia is the central mechanism reflecting and influenced potentially by the direct pathogenic effect on the sinoatrial node as well as cross-talk between the autonomic nervous system and immune system. Cardiac pacemaker cells may act as a target for inflammatory cytokines leading to alteration in heart rate dynamics or their responsiveness to neurotransmitters during systemic inflammation. These factors account for the important role of how the host response to infectious and non-infectious causes influences the appearance of relative bradycardia. We propose several methods that may be useful to confirm the proposed theoretical framework to further enhance our understanding of this paradoxical phenomenon. This includes measuring, during the episode of relative bradycardia, proinflammatory and anti-inflammatory cytokines, monitoring heart rate variability (HRV), and assessing underlying comorbidities and outcomes in patients with the same disease. Introduction Typically in response to infectious (e.g. legionelliosis) and some non-infectious (e.g. drug fever) conditions the pulse rate increases by 10 beats/min for each Fahrenheit degree increase in body temperature from 101 °F (38.3 °C) corresponding to a heart rate of 110 beats/min [1]. Failure of this phenomenon to occur or the dissociation between increase temperature and pulse is referred to as pulse-temperature dissociation or Faget sign [2]. The term “relative bradycardia” is used to describe the paradoxical relationship between pulse and temperature or the failure of the pulse to rise when the temperature exceeds 102 °F [1]. To the best of our knowledge, there is no known unified mechanism to explain relative bradycardia. Relative bradycardia has been most commonly described, although not exclusively seen, in infections caused by intracellular gram negative, non-enteric pathogens as well as certain viral and parasitic protozoan organisms. An intracellular pathogenetic effect does not appear to be sufficient by itself to explain relative bradycardia since it is also seen in patients with Leptospirosis, caused by the extracellular organism Leptospira, and is absent in Brucellosis, the intracellular gramnegative organism Brucella [1]. A variety of non-infectious causes for relative bradycardia have also been reported including lymphoma, ⁎ Corresponding author. E-mail address: steven.yale.md@gmail.com (S. Yale). https://doi.org/10.1016/j.mehy.2018.07.014 Received 16 April 2018; Accepted 14 July 2018 0306-9877/ © 2018 Elsevier Ltd. All rights reserved. factitious fever, drug fever, and central nervous system lesions; the mechanistic effect for this phenomenon has also not been previously accounted [1]. Relative bradycardia, regardless of its cause, is often poorly recognized, significantly underappreciated and underreported. The relative low prevalence of this sign may be due to the lack of a consistent case definition, lack of knowledge regarding its significance, timing of pulse and temperature recordings, and size of the studied population. When observed, this finding may provide important insights into the potential cause of disease. We postulate that HRV serves as a physiological predictor for relative bradycardia. Furthermore, we propose several potential pathways including autonomic nervous and immune mediated mechanisms that may account for the pathogenesis of relative bradycardia in non-physiological conditions. Heart rate variability HRV is a viable physiologic marker to predict relative bradycardia. HRV reflects the continuous oscillation of the RR intervals (beat-to-beat interval) around its mean value. It differs from heart rate, which is a measure of the number of heartbeats as determined by ventricular contraction per minute. Both are primarily determined based on Medical Hypotheses 119 (2018) 63–67 F. Ye et al. augmentation of sympathetic tone, by “decomplexification” or downregulating physiologic signals [22]. Further direct evidence to support a central mechanism is that bilateral microinjection of the doublestranded kB decoy DNA into rostral ventrolateral medulla (RVLM) 24 h before lipopolysaccharide (LPS) treatment significantly reverses sepsis induced complications including hypotension, bradycardia, and the decrease in the power density of vasomotor components [23,24]. Additionally, HRV exhibits a circadian variation under normal conditions [25,26]. It has been demonstrated that stress induces alterations in the homeostatic dynamics of the feedback structures that creates “uncoupling of biologic oscillations” and disrupts these regulatory structures [27]. In the HRV spectra, the high-frequency (HF) component is linked to respiration and is mediated predominantly by cardiac vagal activity, whereas the low-frequency (LF) component is mediated by sympathetic, parasympathetic, and renin–angiotensin system activity occurring in sepsis [28]. Several studies documented impaired sympatho-vagal balance with a low LF/HF ratio in septic patients [29,30]. Imbalance between LF and HF ratio represents progressive crossing of these “tipping points” which would lead to cascading systems failure and the clinical syndrome of sepsis [31]. These factors account for the important role of how the host response to infectious and non-infectious causes influences the appearance of relative bradycardia. modulation of sinus node activity by sympathetic and parasympathetic autonomic nerves. HRV and heart rate reflect different concepts and thus high or low heart rate variability may be found in cases of high or low heart rate. In healthy subjects, for example, there is a fluctuation of the heart rate with respiration or respiratory sinus arrhythmia, increases during inspiration and decreases during expiration with high and low heart rate variability occurring respectively [3]. HRV is affected by a number of acute and chronic pathologic conditions including congestive heart failure (CHF), coronary artery disease (CAD), diabetes, systemic infection, or neurologic diseases [4–7]. For example, following a myocardial infarction, low heart rate variability is associated with higher mortality [8]. Similarly, reduced sympathetically mediated heart rate variability in children recovering from cardiac surgery has been shown to predict a fatal outcome [9]. Therefore, reduction in HRV, a manifestation of altered autonomic function under stress, is useful in predicting disease progression and prognosis [10]. The loss of normal HRV is associated with more severe diseases and worse prognosis [11], while increased HRV is associated with increased probability of successful resuscitation [12]. One study found that a drop in HRV occurs in 25% of patients prior to clinical diagnosis and treatment of sepsis signifying that increased cardiac vagal activity and decreased sympathetic modulation precedes septic shock [13]. The sinoatrial node (SAN) is the dominant pacemaker in the mammalian heart. Biological clocks are the internal mechanisms that orchestrate the periodicity of heart rate and rhythm. ATP is consumed to maintain the basal spontaneous action potential firing rate. Generation and utilization of ATP is modulated via neurotransmitter release from the parasympathetic and sympathetic nerves to the SAN [14]. We propose that relative bradycardia, found in patients with specific diseases is a paradoxical phenomenon representing cross-talk between the autonomic nervous system and the immune system. Cardiac pacemaker cells may act as a target for inflammatory cytokines leading to alteration in heart rate dynamics or their responsiveness to neurotransmitters during systemic inflammation. Proposed mechanism II Immune system We postulate that the degree of alteration of consciousness is associated with the early occurrence of relative bradycardia and may be influenced by endotoxin/LPS and cytokines released by the pathogen and host respectively. Additionally, bacterial LPS have limited ability to pass the blood-brain barrier, so the central effects of LPS are likely mediated by cytokines. The immune response is affected by the activity of circulating immune cells including nature killer cells, T lymphocytes, and various inflammatory cytokines, influenced by input from parasympathetic and sympathetic systems, with cytokines modulating sympathetic and parasympathetic tone. For example, selective proinflammatory cytokines such as tumor necrosis factor (TNF) α, interleukin (IL)-1 and Il-6 may decrease vagal tone while conversely, stimulation of the afferent limb of the vagus nerve decreases levels of proinflammatory cytokines thereby modulating the host response to infection. Further support for this finding is based on the identification of elevated levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), Il-6 and TNF α in a patient with cyclic neutropenia presenting with relative bradycardia and periodic fever [32]. Upstream interactions leading to an accentuated vagal response is a proposed mechanism for the relative bradycardia observed in selected patients. Many cytokines including IL-10, IL-6, IL-8, IL-5, IL-2, IL-1α, IL-17, IL-4, IL-18, TNF-α, and GM-CSF levels are significantly increased during infection [33–35]. Furthermore, their levels likely correlate with specific clinical manifestations and illness severity [36]. Activating innate immune cells and stimulating pathways linked to the production of inflammatory genes such as the mitogen-activated protein kinase (MAPK), nuclear factor kappa light chain enhancer of activated B cells (NF-κB) and Janus kinase-signal transducers and activators of transcription JAK-STAT signaling pathways [37], is reflected in decreased HRV [16]. Suppression of cytokine production with dexamethasone resulted in resolution of abnormal HRV, and is explained by its ability to inhibit LPS-induced elevations in serum TNF-α and IL-6 [38–40]. These findings provide further support of the relationship between cytokines, immune cells and stimulating inflammatory pathways and paradoxical bradycardia measured by HRV. Herein, we proposed some of the most important central mediators potentially involved in relative bradycardia. Proposed mechanism I Autonomic nervous system We postulate that the disturbance in autonomic control of heart rate results from one or more of the following mechanisms including: 1) direct toxic effect of inflammatory factors upon peripheral nerves, 2) alterations in vasomotor activity within the central nervous system, and/or 3) impaired neuronal transmission to the heart or changes in end organ responsiveness caused by polyneuropathy. Interestingly, the very notion of sympathetic versus parasympathetic activation has been challenged, suggesting that the reduction in HRV during sepsis is ascribed to uncoupling of the autonomic and cardiovascular systems and may be helpful in early identification of paradoxical bradycardia [15,16]. This is supported by evidence that vagally mediated pathogen-induced bradycardia is an extension of the cholinergic anti-inflammatory reflex. The rapid onset of bradycardia suggests that pathogens exert a direct effect early on the nervous system, activating vagal sensory neurons either peripherally or within the ganglia via the cytokines or receptors, and later indirectly through cytokines or other secondary mediators [17–19]. This explanation may account for the finding that relative bradycardia may occur early or later in the infection or during the early convalescent period as described in cases of leptospirosis and typhoid fever or signifies delayed fever defervescence in the case of Q-fever or scrub or murine typhus [20]. Both central and peripheral neurological mechanisms maybe responsible for relative bradycardia in diseases. It has been suggested that failure of the core mechanisms that support homeostatic responses to stress, arousal, and vegetative functions is related to brain dysfunction in patients with sepsis [21]. Some mechanisms proposed involve 64 Medical Hypotheses 119 (2018) 63–67 F. Ye et al. Interleukin-6 (IL-6) Among cytokines, IL-6 exhibited the strongest correlation with the indexes of depressed HRV in a variety of clinical conditions with systemic inflammation [64], including congestive heart failure [65], diabetes [66], or sepsis [67]. In experimental sepsis in both animal models and healthy human volunteers, dexamethasone resulted in a dramatic increase in HRV lasting more than 12 h by inhibiting IL-6 production. Lipopolysaccharide (LPS, also called endotoxin) Sepsis is closely linked with slow heart rate as a major determinant of decreased HRV in animal models and in humans of all ages. LPS liberated from the outer walls of gram-negative bacteria results in an inflammatory response causing activation of baroreceptor reflexes, increased vagal activity and reduced chronotropic activity, factors that contribute to early onset of bradycardia in sepsis [16]. Administration of endotoxin in animal studies results in hypotension and bradycardia [40]. In human, endotoxin administration causes systemic inflammation including the release of a variety of mediators (e.g. pro-inflammatory cytokines, cortisol, or catecholamines) reducing the responsiveness of sinoatrial node cells to vagal stimuli [41]. In both human and animal studies a significant decrease in HRV concurrent with other symptoms of illness, such as fever, tachypnea, tachycardia, and hypotension is seen [42]. It is of interest that, endotoxin-induced bradycardia is absent in cats treated with meclofenamate, a nonsteroidal anti-inflammatory drug [43]. Hydrocortisone although reduced LPS-induced inflammatory cytokine levels [44–46], did not influence the LPS-induced decrease in HRV [44,45]. Similarly, dexamethasone blunted but did not block LPS-stimulated cytokine production and similarly shortened but did not eliminate LPS-induced severe systemic inflammation symptoms including pulmonary edema, reduced cardiac performance and bradycardia [47]. Endotoxin interacts with cardiac pacemaker cells through cytokines enhancing acetylcholine (Ach) and impairing norepinephrine (NE) release [48]; activating and sensitizing cardiac hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels, which plays an important role in transmitting sympathetic and vagal signals on heart rate and HRV [49]. Chronic endotoxin exposure also uncouples toll-like receptor 4 (TLR4) receptors from its down-stream signaling component such as MyD88 [50,51], IL-6, IL-10 and IL-1 receptor antagonist, however, the level of transforming growth factor beta (TGF-β) remains elevated during the course of endotoxin tolerance in humans [52]. It is reported that neutralizing antibodies to TGF-β could block LPS-induced endotoxin tolerance in mice [46]. Endothelin-1 (ET-1) ET-1 is a potent endogenous vasoconstrictor, primarily secreted by endothelial cells. It has been shown that infusion of ET-1 exhibited significant negative correlations with the low-frequency power HRV index while administration of ET-1 receptor antagonist ameliorates heart rate variation and improves hemodynamics [68–70]. NADPH oxidase 1 (NoX1) Nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase is a superoxide-generating enzyme comprising multiple subunits. Though marginal levels of Nox1 are detected in cardiomyocytes, a marked elevation occurs after LPS induced sepsis in mice. LPS induced deficiency of Nox1 leads to sinus node dysfunction during hypoxia in part through dysregulation of coronary artery vasomotor tone [71]. Measurement of TNF, Il-6 and ET-1 levels along with other cytokine in gram-negative infection with and without relative bradycardia may provide further insights into the role that these cytokines play on modulating heart rate in humans. Summary Early onset of bradycardia as a major determinant of diminished HRV has been observed in multiple studies of sepsis patients, supporting the hypothesis that major changes in HR are driven by neurohumoral regulation. The mechanisms that have been proposed for relative bradycardia include an imbalance in sympathovagal activation and/or abnormal baroreflex function; however, the mechanism by which systemic inflammation induces regularization of relative bradycardia is unclear. It can be proposed that bradycardia with decreased HRV in sepsis is characterized by high concentrations of circulating catecholamines and impaired sympathetic modulation on cardiovascular system. The presence of circulation cytokines interferes with signal transduction and modulates autonomic activity via sensory feedback, and ponto-sensory interactions, resulting in increased vagal tone and further result in reduced sympathovagal balance Fig. 1. It is difficult to single out any one of these factors as being solely responsible for changes in relative bradycardia in pathological conditions. Prognosis is equally difficult to predict and treatments must be selected carefully. Nitric oxide (NO) In the cardiovascular system, NO-induced cyclic guanosine monophosphate (cGMP) accumulation contributes to vascular hypo-reactivity and the relaxation of vascular smooth muscle cells and myocytes, leading to reduced heart rate [53,54]. Systemic injection with various synthetic Toll-like receptor (TLR)-2 TLR3, or TLR9 causes endogenous inducible nitric oxide synthase (iNOS) and systemic NO induction, identical to that of LPS or TNFs, contributing significantly to the vascular hyporeactivity characteristic of endotoxic shock [55,56]. Extensive studies have demonstrated that many inflammatory cytokines exert their adverse effects via activation of NO production. Activations of iNOS results in an increase in NO that mediates many aspects of the cardiovascular abnormalities occurring during septic shock [57,58], such as shortening of the duration of the action potential in the heart (presumably through a cGMP-dependent pathway), resulting in the electrical instability [24]. Excessive NO may also indirectly reduce heart rate in endotoxaemic conditions by inhibiting both the release and the biological activity [59]. Therefore, NO signaling might act as compensatory mechanism to prevent uncoupling of cardiac pacemaker cells from cholinergic control. Future research direction Since an imbalance in the host-pathogen cytokine interaction and response may account for relative bradycardia, measurement of proinflammatory and anti-inflammatory cytokines and ratios during episodes of relative bradycardia may further clarify their role in this process. Commercially available equipment is available to monitor during hospitalization heart rate and its variability and to correlate those findings to concurrent temperature. Identification of early onset bradycardia and decreased HRV would provide further evidence of the role that the parasympathetic nervous system plays in those conditions associated with relative bradycardia. Of further interest for future studies is to compare HRV among patients with similar infectious (e.g. Legionella) organism to determine the relationship between relative Tumor necrosis factors (TNFs) It has been demonstrated that TNFs exerts its deleterious effects via soluble guanylate cyclase (sGC) activation, which induces severe bradycardia and profound hypotension in 50% of cases [60]. Pre-treatment with methylene blue, an inhibitor of sGC activations, prevents TNFsinduced bradycardia, hypotension and mortality [60–63]. 65 Medical Hypotheses 119 (2018) 63–67 F. Ye et al. Fig. 1. bradycardia and outcomes. 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