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Biomedical subjects

Kimberly A Bazar

Publications and source records attributed to Kimberly A Bazar.

At least 19 recordsLinked to original sources
PubMed2006

Obesity and ADHD may represent different manifestations of a common environmental oversampling syndrome: a model for revealing mechanistic overlap among cognitive, metabolic, and inflammatory disorders.

Obesity and attention-deficit hyperactivity disorder (ADHD) are both increasing in prevalence. Childhood exposure to television has shown linkage to both ADHD and obesity with the former ascribed to dysfunctional cognitive hyperstimulation and the latter to altered patterns of diet and exercise. Empirical evidence has contradicted prior presumptions that the hyperactivity of ADHD would decrease the risk of obesity. Instead, obesity and ADHD demonstrate significant comorbidity. We propose that obesity and ADHD represent different manifestations of the same underlying dysfunction, a phenomenon we term environmental oversampling syndrome. Oversupply of information in the form of nutritional content and sensory content may independently predispose to both obesity and ADHD. Moreover, the pathogenic mechanisms of these conditions may overlap such that nutritional excess contributes to ADHD and cognitive hyperstimulation contributes to obesity. The overlapping effects of medications provide further evidence towards the existence of shared etiologic pathways. Metabolism and cognition may represent parallel systems of intelligence, and oversampling of content may constitute the source of parallel dysfunctions. The emerging association between psychiatric and metabolic disorders suggests a fundamental biologic link between these two systems. In addition, the immune system may represent yet another form of intelligence. The designation of syndrome X subsumes seemingly unrelated metabolic and inflammatory entities. Environmental oversampling syndrome may represent an even more inclusive concept that encompasses various metabolic, inflammatory, and behavioral conditions. Apparently disparate conditions such as insulin resistance, diabetes, hypertension, syndrome X, obesity, ADHD, depression, psychosis, sleep apnea, inflammation, autism, and schizophrenia may operate through common pathways, and treatments used exclusively for one of these conditions may prove beneficial for the others.

Attention Deficit Disorder with Hyperactivity↗
PubMed2006

A new wrinkle: skin manifestations of aging may relate to autonomic dysfunction.

Various mechanisms have been argued for skin wrinkling, one of the hallmarks of aging. We hypothesize that chronic sympathetic bias is a previously unrecognized mechanism for wrinkling. In the acute setting of water immersion, reversible skin wrinkling is a well-known reflex mediated by the autonomic nervous system. We postulate that skin wrinkling results as a local maladaptive manifestation of a global chronic sympathetic bias that emerges during aging. The persistence of such changes may induce additional compensatory remodeling to cause permanent alteration of the skin. Sympatholytic agents may prove beneficial for arresting or ameliorating the development of wrinkles. Conditions that amplify sympathetic bias such as stress, smoking, amphetamine abuse, HIV, heart failure, and transplantation may accelerate wrinkling. Other common diseases of the skin may also arise as particular manifestations of aberrant autonomic activity through induction of vascular and immune dysfunctions. The temporal and spatial distribution of these dermatologic conditions may reflect variation of autonomic balance, which also regulates T helper immune balance. For all of these dermatologic conditions, local and systemic administration of drugs and medical devices that pharmacologically or electrically modulate autonomic nervous system activity may yield benefits as well.

Aging↗
PubMed2005

The dynamic range of biologic functions and variation of many environmental cues may be declining in the modern age: implications for diseases and therapeutics.

We hypothesize that declining dynamic range and variation of environmental cues may contribute to health dysfunctions, and that judicious expansion of biologic dynamic ranges may be beneficial. Three disparate examples involving the endocrine, autonomic, and musculoskeletal systems are discussed. Daytime sheltering, optical shading, and nighttime use of artificial light may reduce circadian luminal variation. The resulting melatonin alterations may contribute to systemic dysfunctions. Loss of temporal variation of other hormones may contribute to biologic dysfunctions, especially those involving the hypothalamic-pituitary axis. Reduced variation of physical exertion, environmental stressors, and thermal gradients that characterize modern lifestyles may reduce the autonomic dynamic range resulting in lowered heart rate variability and a myriad of systemic dysfunctions. The health benefits of activities such as exercise, meditation, acupuncture, coitus, and laughter may operate through increasing autonomic variability. Reduced physical exertion also accounts for declining dynamic range of musculoskeletal function. The resulting muscle atrophy, fat infiltration, and sarcomere shortening may not only have deleterious local effects, but may also be involved in systemic metabolic dysfunctions such as insulin resistance. The extent to which our endogenous systems rely on environmental variation for self-tuning and the impact that under-utilization of compensatory mechanisms has on biologic function are not well understood. Modern therapeutic approaches generally result in reversion to the mean of physiologic functions and may buffer against variation. For example, beta-blockers are given to reduce adrenergic excess, insulin to treat insulin insufficiency, serotonin-reuptake inhibitors for depression, and refractive lenses for myopia. By undermining the demand for native compensatory functions, such therapeutic strategies may actually impair future ability to respond to biologic disequilibria. Generalizing from these observations, we anticipate benefits of therapeutic and lifestyle approaches that expand, rather than reduce, the dynamic range of many biologic experiences.

Animals↗
PubMed2005

"Starve a fever and feed a cold": feeding and anorexia may be adaptive behavioral modulators of autonomic and T helper balance.

Anorexia is a common symptom accompanying infections, but the teleology of the phenomenon remains unexplained. We hypothesize that anorexia may represent a prehistoric behavioral adaptation to fight infection by maintaining T helper (Th)2 bias, which is particularly vital in fighting bacterial pathogens. Specifically, we propose that anorexia may avert the reduction of Th2/Th1 ratio by preventing feeding-induced neurohormonal and vagal output from the gut. Emerging evidence suggests that the vagal and neurohormonal output of the gut during feeding promotes Th1 function, which is desirable in fighting viral infections. Since fever may be an adaptation to fight bacteria and "colds" are generally viral in origin, the adage "starve a fever and feed a cold" may reflect a sensible behavioral strategy to tilt autonomic and Th balance in directions that are optimal for fighting the particular type of infection. The ability to modulate T helper balance through the neurohormonal and autonomic axis by adjusting food intake may be the mechanism behind other unexplained clinical observations such as the improved outcomes of ICU patients after enteric versus parenteric feedings. Compared to the prehistoric period when bacterial infection was commonplace, the anorexic response may be less adaptive today when viruses and cancers have become common triggers of anorexia. By promoting host anorexia, cachexia, and insomnia, cancers and viruses can deter behaviors such as digestion and sleep that would raise vagal and Th1 activity against tumors and viruses. Hydration and sleep, unexplained but widely accepted recommendations for flu patients, may also work by promoting vagal and Th1 functions. Modulating feeding, hydration, and sleep may prove beneficial in treating other conditions associated with abnormal autonomic and Th balance.

Adaptation, Physiological↗
PubMed2005

A new mechanism for diverticular diseases: aging-related vagal withdrawal.

It is widely believed that diverticulosis, a common condition among the elderly, results from repeated colonic barotrauma related to low dietary fiber and low stool bulk. Recent evidence has challenged the dietary-barotrauma hypothesis. We propose an alternative hypothesis that diverticulosis may be attributable to colonic smooth muscle dysfunction that results from vagal attrition associated with aging. We previously proposed that broad aging-related attrition of autonomic nerves may unmask intrinsic sympathetic bias of end-organs, leading to the compendium of familiar conditions associated with senility. Unexplained cholinergic hypersensitivity and receptor over-expression in bowel affected by diverticulosis have recently been observed. These findings are highly suggestive of a compensatory response to loss of vagal innervation. The resulting autonomic dysregulation may induce bowel smooth muscle dysfunction, setting the stage for diverticula formation. Thus, diverticular bowel disease may be a manifestation of the aging-related systemic vagal withdrawal. The framework may extend to diverticula formation in other parts of the gastrointestinal and genitourinary tracts. For instance, aging-related vagal attrition may represent the common upstream mechanism that induces both sphincter of Oddi dysfunction and peri-ampullary duodenal diverticula, conditions that frequently occur together. Novel approaches to preventing and treating diverticular diseases by promoting vagal activity are proposed including the electrical or pharmacologic modulation of the autonomic system.

Aging↗
PubMed2005

Clinical benefits of hydration and volume expansion in a wide range of illnesses may be attributable to reduction of sympatho-vagal ratio.

Hydration and volume expansion regimens are widely thought to offer symptomatic benefit in many human ailments. Many varied theories for the phenomenon exists such as decreased blood viscocity in cardiac disease, dilution of toxins in cancer, and cleansing effect on airways in asthma. While it is plausible that disparate mechanisms are involved in different conditions, we propose an alternative, unifying hypothesis that many of the clinical benefits of hydration and volume expansion are partly related to reduced sympatho-vagal ratio. Hypovolemia triggers baroreceptor-mediated sympathetic response and neurohormonal activation to promote fluid retention. Emerging evidence suggests that many diseases including cardiovascular, neurologic, gastrointestinal, metabolic, inflammatory, thrombotic, viral, and oncologic conditions are manifestations of abnormal sympathetic bias and associated T helper 2 bias. Hypovolemia-induced sympathetic activation, especially if baroreceptor dysfunction is involved, can worsen these conditions. Hydration and volume expansion may lower sympatho-vagal ratio, thereby tempering a wide variety of clinical conditions linked directly or indirectly to adrenergia including, but not limited to, acute coronary syndromes, asthma, cancer, and stroke. Interestingly, isotonic or hypertonic hydration, rather than a low-salt diet, may be a counterintuitive potential strategy to treat some cases of hypertension associated with dehydration and autonomic dysfunction. In contrast to the putative causal relationship between them, perhaps hypertension and end-organ damage represent independent consequences of dysfunctional sympathetic and neurohormonal activation. Venipuncture enables faster volume expansion but may also be a source of sympathetic hyperactivity. Oral hydration may additionally promote vagal tone by triggering gastric distension, a benefit not offered by intravenous fluids. The empiric benefits of hydration and volume expansion portend novel methods to treat a wide range of clinical conditions through pharmacologic or electrical modulation of cardiovascular or gastrointestinal baroreceptors.

Asthma↗
PubMed2005

Can thromboembolism be the result, rather than the inciting cause, of acute vascular events such as stroke, pulmonary embolism, mesenteric ischemia, and venous thrombosis?: a maladaptation of the prehistoric trauma response.

Thromboembolism is considered the inciting cause of many vascular disorders including acute coronary syndrome (ACS), ischemic stroke, pulmonary embolism (PE), deep vein thrombosis (DVT), and mesenteric ischemia. Adrenergia and inflammation are known to accompany these conditions, particularly among arterial thromboembolic disorders, but the teleologic basis of these associations remains poorly understood. We argue that thromboembolism may sometimes be the result, rather than the cause, of acute vascular events, and may be precipitated by underlying adrenergia. Thromboembolic events are most prone to occur during parts of the circadian, seasonal, lifespan, and reproductive cycles with sympathetic dominance, as well as during behavioral, exertional, physiologic, and iatrogenic activation of sympathetic stress. Molecular evidence suggests that adrenergia and inflammation can promote coagulation and lead to co-activation of the pathways. Acute vascular events that occur without angiographic evidence of occlusion suggest that some infarcts may be attributable to adrenergia alone. "Embolic" disorders may represent asynchronous systemic phenomena rather than clot migration. During acute thromboembolism, downstream tissue hypoxia can activate maladaptive self-propelling cycles of sympathetic bias, inflammation, and coagulation. The counterproductive co-activation of these pathways may reflect a maladaptive interlink forged during the primordial evolution of trauma physiology. Their rapid co-mobilization enables rapid control of hemorrhage, microbial defense, and perfusion maintenance during trauma, but the pathways may behave maladaptively in the setting of modern diseases where endothelial injury may be more often precipitated by smoking, diabetes, dyslipidemia, or hypertension. Sympathetic blockade is already employed in ACS, and beta-blockers are used as antihypertensives to prevent stroke. Our hypothesis suggests that the benefits of beta-blockers in stroke may be independent of antihypertensive effects, and that adrenergia may represent a target for managing all thromboembolic disorders, independent of anti-coagulative and thrombolytic therapies. Perhaps reducing adrenergia, rather than maintaining high cerebral perfusion pressure, may represent a counterintuitive strategy for treating stroke and for reducing reperfusion injury. Plausible mechanisms by which autonomic dysfunction may induce venous thrombosis are discussed, especially in those with baroreceptor dysfunction, immobilization, or dehydration. Unexplained hypercoagulability of cancer may also operate through tumor-induced adrenergia and inflammation.

Humans↗
PubMed2005

Paradoxical strategy for treating chronic diseases where the therapeutic effect is derived from compensatory response rather than drug effect.

Reversing chronic conditions remains an elusive goal of medicine. The modern medical paradigm based on blocking overactive pathways or augmenting deficient pathways offers symptomatic benefit, but tolerance to therapy can develop and treatment cessation can produce rebound symptoms due to compensatory mechanisms. We propose a paradoxical strategy for treating chronic conditions based on harnessing compensatory mechanisms for therapeutic benefit. Many current drugs may be repurposed for a paradoxical indication where the therapeutic effect is derived from compensatory response, rather than drug effect. For example, although exercise is associated with acute adrenergia, paradoxical downregulation of baseline sympathovagal ratio occurs as a remodeling response. For conditions that manifest chronic sympathetic bias such as cardiovascular diseases, judicious administration of adrenergic agonists may induce compensatory downregulation of baseline sympathovagal ratio. The concept may generalize to many other diseases, especially those involving pathways which exhibit strong homeostatic tendencies such as the neurologic, immune, and endocrine systems. Careful consideration of chronobiologic features is necessary to optimize dosing strategies for modulating compensatory responses, and eccentric dosing schedules, shorter-acting formulations, or pulsatile delivery may be desirable in some cases. To what extent the effect of desensitization to current therapy is mistaken for disease progression in conditions such as diabetes, myopia, depression, and hypertension warrants investigation. The merits of combining behavioral and drug therapies such as diet-insulin therapy for diabetes and exercise-beta-blockade for cardiovascular disease should be revisited since there is a risk for exacerbating the underlying dysfunction. The reduced dynamic range of various environmental experiences and the tendency to revert to the mean through medical intervention, thermoregulation, and other modern lifestyle changes may play under-recognized roles in human diseases. Perhaps alternating agonists and antagonist may exercise the entire dynamic range of pathways and improve health.

Adrenergic Agonists↗
PubMed2005

The smoking gun: many conditions associated with tobacco exposure may be attributable to paradoxical compensatory autonomic responses to nicotine.

Tobacco exposure is implicated in many illnesses such as cardiovascular disease and cancer, but the mechanisms underlying these associations are poorly understood. The mechanisms by which tobacco induces pro-sympathetic and pro-inflammatory changes also remain elusive. Some studies have attributed these changes to the direct effects of nicotine, but such findings run counter to the pro-vagal, anti-inflammatory nature of the nicotinic pathway. We hypothesize that the illnesses associated with smoking may be partly attributable to autonomic dysfunction, sympathetic bias, and T helper (Th)2 inflammation induced by a paradoxical compensatory response to intermittent nicotinic exposure. The confusion of interpreting the adrenergia and inflammation associated with nicotine as a primary response instead of a secondary compensation may be explained by the unusually rapid absorption, action, and serum elimination of nicotine. Given the fast action and clearance of nicotine, even heavy smokers spend large portions of the day and the entire night in nicotine withdrawal, at which time rebound sympathetic bias may manifest as a result of desensitization of nicotinic receptors. This may help reconcile why the features observed in smokers such as tachycardia, hypertension, inflammation, insomnia, and anxiety, which are perhaps mistakenly attributed to the direct action of nicotine, are identical to those seen during acute nicotine withdrawal after smoking cessation. On the other hand, delayed responses to cessation of smoking such as weight gain and increased heart rate variability are compatible with reduced sympathovagal ratio and resensitization of nicotinic receptors. Sympathetic bias and the associated Th2 inflammation underlie many systemic diseases. Tobacco-related cancers may be partly attributable to immunomodulatory properties of chronic nicotine exposure by dampening Th1 immunity and enabling tumoral evasion of immune surveillance. Other conditions associated with tobacco exposure may also operate through similar autonomic and immune dysfunctions. Therapeutic implications are discussed.

Anxiety↗
PubMed2005

Can chronic use of anti-inflammatory agents paradoxically promote chronic inflammation through compensatory host response?

A higher relative risk of thrombotic cardiovascular complications has recently emerged in studies evaluating the use of non-steroidal anti-inflammatory drugs (NSAIDs) such as rofecoxib, celecoxib, and naproxen. Direct pro-thrombotic effects of selective cyclooxygenase-2 inhibition were originally speculated to be the potential mechanism behind these results, but this proposal fails to explain the pro-thrombotic effects of non-selective NSAIDs. We hypothesize that the paradoxical pro-inflammatory, pro-thrombotic effects associated with chronic use of anti-inflammatory agents are attributable to compensatory host response rather than direct effects of the drugs. Chronic pharmacologic inhibition of inflammation may induce physiologic dependence, and cessation of therapy has been shown to produce rebound effects in aspirin, statins, and other immunomodulatory agents. By down-regulating inflammatory pathways in a pulsatile fashion, chronic use of NSAIDs may promote compensatory up-regulation of these same pathways and shift the host baseline equilibrium towards an inflammatory state. The host may be susceptible to inflammation between intermittent doses and after withdrawal of therapy. Inflammation is a promoter of adrenergia and thrombosis, and the constellation of these effects may predispose to excess risk of acute cardiovascular events.

Animals↗
PubMed2005

The incorporation of iodine in thyroid hormone may stem from its role as a prehistoric signal of ecologic opportunity: an evolutionary perspective and implications for modern diseases.

To optimize fitness under conditions of varying Darwinian opportunity, organisms demonstrate tremendous plasticity in their life-history strategies based on their perception of available resources. Higher-energy environments generally promote more aggressive life-history strategies, such as faster growth, larger adult size, greater genetic variation, shorter lifespan, larger brood sizes, and offspring ratio skewed towards the larger-sized gender. While numerous mechanisms regulate life-history plasticity including genetic imprinting, methylation, and growth factors, evidence suggests that thyroid hormone plays a central role. Given the pivotal adaptive role of thyroid hormone, the teleology of its dependence on dietary iodine for production remains unexplained. We hypothesize that iodine may have emerged as a substrate for production of thyroid hormone in prehistoric ecosystems because the former represented a reliable proxy for ecologic potential that enabled the latter to modulate growth, reproduction, metabolic rate, and lifespan. Such a scenario may have existed in early marine ecosystems where ocean-surface vegetation, which concentrates iodine for its antimicrobial and antioxidant properties, formed the basis of the food chain. Teleologic parallels can be drawn to the food-chain accumulation of antimicrobials that also exhibit antioxidant properties and promote adult size, brood size, and offspring quality by modulating central hormonal axes. As each higher species in the food chain tunes its life-history strategy based on iodine intake, the coupling of this functional role of iodine with its value as a resource signal to the next member of the food-chain may promote runaway evolution. Whereas predators in prehistoric ecosystems successfully tuned their life-history strategy using iodine as a major input, the strategy may prove maladaptive in modern humans for whom the pattern of iodine intake is decoupled from resource availability. Iodine acquired through sodium iodide supplementation may independently contribute to some biologic dysfunctions currently attributed to sodium.

Animals↗
PubMed2005

Adventitial dysfunction: an evolutionary model for understanding atherosclerosis.

Endothelial and smooth muscle dysfunctions are widely implicated in the pathogenesis of atherosclerosis. Modern mechanical and pharmacologic treatments aim to remodel abnormalities of the vessel intima and media. We hypothesize that adventitial dysfunction comprises the dominant source of atherosclerosis by originating many endothelial and smooth muscle abnormalities. The autonomic nervous system innervates the adventitia, and autonomic dysfunction induces many end-organ dysfunctions including inflammation and thrombosis. The link between diabetes and atherosclerosis may operate through adventitial autonomic neuropathy. Smoking may promote atherosclerosis by inducing adventitial autonomic dysfunction related to nicotine-mediated compensatory upregulation of sympathetic bias independent of endothelial injury induced by purported tobacco toxins. While hypertension is thought to cause atherosclerosis, the two conditions may instead represent independent consequences of autonomic dysfunction. The link between aging and atherosclerosis may operate through adventitial dysfunction induced by autonomic dysregulations. Exercise may ameliorate atherosclerosis by restoring adventitial autonomic function, thereby normalizing adventitial regulation of medial and intimal biology. Feed-forward adventitial vascular baroreceptor and chemoreceptor dysregulation may further exacerbate atherosclerosis as intimal plaque interferes with these sensors. Since penetrating external physical injury likely represented a dominant selective force during evolution, the adventitia may be preferentially equipped with sensors and response systems for vessel trauma. The convergent response of adrenergia, inflammation, and coagulation, which is adaptive for physical trauma, may be maladaptive today when different stressors trigger the cascade. Endoluminal therapies including atherectomy, angioplasty, and stent deployment involve balloon expansion that traumatizes all layers of the vessel wall. These interventions may paradoxically reinitiate the cascade of atherogenesis that begins with adventitial dysfunction and leads to restenosis. Methods to reduce adventitial trauma, a maladaptive trigger of adventitial dysfunction, may reduce the risk of restenosis. We envision novel mechanical and biopharmaceutical solutions that target the adventitia to prevent or treat atherosclerosis including novel drug delivery strategies, exo-stents that wrap vessels, and neuromodulation of vessels.

Animals↗
PubMed2005

Integrating the theories of Darwin and Bernoulli: maladaptive baroreceptor network dysfunction may explain the pathogenesis of aortic aneurysms.

Current treatment options for aortic aneurysms are suboptimal and their pathogenic mechanisms remain unclear. We propose the existence of a coordinated multi-node baroreceptor network that measures pressures at all vascular bifurcations and enables system-wide hemodynamic coordination and vasomotor regulation, in accordance with the principle of Bernoulli. While the presence of baroreceptors at bifurcations remains unknown, behavior at the level of systems predicts their existence, possibly as glomus cell derivatives. We propose that pressure misregistration among sensor nodes at different vascular bifurcations can precipitate feed-forward dysfunctions that promote thrombosis, inflammation, and vasomotor dysregulation resulting in aneurysm formation. One example of this phenomenon is aortic aneurysm, which is currently attributed to focal anatomic defects. As plaque builds in the infrarenal aorta, the increased blood velocity through this segment can widen the difference between pressures sensed at the iliac and the renal artery bifurcations. Due to the Bernoulli effect, this change creates an incorrect impression of reduced dynamic pressure at the kidneys. The erroneous perception of hypovolemia can induce a pernicious cycle of maladaptive adrenergia and associated coagulation and thrombosis, particularly in the infrarenal aortic segment as the body attempts to normalize renal perfusion. Atherosclerosis can further exacerbate baroreceptor dysfunction by interfering with sensor biology in feed-forward fashion. Hypertension may be a consequence as well as a source of atherosclerosis and aneurysm. The described system may have evolved when trauma-related hypovolemia was a far more prevalent driver of natural selection but may be rendered maladaptive in the setting of modern stressors. Failure to address these factors may explain the suboptimal long-term outcomes with current surgical and endovascular treatments for aneurysms. Implications for other potential sensor networks including chemoreceptors and lymphoid tissues at bifurcating biologic branch-points such as vessels, airways, nerves, lymphatics, and ducts are discussed. Our framework may also provide a new basis for understanding thoracic aneurysm, renovascular dysfunctions, coronary artery disease, carotid artery disease, pulmonary embolism, portal hypertension, venous thrombosis, biliary disease, pancreatic disease, and neurologic disease. Novel treatment paradigms based on drugs or interconnected networks of devices that modulate sensors are envisioned. Improving the interface between sensors and their substrate information by techniques such as minimally traumatic atherectomy or thrombectomy may also restore appropriate sensor function. Lessons learned from bifurcation sensors and their potential maladaptations may generalize to other types of branching systems including botany, civil engineering, and Pitot tube aeronautics.

Animals↗
PubMed2004

Conditions of aging as manifestations of sympathetic bias unmasked by loss of parasympathetic function.

We propose a unifying hypothesis that many clinical consequences of aging are pleiotropic manifestations of the loss of parasympathetic function that occurs during post-reproductive senescence. The loss of parasympathetic function unmasks the baseline sympathetic bias inherent in the end-organs, resulting in the familiar signs of aging including tachycardia, constipation, insomnia, erectile dysfunction, fluid retention, and systemic inflammation. These consequences in turn may contribute to many of the common diseases associated with aging including type-2 diabetes, Alzheimer's, atherosclerosis, and cancer. Maintenance and restoration of parasympathetic function may enable upstream control over the deleterious aspects of inherent end-organ adrenergic bias.

Aging↗
PubMed2004

Acute coronary syndromes and heart failure may reflect maladaptations of trauma physiology that was shaped during pre-modern evolution.

We hypothesize that the pathophysiology of many cardiovascular diseases reflects a maladaptation of the triad of trauma response: adrenergia, inflammation, and coagulation. During biologic evolution, trauma has likely been a prevailing factor in natural selection. Components of the trauma triad act to limit hemorrhage, defend wounds against microorganisms, and initiate reconstruction. Response pathways that enable survival after trauma confer obvious adaptive advantages especially if the individual goes on to reproduce. Modern humans have shaped their own ecologic environment in such a way that the incidence of trauma has waned and previously unseen pathologies have emerged. Manifestations of modern diet, changing lifestyles, and extended lifespan have suddenly created new pathologic challenges to our prehistoric physiologic system. During our evolutionary heritage, endothelial injury and end-organ hypoxia were likely exclusively associated with physical trauma and the responses of the trauma triad were appropriate. Today, endothelial injury is more often precipitated by distinctly modern stressors such as hypertension, smoking, diabetes, and dyslipidemia. The once-adaptive trauma response can maladaptively initiate dangerous, self-propelling cycles of adrenergia, inflammation, and coagulation. Acute coronary syndromes perhaps best exemplify this phenomenon. Congestive heart failure, which often ensues, can similarly be seen as a maladaptation of the trauma triad. Whereas end-organ hypoxia was once commonly associated with trauma, now hypoxia is more often attributable to distinctly modern stressors such as pump failure. The fluid conservation and inflammation that results from the trauma triad was clearly adaptive in our prehistoric past, but in congestive heart failure the response is maladaptive, engendering self-propelling exacerbations of pump failure and vascular disease. Our maladaptive trauma response hypothesis portends new diagnostic and therapeutic paradigms for cardiovascular diseases and has ramifications for many other conditions such as stroke, venous thrombosis, vasculitis, aortic disease, arterial disease, pulmonary embolism, and restenosis.

Acute Disease↗
PubMed2004

Many diseases may reflect dysfunctions of autonomic balance attributable to evolutionary displacement.

We hypothesize that many ailments are attributable to dysfunctions of autonomic balance. The autonomic system is a primitive, highly-adaptive response system that allows differential allocation of biologic effort under varying conditions. The autonomic system, however, can execute a response that is inappropriate for the system stressor due to evolutionary displacement. Evolutionary displacement is a situation in which a trait that evolved as an adaptive response to certain conditions now faces a new set of conditions. Modern human evolution since the Pleistocene era is characterized by substantial evolutionary displacement, brought on in large part by the accelerating ability of humans to change their own environment. In the setting of evolutionary displacement, previously adaptive systems such as the autonomic system can be rendered unhelpful or even counterproductive. Emergence of chronic conditions, maladaptation of the trauma response, and extension of human lifespan are examples of evolutionary displacements that can induce inappropriate sympathetic bias in hosts. We postulate that many diseases are manifestations of this general phenomenon. Implications for existing and future therapeutic strategies are discussed.

Biological Evolution↗
PubMed2004

Autonomic dysfunction may be an under-recognized cause of female fertility disorders.

Female conditions of impaired fertility comprise a heterogeneous group of disorders that are attributed to various anatomic, hormonal and immunologic disturbances. We hypothesize that autonomic dysfunction may be a previously unrecognized factor in female fertility disorders. Emerging physiologic and molecular evidence suggests that autonomic balance varies during normal menstrual cycles with a shift to sympathetic bias during the luteal phase. Furthermore, many diseases associated with autonomic dysfunction show catamenial variations in patterns consistent with a shift to sympathetic bias occurs during the second half of normal menstrual cycles. The shift to sympathetic bias during the normal luteal phase may be an evolutionary adaptation to address the immunologic and physiologic demands for successful implantation and gestation. Through direct modulation of the lymphoid system and activation of the cortisol pathway, sympathetic bias promotes a shift to relative T helper (Th)-2 biased immunity which may favor maternal tolerance of the embryo by attenuating Th-1 mediated interference of implantation. Indeed, a growing body of evidence has implicated abnormal Th balance in fertility disorders, but the link has been attributed to factors other than autonomic function, such as hormonal factors. After implantation, maternal sympathetic bias may further support gestation through physiologic changes necessary to maintain placental perfusion pressure. We propose that insufficient shift to sympathetic bias during the luteal phase, which manifests in inadequate shift towards Th-2 bias and down-regulation of Th-1 function, may be the mechanism of impaired fertility in certain patients. Our hypothesis portends new potential methods to treat fertility disorders by modulating autonomic balance.

Autonomic Nervous System Diseases↗
PubMed2004

Tumors may modulate host immunity partly through hypoxia-induced sympathetic bias.

Hypoxia can occur in solid tumors when oxygen demand from rapid tumor growth outstrips the blood supply. Once thought to be merely a consequence of tumor physiology, more recent evidence suggests that hypoxia may also be a tumor adaptation to promote its own survival. For example, hypoxic conditions generate local transcriptional changes that enhance angiogenesis and glycolysis, processes that directly promote tumor growth. We hypothesize that maladaptive local chemoreceptor host response to hypoxia may contribute to a shift in immune balance that favors cancer survival. Specifically, we propose that hypoxia in the tumor microenvironment activates local adrenergic activity which in turn inhibits Th1 function while favoring Th2 function. Th1 function is vital to the host defense against cancer, and Th1 depletion is associated with increased cancer risk. In our view, the sympathetic bias induces Th2 bias independent of the direct immunomodulatory effects of tumor-derived cytokines. The hypoxia-induced local adrenergic response may be part of a broad tumor adaptation that enables its evasion of host immune surveillance. That the host response of Th2 bias is so reflexively linked to hypoxia may reflect the likelihood that trauma, rather than modern diseases such as cancer, were the most common causes of hypoxia during our teleologic past when natural selection shaped our biologic pathways. Validation of our hypothesis may shed more light on the biology of cancer and reveal novel diagnostic and therapeutic strategies.

Adaptation, Physiological↗