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Biomedical subjects

John D Doux

Publications and source records attributed to John D Doux.

At least 19 recordsLinked to original sources
PubMed2007

Brewing controversies: Darwinian perspective on the adaptive and maladaptive effects of caffeine and ethanol as dietary autonomic modulators.

Ethanol and caffeine are two of the oldest human drugs. Their pervasive integration into the modern human diet may reflect behavioral attempts to correct maladaptations induced by evolutionary displacement of the autonomic system. The dietary adoption of caffeine may parallel the emergence of cognition as an independent basis of competition. Enhancement of the cognitive ability to gather and process information likely evolved as a valuable adjunct to physical behavior in prehistoric fight-or-flight encounters. Caffeine effectively exploits this pre-existing association between adrenergic activity and cognitive readiness, leading to its use in the modern environment where success in competition increasingly depends on cognitive, rather than physical, prowess. Ethanol may have emerged as a dietary means to buffer the maladaptive chronic sympathetic activation and fear response associated with stressful lifestyles and the social phobias associated with the dissolution of kin networks. We explore the health implications of ethanol and caffeine use, with particular attention to their acute and chronic effects on the autonomic axis. The putative protective effects of ethanol in surviving major trauma or reducing inflammation and heart disease may relate to tempering the behavioral and cardiovascular consequences of catastrophic or chronic sympathetic activation. Acute or chronic abuse of ethanol manifests paradoxical pro-adrenergic effects such as tremors and insomnia that may partly represent compensatory responses. Compensatory remodeling may also explain why confirmation of detrimental effects related to caffeine-induced sympathetic activation has proven elusive; indeed, paradoxical pro-vagal benefits may eventually be recognized. Ethanol and caffeine are potential agents that may beneficially expand the dynamic range of the autonomic system. In an environment where the Darwinian value of knowledge has increasingly supplanted that of physical traits, the consumption of caffeine and alcohol may represent both a cause and an effect of modern human evolution.

Adaptation, Physiological↗
PubMed2006

Stress dysfunctions as a unifying paradigm for illness: repairing relationships instead of individuals as a new gateway for medicine.

Stress has been implicated as a risk factor for most diseases, but a mechanistic explanation behind such associations remains elusive. As emergent responses to stress, adaptations range from acute responses where extant system capabilities mitigate current stress, to longer-term responses where system plasticity buffers against future stress. The long compendium of human ailments manifests through a much shorter set of symptoms that may operate through the stress axis. We propose a unifying ontology for human illnesses that classifies stress dysfunctions according to types of Darwinian dysfunction - inadequate response with adequate adaptation, inadequate adaptation, inappropriate adaptation, and epiphenomena of adaptation. Examples include cancer as a bystander effect of increased biologic plasticity in response to stress, and infectious illness as a manifestation of mutually escalating stress in an otherwise commensal relationship between hosts and microbes. We explore the contributing role of man-made stresses that have emerged as humans increasingly remodel their environment. Examples include biologic decompensation associated with reliance on technology to buffer stress, and behavioral stress caused by the dislocation of kin networks that promotes illegitimate signaling. Dysfunctional relationships engender stress not only among humans, but also among individual organs; heart failure, renal failure, and carotid stenosis may represent examples of such conditions. If stress dysfunction is the Occam's razor of human illnesses, and derangements in biologic relationships induce stress dysfunctions, then the study of relationships - an incarnation of systems biology - may represent a new gateway for medicine.

Adaptation, Psychological↗
PubMed2006

Peripheral arterial disease: a manifestation of evolutionary dislocation and feed-forward dysfunction.

Peripheral arterial disease in the legs represents a subset of atherosclerosis that manifests a particularly sinister profile. A predominance of sympathetic activity in the periphery favors the development of neurogenic atherosclerosis. Atherosclerosis may then produce flow derangements and decreased physical activity that serves to escalate sympathetic bias in a vicious cycle. Restoration of normal flow in peripheral arterial disease may not only produce local benefit due to improved perfusion, but also represent a gateway to correcting many systemic conditions that may at first glance appear unrelated but share a common etiology of autonomic dysfunction, such as gout, acute coronary syndromes, stroke, sleep apnea, arrhythmias, depression, erectile dysfunction, inflammation, hypercoagulability, sleep disorders, bowel dysfunction, renal failure, and aging.

Atherosclerosis↗
PubMed2006

A paradigm for viewing biologic systems as scale-free networks based on energy efficiency: implications for present therapies and the future of evolution.

A network constitutes an abstract description of the relationships among entities, respectively termed links and nodes. If a power law describes the probability distribution of the number of links per node, the network is said to be scale-free. Scale-free networks feature link clustering around certain hubs based on preferential attachments that emerge due either to merit or legacy. Biologic systems ranging from sub-atomic to ecosystems represent scale-free networks in which energy efficiency forms the basis of preferential attachments. This paradigm engenders a novel scale-free network theory of evolution based on energy efficiency. As environmental flux induces fitness dislocations and compels a new meritocracy, new merit-based hubs emerge, previously merit-based hubs become legacy hubs, and network recalibration occurs to achieve system optimization. To date, Darwinian evolution, characterized by innovation sampling, variation, and selection through filtered termination, has enabled biologic progress through optimization of energy efficiency. However, as humans remodel their environment, increasing the level of unanticipated fitness dislocations and inducing evolutionary stress, the tendency of networks to exhibit inertia and retain legacy hubs engender maladaptations. Many modern diseases may fundamentally derive from these evolutionary displacements. Death itself may constitute a programmed adaptation, terminating individuals who represent legacy hubs and recalibrating the network. As memes replace genes as the basis of innovation, death itself has become a legacy hub. Post-Darwinian evolution may favor indefinite persistence to optimize energy efficiency. We describe strategies to reprogram or decommission legacy hubs that participate in human disease and death.

Animals↗
PubMed2006

Efficient inefficiency: biochemical "junk" may represent molecular bridesmaids awaiting emergent function as a buffer against environmental fluctuation.

The biochemical function of many parts of the genome, transcriptome, proteome, and interactome remain largely unknown. We propose that portions of these fundamental building blocks of life have no current biochemical function per se. Rather, sections of these "omes" may contribute to an inventory of biochemical parts and circuits that participate in the development of emergent functions. Low fidelity deoxyribonucleic acid replication, transcription, translation, and post-translational modification all represent potential mechanisms to produce an inventory of parts. Stochastic processes that influence the conformations of ribonucleic acid molecules and proteins may also contribute to potential biochemical inventory. Some components of the biochemical inventory may enable future adaptations, some may produce disease, and some may remain useless. The function of many of these components await discovery, not by science, but by evolution. While carrying such purposeless biochemical units may appear to dilute fitness by exacting a thermodynamic cost, we argue that net fitness becomes enhanced when considering the value for potential future innovations. One can envision components that intermingle, interact, and act out mock pathways, but in most cases remain molecular bridesmaids. Given sufficiently low thermodynamic cost, such stochastic cycling may persist until a markedly advantageous or cataclysmically disadvantageous trait emerges. Maladaptive screening and utilization of inventory content can lead to disease phenotypes, a process buffered and regulated in part by the heat shock protein and stress response network. Whereas failure of the ubiquitin pathway to recycle misfolded proteins has become increasingly recognized as a source of disease, protein misfolding may itself represent one step in a process that maximizes functional innovation through increasing proteomic diversity. Fractal correlates of these processes occur at the organizational level of cells and organisms. That the abnormal accumulation of units induces local collapse may serve to limit the extension of damage to the greater system at large. The immune and cognitive systems that selectively sample and prune environmental content may serve as additional portals for innovation.

Adaptation, Physiological↗
PubMed2006

Opening the floodgates: benign prostatic hyperplasia may represent another disease in the compendium of ailments caused by the global sympathetic bias that emerges with aging.

We have previously posited that the global sympathetic bias that emerges with aging may constitute the common etiologic thread that links a myriad of ailments associated with aging. Recent data suggests that benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) may also be caused by sympathetic bias as an independent etiology from androgen dysfunction. The association of BPH with heart disease, independent of other variables, supports the view that both entities represent downstream manifestations of global sympathetic bias. The risk for development of BPH increases with caffeine intake and decreases with alcohol consumption, factors which wield opposing effects on autonomic balance. Heavy smoking, which induces chronic sympathetic bias, also increases the risk of BPH, a link also previously attributed to hormonal alterations. Sympathetic dysfunction appears to have a mitogenic effect on the prostate. The high prevalence of prostate cancer, a condition detected in the autopsy of many elderly men, may arise from this activity combined with a Th2 shift induced by sympathetic bias, leading to decreased cancer surveillance by the immune system. Exercise may improve BPH by restoring autonomic balance and normalizing the sympathovagal ratio. The benefits of alpha-adrenergic blockers on BPH, generally felt to achieve symptomatic relief afforded by bladder wall and sphincter remodeling, may independently exert a direct effect on prostate growth and enlargement. Sympathetic bias may play a role in adaptive enlargement of other organs such as the salivary glands, heart, liver, spleen, and skeletal muscles in response to stress. We envision novel pharmacologic and device-based neuromodulation therapies for BPH and related urologic dysfunctions based on these principles.

Adrenergic alpha-Antagonists↗
PubMed2006

When normal is not: the dilemma of interpreting laboratory averages of bioactive molecules subject to heterogeneous regulatory feedback and epigenetic mosaicism.

Complex regulatory systems control the levels of many bioactive molecules in the serum. These systems involve the integration of feedback responses from numerous tissues. End-organs and tissues can manifest epigenetic mosaicism, particularly with aging or disease states. We propose that an isolated lab value may reflect a blended average of inhomogeneous feedback responses from target tissues in various states of dysfunction. Reliance on such data may underestimate the state of systemic dysfunction. Yet in clinical practice, normal serum levels of a given molecule and its associated regulatory machinery are often assumed to reflect normal body homeostasis and tissue function. Organism-wide integration of abnormally high and low levels of bioactivity of a molecule in different tissues may yield apparently normal serum values of the bioactive molecule and known components of its regulatory system. We specifically discuss thyroid hormone regulation and function as a case example. Epigenetic reprogramming of either regulatory loops or tissue responses represents another way in which normal serum levels of the molecule may obscure target-organ dysfunction. The proposed idea has broad implications for disease pathogenesis, diagnosis, and therapies. A model where individual tissues employ illegitimate signaling to subvert the concerns of the organism as a whole is also proposed.

Animals↗
PubMed2006

Are we eating more than we think? Illegitimate signaling and xenohormesis as participants in the pathogenesis of obesity.

Resource utilization may represent a central force driving evolution. A tight link between sensing energy availability and managing energy acquisition and utilization constitutes a common feature among all organisms. While such a link was likely adaptive during prehistoric evolution, modern lifestyles may decouple perceived cues from actual energy availability so as to promote obesity in humans. A particular illegitimate signal is chronic stress, which may shift body phenotype to suit a more conservative state of energy management. In prehistoric times, such a response likely aided survival during periods of low resource availability. However, new sources of chronic stress have emerged that bear little relationship to contextual energy, which is generally abundant in the modern world. In addition, modern techniques of husbandry and agriculture can produce stress in the food chain, such that food itself can act as an illegitimate signal of chronic stress. Obese livestock and unusual fat profiles in farmed fish, meat, and eggs may reflect stress phenotypes. Consumers of stressed foods may sense those signals--a phenomenon known as xenohormesis--and assume the stressed phenotype. This maladaptive process may promote obesity by erroneously biasing hosts towards caloric accumulation in the context of energy abundance. Regional tissue accumulation of fat may indicate local tissue stress. Atherosclerosis may result from stress signals that induce sympathetic bias and regional fat accumulation in vessel adventitia. Medications such as neuroleptics and foods such as diet drinks may generate illegitimate signals by mimicking molecules used for energy management. Implications for the prevention and treatment of dysfunctions related to these derangements are discussed. New strategies for manufacturing biologics by manipulating stress conditions or controlling fatty acid attachments to proteins are envisioned.

Adipose Tissue↗
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

The link between carotid artery disease and ischemic stroke may be partially attributable to autonomic dysfunction and failure of cerebrovascular autoregulation triggered by Darwinian maladaptation of the carotid baroreceptors and chemoreceptors.

Carotid artery stenosis is generally thought to induce stroke by either compromising cerebral perfusion or inciting embolic phenomena. Carotid baroreceptors and chemoreceptors are vital adaptations for cerebrovascular autoregulation that can behave mal-adaptively in the setting of modern diseases such as atherosclerosis. We hypothesize that acute cerebrovascular events may be partially attributable to autonomic dysfunction and cerebrovascular autoregulatory failure secondary to carotid sensor maladaptations. Specifically, we propose that atherosclerotic disease at the carotid bifurcation can interfere with baroreceptor and chemoreceptor function by buffering against accurate detection of physical and chemical parameters. Misperceptions of hypoxia and hypotension can trigger sympathetic bias and autonomic dysfunction which perturb cerebrovascular autoregulation and vasomotor tone, thereby compromising cerebral perfusion. The preferential association of strokes with morning arousal, stress, acute physical activity, winter months, illness, and older age may relate to this phenomenon. Sympathetic bias promotes inflammation and coagulation, a link likely forged during prehistoric evolution when trauma represented a more significant factor in natural selection. In the setting of carotid sensor dysfunction, the resulting inflammation and coagulation can promote acute cardiovascular events. The ensuing cerebral ischemia can induce further derangement of cerebrovascular autoregulation and upregulate adrenergia, inflammation, and coagulation in a feed-forward manner. Inflammation and coagulation can also exacerbate carotid sensor dysfunction by iteratively worsening atherosclerosis. Angioplasty, stenting, and endarterectomy may inadvertently cause acute and chronic carotid sensor dysfunction through manipulation, material interposition, and balloon-induced baroreceptor injury. Acute strokes during these procedures may result from carotid sensor dysfunction rather than embolization. Carotid body and sinus electro-modulation and non-balloon atherectomy represent new methods to prevent or treat cerebrovascular events. Pharmacologic modulation of autonomic balance, such as adrenergic blockade, long presumed contraindicated due to risk of cerebral hypoperfusion, may counter-intuitively offer benefit during acute strokes. Novel diagnostic paradigms may include functional analysis of carotid sensors as well as measurement of the anatomic thickness of calcified and non-calcified plaque near the carotid body. Carotid sensor dysfunction may be a source of systemic sympathetic bias and autonomic dysfunction observed during aging and, by association, many of the ailments associated with senescence. Modulation of carotid sensors may yield pervasive health benefits beyond those found by treating cerebrovascular disease.

Adaptation, Physiological↗
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

Contrast nephropathy may be partly mediated by autonomic dysfunction: renal failure considered as a modern maladaptation of the prehistoric trauma response.

The mechanism behind iodinated radiocontrast nephropathy remains elusive. Direct oxidative damage is the prevailing hypothesis, but the apparent protective effect of iodine against oxidation contradicts this view. We propose that autonomic dysfunction participates in the pathogenesis of radiocontrast nephropathy and may account for other contrast-associated reactions previously attributed to allergy. Iodine, through its effects on thyroid function and chemoreceptor response to metabolic acidosis, may induce hyperadrenergia and consequently diminish renovascular flow and urine output. The renal response to adrenergia likely served an adaptive function during prehistoric evolution when trauma was a dominant source of hypovolemia and adrenergia, but the response may behave maladaptively today as evolutionarily nai ve triggers for adrenergia have emerged. Autonomic dysfunction can further impair renal function by deranging renovascular autoregulation and inducing oxidative reperfusion injury as a secondary phenomenon. Many other causes of acute renal failure such as drug toxicity, surgery, hospitalization, and diabetes may operate through hyperadrenergia, impaired renovascular autoregulation, and oxidative reperfusion injury. Dialysis, a volume reduction therapy for renal failure, can counterintuitively worsen renal dysfunction by exacerbating adrenergia, which may explain its association with accelerated atherosclerosis, inflammation, and cancer. Other examples of vicious cycles that perpetuate renal dysfunction may include renal artery stenosis, carotid stenosis, and atherosclerosis as well as the cardio-renal, hepato-renal, and pulmonary-renal syndromes. The benefits of hydration and bicarbonate in protecting renal function may operate in part through baroreceptor- and chemoreceptor-mediated reduction of sympathovagal ratio, respectively. New treatment paradigms for renal failure including pharmacologic and electro-mechanical therapies are envisioned based on autonomic remodeling, reduced sympathovagal ratio, and neuromodulation of pathways typically associated with trauma such as renin, angiotensin, vasopressin, and aldosterone.

Adaptation, Physiological↗
PubMed2005

A general theory of evolution based on energy efficiency: its implications for diseases.

We propose a general theory of evolution based on energy efficiency. Life represents an emergent property of energy. The earth receives energy from cosmic sources such as the sun. Biologic life can be characterized by the conversion of available energy into complex systems. Direct energy converters such as photosynthetic microorganisms and plants transform light energy into high-energy phosphate bonds that fuel biochemical work. Indirect converters such as herbivores and carnivores predominantly feed off the food chain supplied by these direct converters. Improving energy efficiency confers competitive advantage in the contest among organisms for energy. We introduce a term, return on energy (ROE), as a measure of energy efficiency. We define ROE as a ratio of the amount of energy acquired by a system to the amount of energy consumed to generate that gain. Life-death cycling represents a tactic to sample the environment for innovations that allow increases in ROE to develop over generations rather than an individual lifespan. However, the variation-selection strategem of Darwinian evolution may define a particular tactic rather than an overarching biological paradigm. A theory of evolution based on competition for energy and driven by improvements in ROE both encompasses prior notions of evolution and portends post-Darwinian mechanisms. Such processes may involve the exchange of non-genetic traits that improve ROE, as exemplified by cognitive adaptations or memes. Under these circumstances, indefinite persistence may become favored over life-death cycling, as increases in ROE may then occur more efficiently within a single lifespan rather than over multiple generations. The key to this transition may involve novel methods to address the promotion of health and cognitive plasticity. We describe the implications of this theory for human diseases.

Animals↗
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↗