Victoria E. Claydon

Adaptation and Mal-Adaptation to Ambient Hypoxia; Andean, Ethiopian and Himalayan Patterns

The study of the biology of evolution has been confined to laboratories and model organisms. However, controlled laboratory conditions are unlikely to model variations in environments that influence selection in wild populations. Thus, the study of “fitness” for survival and the genetics that influence this are best carried out in the field and in matching environments. Therefore, we studied highland populations in their native environments, to learn how they cope with ambient hypoxia. The Andeans, African highlanders and Himalayans have adapted differently to their hostile environment. Chronic mountain sickness (CMS), a loss of adaptation to altitude, is common in the Andes, occasionally found in the Himalayas; and absent from the East African altitude plateau. We compared molecular signatures (distinct patterns of gene expression) of hypoxia-related genes, in white blood cells (WBC) from Andeans with (n = 10), without CMS (n = 10) and sea-level controls from Lima (n = 20) with those obtained from CMS (n = 8) and controls (n = 5) Ladakhi subjects from the Tibetan altitude plateau. We further analyzed the expression of a subset of these genes in Ethiopian highlanders (n = 8). In all subjects, we performed the studies at their native altitude and after they were rendered normoxic. We identified a gene that predicted CMS in Andeans and Himalayans (PDP2). After achieving normoxia, WBC gene expression still distinguished Andean and Himalayan CMS subjects. Remarkably, analysis of the small subset of genes (n = 8) studied in all 3 highland populations showed normoxia induced gene expression changes in Andeans, but not in Ethiopians nor Himalayan controls. This is consistent with physiologic studies in which Ethiopians and Himalayans show a lack of responsiveness to hypoxia of the cerebral circulation and of the hypoxic ventilatory drive, and with the absence of CMS on the East African altitude plateau.

The relationship between orthostatic hypotension and falling in older adults

Falls are devastating events and are the largest contributor towards injury-related hospitalization of older adults. Orthostatic hypotension (OH) represents an intrinsic risk factor for falls in older adults. OH refers to a significant decrease in blood pressure upon assuming an upright posture. Declines in blood pressure can reduce cerebral perfusion; this can impair consciousness, lead to dizziness, and increase the likelihood of a fall. Although theoretical mechanisms linking OH and falls exist, the magnitude of the association remains poorly characterized, possibly because of methodological differences between previous studies. The use of non-invasive beat-to-beat blood pressure monitoring has altered the way in which OH is now defined, and represents a substantial improvement for detecting OH that was previously unavailable in many studies. Additionally, there is a lack of consistency and standardization of orthostatic assessments and analysis techniques for interpreting blood pressure data. This review explores the previous literature examining the relationship between OH and falls. We highlight the impact of broadening the timing, degree, and overall duration of blood pressure measurements on the detection of OH. We discuss the types of orthostatic stress assessments currently used to evaluate OH and the various techniques capable of measuring these often transient blood pressure changes. Overall, we identify future solutions that may better clarify the relationship between OH and falling risk in order to gain a more precise understanding of potential mechanisms for falls in older adults.

The role of the autonomic nervous system in arrhythmias and sudden cardiac death.

The autonomic nervous system (ANS) is complex and plays an important role in cardiac arrhythmia pathogenesis. A deeper understanding of the anatomy and development of the ANS has shed light on its involvement in cardiac arrhythmias. Alterations in levels of Sema-3a and NGF, both growth factors involved in innervation patterning during development of the ANS, leads to cardiac arrhythmias. Dysregulation of the ANS, including polymorphisms in genes involved in ANS development, have been implicated in sudden infant death syndrome. Disruptions in the sympathetic and/or parasympathetic systems of the ANS can lead to cardiac arrhythmias and can vary depending on the type of arrhythmia. Simultaneous stimulation of both the sympathetic and parasympathetic systems is thought to lead to atrial fibrillation whereas increased sympathetic stimulation is thought to lead to ventricular fibrillation or ventricular tachycardia. In inherited arrhythmia syndromes, such as Long QT and Catecholaminergic Polymorphic Ventricular Tachycardia, sympathetic system stimulation is thought to lead to ventricular tachycardia, subsequent arrhythmias, and in severe cases, cardiac death. On the other hand, arrhythmic events in Brugada Syndrome have been associated with periods of high parasympathetic tone. Increasing evidence suggests that modulation of the ANS as a therapeutic strategy in the treatment of cardiac arrhythmias is safe and effective. Further studies investigating the involvement of the ANS in arrhythmia pathogenesis and its modulation for the treatment of cardiac arrhythmias is warranted.

Cardiovascular function after spinal cord injury: prevalence and progression of dysfunction during inpatient rehabilitation and 5 years following discharge.

Background. Autonomic dysfunction after spinal cord injury (SCI) is an under-researched area when compared with motor and sensory dysfunction. Cardiovascular autonomic dysfunction is a particular concern, leading to impaired control of blood pressure and heart rate. Objectives. (1) To determine the prevalence of hypotension in individuals with SCI during and after rehabilitation; (2) To investigate changes in cardiovascular variables during and after rehabilitation; (3) To evaluate the influence of personal and lesion characteristics on cardiovascular variables. Methods. Cardiovascular variables (resting systolic [SAP] and diastolic [DAP] arterial pressures and resting [HRrest] and peak heart rates [HRpeak]) were measured on 5 test occasions: start of inpatient rehabilitation, 3 months later, at discharge, and at 1 and 5 years after discharge. The time course and effects of personal and lesion characteristics on cardiovascular variables were studied using multilevel regression analyses. Results. The prevalence of hypotension was unchanged during rehabilitation and for 5 years after discharge. Odds for hypotension were highest in those with cervical and high thoracic lesions, younger individuals, and men. DAP increased during the 5 years after discharge. HRrest decreased during and after rehabilitation. SAP, DAP, HRrest, and HRpeak were lowest in those with cervical and high thoracic lesions. SAP and DAP increased with age; HRpeak decreased with age. Conclusions. These longitudinal data provide normative values for blood pressure and heart rate changes with time after injury according to lesion and personal characteristics. These results can be used to guide clinical practice and place changes in cardiovascular function caused by interventions in perspective.

Exercise and the Multidisciplinary Holistic Approach to Adolescent Dysautonomia.

To determine whether an eight‐week strength training programme as part of a multidisciplinary approach would minimise symptoms and improve quality of life in patients with dysautonomia.

Ischemia–reperfusion destabilizes rhythmicity in immature atrioventricular pacemakers: A predisposing factor for postoperative arrhythmias in neonate rabbits

BACKGROUND Postoperative arrhythmias such as junctional ectopic tachycardia and atrioventricular block are serious postoperative complications for children with congenital heart disease. We hypothesize that ischemia-reperfusion (I/R) related changes exacerbate these postoperative arrhythmias in the neonate heart and administration of postoperative inotropes is contributory. OBJECTIVE The purpose of this study was to study the effects of I/R and postischemic dopamine application on automaticity and rhythmicity in immature and mature pacemaker cells and whole heart preparations. METHODS Single pacemaker cells and whole heart models of postoperative arrhythmias were generated in a rabbit model encompassing 3 primary risk factors: age, I/R exposure, and dopamine application. Single cells were studied using current clamp and line scan confocal microscopy, whereas whole hearts were studied using optical mapping. RESULTS Four responses were observed in neonatal atrioventricular nodal cells (AVNCs): slowing of AVNC automaticity (from 62±10 to 36 ± 12 action potentials per minute, P<.05); induction of arrhythmicity or increased beat-to-beat variability (0.08 ± 0.04 to 3.83 ± 1.79, P<.05); altered automaticity (subthreshold electrical fluctuations); and disruption of calcium transients. In contrast, these responses were not observed in mature AVNCs or neonatal sinoatrial cells. In whole heart experiments, neonatal hearts experienced persistent postischemia arrhythmias of varying severity, whereas mature hearts exhibited no arrhythmias or relatively transient ones. CONCLUSION Neonatal pacemaker cells and whole hearts demonstrate a susceptibility to I/R insults resulting in alterations in automaticity, which may predispose neonates to postoperative arrhythmias such as junctional ectopic tachycardia and atrioventricular block.

Autonomic Nervous System and Stress to Predict Secondary Ischemic Events after Transient Ischemic Attack or Minor Stroke: Possible Implications of Heart Rate Variability

Transient ischemic attack (TIA) and minor stroke have high risks of recurrence and deterioration into severe ischemic strokes. Risk stratification of TIA and minor stroke is essential for early effective treatment. Traditional tools have only moderate predictive value, likely due to their inclusion of the limited number of stroke risk factors. Our review follows Hans Selye’s fundamental work on stress theory and the progressive shift of the autonomic nervous system (ANS) from adaptation to disease when stress becomes chronic. We will first show that traditional risk factors and acute triggers of ischemic stroke are chronic and acute stress factors or “stressors,” respectively. Our first review shows solid evidence of the relationship between chronic stress and stroke occurrence. The stress response is tightly regulated by the ANS whose function can be assessed with heart rate variability (HRV). Our second review demonstrates that stress-related risk factors of ischemic stroke are correlated with ANS dysfunction and impaired HRV. Our conclusions support the idea that HRV parameters may represent the combined effects of all body stressors that are risk factors for ischemic stroke and, thus, may be of important predictive value for the risk of subsequent ischemic events after TIA or minor stroke.

Endovascular procedures for the treatment of autonomic dysfunction

Dysautonomias are a heterogeneous group of disorders with pathologic changes confined to the central nervous system, the peripheral nervous system or both, depending on the underlying condition [1–3]. Autonomic dysfunction, including postural tachycardia syndrome (POTS), Parkinson’s disease, multiple system atrophy and autonomic neuropathies are major public health problems with a large unmet clinical need [4, 5]. However, advances in therapies that have an immediate impact on quality of life and outcomes in patients with autonomic disorders have been limited. Due to the limitations of many treatment options, particularly in disorders such as POTS, novel treatments have been considered. Into this therapeutic void a therapy for modulation of autonomic function is being advocated as a clinical treatment for autonomic dysfunction of all types. This therapy, described as transvascular autonomic modulation, utilizes an endovascular approach to dilate the thoracic venous system, resulting in mechanical stretching of the autonomic nerves and ‘resetting’ of the autonomic nervous system. The scientific rationale for this procedure is not well described, nor does there appear to be any clear evidence supporting the use of this technique in a diverse group of autonomic disorders. This method reports mechanical disruption of baroreceptors in the venous system using transvenous balloon inflation as a method to improve autonomic dysfunction. There are several major scientific concerns with this statement. First, there is no evidence of such venous baroreceptors. Second, patients with Parkinson’s disease have progressive autonomic nerve fiber dysfunction due to axon loss. There is no evidence, practical or theoretical, to suggest that inflating a balloon in a vein would halt or reverse the loss of nerve fibers secondary to alpha-synuclein deposition in a progressive neurodegenerative condition [6–8]. Promoting a single therapy to treat a group of diseases such as multiple sclerosis, postural tachycardia syndrome and Parkinson’s disease suggests a serious deviation from scientific understanding of disease pathophysiology [9]. We performed an exhaustive review of all available literature describing this procedure through a search of Pubmed and Google Scholar (covering articles published from 1 January 1970 to 9 January 2013). We did not find a single published report describing this procedure. A number of reports have been published describing a similar procedure that has been proposed for the treatment of chronic cerebrospinal venous insufficiency. Originally developed as a possible treatment for multiple sclerosis, this therapeutic approach currently has a negative FDA advisory statement because of complications that include stroke, blood clots, nerve damage and death [10]. We strongly encourage the development of novel approaches and therapeutic interventions for dysautonomia, but only when they are based on scientific rationale and supported by evidence of both safety and efficacy. At this stage, there are no data at all to support the clinical utility of transvascular autonomic modulation and there is no scientific rationale for the procedure. Until randomized blinded trials are completed to ensure adequate understanding of safety and efficacy, we cannot recommend transvascular modulation, or any other unproven surgical procedure, as a treatment for autonomic dysfunction.

A Longitudinal Study of the Association of Clinical Indices of Cardiovascular Autonomic Function with Breast Cancer Treatment and Exercise Training

BACKGROUND Cardiovascular autonomic dysfunction is an early marker for cardiovascular disease. Anthracycline chemotherapy and left-sided radiation for breast cancer are associated with negative autonomic function changes. This studys objectives were to characterize changes in, and the association of exercise training with, clinical indices of cardiovascular autonomic function across the trajectory of breast cancer therapy. SUBJECTS, MATERIALS, AND METHODS Seventy-three patients receiving adjuvant chemotherapy participated to varying degrees in supervised aerobic and resistance exercise during chemotherapy ± radiation and for 20 weeks after. Resting heart rate (HRrest) and blood pressure were measured weekly during chemotherapy. HRrest, exercise heart rate recovery (HRrecovery), and aerobic fitness were measured at enrollment, end of chemotherapy ± radiation, and 10 and 20 weeks after treatment. RESULTS During chemotherapy, HRrest increased in a parabolic manner within a single treatment and with increasing treatment dose, whereas systolic and diastolic blood pressure decreased linearly across treatments. Tachycardia and hypotension were present in 32%-51% of participants. Factors associated with weekly changes during chemotherapy included receiving anthracyclines or trastuzumab, days since last treatment, hematocrit, and exercise attendance. Receipt of anthracyclines, trastuzumab, and left-sided radiation individually predicted impairments of HRrest and HRrecovery during chemotherapy ± radiation; however, aerobic fitness change and at least twice-weekly exercise attendance predicted improvement. By 10 weeks after treatment, HRrest and blood pressure were not different from prechemotherapy. CONCLUSION In this study, chemotherapy resulted in increased HRrest and tachycardia, as well as decreased blood pressure and hypotension. Anthracyclines, trastuzumab, and left-sided radiation were associated with HRrest elevations and impairments of HRrecovery, but exercise training at least twice a week appeared to mitigate these changes. IMPLICATIONS FOR PRACTICE This study characterized changes in clinically accessible measures with well-established prognostic value for cardiovascular disease, and investigated associations with cardiotoxic treatments and the positive influence of exercise. The chemotherapy-related incremental increase in resting heart rate, with tachycardia occurring in one third of patients, and decrease in blood pressure, with hypotension occurring in one half of the patients, is relevant to oncology practitioners for clinical examination or patient report of related symptoms (i.e., dizziness). The weekly dose of two 60-minute sessions of moderate-intensity aerobic and resistance exercise that was identified as protective of cardiovascular autonomic impairments can easily be prescribed to patients by oncologists.

Polymorphic ventricular tachycardia associated with an episode of reflex syncope: Is this the needle in the haystack?

Introduction Syncope is common, occurring in approximately 30%–40% of the population by age 60 years. Reflex syncope presents as loss of consciousness and postural tone with spontaneous recovery. The ultimate cause is cerebral hypoperfusion, although the underlying mechanism(s) is not completely understood. The final pathway results in impairments of cerebral perfusion and cardiac output that have vasodepressor, cardioinhibitory, or mixed vasodepressor and cardioinhibitory origins. Reflex syncope is most commonly triggered by postural or orthostatic stress, but other well-documented triggers include stereotypical situations such as micturition and defecation syncope. The most informative diagnostic test is an accurate, detailed history, ideally from the patient. Confirming typical triggers for the syncope is reassuring and implies a benign prognosis. Recurrence is predicted primarily by the frequency of recent syncopal episodes. There is concern that syncopal events may be a marker of an underlying potentially lethal cardiac condition, so investigations are often extensive in individuals with syncope but invariably yield little information. Moreover, sudden cardiac arrest (SCA) is an uncommon problem in the young. Although so-called warning events are frequent in cohorts of patients who subsequently have a cardiac arrest, identifying the 1 in 5000 individuals with syncope who may go on to have SCA is difficult and expensive. We present an unusual case of seemingly typical reflex syncope, in the form of defecation syncope, in a patient who had a pacemaker in situ. The device recorded