The Applicability of Nonlinear Systems Dynamics Chaos Measures to Cardiovascular Physiology Variables

Three measures of nonlinear chaos (fractal dimension, Approximate Entropy (ApEn), and Lyapunov exponents) were studied as potential measures of cardiovascular condition. It is suggested that these measures have potential in the assessment of cardiovascular condition in environments of normal cardiovascular stress (normal gravity on the Earth surface), cardiovascular deconditioning (microgravity of space), and increased cardiovascular stress (lower body negative pressure (LBNP) treatments)

Effectiveness of the Travelers Summer Research Fellowship Program in Preparing Premedical Students for a Career in Medicine

This study measured the effectiveness of the Travelers Summer Research Fellowship (T-SRF) Program for Premedical Students. No in-depth study has been conducted on the impact of its activities. A program-oriented qualitative summative evaluation approach and a logic model design were used to analyze survey responses for participants from four program years randomly chosen from 2000 to 2015, medical school enrollment records for participants from 1969 to 2015, physician practice locations for participants from 1969 to 2009, and interviews with a purposeful random sample of 10 physicians who were program participants from 2004 to 2008. Narrative inquiry consisted of audio recording, transcription, and analysis of individual accounts and participant experiences. The study revealed that participants valued interactions with physicians from backgrounds underrepresented in medicine. Talks on careers in medicine increased participants’ knowledge, and research projects helped develop skills. Cardiovascular physiology lectures introduced participants to the medical school learning experience and increased their confidence to apply to medical school successfully. T-SRF enhanced participants’ medical school applications and sharpened interviewing skills; 83% matriculated into medical school, 90% graduated, and 45% practice in HPSAs, MUAs/Ps, and rural areas. Recommendations included improving program orientation, making the cardiovascular physiology lectures and examinations more valuable experiences, re-evaluating the study skills curriculum, providing more clinical experiences, increasing the weekly stipend, improving maintenance of the alumni database, formally partnering admissions with the T-SRF program, helping alumni return to Weill Cornell as residents or fellows, and considering other ways to measure social concern. Further studies of T-SRF should be undertaken

Publications of the Space Physiology and Countermeasures Program, Cardiopulmonary Discipline: 1980-1990

A 10-year cumulative bibliography of publications resulting from research supported by the Cardiopulmonary Discipline of the Space Physiology and Countermeasures Program of NASA's Life Sciences Division is provided. Primary subjects included in this bibliography are Fluid Shifts, Cardiovascular Fitness, Cardiovascular Physiology, and Pulmonary Physiology. General physiology references are also included. Principal investigators whose research tasks resulted in publication are identified. Publications are identified by a record number corresponding with their entry in the Life Sciences Bibliographic Database, maintained at the George Washington University

The Impact of Food Deprivation on Cardiovascular Physiology

Introduction: Despite the commonality of fasting, there still remains a lack of scientific research, specifically in regard to the impact of fasting on cardiovascular physiology. Thus, the goal of this research project was to further explore the relationship between fasting and cardiovascular physiology. Hypothesis: The hypothesis of this research project was that a 24-hr fast would likely lead to increased BP and HR, along with blood biomarker changes, and that experiencing this 24-hr fast twice a week would lead to reduced BP and HR along with altered circulating blood biomarker levels. Methods: In order to test these hypotheses, cardiovascular and blood biomarker factors were assessed both before, during and after a 24-hr fast, and throughout a 4-wk period of two 24-hr fasts per week. Results: After the 24-hr fast there was increased resting BP (SBP, p=0.062; DBP, p=0.101) and HR (p=0.125), in addition to decreased overall average ambulatory BP (SBP, p=0.159; DBP, p=0.167) and HR (p=0.076) throughout the 24-hr fast. Blood glucose (p=0.012) and plasma NPY (p=0.007) were decreased, and plasma ghrelin (p=0.171) and plasma LEAP2 (p=0.203) were increased after the 24-hr fast. Resting BP (SBP, p=0.004; DBP, p=0.202) was decreased, and autonomic function showed a shift toward lessened sympathetic activity (↑ RRI, p=0.125; ↓ RRI-LF/HF ratio, p=0.293) at the end of the 4 weeks of fasting, and the decrease in BP was seen as early as 2 weeks of fasting. Plasma ghrelin (p=0.372) was increased at the end of the 4 weeks of fasting with little to no change in blood glucose (p=1.000), plasma LEAP2 (p=1.000) and plasma NPY (p=1.000). Plasma LEAP2 (p=0.693) and plasma NPY (p=0.473) did decrease after 2 weeks of fasting before returning to approximately baseline levels after 4 weeks of fasting. The cardiovascular changes from 24 hours of fasting were most correlated to blood glucose and plasma ghrelin, and the changes from 4 weeks of fasting were most correlated to plasma ghrelin and plasma NPY. Discussion: It appears that fasting may have a mild impact on cardiovascular physiology; both during a 24-hr fast and as an adaptation to 4 weeks of fasting

Endothelin system in human cardiovascular physiology and pathophysiology

The experiments presented here arose from an interest in endothelial function and, particularly, a wish to better understand the pharmacology and physiology of the endothelin (ET) system in human blood vessels in health, and the influence of cardiovascular disease on the ET system. This work followed from the discovery of ET-1 as a peptide endothelial mediator of vascular tone in 1988. Publications are grouped into sections representing different aspects of the work.Section 1 is concerned with exploring pharmacological responses to the ET family of peptides, the sarafotoxin analogue peptides, and ET antagonists, in human blood vessels in vivo. This was amongst the first work with ET-1 in humans, and certainly the first to use the sarafotoxins, ET receptor antagonists and ET converting enzyme (ECE) inhibitors. After characterisation of the pharmacological tools, it was possible to show clearly that endogenous ET-1 plays a physiological role in the control of peripheral resistance and blood pressure in healthy humans, suggesting important clinical applications for these agents. It was also shown that the ETA receptor is the major vasocontrictor receptor and that the major role in health of the ETB receptor is endothelium-dependent vasodilatation, enhancement of which may contribute to the beneficial clinical attributes of ETA receptor antagonism. In addition, local ET-1 infusion in the forearm circulation was shown to be a system whereby the clinical efficacy of systemically administered ET receptor antagonists could be modelled pharmacodynamicallySections 2-4 cover work confirming the substantial clinical utility of ET receptor antagonists and ECE inhibitors as vasodilators, particularly in essential hypertension, heart failure and renal failure. Other work, following congenital heart surgery, suggests that a cautious approach may be needed in some cases of pulmonary hypertension. Studies with neutral endopeptidase (NEP) inhibitors show unequivocally, but unexpectedly, that these agents are peripheral vasoconstrictors, and the evidence presented is consistent with this effect occurring because endogenously generated vascular ET-1 is an important substrate for NEP.Section 5 contains some miscellaneous but related studies, together with a series of review articles written from 1991-98 synthesising the literature at each stage and drawing conclusions about potential areas of major clinical interest in cardiovascular diseasePUBLICATIONS: • SECTION 1: CARDIOVASCULAR PHYSIOLOGY, Papers 1-19 • 1. Clarke JG, Benjamin N, Larkin SW, Webb DJ, Davies GJ, Maseri A. Endothelin is a potent long-lasting vasoconstrictor in men. Am J Physiol 1989;257:H2033-5. • 2. Cockcroft JR, Clarke JG, Webb DJ. The effect of intra-arterial endothelin on resting blood flow and sympathetically mediated vasoconstriction in the forearm of man. Br J Clin Pharmacol 1991;31:521-4. • 3. Waugh CJ, Dockrell MEC, Haynes WG, Olverman HJ, Williams BC, Webb DJ. The potassium channel opener BRL 38227 inhibits binding of [l25I]-labelled endothelin-1 to rat cardiac membranes. Biochem Biophys Res Commun 1992;185:630-5. • 4. Haynes WG, Webb DJ. Endothelium dependent modulation of responses to endothelin-1 in human veins. Clin Sci 1993;84:427-33. • 5. Dockrell MEC, Haynes WG, Williams BC, Webb DJ. Endothelin-1 and aggregation of human platelets in vitro. J Cardiovasc Pharmacol 1993;22(suppl 8), S204-6. • 6. Haynes WG, Webb DJ. Venoconstriction to endothelin-1 in humans: role of calcium and potassium channels. Am J Physiol 1993;265:H1676-81. • 7. Haynes WG, Webb DJ. Contribution of endogenous generation of endothelin-1 to basal vascular tone. Lancet 1994;344:852-4. • 8. Haynes WG, Strachan FE, Webb DJ. Endothelin ETA and ETb receptors cause vasoconstriction of human resistance and capacitance vessels in vivo. Circulation 1995;92:357-63. • 9. Strachan FE, Haynes WG, Webb DJ. Endothelium-dependent modulation of venoconstriction to sarafotoxin S6c in human veins in vivo. J Cardiovasc Pharmacol 1995;26(suppl. 3):S 180-2. • 10. Smith PJW, McQueen DS, Webb DJ. The effect of cooling on the contractile response to endothelin-1 in small arteries from humans. J Cardiovasc Pharmacol 1995;26(suppl3):S230-2. • 11. Plumpton C, Haynes WG, Webb DJ, Davenport AP. Phosphoramidon inhibition of the in vivo conversion of big endothelin-1 to endothelin-1 in the human forearm. Br J Pharmacol 1995; 116:1821-8. • 12. Haynes WG, Moffat S, Webb DJ. An investigation into the direct and indirect venoconstrictor effects of endothelin-1 and big endothelin-1 in man. Br J Clin Pharmacol 1995;40:307-11. • 13. Haynes WG, Ferro CJ, O'Kane KPJ, Somerville D, Lomax CC, Webb DJ. Systemic endothelin receptor blockade decreases peripheral vascular resistance and blood pressure in humans. Circulation 1996;93:1860-70. • 14. Dockrell MEC, Webb DJ, Williams BC. Activation of the endothelin B receptor causes a dose-dependent accumulation of cyclic GMP in human platelets. Blood Coag Fibrinolysis 1996;7:178-80. • 15. Plumpton C, Ferro CJ, Haynes WG, Webb DJ, Davenport AP. The increase in human plasma immunoreactive endothelin but not big endothelin-1 or its C-terminal fragment induced by systemic administration of the endothelin antagonist TAK-044. Br J Pharmacol 1996;119:311-4. • 16. Haynes WG, Hand MH, Dockrell MEC, Eadington DW, Lee MR, Benjamin N, Webb DJ. Physiological role of nitric oxide in regulation of renal function in humans. Am J Physiol 1997;272:F364-71. • 17. Ferro CJ, Haynes WG, Johnston NR, Lomax CC, Newby DE, Webb DJ. The peptide endothelin receptor antagonist, TAK-044, produces sustained inhibition of endothelin1 mediated arteriolar vasoconstriction. Br J Clin Pharmacol 1997;44:377-383. • 18. Verhaar MC, Strachan FE, Newby DE, Cruden NL, Koomans HA, Rabelink TJ, Webb DJ. Endothelin-A receptor antagonist-mediated vasodilatation is attenuated by inhibition of nitric oxide synthesis and by endothelin-B receptor blockade. Circulation 1998;97:752-6. • 19. Strachan FE, Spratt JC, Wilkinson IB, Gray GA, Johnston NR, Webb DJ. Systemic blockade of the endothelin-B receptor increases peripheral vascular resistance in healthy men. Hypertension 1999;33:581-5. • SECTION 2: HYPERTENSION AND RENAL DYSFUNCTION Papers 20-24 | 20. Haynes WG, Hand MF, Johnstone HA, Padfield PL, Webb DJ. Direct and sympathetically mediated venoconstriction in essential hypertension: enhanced responses to endothelin-1. J Clin Invest 1994;94:1359-64. • 2 1. Sturrock NDC, Lang CC, MacFarlane LJ, Dockrell MEC, Ryan M, Webb DJ, Struthers AD. Serial changes in blood pressure, renal function, endothelin and lipoprotein (a) during the first 9 days of cyclosporin therapy in males. J Hypertens 1995;13:667-73. • 22. Hand MF, Haynes WG, Johnstone HA, Anderton JL, Webb DJ. Erythropoietin enhances vascular responsiveness to norepinephrine in renal failure. Kidney Int 1995;48:806-13. • 23. Ferro CJ, Spratt JCS, Haynes WG, Webb DJ. Inhibition of neutral endopeptidase causes vasoconstriction of human resistance vessels in vivo. Circulation 1998;97:2323-30. • 24. Hand MH, Haynes WG, Webb DJ. Reduced endogenous endothelin-1-mediated vascular tone in chronic renal failure. Kidney Int 1999;55:613-20. • SECTION 3 | ISCHAEMIC HEART DISEASE Papers 25-27 | 25. Wieczorek I, Haynes WG, Webb DJ, Ludlam CA, Fox KAA. Raised plasma endothelin in unstable angina and non-Q wave myocardial infarction: relation to cardiovascular outcome. Br Heart J 1994;72:436-41. • 26. Flaynes WG, Hamer DW, Robertson CE, Webb DJ. Plasma endothelin following cardiac arrest: differences between survivors and non-survivors. Resuscitation 1994;27:117-22. • 27. Newby DE, Flint LL, Fox KAA, Boon NA, Webb DJ. Reduced responsiveness to endothelin-1 in peripheral resistance vessels of patients with syndrome X. J Am Coll Cardiol 1998;31:1585-90. • SECTION 4 | HEART FAILURE AND PULMONARY HYPERTENSION Papers 28-30 | 28. Davidson NC, Coutie WJ, Webb DJ, Struthers AD. Hormonal and renal differences between low dose and high dose angiotensin converting enzyme inhibitor treatment in patients with chronic heart failure. Heart 1996;75:576-81. • 29. Love MP, Haynes WG, Gray GA, Webb DJ, McMurray JJV. Vasodilator effects of endothelin-converting enzyme inhibition and endothelin ETA receptor blockade in chronic heart failure patients treated with ACE inhibitors. Circulation 1996;94:2131-7. • 30. Prendergast B, Newby DE, Wilson LE, Webb DJ, Mankad PS. Early therapeutic experience with the endothelin antagonist, BQ-123, in pulmonary hypertension after congenital heart surgery. Heart 1999;82:505-8 • SECTION 5 | MISCELLANEOUS TOPICS AND REVIEWS Papers 31-34 and 35-46 | 31. Sanai L, Haynes WG, McKenzie A, Grant IS, Webb DJ. Endothelin production in sepsis and the adult respiratory distress syndrome. Intens Care Med 1996;22:52-6. • 32. Mickley EJ, Gray GA, Webb DJ. Activation of endothelin ETa receptors masks the constrictor role of endothelin ETg receptors in rat isolated small esenteric arteries. Br J Pharmacol 1997;120:1376-82. • 33. McEwan PE, Valdenaire O, Sutherland L, Webb DJ, Gray GA. A non-radioactive method for localization of endothelin receptor mRNA in situ. J Cardiovasc Pharmacol 1998;31(suppl l):S443-6. • 34. Smith PJW, Ferro CJ, McQueen DS, Webb DJ. Functional studies in small arteries do not support a primary role for endothelin in the pathogenesis of Raynaud's disease. J Cardiovasc Pharmacol 1998;31(suppl l):S473-6. • 35. Webb DJ. Endothelin receptors cloned, endothelin converting enzyme characterised and pathophysiology explored. TiPS 1991;12:43-6. • 36. Haynes WG, Webb DJ. The endothelin family of peptides: local hormones with diverse roles in health and disease. Clin Sci 1993;84:485-500. • 37. Haynes WG, Davenport AP, Webb DJ. Endothelin: progress in pharmacology and physiology. TiPS 1993;14:225-8. • 38. Kennedy RL, Haynes WG, Webb DJ. Endothelins as regulators of growth and function in endocrine tissues. Clin Endocrinol 1993;39:259-65. • 39. Webb DJ, Haynes WG. Endothelins come of age. Lancet 1993;342:1439-40. • 40. Webb DJ. Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure: endothelin antagonism in heart failure. Circulation 1995;92:3372. • 41. Ferro CJ, Webb DJ. The clinical potential of endothelin receptor antagonists in cardiovascular medicine. Drugs 1996;51:12-27. • 42. Gray GA, Webb DJ. The endothelin system and its potential as a therapeutic target in cardiovascular disease. Pharmacol Ther 1996;72:109-48. • 43. Newby DN, Webb DJ. The endothelin system in cardiovascular disease: discovery to drug development in under a decade. BMJ 1997;314:531-2. • 44. Webb DJ. Endothelin: from molecule to man [BPS Research Prize Lecture]. Br J Clin Pharmacol 1997;44:9-20. • Webb DJ, Monge JC, Rabelink A, Yanagisawa M. Endothelin: new discoveries and rapid progress in the clinic. Trends Pharmacol Sci 1998;19:5-8. • 46. Haynes WG, Webb DJ. Endothelin as a regulator of cardiovascular function in health and disease. J Hypertens 1998;16:1081-98

Computer modeling and signal analysis of cardiovascular physiology

This dissertation aims to study cardiovascular physiology from the cellular level to the whole heart level to the body level using numerical approaches. A mathematical model was developed to describe electromechanical interaction in the heart. The model integrates cardio-electrophysiology and cardiac mechanics through excitation-induced contraction and deformation-induced currents. A finite element based parallel simulation scheme was developed to investigate coupled electrical and mechanical functions. The developed model and numerical scheme were utilized to study cardiovascular dynamics at cellular, tissue and organ levels. The influence of ion channel blockade on cardiac alternans was investigated. It was found that the channel blocker may significantly change the critical pacing period corresponding to the onset of alternans as well as the alternans’ amplitude. The influence of electro-mechanical coupling on cardiac alternans was also investigated. The study supported the earlier assumptions that discordant alternans is induced by the interaction of conduction velocity and action potential duration restitution at high pacing rates. However, mechanical contraction may influence the spatial pattern and onset of discordant alternans. Computer algorithms were developed for analysis of human physiology. The 12-lead electrocardiography (ECG) is the gold standard for diagnosis of various cardiac abnormalities. However, disturbances and mistakes may modify physiological waves in ECG and lead to wrong diagnoses. This dissertation developed advanced signal analysis techniques and computer software to detect and suppress artifacts and errors in ECG. These algorithms can help to improve the quality of health care when integrated into medical devices or services. Moreover, computer algorithms were developed to predict patient mortality in intensive care units using various physiological measures. Models and analysis techniques developed here may help to improve the quality of health care