Machine learning approaches for early prediction of hypertension.

Hypertension afflicts one in every three adults and is a leading cause of mortality in 516, 955 patients in USA. The chronic elevation of cerebral perfusion pressure (CPP) changes the cerebrovasculature of the brain and disrupts its vasoregulation mechanisms. Reported correlations between changes in smaller cerebrovascular vessels and hypertension may be used to diagnose hypertension in its early stages, 10-15 years before the appearance of symptoms such as cognitive impairment and memory loss. Specifically, recent studies hypothesized that changes in the cerebrovasculature and CPP precede the systemic elevation of blood pressure. Currently, sphygmomanometers are used to measure repeated brachial artery pressure to diagnose hypertension after its onset. However, this method cannot detect cerebrovascular alterations that lead to adverse events which may occur prior to the onset of hypertension. The early detection and quantification of these cerebral vascular structural changes could help in predicting patients who are at a high risk of developing hypertension as well as other cerebral adverse events. This may enable early medical intervention prior to the onset of hypertension, potentially mitigating vascular-initiated end-organ damage. The goal of this dissertation is to develop a novel efficient noninvasive computer-aided diagnosis (CAD) system for the early prediction of hypertension. The developed CAD system analyzes magnetic resonance angiography (MRA) data of human brains gathered over years to detect and track cerebral vascular alterations correlated with hypertension development. This CAD system can make decisions based on available data to help physicians on predicting potential hypertensive patients before the onset of the disease

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