Small artery remodelling in hypertension: causes, consequences and therapeutic implications

Essential hypertension is treated primarily with a view to reducing blood pressure, and not with regard to normalizing the main pathological changes: the peripheral resistance and the cardiovascular structure. The aim of this review is to discuss whether normalization of the latter parameters, in particular resistance vessel structure, may also be a target for therapy. The review presents first the evidence for altered structure of the resistance vasculature, an increase in the media:lumen ratio of the vessels due to inward eutrophic remodelling. Secondly the degree to which it may be possible to rectify the abnormal structure is discussed, where it is shown that there is strong evidence that this requires a therapy which causes vasodilatation in the patient concerned. Thirdly evidence is presented that altered small artery structure appears to have prognostic consequences. Fourthly, the cellular mechanisms which may be involved are discussed, where there is evidence that vasoconstriction in itself can cause inward remodelling, and that this can be prevented by vasodilators. Finally, the consequences of these findings are considered as regards clues for strategies that may be able to improve the outcome of antihypertensive therapy. The review concludes that there is reasonably strong evidence that a treatment which reduces peripheral resistance in the individual patient will, apart from reducing blood pressure, also improve the abnormal structure.

[1]  E. Schiffrin,et al.  Effect of crossing over hypertensive patients from a beta-blocker to an angiotensin receptor antagonist on resistance artery structure and on endothelial function , 2002, Journal of hypertension.

[2]  W. Hollander,et al.  Chlorothiazide: a new type of drug for the treatment of arterial hypertension. , 1957, BMQ; the Boston medical quarterly.

[3]  J. Spaan,et al.  Calcium channel blockade prevents pressure-dependent inward remodeling in isolated subendocardial resistance vessels. , 2006, American journal of physiology. Heart and circulatory physiology.

[4]  M. Mulvany,et al.  Activation of Resistance Arteries with Endothelin-1: From Vasoconstriction to Functional Adaptation and Remodeling , 2004, Journal of Vascular Research.

[5]  M. Mulvany,et al.  Small artery stucture adapts to vasodilatation rather than to blood pressure during antihypertensive treatment , 2007, Journal of hypertension.

[6]  P. Lund-johansen Haemodynamics in essential hypertension. , 1980, Clinical science.

[7]  P. Friberg,et al.  Candesartan cilexetil in hypertension: effects of six weeks' treatment on haemodynamics, baroreceptor sensitivity and the renin-angiotensin-aldosterone system. , 1999, Blood pressure.

[8]  E. Schiffrin,et al.  Endothelium-dependent relaxation of small arteries from essential hypertensive patients: mechanisms and comparison with normotensive subjects and with responses of vessels from spontaneously hypertensive rats. , 1995, Clinical science.

[9]  E. Schiffrin,et al.  Structure and function of resistance arteries of hypertensive patients treated with a p-blocker or a calcium channel antagonist , 1996, Journal of hypertension.

[10]  Mauro Piacentini,et al.  Transglutaminase 2: an enigmatic enzyme with diverse functions. , 2002, Trends in biochemical sciences.

[11]  N. Markandu,et al.  Structural skin capillary rarefaction in essential hypertension. , 1999, Hypertension.

[12]  E. Schiffrin,et al.  Blunted effects of endothelin upon small subcutaneous resistance arteries of mild essential hypertensive patients. , 1992, Journal of hypertension.

[13]  B. Davis,et al.  Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). , 2002, JAMA.

[14]  Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. , 1967, JAMA.

[15]  P. Lund-johansen Hemodynamic changes in long-term diuretic therapy of essential hypertension. A comparative study of chlorthalidone, polythiazide and hydrochlorothiazide. , 2009, Acta medica Scandinavica.

[16]  M. Mulvany,et al.  Chronic Cystamine Treatment Inhibits Small Artery Remodelling in Rats , 2007, Journal of Vascular Research.

[17]  Adrian Pistea,et al.  Flow-Dependent Remodeling of Small Arteries in Mice Deficient for Tissue-Type Transglutaminase: Possible Compensation by Macrophage-Derived Factor XIII , 2006, Circulation research.

[18]  W. Burke,et al.  Occurrence of a new class of tetrahydroisoquinoline alkaloids in L-dopa-treated parkinsonian patients , 1977, Nature.

[19]  J. Mullins,et al.  &agr;V Integrins Are Necessary for Eutrophic Inward Remodeling of Small Arteries in Hypertension , 2006, Hypertension.

[20]  Ulrich Pohl,et al.  Acute mechanoadaptation of vascular smooth muscle cells in response to continuous arteriolar vasoconstriction: implications for functional remodeling , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[21]  S. Oparil,et al.  Pulsology rediscovered: commentary on the Conduit Artery Function Evaluation (CAFE) study. , 2006, Circulation.

[22]  M. Mulvany,et al.  Vasodilatation, not hypotension, improves resistance vessel design during treatment of essential hypertension: a literature survey , 2001, Journal of hypertension.

[23]  Rita Casadio,et al.  Transglutaminases: nature's biological glues. , 2002, The Biochemical journal.

[24]  A. Heagerty,et al.  Evidence for increased media thickness, increased neuronal amine uptake, and depressed excitation--contraction coupling in isolated resistance vessels from essential hypertensives. , 1987, Circulation research.

[25]  S. Oparil,et al.  Effects of candesartan cilexetil in patients with systemic hypertension. Candesartan Cilexetil Study Investigators. , 1998, The American journal of cardiology.

[26]  C. de Ciuceis,et al.  Prognostic Significance of Small-Artery Structure in Hypertension , 2003, Circulation.

[27]  IanSchofield,et al.  Vascular Structural and Functional Changes in Type 2 Diabetes Mellitus , 2002 .

[28]  M. Mulvany,et al.  Mechanical properties of vascular smooth muscle cells in situ , 1976, Nature.

[29]  M. Mulvany,et al.  Effect of antihypertensive treatment on small arteries of patients with previously untreated essential hypertension. , 1995, Hypertension.

[30]  M. Mulvany,et al.  Small artery structure in hypertension. Dual processes of remodeling and growth. , 1993, Hypertension.

[31]  M. Mulvany,et al.  Histology of subcutaneous small arteries from patients with essential hypertension. , 1993, Hypertension.

[32]  E. Porteri,et al.  Structural Alterations in Subcutaneous Small Arteries of Normotensive and Hypertensive Patients With Non–Insulin-Dependent Diabetes Mellitus , 2001, Circulation.

[33]  E. vanBavel,et al.  Organoid culture of cannulated rat resistance arteries: effect of serum factors on vasoactivity and remodeling. , 2000, American journal of physiology. Heart and circulatory physiology.

[34]  K. Thygesen,et al.  Small artery structure is an independent predictor of cardiovascular events in essential hypertension , 2006, Journal of hypertension.

[35]  C. Reid,et al.  A comparison of outcomes with angiotensin-converting--enzyme inhibitors and diuretics for hypertension in the elderly. , 2003, The New England journal of medicine.

[36]  MRC trial of treatment of mild hypertension: principal results. Medical Research Council Working Party. , 1985, British medical journal.

[37]  S. Oparil,et al.  Effects of candesartan cilexetil in patients with severe systemic hypertension. Candesartan Cilexetil Study Investigators. , 1998, The American journal of cardiology.

[38]  L. Fratta,et al.  Cardiovascular Influences of &agr;1b-Adrenergic Receptor Defect in Mice , 2002, Circulation.

[39]  E. Schiffrin,et al.  Correction of arterial structure and endothelial dysfunction in human essential hypertension by the angiotensin receptor antagonist losartan. , 2000, Circulation.

[40]  E. Porteri,et al.  Vascular hypertrophy and remodeling in secondary hypertension. , 1996, Hypertension.

[41]  M. Mulvany,et al.  Dose-dependent effects of perindopril on blood pressure and small-artery structure. , 1994, Hypertension.

[42]  K. Thygesen,et al.  Effect of antihypertensive treatment on cardiac and subcutaneous artery structure: a comparison between calcium channel blocker and thiazide-based regimens. , 1998, American journal of hypertension.

[43]  E. Schiffrin,et al.  Effects of a beta-blocker or a converting enzyme inhibitor on resistance arteries in essential hypertension. , 1994, Hypertension.

[44]  Hans Eiskjær,et al.  Treatment of Young Subjects at High Familial Risk of Future Hypertension With an Angiotensin-Receptor Blocker , 2007, Hypertension.

[45]  P. Okin,et al.  Prognostic implications of left ventricular hypertrophy. , 2001, American heart journal.

[46]  A. Heagerty,et al.  In vitro perfusion studies of human resistance artery function in essential hypertension. , 1994, Hypertension.

[47]  B. Strauer,et al.  Structural and functional alterations of the intramyocardial coronary arterioles in patients with arterial hypertension. , 1993, Circulation.

[48]  R. Zulli,et al.  Media: lumen ratio in human small resistance arteries is related to forearm minimal vascular resistance , 1995, Journal of hypertension.

[49]  S. Oparil,et al.  Feasibility of treating prehypertension with an angiotensin-receptor blocker. , 2006, The New England journal of medicine.

[50]  Vincent Everts,et al.  Inward Remodeling Follows Chronic Vasoconstriction in Isolated Resistance Arteries , 2002, Journal of Vascular Research.

[51]  H. Schunkert A dream yet to become true. , 2007, Hypertension.

[52]  S. Laurent,et al.  Aortic Stiffness Is an Independent Predictor of Primary Coronary Events in Hypertensive Patients: A Longitudinal Study , 2002, Hypertension.

[53]  M. Omura,et al.  Prospective study on the prevalence of secondary hypertension among hypertensive patients visiting a general outpatient clinic in Japan. , 2004, Hypertension research : official journal of the Japanese Society of Hypertension.

[54]  Jop Perree,et al.  Small Artery Remodeling Depends on Tissue-Type Transglutaminase , 2004, Circulation research.

[55]  K. Thygesen,et al.  Myocardial Perfusion During Long-Term Angiotensin-Converting Enzyme Inhibition or &bgr;-Blockade in Patients With Essential Hypertension , 2004, Hypertension.

[56]  B. Strauer,et al.  Left ventricular remodeling impairs coronary flow reserve in hypertensive patients , 2002, Journal of hypertension.

[57]  M. Nieminen,et al.  For Personal Use. Only Reproduce with Permission from the Lancet Publishing Group , 2022 .

[58]  G. Grassi,et al.  Sympathetic activation in the pathogenesis of hypertension and progression of organ damage. , 1999, Hypertension.

[59]  O. N. Mathiassen,et al.  Forearm plethysmography in the assessment of vascular tone and resistance vasculature design: new methodological insights , 2006, Acta physiologica.