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Structural and functional changes in the artery wall in hypertension
AJH-APRJL 1997-VOL. 10, NO. 4, PART 2
W U D
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SPECIAL SYMPOSIA
C 3 p T O
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C 3 ep T O
Preventionof CerebralConsequencesof Hypertension JD Spence,Universityof WesternOntario,London,Canada
Preventionof MyocardialDamagein Hypertension HarakirnbosGavras, M.D., Boston University School of Medicine,Boston,MA
High bloodpressurecauses strokesdue to fibrinoidnecrosis and hyalinedegenerationof small resistancevessels, so treatinghigh blood pressurepreventslacunarinfarctionsand intracerebralhemorrhages.
AngiotensirrII (Ang11)has longbeen knownas a piXent vasconstrictorand stimulatorof adrenal steroid synthesis. The coromry, renal and cerebralvasculafnreare far more sensitiveto the pressoreffectof Ang II than vascrdafureof musculocutaneoustissues. Ang 11excess is cardiotoxic, causingwidespreadareas of myocardialnecrosis. Ang II receptorblcckadeor angiotensin-converging enzyme(ACE) inhibitionincreaseregionatbloodflowsto vifatorgans and exertcardioprotectiveand renoprotectiveeffects. They can also reverse cerebral vasospasm following subarachnoid hemorrhage. More recentlyAng II has been recognizedto havetrophicand mitogenicactionsin selectedtissues, thus causinghypertrophyand/orproliferationof cardiomyocytes andvascnfarsmoothmusclecells. ChronicACE inhibition, even in nonhypotenaivedoses, was shown to reverse left ventricular hypertrophy and vascular wall thickening in hypertensivesubjects. Comparativeexperimentsusing an ACE inhibitor and a selective AT, receptor antagonist suggest that the systemic hemodynarniceffects of ACE inhibitionare mostJydue to suppressionof Ang II, whereas regionaltissueeffectsare partlymediatedby bradykininand local autacoids. The favorablehemodynarnicpropertiesof ACE inhibition haveafreadyestablishedthisclassof drugs as a treatmentof choicein hypertensionand congestiveheart faifure. Ang 11 receptor blockade has the same clinical eftlcacy in the treatrnenfof theseconditions,withoutthe ticfdishdry cough which is the most connnon cause of intoleranceto ACE inhibition.
An importantprinciplein managementof in hypertensive emergenciesis that abruptdrops in blood pressureshould be avoided;this meansthat sublingualnifedipine,intramuscular hydralazineand other treatmentsthat cannotbe controlled shouldnot be used. Atheroscleroticstrokesare not affectedto any great extent by loweringblood pressure;in orderto prevent strokesit is thereforeimportantto treat atheroscleroticrisk factors,use antiplateletagents,anticoagulantsand carotid endarterectomy in appropriatecases, In most cases this means appropriate selectionof high risk patients. Patientswith carotidstenosishave a NumberNeededto be Treated(NNT)by endarterectomy,of 4 patients with symptomsvs 29 without symptoms,to prevent 1 ipsilaterrd strokein 3 years; 6.5 patientswith aaymptomaticcarotid stenosismust be treatedonly 4 years with lipid loweringto preventa myocardialinfwction;this compareswith an NNT of 26 patientsfor 6 years, for treatmentof isolated systolic hypertensionto preventa stroke.
KeyWords: KeyWords:
237A
a
AngiotensinII, ACEInhibition,AT, receptor inhibition,cardioprotection
Stroke,Antiplateletagents, Lipids, Surgery
W M E o H t A V
2
B A
STRUCTURAL AND FUNCTIONAL ARTERY WALL IN HYPERTENSION
C 7 a
p D
CHANGES
W M E o H t A V
o IN THE
M.J. Mulvany. Department of Pharmacology, University Aarhus, University Park 240, 8000 Aarhus C., Denmark.
of
Essential hypertension is associated with a decrease in the lumen diameter and an increase in the wall thickness to lumen diameter ratio of the resistance vessels. Recently it has been clarified that this alteration does not necessarily involve vascular growth, but could be due to a rearrangement of the same amount of material (Baumbach & Heistad, Hypertension 13, 968-972, 1989), a phenomenon termed “eutrophic remodeling” (Mulvany et al. Hypertension 28,505-506, 1996). In essential hypertension, the changes seen in subcutaneous small arleries appear mainly due to eutrophic remodeling and only slightly to growth (Heagerfy et al., Hypertension 22, 523-526, 1993). In spontaneously hypertensive rats (SHR), the remodeling of small arteries is eutrophic, and hypotrophic in arterioles (Thybo et al., Hypertension 23, 659-666, 1994; Skov et al. Hypertension 26: 464-471, 1996). Antihypertensive treatment of SHR with ACE-inhibitors causes dose-dependent regression of the media:lumen ratio of small arteries and arterioles (Thybo et al., Skov et al., ibid). Clinical studies confirm these findings, showing that when previously untreated essential hypertensive patients are treated with the ACE-inhibitor perindopril, the abnormal structure of resistance vessels regresses towards normal values; in contrast, treatment with the beta-blocker atenolol does not affect the abnormal vascular structure (Schiffrin et al., Hypertension 23, 83-91, 1994; Thybo et al., Hypertension 25,474-481, 1995). The evidence thus indicates that ACE-inhibitors can normalise the abnormal resistance vessel structure seen in essential hypertension, an effect not only dependent on their ability to reduce blood pressure, Key Words: resistance vessels, remodeling, therapy
hypertension,
2 y
B A
C 7 ep a D a
a o
NewConceptsandMethodsforEvatrradngArterialStiffness I&n J. Bank,Universityof Minnesota,Minneapolis,MN. Wehavedevelo~ a newintravascularultraaourxt(IVUS) techniqueto measurehumanbrsctsistarteryelasticpropertiesin vivo. A 30MHz,3.5FfVUScatheteris placedthough a sheatlr intothebrachialartery. Intra-arterialpressure(P)is measured rfrroughfiesheathsidearm TransmuralP is reducedby intlatinganup~r srrnbloodpressurecuffcentesedovwthe IVUScatheterandcalculatedaaintra-arteristminuscuffP. Uhaound imagesandsimultaneousarterialP arerecordedon videotape,digitisedandanatyzedoff-line.Usingthistechnique, transmrrralP, croaa-sectionat area(A)andwatlthicknesswere measuredat baselineandfollowingintia-artcrislinfusionof norepinephrine (1.2mcg)andnitroglycexhr (100mcg)in normal bumsnsubjects.Artairdcompliance(C),unstmwedA, atm?ss, strain,elasticmodulus(E)andpulsewavevelocity(PWV)wme csfculatedovera P rangefromOto ltXJnrnrHg.P vs A and stressvs atrsindatawerefittedtu anon-linearsrctangent equation(r> 0.96forindividualcurves).Nitmglycmin signiticsntfy(pcO.05)decreasedA,C andPWVovertheentire presaurerangebutdidma changeE. NT(IshiftedtheatmssstrshrandE-strahrcnrve$towardthestrrdnaxis. Norepineptrrine producedsirnihrchangesinoppositedirections.Usinga moditiedMaxweUmodelweestimatedthecontributionsof collagen,elaatin,andsmoothmuscleto hnrnanbmchistartery waflmechanicsandcatcnlatedE ofelastinas 3 x 106dynes/cm2 andecdlagenfiberrecmitsnentat IOOmnrHgas5-6%under eachcondition.Afthorrgh thistechniqueis invasiveandnot applicableto largegroupsofpadenrs,it offersUKopporhudtytn m-e a numberofvadatdeaforthefirsttimein human subjectsin vivo,including:1)unstm?.saed aeteriafarea,2) effects ofisnmetdccontractionw relaxationon wattatmssandE, and 3)pressure-are& sfrms-strrdnarsdE-straincurvesovera wide rangeof pressureandsruonthmuscletone.
KeyWords:
compliance;elsstic mndufus;brachhd arteq; smoothmuaclejntiavascularuftrasmnsd
f r
y
W U D
M i H
2
B a
SPECIAL SYMPOSIA
C 3 p T O
W U D
M i H
2
B y a
C 3 ep T O
Preventionof CerebralConsequencesof Hypertension JD Spence,Universityof WesternOntario,London,Canada
Preventionof MyocardialDamagein Hypertension HarakirnbosGavras, M.D., Boston University School of Medicine,Boston,MA
High bloodpressurecauses strokesdue to fibrinoidnecrosis and hyalinedegenerationof small resistancevessels, so treatinghigh blood pressurepreventslacunarinfarctionsand intracerebralhemorrhages.
AngiotensirrII (Ang11)has longbeen knownas a piXent vasconstrictorand stimulatorof adrenal steroid synthesis. The coromry, renal and cerebralvasculafnreare far more sensitiveto the pressoreffectof Ang II than vascrdafureof musculocutaneoustissues. Ang 11excess is cardiotoxic, causingwidespreadareas of myocardialnecrosis. Ang II receptorblcckadeor angiotensin-converging enzyme(ACE) inhibitionincreaseregionatbloodflowsto vifatorgans and exertcardioprotectiveand renoprotectiveeffects. They can also reverse cerebral vasospasm following subarachnoid hemorrhage. More recentlyAng II has been recognizedto havetrophicand mitogenicactionsin selectedtissues, thus causinghypertrophyand/orproliferationof cardiomyocytes andvascnfarsmoothmusclecells. ChronicACE inhibition, even in nonhypotenaivedoses, was shown to reverse left ventricular hypertrophy and vascular wall thickening in hypertensivesubjects. Comparativeexperimentsusing an ACE inhibitor and a selective AT, receptor antagonist suggest that the systemic hemodynarniceffects of ACE inhibitionare mostJydue to suppressionof Ang II, whereas regionaltissueeffectsare partlymediatedby bradykininand local autacoids. The favorablehemodynarnicpropertiesof ACE inhibition haveafreadyestablishedthisclassof drugs as a treatmentof choicein hypertensionand congestiveheart faifure. Ang 11 receptor blockade has the same clinical eftlcacy in the treatrnenfof theseconditions,withoutthe ticfdishdry cough which is the most connnon cause of intoleranceto ACE inhibition.
An importantprinciplein managementof in hypertensive emergenciesis that abruptdrops in blood pressureshould be avoided;this meansthat sublingualnifedipine,intramuscular hydralazineand other treatmentsthat cannotbe controlled shouldnot be used. Atheroscleroticstrokesare not affectedto any great extent by loweringblood pressure;in orderto prevent strokesit is thereforeimportantto treat atheroscleroticrisk factors,use antiplateletagents,anticoagulantsand carotid endarterectomy in appropriatecases, In most cases this means appropriate selectionof high risk patients. Patientswith carotidstenosishave a NumberNeededto be Treated(NNT)by endarterectomy,of 4 patients with symptomsvs 29 without symptoms,to prevent 1 ipsilaterrd strokein 3 years; 6.5 patientswith aaymptomaticcarotid stenosismust be treatedonly 4 years with lipid loweringto preventa myocardialinfwction;this compareswith an NNT of 26 patientsfor 6 years, for treatmentof isolated systolic hypertensionto preventa stroke.
KeyWords: KeyWords:
237A
a
AngiotensinII, ACEInhibition,AT, receptor inhibition,cardioprotection
Stroke,Antiplateletagents, Lipids, Surgery
W M E o H t A V
2
B A
STRUCTURAL AND FUNCTIONAL ARTERY WALL IN HYPERTENSION
C 7 a
p D
CHANGES
W M E o H t A V
o IN THE
M.J. Mulvany. Department of Pharmacology, University Aarhus, University Park 240, 8000 Aarhus C., Denmark.
of
Essential hypertension is associated with a decrease in the lumen diameter and an increase in the wall thickness to lumen diameter ratio of the resistance vessels. Recently it has been clarified that this alteration does not necessarily involve vascular growth, but could be due to a rearrangement of the same amount of material (Baumbach & Heistad, Hypertension 13, 968-972, 1989), a phenomenon termed “eutrophic remodeling” (Mulvany et al. Hypertension 28,505-506, 1996). In essential hypertension, the changes seen in subcutaneous small arleries appear mainly due to eutrophic remodeling and only slightly to growth (Heagerfy et al., Hypertension 22, 523-526, 1993). In spontaneously hypertensive rats (SHR), the remodeling of small arteries is eutrophic, and hypotrophic in arterioles (Thybo et al., Hypertension 23, 659-666, 1994; Skov et al. Hypertension 26: 464-471, 1996). Antihypertensive treatment of SHR with ACE-inhibitors causes dose-dependent regression of the media:lumen ratio of small arteries and arterioles (Thybo et al., Skov et al., ibid). Clinical studies confirm these findings, showing that when previously untreated essential hypertensive patients are treated with the ACE-inhibitor perindopril, the abnormal structure of resistance vessels regresses towards normal values; in contrast, treatment with the beta-blocker atenolol does not affect the abnormal vascular structure (Schiffrin et al., Hypertension 23, 83-91, 1994; Thybo et al., Hypertension 25,474-481, 1995). The evidence thus indicates that ACE-inhibitors can normalise the abnormal resistance vessel structure seen in essential hypertension, an effect not only dependent on their ability to reduce blood pressure, Key Words: resistance vessels, remodeling, therapy
hypertension,
2 y
B A
C 7 ep a D a
a o
NewConceptsandMethodsforEvatrradngArterialStiffness I&n J. Bank,Universityof Minnesota,Minneapolis,MN. Wehavedevelo~ a newintravascularultraaourxt(IVUS) techniqueto measurehumanbrsctsistarteryelasticpropertiesin vivo. A 30MHz,3.5FfVUScatheteris placedthough a sheatlr intothebrachialartery. Intra-arterialpressure(P)is measured rfrroughfiesheathsidearm TransmuralP is reducedby intlatinganup~r srrnbloodpressurecuffcentesedovwthe IVUScatheterandcalculatedaaintra-arteristminuscuffP. Uhaound imagesandsimultaneousarterialP arerecordedon videotape,digitisedandanatyzedoff-line.Usingthistechnique, transmrrralP, croaa-sectionat area(A)andwatlthicknesswere measuredat baselineandfollowingintia-artcrislinfusionof norepinephrine (1.2mcg)andnitroglycexhr (100mcg)in normal bumsnsubjects.Artairdcompliance(C),unstmwedA, atm?ss, strain,elasticmodulus(E)andpulsewavevelocity(PWV)wme csfculatedovera P rangefromOto ltXJnrnrHg.P vs A and stressvs atrsindatawerefittedtu anon-linearsrctangent equation(r> 0.96forindividualcurves).Nitmglycmin signiticsntfy(pcO.05)decreasedA,C andPWVovertheentire presaurerangebutdidma changeE. NT(IshiftedtheatmssstrshrandE-strahrcnrve$towardthestrrdnaxis. Norepineptrrine producedsirnihrchangesinoppositedirections.Usinga moditiedMaxweUmodelweestimatedthecontributionsof collagen,elaatin,andsmoothmuscleto hnrnanbmchistartery waflmechanicsandcatcnlatedE ofelastinas 3 x 106dynes/cm2 andecdlagenfiberrecmitsnentat IOOmnrHgas5-6%under eachcondition.Afthorrgh thistechniqueis invasiveandnot applicableto largegroupsofpadenrs,it offersUKopporhudtytn m-e a numberofvadatdeaforthefirsttimein human subjectsin vivo,including:1)unstm?.saed aeteriafarea,2) effects ofisnmetdccontractionw relaxationon wattatmssandE, and 3)pressure-are& sfrms-strrdnarsdE-straincurvesovera wide rangeof pressureandsruonthmuscletone.
KeyWords:
compliance;elsstic mndufus;brachhd arteq; smoothmuaclejntiavascularuftrasmnsd
f r
y