Hypertension_CVS-K43.ppt

Bagian Fisiologi FK USU Medan Abdul Majid/ Eka Roina MTHE PATHOPHYSIOLOGY OF HYPERTENSION

Learning ObjectivesDefine HypertensionDefine the types of hypertensionUnderstand the risk factors of developing essential hypertension.Understand the end-organ damage due to hypertension. Understand the goals and objectives of treating hypertension.

Types of hypertensionEssential (Primary) Hypertensionhypertension with no apparent cause 90-95%

Secondary Hypertensionhypertension of known cause

ESH 2003 & JNC VII(2003) > 140< 90 JNC 7 2003

ESH-ESC 2003BP ClassificationBP BPJNC VII(2003)Bp ClassificationOptimal110Isolated Systolic HypertensionIsolated Systolic Hypertension

Hypertension is defined as an arterial pressure greater than 140/90 mm Hg in adults on at least three consecutive visits to the doctor's office.Symptoms, nonspecific; headaches, fatigue, and dizziness "the silent killer"

Hypertension SyndromeIts More Than Just Blood PressureDecreased Arterial ComplianceEndothelial DysfunctionAbnormal Glucose MetabolismNeurohormonal DysfunctionRenal-Function ChangesBlood-Clotting Mechanism ChangesObesityAbnormal Insulin MetabolismLV Hypertrophy and DysfunctionAccelerated AtherogenesisAbnormal Lipid MetabolismHypertensionKannel WB. JAMA. 1996;275:1571-1576. Weber MA et al. J Hum Hypertens. 1991;5:417-423. Dzau VJ et al. J Cardiovasc Pharmacol. 1993;21(suppl 1):S1-S5.

Patho-physiology of HypertensionIn primary hypertension , the precise etiology is unknown, but it is probably multi factorialHTN develop gradually over a long period of time.The development of HTN requires the adjustment of several compensatory mechanisms over time.Several hypothesis exists for the original pathogenesis of HTN:Excess Na intakeRenal Na retentionRenal Angiotensin System (RAS)Stress & sympathetic over activityPeripheral resistancecell membrane and endothelial dysfunctionObesityinsulin resistanceGenetic susceptibility

Excess NaintakeReduced Nephron NumbersStressGenetic AlterationsObesity Endotheliumderived factorsRenal NaretentionDecreased filtrationsurfaceSympatheicOver activityRASExcessCell-membranealterationsHyperinsulinemia Fluid VolumeVenousconstriction Preload ContractibilityFunctionalconstrictionStructuralhypertrophyBlood pressure=HTNCardiac OutputPeripheral ResistanceXand/orPatho-physiology of Hypertension

Pathophysiology of blood pressure changesBLOOD PRESSURECARDIACOUTPUTPERIPHERALRESISTANCEBLOOD VOLUMECONTRACTILITYPULSE RATESTRUCTURAL HYPERTROPHYFUNCTIONAL VASOCONSTRICTIONNormalRemodelingBLOOD VISCOSITY

Renin-Angiotensin SystemThe Damaging Effects ofAngiotensin II

Renin-Angiotensin SystemAngiotensinogenAngiotensin IAngiotensin IIReninACEChymasetPACatepsinAT1-RAT2-R?BradykininInactive quininesB1-RB2-R

A-IIVasoconstrictionCell GrowthCell ProliferationAnti-NatriuresisVasodilation? Inhibition of Cell GrowthCell DifferentiationApoptosisNatruiresis

DIFFERENTIAL EFFECTS OF ANGIOTENSIN RECEPTORS Production:- aldosterone, endothelin,catecholamines, PAI-1adhesion molecules, growth factorsProduction :-Nitric OxideAT1ANG IIAT2ANG II

Effects of angiotensin II Peripheral vasoconstriction Vascular proliferation Adrenergic activity Renin secretion Aldosterone secretion Thirst mechanism Water and sodium retention Efferent arteriole vasoconstrictionAIIAT1-R

Clinical Presentationabsent in early hypertensionin advanced severe cases; hypertensive retinopathy (ie, narrowed arterioles seen on funduscopic examination), retinal hemorrhages and exudates along with swelling of the optic nerve head (papilledema)left ventricular hypertrophyrenal hypertension

IMPACT OF HYPERTENSION ON TARGET ORGANS

Retinopathy Heart diseasesStroke or TIA

Nephropathy,Proteinuria, CrCl

Peripheral arterial Disease (atherosclerotic plaque iliac,carotid, femoral artery, aorta)

Sequelae of HypertensionComplications of HTNCardiac

CNS

Vascular

Retinal

Renal

Renal ComplicationsBenign arteriolar NephrosclerosisMalignant arteriolar NephrosclerosisChronic Renal Failure

How does HT damage the kidney? RENAL ISCHEMIAGLOMERULARHYPERPRESSUREAtherosclerosisVasoconstriction of preglomerular vesselsTubulo-interstitialchangesGlomerularchangesDecrease ofthe number ofnephronsImbalanceof afferent and efferent arteriolar tone

CNS ComplicationsHypertensive encephalopathyCerebral hemorrhageIschemic strokeTIAs

Development of Central Nervous System Lesions due to HypertensionISCHEMIAHEMORRHAGEAtherosclerosisSmall vesselsHyaline SclerosisDementiaStrokeCharcot microaneurysmsLoss of Self-regulationEDEMAEncephalopathy

Retinal complicationsHypertensive retinopathy

Vascular ComplicationsArtherioscelorosis wall:lumen ratioremodelingAtherosclerosis PlaqueFibrous capnecrotic centerFibrinoid necrosis.Aortic dissection.

NormalRemodeling

Cardiac Damage in HypertensionHT is the main risk factor for heart failure and one of the main risk factors for ischemic cardiomyopathy CHF prevalence is increasing, whereas the incidence of ischemic cardiomyopathy is decreasingAntihypertensive treatment reduces ischemic heart disease risk by 16% at 10 years and up to 25% after a longer period

Cardiac Sequelae of Hypertension

Left Ventricle Hypertrophy

Heart failure

ArrhythmiasCoronary Heart Disease

Development of Cardiac Lesions due to HypertensionLEFT VENTRICULARHYPERTROPHYISCHEMIAMyocardial fibers hypertrophyGreater collagen contentHeartfailureArrhythmiasAtherosclerosis of epicardiac coronary arteriesMicrovasculardamageIschemiccardiomyopathy

Pathogenesis of LVHPressure Volume OverloadAgeGenderGeneticsRaceObesityNeurohormonal FactorsAngiotensin IIAldosteroneACE

Pathogenesis of LVHPressure Volume OverloadAgeGenderGeneticsRaceObesityNeurohormonal FactorsAngiotensin IIAldosteroneACEMyocardialIschemiaImpairedcontractilityImpairedLV FillingVentricularArrhythmiasInfarctionCongestive Heart FailureSudden Death

ObesityDM

Hypertension

SmokingDyslipidemiaDMLVHMISystolic dysfunctionDiastolic dysfunction DeathCHF Normal LV Subclinical Overtstructure and functionLV remodellingLV dysfunction heart failure Time Time(decades) (months)Progression from hypertension to heart failureArch Intern Med 1996;156

Types of hypertensionEssential (Primary) Hypertensionhypertension with no apparent cause 90-95%

Secondary Hypertensionhypertension of known cause

Causes of Secondary HTNCommonIntrinsic Renal DiseaseRenovascular DzMineralocorticoid excess/ aldosteronism? Sleep Breathing d/oUncommonPheochromocytomaGlucocorticoid excess/ Cushings dzCoarctation of AortaHyper/hypothyroidism

Renal Parenchymal DiseaseCommon cause of secondary HTN (2-5%)HTN is both cause and consequence of renal diseaseMultifactorial cause for HTN including disturbances in Na/water balance, depletion or antagonism of vasodepressors/ prostaglandins, pressor effects on TPR Renal disease from multiple etiol, treat underlying disease, dialysis/ transplant if necessary

Renovascular HTNIncidence 1-30%Etiology Atherosclerosis 75-90%Fibromuscular dysplasia 10-25%OtherAortic/renal dissectionTakayasus arteritisThrombotic/cholesterol emboliCVDPost transplantation stenosisPost radiation

Renovascular HTN - PathophysiologyDecrease in renal perfusion pressure activates RAAS, renin release converts angiotensinogen Ang I; ACE converts Ang I Ang IIAng II causes vasoconstriction (among other effects) which causes HTN and enhances adrenal release of aldosterone; leads to sodium and fluid retention Contralateral kidney (if unilateral RAS) responds with diuresis/ Na, H2O excretion which can return plasma volume to normal with sustained HTN, plasma renin activity decreases (limited usefulness for dx Bilateral RAS or solitary kidney RAS leads to rapid volume expansion and ultimate decline in renin secretion

Renovascular HTN - ClinicalHistory onset HTN age 55Sudden onset uncontrolled HTN in previously well controlled ptAccelerated/malignant HTNIntermittent pulm edema with nl LV fxnPE/LabEpigastric bruit, particulary systolic/diastolicAzotemia induced by ACEIUnilateral small kidney

Primary AldosteronismPrevalence .5- 2.0% (5-12% in referral centers)EtiologyAdrenal adenomaOther: bilat adrenal hyperplasia, glucocorticoid suppressible hyperaldo, adrenal carcinomaClinical: May be asymptomatic; headache, muscle cramps, polyuriaRetinopathy, edema uncommonHypokalemia (K normal in 40%), metabolic alkalosis, high-nl Na

Obstructive Sleep ApneaPublished reports estimate incidence of 30-80% of pt with essential HTN have OSA and 50% pt with OSA have HTN1Prospective studies show link between OSA (apneic-hyponeic index) and development of HTN independent of other risk fx2ClinicalDaytime somnolescence, am headaches, snoring or witnessed apneic episodesDx Sleep studiesRx wt loss, CPAP, surgical (UPPP)1Silverberg, et al.Curr Opinion Nephrol Hyperten 1998:7;353-3612 Peppard, et al. NEJM 2000:342:1378-1384

CommonCauses of Secondary HTNCommonIntrinsic Renal DiseaseRenovascular DzMineralocorticoid excess/ aldosteronism? Sleep Breathing d/oUncommonPheochromocytomaGlucocorticoid excess/ Cushings dzCoarctation of AortaHyper/hypothyroidism

PheochromocytomaRare cause of HTN (.1-1.0%)Tumor containing chromaffin cells which secrete catecholaminesYoung-middle age with female predominanceClinicalIntermittent HTN, palpitations, sweating, anxiety spellsMay be provoked by triggers such as tyramine-containing foods (beer,cheese,wine), pain, trauma, drugs (clonidine, TCA, opiates)

Pheochromocytoma - ScreenBest detected during or immediately after episodesLenders, et al. JAMA 2002 Mar 20;287(11):1427-34

SensitivitySpecificityPlasma free metanephrine >.66nmol/L99%89%24hr urine metanephrine(>3.7nmol/d)77% (95%)93% (96%)24 urine VMA64%95%

Pheochromocytoma - DiagnosisImaging for localization of tumorAkpunonu, et al. Dis Month.October 1996, p688

SensSpecPPVNPV(MIBG) scintigraphy78%100%100%87%CT98%70%69%98%MRI100%67%83%100%

Cushings syndrome/ hypercortisolismRare cause of secondary HTN (.1-.6%)Etiology: pituitary microadenoma, iatrogenic (steroid use), ectopic ACTH, adrenal adenomaClinicalSudden weight gain,truncal obesity, moon facies, abdominal striae, DM/glucose intolerance, HTN,prox muscle weakness, skin atrophy, hirsutism/acne

Cushings syndrome

Cushings syndrome - dxScreen:24 Hr Urine free cortisol>90ug/day is 100% sens and 98% spec false + in Polycystic Ovarian Syndrome, depressionConfirmLow dose dexamethasone suppression test 1mg dexameth. midnight, measure am plasma cortisol (>100nmol is +)Other tests include dexa/CRH suppresion testImagingCT/MRI head (pit) chest (ectopic ACTH tumor)

Coarctation of AortaCongenital defect, male>femaleClinicalDifferential systolic BP arms vs legs (=DBP)May have differential BP in arms if defect is prox to L subclavian artDiminished/absent femoral art pulseOften asymptomaticAssoc with Turners, bicuspid AVIf uncorrected 67% will develop LV failure by age 40 and 75% will die by age 50Surgical Rx, long term survival better if corrected early

Coarctation of AortaBrickner, et al. NEJM 2000;342:256-263

Hyperthyroidism33% of thyrotoxic pt develop HTNUsually obvious signs of thyrotoxicosisDx: TSH, Free T4/3, thyroid RAIURx: radioactive ablation, propanolol

Hypothyroidism25% hypothyroid pt develop HTNMechanism mediated by local control, as basal metabolism falls so does accumulation of local metabolites; relative vasoconstriction ensues

Let it beat!

ConclusionsRemember clinical/diagnostic features of common forms of secondary HTNImportant to appropriately screen pt suspected of having potentially correctable causes of HTNUnderstand limitations of screening/treatment (atherosclerotic RAS)

Hypertensive vascular diseaseHypertension not only accelerates atherosclerosis, but it also results in characteristic changes to arterioles and small arteries, include:In arteries muscular hypertrophy of the media, reduplication of the external lamina, and intimal thickeningIn arterioles hyaline arteriosclerosis (hyaline deposits in walls)

In vessels of the brain micro aneurysms (Charcot Bouchard aneurysms) can occur.

Hypertensive heart diseaseSystemic (left sided) hypertensive heart diseaseHistory of hypertension (>140/90 mmHg)Left ventricular hypertrophy (wall thickness measuring >15 mm, weighing > 500mg)Absence of any other causes of hypertrophy

Pulmonary hypertensive heart disease (cor pulmonale)Pulmonary hypertensive heart disease can defined as right ventricular hypertrophy (wall thickness measuring > 10 mm) as a result in the pulmonary circulation caused by a lung disorder

Pulmonary hypertension can be classified as either;Right ventricular hypertrophy and failure (chronic pulmonary hypertension or cor pulmonale) Acute pulmonary hypertension (a sudden onset, usually after a large pulmonary embolus)

*Increase in cardiac output in hyperthyroidism & beri-beri, increased blood volume in mineralocorticoid excess or renal failure*The renin-angiotensin system (RAS) has an effector component, which is angiotensin II. Angiotensin II is produced from angiotensinogen through renin action, which generates angiotensin I. Angiotensin I is transformed in angiotensin II through angiotensin converting enzyme (ACE). There are alternative pathways that can lead to the production of angiotensin II through the action of chimases, catepsine or tPA (tissue plasminogen activator). The meaning of these pathways in pathological states or after chronic blockage of the classic pathway has not been determined yet. Angiotensin II exerts its action by interacting with specific receptors. AT1 and AT2 are known to exist in humans. Nearly all the well known effects of angiotensin II are mediated by AT2.Another system that is partially related to the RAS is the quinine system, since ACE is involved in bradykinin degradation. *(Left panel) The degree of RAS activation varies among hypertensive patients and follows a quasi-normal distribution. However, patients with primary hyperaldosteronism have suppressed plasma renin activity, whereas patients with renovascular hypertension are in the opposite situation. (Right panel). Plasma renin activity depends on sodium intake, but there are some essential hypertensive patients who, despite high sodium intake, have high levels of RAS activity. Others have low levels and still other hypertensive patients have a medium level of RAS activity. Renin activity inHypertension (HT) Sodium Daily IntakePlasma Renin ActivityHigh ReninNormal ReninLow ReninESSENTIAL HTLowNormalHighPrimary hyperaldosteronismVasculo-renal HTEssential AHPlasma Renin Activity*Renal lesions are produced through two mechanisms. First, renal ischemia, due either to renal artery damage or to vasoconstriction of preglomerular vessels. Second, due to glomerular hyperpressure, as a result of an imbalance between afferent and efferent tone of the arteriole. Both mechanisms eventually lead to nephosclerotic glomerular disorders and tubulo-interstitial disorders. *The pathogenesis of CNS lesions can be: ischemia, which is favoured by atherosclerosis or microvascular lesions. Ischemia may lead either to stroke or to dementia. hemorrhage, as a result of Charcots microaneurysms. sudden edema, if the self-regulation ability of cerebral vessels is surpassed. As a result, blood flow increases abruptly and edema is produced. This situation occurs in hypertensive encephalopathy.*Hypertension is one of the main risk factors for the development of heart failure and one of the main predictors of ischemic cardiomyopathy. Even though antihypertensive treatment allows an initial reduction of heart failure, the incidence of this disease is on the rise. This is due to higher survival figures, which enables a greater number of subjects at risk to live longer. However, the incidence of ischemic cardiomyopathy is gradually declining. It is estimated that antihypertensive treatment reduces risk by 16%, according to data from the most important intervention studies. This figure is lower than the expected 25% reduction rate suggested by population studies. The longer the treament, the more the benefits (data from the Framinghan study).

*The factors involved in the development of these heart diseases are: left ventricular hypertrophy and remodeling, which lead to heart failure and more frequent arrhythmias, and coronary ischemia, which is produced either by lesions of the epicardial coronary arteries and/or by microvascular damage coupled with a decrease in coronary reserve.