Systemic Hypertension: Mechanisms and Diagnosis

Systemic Hypertension: Therapy

Presenter: Cheng-Han Lee

Supervisor: Wei-Chuan Tsai

Heart Disease

Braunwald

BP Measurement Techniques

Method Brief Description

In-office Two readings, 5 minutes apart, sitting in chair. Confirm elevated reading in contralateral arm.

Ambulatory BP monitoring

Indicated for evaluation of “white-coat” HTN. Absence of 10–20% BP decrease during sleep may indicate increased CVD risk.

Self-measurement Provides information on response to therapy. May help improve adherence to therapy and evaluate “white-coat” HTN.

Measurement of BP

Elevated BP soon after awakening Usual nocturnal fall in BP Exaggerated response in normotensive adul

ts rise in SBP ≧60mmHg at 5 mins of exercise

(6.3METS) or ≧70mmHg at 10 mins or rise in DBP ≧10mmHg at any time

≧3-fold HTN over 5-15 years

Ambulatory BP monitoring

Components of Cardiovascular Risk Stratificai

ton in Patients with HypertensionComponents of Cardiovascular Risk Stratificai

ton in Patients with Hypertension

Major Risk FactorsMajor Risk FactorsSmokingSmokingDyslipidemiaDyslipidemiaDiabetes mellitusDiabetes mellitusAge older than 60 yearsAge older than 60 yearsSex (men and postmenopausal women)Sex (men and postmenopausal women)Family history of cardiovascular disease:Family history of cardiovascular disease:

women under age 65 or men under age 55women under age 65 or men under age 55

Stroke and CAD Vs Diastolic BP

Cardiovascular risks of HTN

Components of Cardiovascular Risk Stratificai

ton in Patients with HypertensionComponents of Cardiovascular Risk Stratificai

ton in Patients with Hypertension

Target Organ Damage/Clinical Cardiovascular Target Organ Damage/Clinical Cardiovascular DiseaseDisease

Heart diseasesHeart diseases** Left ventricular hypertrophyLeft ventricular hypertrophy** Angina/prior myocardial infarctionAngina/prior myocardial infarction** Prior coronary revascularizationPrior coronary revascularization** Heart failureHeart failureStroke or transient ischemic attackStroke or transient ischemic attackNephropathyNephropathyPeripheral arterial diseasePeripheral arterial diseaseRetinopathyRetinopathy

HTN Vs LVH

HTN Vs CHF

Mechanisms of Primary HTNLow birth weight

Neurohumoral causes of primary HTN

Sympathetic nervous hyperactivity Renin-Angiotensin system Hyperinsulinemia/insulin resistence Endothelial cell dysfunction

Renin-Angiotensin system

Hyperinsulinemia/insulin resistence

Endothelial Dysfunction

Types of HTN

Essential (primary or idiopathic) HTN Secondary HTN (identifiable etiologies) Systolic HTN

Increased cardiac output

AR, AVF, PDA, Thyrotoxicosis, Paget

disease of bone, beriberi, hyperkinetic

Rigidity of aorta (atherosclerosis)

Secondary HTN

Secondary” HTN accounts for ~5-10% of other cases and represents potentially curable disease

Often overlooked and underscreened Controversy over screening and treatment i

n some cases

Features of Inappropriate hypertension

1. 1. Onset before age 20 or after age 50Onset before age 20 or after age 502.  2.  Level of BP > 180/110 mmHgLevel of BP > 180/110 mmHg3. 3. Organ damageOrgan damage              A. A. Funduscopic findings of grade 2 or higherFunduscopic findings of grade 2 or higher              B. B. Serum creatinine > 1.5 mg/100mlSerum creatinine > 1.5 mg/100ml              C. C. Cardiomegaly or LVHCardiomegaly or LVH4. 4. Feature indicative of secondary causesFeature indicative of secondary causes              A. A. Unprovoked hypokalemiaUnprovoked hypokalemia              B. B. Abdominal bruitAbdominal bruit            C. C. Variable pressure with tachycardia, sweating.Variable pressure with tachycardia, sweating.              D. D. Family history of renal disease Family history of renal disease 5. 5. Poor response to therapyPoor response to therapy

Causes of Secondary HTN

Common Intrinsic Renal Disea

se(GN, PCD..) Renovascular Dz Mineralocorticoid exc

ess/ aldosteronism Neurological disorder

s (sleep apnea, IICP..)

Uncommon Pheochromocytoma Glucocorticoid exces

s/ Cushing’s dz Coarctation of Aorta Hyper/hypothyroidis

m

Oral contraceptive and postmenopausal estrogen

The most common cause of 2nd HTN in young women----oral contraceptive

5% within 5 years develop HTN Easy develop if women> 35ys, obese or

drink large alcohol Most adverse effects develop with more

than 50ug of estrogen When discontinued, BP falls to normal within

3-6 months in about 50% patients

Renal parenchymal disease

The most common cause of 2nd HTN-2-5%

Renovascular HTN Incidence: < 1% Type: Atherosclerosis: 65%, pr

oximal 2cm, progression in 50% Fibromuscular dysplasia

(medial): 35%, midportion or distal segme

nt, branch; progression in 33% Others--Other

Aortic/renal dissection Takayasu’s arteritis Thrombotic/cholesterol embo

li CVD Post transplantation stenosis Post radiation

Renovascular HTN - Pathophysiology

Decrease in renal perfusion pressure activates RAAS, renin release converts angiotensinogen Ang I; ACE converts Ang I Ang II

Ang II causes vasoconstriction (among other effects) which causes HTN and enhances adrenal release of aldosterone; leads to sodium and fluid retention

Renovascular HTN - Clinical History

Sudden onset uncontrolled HTN in previously well controlled pt

Accelerated/malignant HTN Intermittent pulm edema

PE/Lab Epigastric bruit, particulary systolic/diastoli

c Azotemia induced by ACEI Unilateral small kidney

Clinical index of suspicion Low (should not be tested) borderline, mild, or moderate HTN, in the absence of clinical clues

Moderate (noninvasive tests ) 1. severe HTN (DBP>120mmHg)

2. HTN refractory to standard treatment

3. Abrupt sustained, moderate to severe HTN at age<20 or >50

4. HTN with a suggestive abdominal bruit

5. Moderate HTN (DBP>105) in a smoker, occlusive vascular

disease

6. Normalization of BP by ACE i , particular in smoker or recent

HTN

Clinical index of suspicion

High (may consider direct angiography) 1.Severe HTN (DBP>120 with renal insufficiency or refractory

medical therapy) especially in smoker or occlusive artery dz.

2. Accelerated or malignant HTN (grade 3 or 4 retinopathy)

3. HTN with recent elevated creatinine (ACEi induce or normalize)

4. Moderate to severe HTN with incidentally detected asymmetry

of renal size.

RAS screening/diagnosticsSens Spec Limitation/Etc

Duplex U/S90-

95%60-

90%

Operator dependent

Captopril Renography

73-100%

73-95%

Meds, accuracy reduced in pt with renal insufficiency, lacks anatomical info; good predictor of BP response

MRA88-

95%95%

False positive artifact resp, peristalsis, tortuous vessels; cost

AngiographyGold std

Gold std

Invasive, nephrotoxicity, little value in predicting BP response

Adrenal causes of HTN

Primary Aldosteronism Cushing Syndrome Congenital adrenal hyperplasia Pheochromocytoma

Primary Aldosteronism Etiology

Adrenal adenoma Other: bilat adrenal hyperplasia (1/3), glucocorticoid s

uppressible hyperaldo, Licorice, Liddle syndrome, adrenal carcinoma

Clinical: May be asymptomatic; headache, muscle cramps, polyu

ria Retinopathy, edema uncommon Hypokalemia (K normal in 40%), metabolic alkalosis,

high-nl Na

Primary Aldosteronism

Familial glucocorticoid-suppressible aldosteronism

1. unequal crossing over of CYP11B1 (11beta-hydroxylase gene)

and CYP11B2 (aldosterone synthase gene) during meiosis,

producing a fusion product that couples the ACTH-sensitive

promoter of CYP11B1 to the CYP11B2 gene

2. ACTH-dependent aldosterone production and production of 17-

hydroxylated analogs of 18-hydroxycortisol under ACTH regulation

from ectopic enzyme expression in the zona fasciculata.

Primary Aldosteronism

Hypokalemia, metabolic alkalosis and urinary K excretion > 30mmol/day

Screening test: serum Aldo/renin> 30

Primary Aldosteronism

Solitary adenoma surgery Bilateral adrenal hyperplasia spironolacto

ne

Cushing Syndrome

24h urine free cortisol> 90-100ug

Diagnosis Screening test: 1. 24h urine free cortisol level 2. Overnight dexamethasone 1mg suppression ( normal cortisol at 8am: <2ug/100mg) specificity: 87% 3. 0.5mg q6h for 2 days dexa. specificity: 100% Confirm test: 1. high dose 2mg q6h for 2 days dexa. cortisol was suppressed to <40% control pituitary origin 2. Plasma ACTH and cortisol at 4pm or later A. plasma cortisol >15 mg/dl and the corticotropin concentration is less than 5 pg/dl, cortisol secretion is corticotropin-independent B. plasma corticotropin > 15 pg /ml, the cortisol secretion is corticotropin-dependent

Features Suggestive of Pheochromocytoma

Hypertension: Persistent or Paroxysmal Markedly variable blood pressures (± orthostatic hypotension)

Sudden paroxysms (± subsequent hypertension) in relation to   Stress: anesthesia, angiography

  Pharmacological provocation: histamine, nicotine, caffeine, beta blockers, glucocorticoids, tricyclic antidepressants

  Manipulation of tumors: abdominal palpation, urination Rare patients persistently normotensive Unusual settings  Childhood, pregnancy, familial   Multiple endocrine adenomas: medullary carcinoma of the thyroid

(MEN-2), mucosal neuromas (MEN-2B)  Neurocutaneous lesions: neurofibromatosis

Associated SymptomsSudden spells with headache, sweating, palpitations, nervousness, nausea, and vomitingPain in chest or abdomen-associated SignsSweating, tachycardia, arrhythmia, pallor, weight loss

Pheochromocytoma

85% arise in adrenal medulla 10% are bilateral 10% are malignant Epinephrine from adrenal medulla Norepinephrine from extraadrenal tumors May be provoked by triggers such as tyramine-con

taining foods (beer,cheese,wine), pain, trauma, drugs (clonidine, TCA, opiates)

Pheochromocytoma - Screen Best detected during or immediately

after episodesSensitivity Specificity

Plasma free metanephrine >.66nmol/L

99% 89%

24hr urine metanephrine

(>3.7nmol/d)

77% (95%) 93% (96%)

24 urine VMA 64% 95%

Lenders, et al. JAMA 2002 Mar 20;287(11):1427-34

Pheochromocytoma - treatment Surgical removal of tumor

Anesthesia- avoid benzo, barbiturates or demerol which can trigger catechol release

Complications include ligation of renal artery, post op hypoglycemia, hemorrhage and volume loss

Mortality 2%, 5 yr survival 95% with <10% recurrence

Caution with Beta blocker – can cause unopposed alpha stimulation/pheo crisis

BP control with alpha blockers (phentolamine, phenoxybenzamine, and prazosin)

Coarctation of Aorta

Just beyond the origin of left subclavian a. or distal to the insertion of the ligmentum arteriosum

Coarctation of Aorta

Congenital defect, male>female Clinical

Differential systolic BP arms vs legs (=DBP) May have differential BP in arms if defect is prox to L su

bclavian art Diminished/absent femoral a. pulse Often asymptomatic Assoc with Turners, bicuspid AV

If uncorrected 67% will develop LV failure by age 40 and 75% will die by age 50

Surgical Rx, long term survival better if corrected early

Hypertension during pregnancy

Chronic HTN before GA 20 weeks Gestational HTN after GA 20 weeks more frequent in primigravid or in subsequent pregnancy with a d

ifferent father, increased age, black, multiple gestations, concomitant renal and heart disease

Preeclampsia gestational HTN, edema, proteinuria, thrombocytopenia or thrombocytopenia

Eclampsia convulsions and preeclampsia

Hypertension during pregnancy

Most authorities recommend anti-HTN therapy if DBP>100mmHg

ACEi and ARB are contraindicated Methyldopa and hydralazine are first choice

HTN Crisis

HTN emergency need reduction of BP within 1 hour

HTN urgency reduction of BP more slowly Persistent DBP>130mmHg vascular injury Most HTN crisis appear in preexisting

primary HTN

CIRCUMSTANCES REQUIRING RAPID TREATMENT OF HYPERTENSION

Accelerated-malignant hypertension with papilledema( or exudate, hemorrhage) Cerebrovascular   Hypertensive encephalopathy  Atherothrombotic brain infarction with severe hypertension  Intracerebral hemorrhage  Subarachnoid hemorrhageCardiac   Acute aortic dissection  Acute left ventricular failure  Acute or impending myocardial infarction  After coronary bypass surgeryRenal   Acute glomerulonephritis  Renal crises from collagen-vascular diseases  Severe hypertension after kidney transplantationExcessive circulating cathecholamines   Pheochromocytoma crisis  Food or drug interactions with monoamine oxidase inhibitors  Sympathomimetic drug use (cocaine)  Rebound hypertension after sudden cessation of antihypertensive drugsEclampsiaSurgical   Severe hypertension in patients requiring immediate surgery  Postoperative hypertension  Postoperative bleeding from vascular suture linesSevere body burnsSevere epistaxis

CLINICAL CHARACTERISTICS OF HYPERTENSIVE CRISIS

Blood pressure: Usually >140 mm Hg diastolic Funduscopic findings: Hemorrhage, exudate, papilledema

Neurological status: Headache, confusion, somnolence, stupor, visual loss, focal deficits, seizures, coma

Cardiac findings: Prominent apical impulse, cardiac enlargement, congestive failure

Renal: Oliguria, azotemia

Gastrointestinal: Nausea, vomiting

CONDITIONS TO BE DIFFERENTIATED FROM A HYPERTENSIVE CRISIS

Acute left ventricular failure

Uremia from any cause, particularly with volume overload

Cerebrovascular accident

Subarachnoid hemorrhage

Brain tumor

Head injury

Epilepsy (postictal)

Collagen diseases, particularly lupus, with cerebral vasculitis

Encephalitis

Overdose and withdrawal from narcotics, amphetamines, etc.

Hypercalcemia

Acute anxiety with hyperventilation syndrome

Chap 29 Systemic HTN-Therapy

Benefits of Lowering BP

Average Percent Reduction

Stroke incidence 35–40%

Myocardial infarction 20–25%

Heart failure 50%

Goals of Therapy

Reduce CVD and renal morbidity and mortality.

Treat to BP <140/90 mmHg or BP <130/80 mmHg in patients with diabetes or chronic kidney disease.

Achieve SBP goal especially in persons >50 years of age.

Therapy

MODIFICATION RECOMMENDATIONAPPROXIMATE SBP

REDUCTION (RANGE)

Weight reduction body weight (body mass index 18.5–24.9

kg/m2 ).

5–20 mmHg/10 kg weight loss]

Adopt DASH eating plan diet rich in fruits, vegetables, and low

fat.

8–14 mmHg]

Dietary sodium reduction

Reduce Na to no more than 100 mmol per

day (2.4 g sodium or 6 g sodium chloride).

2–8 mmHg]

Physical activity regular aerobic activity such as brisk walking (at least 30 min per

day)

4–9 mmHg]

Moderation of alcohol consumption 2 drinks/D (30 mL ethanol) in most men and to no more than 1 drink per day in w

omen

2–4 mmHg

.

(Circulation. 2004;109:3081-3088.)

Diuretics

Thiazide Loop diuretics Potassium-sparing diurectics- amiloride, tria

mterene, spironolactone When Cre< 2mg/dl, thiazide is adequate; if

Cre> 2mg/dl or Ccr<25ml/min, thiazide is not effective

Diurectics

Initial effect

Adrenergic Inhibitors

Peripheral neuronal inhibitors—reserpine, guanethidine

Central adrenergic inhibitors—methyldopa, clonidine, guanabenz

α-receptor blocker—non-selective blocker (phentolamine); α1 blocker—doxazolin, prazosin, terazosin(hytrin)

β-blocker α, and β-blocker—labetalol, carvedilol

Deplete norepinephrine

Inhibit norepinephrine release

Reduce central sympathetic outflow

α-receptor blockers

Can be safely used in renal failure Improve lipid profiles Mildly increase insulin sensitivity Excellent choice for older man with BPH However, in ALLHAT trial (>55ys, doxazosi

n), higher risk for stroke and CHF compared with chlorthalidone

β-blockers

ISA—intrinsic sympathomimetic activity measureable agonist and greater antagonist effect less decline in HR, cardiac output and renin

β-blockers Lipid solubility atenolol and nadolol are le

ast lipid soluble less CNS side effects Side effects fatigue, insomnia, nightmares,

hallucinations Non-selective agents cause greater rise in T

G and reduction in HDL Use in pregnancy fetal retardation

Vasodilators

relative action on artery or vein

Direct

Hydralazine A>>V

Minoxidil (opening K channel) A>>V hirsutism, pericardial effu.

Nitroprusside A=V

NTG A<V

CCB A>>V

ACEi, ARB A>V

α-blocker A=V

Causes of Resistant Hypertension Improper BP measurement Excess sodium intake Inadequate diuretic therapy Medication

• Inadequate doses• Drug actions and interactions (e.g., nonsteroidal anti-inflammatory

drugs (NSAIDs), illicit drugs, sympathomimetics, oral contraceptives)• Over-the-counter (OTC) drugs and herbal supplements

Excess alcohol intake Identifiable causes of HTN

Therapy for HTN crisis

If DBP persistently >140mmHg combines with acute target organ damages, immediately reduce 20-25% BP within 1 hour

Drug Dosage Onset

Nitroprusside 0.25-10ug/kg/min immediate

NTG 5-100ug/min 2-5 mins

Nicardipine 5-15mg/hr 5-10 mins

Hydralazine 10-20 IV bolus 10-20 mins

Enalapril 1.25-5mg IV bolus 15 mins

Fenoldopam 0.1-0.3ug/kg/min <5 mins

Phentolamine 5-15mg IV bolus 1-2 mins

Esmolol 500ug/kg/min for 4 mins then 150-300ug/kg/min 1-2 mins

Labetalol 20-80mg IV bolus q10mins;2mg/min

5-10 mins

Seventh Report of the Joint National Committee (JNC 7)

on Prevention, Detection, Evaluation, and Treatment of High BP

older than 50 y/o, SBP≧ 140 mmHg is a much more important cardiovascular disease (CVD) risk factor than DBP

The risk of CVD beginning at 115/75 mmHg doubles with each increment of 20/10 mmHg; individuals who are normotensive at age 55 have a 90 percent lifetime risk for developing hypertension.

JNC (7)

Individuals with SBP of 120–139 mmHg or a DBP of 80–89 mmHg prehypertensive and require health-promoting lifestyle modifications to prevent CVD

Thiazide-type diuretics should be used in drug treatment for most patients with uncomplicated hypertension

Certain high-risk conditions are compelling indications for the initial use of other antihypertensive drug classes (ACEI, ARB, beta-blockers, CCB)

JNC (7)

Most patients with hypertension will require two or more antihypertensive medications to achieve goal blood pressure (<140/90 mmHg, or <130/80 mmHg for patients with diabetes or chronic kidney disease).

• If blood pressure is >20/10 mmHg above goal blood pressure, consideration should be given to initiating therapy with two agents, one of which usually should be a thiazide-type diuretic

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