Beijing Friendship Hospital Cardiology Center

Pro Yongquan Wu
2013/5/8 1

Contents
1
2 3 Epidemiology Pathphysiology Diagnosis

Treatment

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Epidemiology

Rate of age-related blood pressure increase Prevalence vary among countries and subpopulations Present in all populations Accounts for 6% of deaths worldwide Associated with growth and maturation in children and adolescents SBP increases progressively with age until ~55 years decrease after ~55years A widening of pulse pressure beyond age 60

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Potentially Preventable Causes of Death in the World

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the World Health Organization. http://www.who.int/hpr/NPH/docs/whr_2002_risk_factors.pdf.

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Absolute Risks of CAD and Stroke Mortality for Each Decade of Life by Usual SBP Level

Prospective Studies Collaboration. Lancet 360:1903, 2002.

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Determinants of Human Blood Pressure Variation

Environment
High NaCl intake
Low Ca/K intake Obesity Alcohol consumption Psychosocial stresss Lack of physical activity

Genetics
Polygenic disorder Different subsets and phenotypes ACE polymorphisms Genes encoding adducin, AT1 receptor, aldosterone synthase, 2-adrenoreceptor
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Mechanism
Intravascular Volume Neural Mechanisms Vascular Mechanisms Renal Mechanisms Hormone Mechanisms

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Intravascular Volume

Primary determinant of arterial pressure Alterate extracellular fluid volume Sodium is primary determinant of extracellular fluid volume NaCl intake > kidney excretion Vascular volume expands and cardiac output increases Vascular beds (e.g. kidney and brain) autoregulate blood flow Arterial pressure increase Resistance increase
Blood flow =
Pressure across the vascular bed Vascular resistance
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Intravascular Volume
Vascular

volume expansion Elevation of BP Increased cardiac output Sodium with chloride can effect BP Non-chloride salts of sodium have little effect on BP

Arterial pressure increases to achieve natriuresis and sodium balance

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Neural Mechanisms
In young adults

Increased HR and CO Plasma and urinary norepinephrine levels Regional norepinephrine spillover Peripheral postganglionic sympathetic nerve firing -adrenergic receptor mediated vasoconstrictor

Sympathetic overactivity in established HT besides

essential HT

Obesity Sleep apnea Early type 2 diabetes mellitus and prediabetes Chronic kidney disease Heart failure Immunosuppressive therapy with calcineurin inhibitor
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Neural and Circulatory Changes in Obstructive Sleep Apnea

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Renal Mechanisms
Renal

sodium retention

Expands the plasma volume Increases cardiac output Triggers autoregulatory responses
Increase

systemic vascular resistance Salt retention augments the smooth muscle contraction Resetting of Pressure-Natriuresis Low Birth Weight Genetic Contributions
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Vascular Mechanisms
Endothelial Cell Dysfunction
Major

defense against hypertension Impaired release of endothelial-derived relaxing factors(nitric oxide, endotheliumderived hyperpolarizing factor) Enhanced release of endothelium-derived constricting, proinflammatory, prothrombotic, and growth factors(endothelin, thromboxane, transforming growth factor-)
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Vascular Mechanisms
Vascular Remodeling

Small artery remodeling Large artery remodeling

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Duprez DA. J Hypertens 24:983, 2006.

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Hormone Mechanisms Renin-Angiotensin-Aldosterone System

RAAS Activation endothelial cell dysfunction, vascular remodeling, and hypertension

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Hormone Mechanisms
Aldosterone and Epithelial Sodium Channel Regulation

Interaction of aldosterone with cytosolic mineralocorticoid receptors recruits sodium channels The epithelial sodium channels (ENaCs) increase sodium reabsorption Reexpanding plasma volume Modern high-salt diets feedback inhibiting RAAS Suppression of serum aldosterone sequestrates ENaCs Shrinking plasma volume
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Hormone Mechanisms
Receptor-mediated Actions of Angiotensin II

AT1-mediated signaling enhanced

Elevated BP Insulin resistance Atherosclerosis

Major therapeutic target by vascular remodeling

In rodents, AT2 receptor activation opposes deleterious effects of AT1 receptors Recent animal studies : AT2 receptors can be profibrotic
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Hormone Mechanisms
Receptor-mediated Actions of Renin and Prorenin

Prorenin and renin as direct cardiac and renal toxins Inactive prorenin active renin in kidneys Circulating prorenin binds to (pro)renin receptor in heart and kidneys the hinge is opened prorenin activates TGF- production is accelerated collagen deposition and fibrosis Independent of A II generation and unaffected by ACEIs and ARBs
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Pathologic Consequences 1.Heart

Structural and

functional adaptations Left ventricular hypertrophy

Both genetic and hemodynamic factors Electrocardiogramechocardiography Increase risk for CHD, stroke, CHF, and sudden death Aggressive control of BP
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Pathologic Consequences 1.Heart

Diastolic dysfunction Early consequence of hypertension-related heart disease Exacerbated by left ventricular hypertrophy and ischemia. Echocardiography and radionuclide angiography. Asymptomatic heart failure 1/3 normal systolic function but abnormal diastolic function
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Pathologic Consequences 2.Brain

Risk

factor for brain infarction and hemorrhage 85% infarction & 15% hemorrhage In elderly adults or aging population
The incidence of stroke rises progressively with BP esp SBP Impaired cognition and dementia due to hypertension

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Pathologic Consequences 3.Kidney

Risk factor for renal injury and ESRD Graded, continuous, and present throughout the entire distribution of BP Renal risk be more closely related to SBP than to DBP Black men are at greater risk than white men for developing ESRD

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Pathologic Consequences Peripheral Arteries

Stenotic lesions of the lower extremities may be asymptomatic Intermittent claudication is classic symptom of PAD The ankle-brachial index is a useful approach for evaluating PAD Ankle-brachial index < 0.90 is considered diagnostic of PAD and is associated with >50% stenosis Ankle-brachial index < 0.80 is associated with elevated BP, particularly SBP
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Pathologic Consequences 5. Hypertension retinopathy

A:Mild diffuse arteriolar narrowing B:Arteriovenous nicking C:Hemorrhages and exudates D:Papilledema

Grosso A, Veglio F, Porta M, et al. Br J Ophthalmol 89:1646, 2005.

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Mild diffuse arteriolar narrowing

Arteriovenous nicking

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Hemorrhages and exudates

Papilledema

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Definition and Classification

Category Normal Systolic <120 and Diastolic <80

High normal
Grade1 Grade 2 Grade 3

120-139
140-159 160-179 180

and/or
and/or and/or and/or

80-89
90-99 100-109 110

Isolated systolic hypertension*

*ISH should be graded
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>140

and

<90

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Components of Cardiovascular Risk Stratification in Patients with Hypertesion

Risk Factors
High SBP and/or DBP (Grade1,2,3) Male>55,Female>65 Smoking Dyslipidemia: TC>5.7,LDL-C>3.3mmol/L HDL-C<1.0mmol/L Family history or HTN Abdominal obesity

Target Organ Damages Related Diseases or Diabetes

LVH Carotid wall thickening (IMT>0.9mm) or plaque Slight increase in plasma creatinine: male:115-133umol/L female107-124umol/L Microalbuminuria 30-300mg/24h Proteinuria:>300mg/24h FBG:>7.0mmol/L PBG:>11.0mmol/L Stroke or TIA Angina or prior MI, PTCA/CABG Heart failure Nephropathy Cr:male>133umol/L female>124umol/L Renal failure Cr>177umol/L Peripheral arterial diseases Retinopathy
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Cardiovascular Risk Stratification in Patients with Hypertension according to the Grades of Hypertension, Coexisting Risk Factors, Organ Damages and Vascular Diseases
Other risk factors, organ damege or diseases

Normal SBP 120-129 or DBP80-84

High normal SBP130-139 or DBP85-59

Grade1 HT SBP140-159 or DBP90-99

Grade2 HT SBP160-179 or DBP100-109

Grade3 HT SBP180 or DBP110

No other factors

Average risk

Average risk

Low added risk

Moderate added risk

High added risk

1-2 risk factors

3 or more risk factors, MS,OD or diabetes Established CV or renal diseases

Low added risk

Moderate added risk

Low added risk

High added risk

Moderate added risk

High added risk

Moderate added risk

High added risk

Very high added risk

Very high added risk

Very high added risk

Very high added risk

Very high added risk

Very high added risk

Very high added risk

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Secondary Causes of Hypertension

Renal Renovascular
Adrenal Aortic coarctation Parenchymal diseases, renal cysts (including polycystic kidney disease), renal tumors (including renin-secreting tumors), obstructive uropathy

Arteriosclerotic, fibromuscular dysplasia

Primary aldosteronism, Cushing's syndrome, 17-hydroxylase deficiency, 11-hydroxylase deficiency, 11-hydroxysteroid dehydrogenase deficiency (licorice), pheochromocytoma

Obstructive sleep apnea Preeclampsia/eclampsia Neurogenic Miscellaneous endocrine

Medications Psychogenic, diencephalic syndrome, familial dysautonomia, polyneuritis (acute porphyria, lead poisoning), acute increased intracranial pressure, acute spinal cord section

Hypothyroidism, hyperthyroidism, hypercalcemia, acromegaly

High-dose estrogens, adrenal steroids, decongestants, appetite suppressants, cyclosporine, tricyclic antidepressants, monamine oxidase inhibitors, erythropoietin, nonsteroidal anti-inflammatory agents, cocaine
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Mendelian Forms of Hypertension

Glucocorticoid-remediable hyperaldosteronism 17-hydroxylase deficiency 11-hydroxylase deficiency 11-hydroxysteroid dehydrogenase deficiency (apparent mineralocorticoid excess syndrome) Liddle's syndrome Pseudohypoaldosteronism type II (Gordon's syndrome) Hypertension exacerbated in pregnancy
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Autosomal dominant.Absent or mild hypokalemia Chimeric 11-hydroxylase/aldsoterone gene on chromosome 8

Autosomal recessive.Males: pseudohermaphroditism.Females: primary amenorrhea, absent secondary sexual characteristics. Random mutations of the CYP17 gene on chromosome 10
Autosomal recessive. Masculinization.Mutations of the CYP11B1 gene on chromosome 8q21-q22 Autosomal recessive. Hypokalemia, low renin, low aldosterone. Mutations in the 11-hydroxysteroid dehydrogenase gene Autosomal dominant. Hypokalemia, low renin, low aldosterone. Mutation subunits of the epithelial sodium channel SCNN1B and SCNN1C genes Autosomal dominant. Hyperkalemia, normal glomerular filtration rate. Linkage to chromosomes 1q31-q42 and 17p11-q21 Autosomal dominant. Severe hypertension in early pregnancy. Missense mutation with substitution of leucine for serine at codon 810 (MRL810)
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Approach to the Patient:Hypertension

A complete history and physical examination Confirm a diagnosis of hypertension Screen for other cardiovascular disease risk factors Screen for secondary causes of hypertension Identify cardiovascular consequences of hypertension and other comorbidities Assess blood pressurerelated lifestyles Determine the potential for intervention

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Approach to the Patient:Hypertension

No specific symptoms Headache generally occurs only in severe hypertension Hypertensive headache" occurs in the morning and localized to the occipital region Other nonspecific symptoms include dizziness, palpitations, easy fatigability, and impotence

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Patient's Relevant History

Duration of hypertension Previous therapies: responses and side effects Family history of hypertension and cardiovascular disease Dietary and psychosocial history

Other risk factors: Weight change, Dyslipidemia, Smoking, Diabetes, Physical inactivity

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Patient's Relevant History

Evidence of secondary hypertension:

History of renal disease Change in appearance Muscle weakness Spells of sweating, palpitations, tremor Erratic sleep, snoring, daytime somnolence Symptoms of hypo- or hyperthyroidism Use of agents that may increase blood pressure

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Patient's Relevant History

Evidence of target organ damage:

History of TIA, stroke, transient blindness Angina, myocardial infarction, congestive heart failure Sexual function

Other comorbidities

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Ambulatory Monitoring

Provides automated measurements of BP over a 24-hour Prospective outcome studies showed ambulatory BP measurement predicts fatal and nonfatal myocardial infarction and stroke better than standard office measurement Recommended normal values Average daytime BP <135/85 mmHg Nighttime BP < 120/70 mmHg 24-hour BP <130/80 mmHg Some experts have recommended a lower cutoff value of 130/80 mm Hg as a more stringent definition of normal daytime BP
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White Coat Hypertension

Up to 1/3 of patients with elevated office BPs have normal home or ambulatory BPs Definition: If the daytime BP <135/85 mmHg (or preferably below 130/80 mmHg) and without target organ damage despite consistently elevated office readings A transient adrenergic response Increasing evidence suggested that this condition is not as benign as previously assumed

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Physical Examination
Body habitus Weight and height BP measured in both arms BP in the supine, sitting, and standing positions BP measured in the lower extremity when patients<30 year Heart rate Neck palpated for an enlarged thyroid gland Signs of hypo- and hyperthyroidism

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Physical Examination

Funduscopic examination Palpation of femoral and pedal pulses Examination of the heart Loud second heart sound Left ventricular hypertrophy Displaced apical impulse Abdominal bruit Polycystic kidney may be palpable in the abdomen Signs of CHF Neurologic examination
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Laboratory Testing
Renal function Serum electrolytes Fasting glucose Lipids More extensive laboratory testing is appropriate for drug-resistant or secondary hypertension

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Basic Laboratory Tests for Initial Evaluation

System Renal Test Microscopic urinalysis, albumin excretion, serum BUN and/or creatinine

Endocrine Serum sodium, potassium, calcium, ?TSH Metabolic Fasting blood glucose, total cholesterol, HDL and LDL (often computed) cholesterol, triglycerides Other Hematocrit, electrocardiogram

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TreatmentLifestyle Interventions

Both the prevention and treatment of hypertension Health-promoting lifestyle modifications for prehypertension and drug therapy in hypertensive Address overall cardiovascular disease risk Prevention and treatment of obesity Regular physical activity NaCl intake Increased potassium intake Moderation of alcohol consumption

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Lifestyle Modifications to Manage Hypertension

Weight reduction Dietary salt reduction Adapt DASH-type dietary plan Attain and maintain BMI < 25 kg/m2 < 6 g NaCl/d

Diet rich in fruits, vegetables, and low-fat dairy products with reduced content of saturated and total fat Moderation of For those who drink alcohol, consume 2 alcohol consumption drinks/day in men and 1 drink/day in women Physical activity Regular aerobic activity, e.g., brisk walking for 30 min/d
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TreatmentLifestyle Interventions
The DASH trial Dietary Approaches to Stop Hypertension 8-week period a diet high in fruits, vegetables, and low-fat dairy products lowers blood pressure Reduction of daily NaCl intake to <6 g Fruits and vegetables are enriched sources of potassium, magnesium, fiber Calcium

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TreatmentPharmacologic Therapy
Drug therapy when BP 140/90 mmHg Lowering SBP by 1012mmHg and DBP by 56mmHg

3540% for stroke 1216% for CHD within 5 years >50% for heart failure

Relative risk reduction

Selection and combination of agents, be individualized

Age severity of hypertension other cardiovascular disease risk factors comorbid conditions practical considerations related to cost, side effects, and frequency of dosing
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Class of Drug Indications

Diuretics
Heart Failure Advanced age Systolic hypertension Angina or previous myocardial infarction Heart failure Tachyarrhythmias Migraine Prestatic hypertrophy Advanced age Systolic hypertension Cyclosporine-induced hypertension Heart failure or left ventricular dysfunction Previous myocardial infarction Diabetic or other nephropathy or proteinuria

Contraindications
Gout

Beta blockers

Asthma or chronic obstructive pulmonary disease Heart block

blockers Calcium channel blockers Angiotensinconverting enzyme inhibitors

Incipient heart failure Heart block(verapamil, diltiazem)

Pregnancy Bilateral renal artery stenosis Hyperkalemia

Angiotensin receptor blockers

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Angiotensin-converting enzyme inhibitorassociated cough Diabetic or other nephropathy Congestive heart failure

Pregnancy
Bilateral renal artery stenosis Hyperkalemia

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DiureticsThiazides
Low-dose thiazide diuretics as first-line agents Alone or in combination with other drugs Safe, efficacious, and inexpensive and reduce clinical events Combined with blockers, ACEIs or ARB is more effective Combined with CCB is less effective Metabolic side effects (hypokalemia, insulin resistance, increased cholesterol) Higher doses are not recommended

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DiureticsNon-thiazides

Potassium-sparing diuretics
e.g. amiloride and triamterene Combination with thiazide to protect against hypokalemia

Loop diuretics

Hypertension with reduced glomerular filtration rates Reflected in serum creatinine > 220 mol/L (>2.5 mg/dL) CHF Sodium retention and edema

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Blockers of the Renin-Angiotensin System

ACE

inhibitors Decrease the production of angiotensin II Increase bradykinin levels Reduce sympathetic nervous system activity Angiotensin II receptor blockers Selective blockade of AT1 receptors Augment the hypotensive effect

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Blockers of the Renin-Angiotensin System

Monotherapy or

combination with diuretics, CCB, and -blocking agents Side effects Functional renal insufficiency Dry cough occurs in ~15% of patients Angioedema occurs in <1% of ACEI Hyperkalemia

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Aldosterone Antagonists
Used alone or combined with thiazide diuretic Effective in low-renin essential hypertension, resistant hypertension, and primary aldosteronism In CHF, low-dose spironolactone combination with ACEI, digoxin, and loop diuretics reduces mortality and hospitalizations Side effects: gynecomastia, impotence, and menstrual abnormalities

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Beta Blockers
Reduce heart rate and contractility, decrease cardiac output Central nervous system effect, and inhibition of renin release Particularly effective in hypertension with tachycardia Lower doses selectively inhibit cardiac 1 receptors and less influence on 2 receptors No difference in the antihypertensive potencies of cardio-selective and non-selective blockers

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Beta Blockers
Certain blockers have intrinsic sympathomimetic activity blockers without intrinsic sympathomimetic activity decrease sudden death, overall mortality, and recurrent myocardial infarction In CHF, blockers reduce hospitalization and mortality Carvedilol and labetalol block both -receptors and peripheral -adrenergic receptors

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Adrenergic Blockers

Selective -adrenoreceptor antagonists

Decreasing peripheral vascular resistance Monotherapy or combined with other agents blockade shown no reduction in cardiovascular morbidity and mortality Effective in treating lower urinary tract symptoms in men with prostatic hypertrophy

Nonselective -adrenoreceptor antagonists

Bind to postsynaptic and presynaptic receptors Treat pheochromocytoma

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Sympatholytic Agents
Decrease peripheral resistance Used in autonomic neuropathy with wide variations in BP Drawbacks: somnolence, dry mouth, and rebound hypertension on withdrawal Peripheral sympatholytics decrease peripheral resistance and venous constriction Limited by orthostatic hypotension, sexual dysfunction, and drug-drug interactions

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Calcium Channel Blockers

Reduces intracellular calcium and blunts vasoconstriction Reduce vascular resistance Monotherapy or combined with other agents (ACE inhibitors, beta blockers,1-adrenergic blockers) Flushing, headache, and edema with dihydropyridine

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Direct Vasodilators

Decrease peripheral resistance Defend arterial pressure by mechanism with The sympathetic nervous system The renin-angiotensin-aldosterone system Sodium retention Not considered first-line agents Effective when combined with a diuretic or a beta blocker Hydralazine
Direct vasodilator Antioxidant and nitric-oxide enhancing actions May induce a lupus-like syndrome
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Blood Pressure Goals of Antihypertensive Therapy

SBP<135140 & DBP<8085 mmHg More aggressive BP control for diabetes, CHD, chronic kidney disease, or additional cardiovascular disease risk factors Require treatment with more than one drug BP reduction at half-standard doses is only ~20% less than at standard doses Combination at lower doses have less side effects

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Resistant Hypertension
Definition: patients with blood pressures persistently >140/90 mmHg despite taking three or more antihypertensive agents, including a diuretic, in reasonable combination and at full doses Common in patients >60 years than in younger patients Causes include : "pseudoresistance, nonadherence to therapy, use of nonprescription drugs, severely sclerotic arteries in older patients Evaluation include home blood pressure monitoring and secondary form of hypertension screening

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An Algorithm for the Decision to Manage Patients with Different Average Blood Pressure

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Guidelines for Combination of Hypertension Therapy

2003 ESH-ESC Guideline 2009 ESH-ESC Guideline

ACEI
CCB
blocker

ACEI
CCB
blocker

ARB

blocker

ARB

blocker

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