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TREATMENT OF COMPLICATED HYERTENSION Joseph L. Izzo Jr, MD Professor of Medicine, Pharmacology, and Toxicology SUNY-Buffalo. Diastolic vs systolic hypertension Prevention vs treatment Compelling indications Other high risk conditions. ISH (SBP >140 mm Hg and DBP <90 mm Hg)

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slide1

TREATMENT OF COMPLICATED HYERTENSIONJoseph L. Izzo Jr, MDProfessor of Medicine, Pharmacology, and ToxicologySUNY-Buffalo

slide2
Diastolic vs systolic hypertension
  • Prevention vs treatment
  • Compelling indications
  • Other high risk conditions
slide3
ISH (SBP >140 mm Hg and DBP <90 mm Hg)

SDH (SBP >140 mm Hg and DBP >90 mm Hg)

IDH (SBP <140 mm Hg and DBP >90 mm Hg)

100

80

60

40

20

0

Hypertension Subtypes by Age

(NHANES III Untreated Hypertensives)

17%

16%

16%

20%

20%

11%

Frequency of hypertension

subtypes in all untreated hypertensives

(%)

<40

40-49

50-59

60-69

70-79

80+

Age (y)

Percentages represent the overall distribution of untreated hypertension by age.

Franklin et al. Hypertension 2001;37: 869-874.

anatomy of a central arterial pulse wave
Anatomy of aCentral Arterial Pulse Wave

Augmentation Index = AP/PP

Reflected wave

Systolic BP

Augmentation Pressure (AP)

Incident wave

Pulse pressure (PP)

Mean Arterial Pressure

Dicrotic notch

Diastolic BP

mean arterial vs pulse pressure different information provided
MAP

Integrated static “DC” signal

Determined by the CO-SVR product

Mainly indicative of distal vasoconstriction

Closely related to diastolic pressure

PP

Pulsatile dynamic “AC” signal

Determined by “ventricular-vascular interactions”

Early systole: Aortic impedance

Late systole: Wave reflections

Closely related to systolic pressure

Mean Arterial vs. Pulse Pressure: Different Information Provided
pathogenesis of systolic and diastolic hypertension
InhibitsPromotesPathogenesis of Systolic and Diastolic Hypertension

SYSTOLIC HYPERTENSION

 Stroke Volume

Central Artery Stiffness

Arteriolar Constriction

DIASTOLIC HYPERTENSION

bp responses to vasodilators decrease in map of 10 mmhg
BP RESPONSES TO VASODILATORS (Decrease in MAP of 10 mmHg)

SYSTOLIC HYPERTENSION

-20 - 5

Change in Systolic Pressure (mmHg)

DIASTOLIC HYPERTENSION

- 6 -12

Change in Diastolic Pressure (mmHg)

(modified from Koch-Weser 1973)

slide8
ACE and ACE-NEP Inhibitor Effects on Aortic Impedance(Mitchell G, Izzo JL Jr, et al. Circulation 2002, in press)
slide9
Diastolic vs systolic hypertension
  • Prevention vs treatment
  • Compelling indications
  • Other high risk conditions
systolic bp reduction and cvd mortality
Systolic BP Reduction and CVD Mortality

1.50

MIDAS/NICS/VHAS

UKPDS C vs A

1.25

P = 0.003

NORDIL

INSIGHT

HOT L vs H

STOP2/ACEIs

HOT M vs H

Cardiovascular

Mortality

Odds Ratio

MRC1

1. 00

MRC2

STOP2/CCBs

SHEP

STONE

HEP

CAPPP

0.75

EWPHE

HOPE

Syst-Eur

UKPDS L vs H

Syst-China

RCT70-80

0.50

PART2/SCAT

STOP1

ATMH

0.25

-5

0

5

10

15

20

25

 Systolic BP (control - experimental, mmHg)

Staessen JA, et al. Lancet 2001;358:1305–1315.

clinical trialists view
Clinical Trialists View

Amount of BP lowering is more important than choice of drug class in overall disease prevention

slide13
JNC 7 Medication Algorithm

Initial Drug Choices

Without Compelling Indications

With Compelling Indications

Stage 1 Hypertension(SBP 140–159 or DBP 90–99 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination

Stage 2 Hypertension(SBP >160 or DBP >100 mmHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI or ARB or BB or CCB)

Drug(s) for the compelling indications

Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed

Not at Goal BP

Optimize dosages or add additional drugsuntil goal BP is achieved.Consider consultation with hypertension specialist.

why the discrepancies
Why the “discrepancies”?

HETEROGENEITY !!!!!

Even if we are all created equal (ethically and legally), we are not created equal biologically.

slide15
Diastolic vs systolic hypertension
  • Prevention vs treatment
  • Compelling indications
  • Other high risk conditions
jnc 7 compelling indication definition
JNC 7 Compelling Indication: Definition

A high-risk condition associated with hypertension for which there is clinical trial evidence of a specific outcome benefit of a given class of antihypertensive drugs

jnc 7 compelling indications for individual drug classes o updated
JNC 7 Compelling Indications for Individual Drug Classes (o = Updated)

Compelling Indication

Basis

Initial Therapy Options

TZ BB ACE ARB CCB AA

ACC/AHA HF Guideline,MERIT-HF, COPERNICUS, AIRE, SOLVD, RALES, CIBIS, TRACE, Val-HEFT, CHARM

ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS, VALIANT

ALLHAT, HOPE, ANBP2, LIFE, VALUE, CONVINCE, EUROPA

oo o o o o

• • •

• • • •

• • O •

• • • OO

A

B

C

D

HEART

FAILURE

(STAGE)

POST-MI

HIGH CAD RISK

components of cardiac afterload
Components of Cardiac Afterload

Late-systolic pressure augmentation (wave reflection)

Contractility/Aortic impedance (“ventricular-vascular coupling”)

Residual systemic (diastolic) pressure (SVR)

(DBP > Aortic impedance > Augmentation)

age and components of cardiac afterload
Age and Components of Cardiac Afterload

Augmentation

Component

Younger

Older

progression of cardiovascular disease
Heart

Failure

Death

Possible pathway

of progression

Progression of Cardiovascular Disease

Smoking

Dyslipidemia

Diabetes

MI

Systolic

Dysfunction

 SBP

Diastolic

Dysfunction

Obesity

Diabetes

LVH

Normal LV

structure

& function

LV

remodeling

Subclinical

LV

dysfunction

Overt

Failure

Months

Years

Adapted from Levy D. J Am Coll Cardiol 1993

slide23
Therapy for CHF

NYHA Class

Agent

I

II

III

IV

Statins

Diuretics

ACEI/ARB

Beta Blockers

Digoxin

Spironolactone

???

???

No proven mortality benefit, used in symptomatic patients

May offer mortality benefit

No data for or against

???

Should not be used in this Class

Use for mortality benefit

Mod. From Eichhorn EJ. Clin Cardiol. 1999;22bb:V21-V29.

8

jnc 7 compelling indications for individual drug classes o updated24
JNC 7 Compelling Indications for Individual Drug Classes (o = Updated)

Compelling Indication

Initial Therapy Options

TZ BB ACE ARB CCB AA

Basis

DIABETESCHRONIC KIDNEY DISEASE

RECURRENT STROKE

NKF-ADA Guideline,UKPDS, ALLHAT

• • • • •

• •

• ?O O

NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK

PROGRESS, MIRACLE

mdrd study impact of bp control
MDRD Study: Impact of BP Control
  • Hebert, et al. Hypertension 30;1997.428-35
aggressive bp goals consensus across treatment guidelines
Aggressive BP Goals: Consensus Across Treatment Guidelines

Organization Patient Type BP Goals (mm Hg)

ADA Diabetes <130/80

ISHIB African American <140/90

Plus DM or proteinuria >1 g/24 h <130/80

JNC 7 Uncomplicated HTN <140/90

With DM, CKD <130/80

NKF Albuminuria (>300 mg/d or >200 mg/g creatinine), <130/80

with or without diabetes

Proteinuria (protein to creatinine ratio “Consider even >500-1000 mg/g) lower than

<130/80”

WHO-ISH Low risk for CVD SBP<140

Presence of DM, target organ damage,

or associated clinical conditions <130/80

ADA: American Diabetes Association; ISHIB: International Society on Hypertension in Blacks; JNC 7: The Seventh Report of the

Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

NKF: National Kidney Foundation; WHO-ISH: World Health Organization/International Society on Hypertension

acei in diabetic renal disease
100

90

80

70

60

50

40

30

20

10

0

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

ACEI in Diabetic Renal Disease

Overall Deaths:

Captopril: 8/207=4%

Placebo: 14/202=7%

Placebo SCr1.5

Death

Dialysis or Transplant

(%)

*P=.002 vs placebo (Scr1.5 )

Captopril* SCr1.5

Placebo SCr<1.5

Captopril SCr<1.5

Years of Follow Up

Lewis EJ et al. N Engl J Med 1993;329:1456-1462.

slide28
30

20

10

30

0

0

12

24

36

48

P

20

L

10

50

0

40

0

12

24

36

48

30

20

10

0

0

12

24

36

48

P (+ CT)

P (+ CT)

L (+ CT)

L (+ CT)

ESRD

RENAAL 10 Components

Risk Reduction: 28%

p=0.002

P

% with event

L

Doubling of Serum Creatinine

Risk Reduction: 25%

p=0.006

Months

762

715

610

347

42

751

714

625

375

69

% with event

ESRD or Death

Risk Reduction: 20%

p=0.010

P

% with event

L

Months

P (+ CT)

295

762

689

554

36

L (+ CT)

52

751

692

583

329

Months

762

715

610

347

42

751

714

625

375

69

bp drugs in chronic kidney disease
Any anti-

hypertensive

BP Drugs in Chronic Kidney Disease

Pathogenetic steps

Increased renal perfusion pressure

Glomerular capillary hypertension

Proteinuria

Focal glomerulosclerosis

Glomerular and tubular dropout

End-Stage Disease

ACEI or ARB

clinical trials and renal outcomes based on proteinuria reduction
Clinical Trials and Renal Outcomes Based on Proteinuria Reduction

Progression of diabetic nephropathy/ESRD

Protection

No Protection

  • Captopril
  • Ramipril (AASK/REIN)
  • Losartan (RENAAL)
  • Irbesartan (IDNT)
  • Amlodipine (IDNT)
  • Amlodipine (AASK)
  • Isradipine (STENO)
  • Nifedipine

30-35% proteinuria

No proteinuria

ESRD = End Stage Renal Disease

Lewis EJ et al. N Engl J Med. 1993;329:1456-1462; Wright JT et al. JAMA. 2002; 288(19):2421-2431; Ruggenenti P et al. Lancet. 1999;354(9176):359-364; Brenner BM et al. N Engl J Med. 2001;345(12):861-869; Lewis EJ et al. N Engl J Med. 2001;345(12):851-860; Norgaard K et al. Blood Press.1993;2(4):301-308; Abbott K et al. J Clin Pharmacol. 1996;36;274-279.

jnc 7 bp thresholds and goals for initial use of 2 drug combinations
JNC 7: BP Thresholds* and Goals for Initial Use of 2-Drug Combinations

Initial BP Goal BP

(mmHg) (mmHg) Condition

>160/100* <140/90 No diabetes or chronic kidney disease (CKD)

>150/90* <130/80 Diabetes (FBS > 125 mg/dL x 2)

CKD: (eGFR < 60 or albuminuria > 300 mg/d)

* >20/10 mmHg above goal

probable dose response relationships for bp and albuminuria
Probable dose-response relationships for BP and albuminuria

BP

Albuminuria

Effect 

l l l l

Log Dose 

combination therapy is usually required to reach jnc goals
Combination Therapy Is Usually Requiredto Reach JNC Goals

“Most patients with HTN will require 2 or more agents to achieve goal of <140/90 (<130/90 in DM or CKD)”

-JNC 7

Trial

SBP mm Hg

Mean Number of Agents

AASK 128

INVEST 133

HOT 138

ALLHAT 138

IDNT 138

RENAAL 141

UKPDS 144

2.4

2.0

Mean 2.0, Median 2.8 agents

Met

JNC

Goals

3.0

1.9

4.0

SBP <140

4.1

Did not

Meet JNC

Goals

3.0

75% of patients required3 or more agents

Chobanian AV et al. Hypertension. 2003; 42(6):1206-1252; Chart adapted from Bakris GL et al. Am J Kidney Dis. 2000;36:646-661;

ALLHAT Officers. JAMA. 2002;288:2981-2997;Hansson L et al. Lancet. 1998;351:1755-1762; Pepine CJ et al. JAMA. 2003;290(21):2805-2816; Wright JT et al. Arch Intern Med. 2002;162:1636-1643; UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713; Brenner BM et al.

N Engl J Med. 2001;345(12):861-869; Sica DA, Bakris GL. J Clin Hypertension. 2002;4(1):52-57.

slide34
Diastolic vs systolic hypertension
  • Prevention vs treatment
  • Compelling indications
  • Other high risk conditions
resistant hypertension
Resistant hypertension

BP above target despite use of 3 or more antihypertensive drugs, one of which is a diuretic

selected conditions associated with resistant hypertension
Selected conditions associated with resistant hypertension
  • Non-adherence
  • Sleep apnea
  • Renal failure
  • Interfering drugs
slide37

TREATMENT OF COMPLICATED HYERTENSIONJoseph L. Izzo Jr, MDProfessor of Medicine, Pharmacology, and ToxicologySUNY-Buffalo

primary composite endpoint of life trial stratified by time varying albuminuria
0

6

12

18

24

30

36

42

48

54

60

66

Month

RAAS Blockade: Treatment Benefit Seen at All Albuminuria Baseline Levels

Primary Composite Endpoint of LIFE Trial Stratified by Time-varying Albuminuria

24

Albuminuria

(urine albumin/creatinine ratio

in mg/g)

20

 44

45 - 88

89 - 265

16

> 265

Losartan

Endpoint (Event Rate in %)

Atenolol

12

8

4

0

Ibsen H et.al J Hypertension. 2004;22:1805-1811.

older concepts of systolic hypertension
Older Concepts of Systolic Hypertension
  • Basically a function of aging; accelerated by hypertension
  • Irreversible process involving increased aortic stiffness due to
    • Aortic dilatation (increased wall tension)
    • Aortic wall thickening
    • Replacement of elastin with collagen
  • Therapy directed at lowering vascular resistance
newer concepts of systolic hypertension
Newer Concepts of Systolic Hypertension
  • Can occur at any age (esp. in women)
  • Increased aortic stiffness can be structural or functional
    • Can be caused by smaller aorta with normal elastic properties (radius is a major factor in aortic impedance)
  • Age-related dilation (remodeling) may be a secondary adaptation to reduce PP
  • Therapy may be directed at reducing vasoconstriction or increasing aortic elasticity
compartments of the cardiovascular system
“Compartments” of the Cardiovascular System
  • Heart
  • Central arteries (aorta)
  • Peripheral conduit arteries (brachial, etc)
  • Arterioles (resistance vessels)
  • Capillaries
  • Veins

Key Concept: Changes in these vascular “compartments” with aging and hypertension are non-uniform but are interdependent

central arterial stiffness and pp pathophysiology elastic vessels inelastic vessels
Central Arterial Stiffness and PPPathophysiologyElastic vessels Inelastic vessels

SYSTOLE

DIASTOLE

SYSTOLE

DIASTOLE

STROKE

VOLUME

STROKE

VOLUME

(

)

AORTA

AORTA

RESISTANCE

ARTERIOLES

RESISTANCE

ARTERIOLES

Increased SBP

PRESSURE

(FLOW)

PRESSURE

(FLOW)

Wide PP

Decreased DBP

Adapted from Izzo JL. J Am Geriatr Soc. 1981;29:520-524.

impedance and arterial radius
Impedance and arterial radius
  • Impedance is the pulsatile equivalent of resistance

Characteristic aortic impedance:

Zc  √Eh/r5

E = elastic modulus; h = wall thickness; r = radius

Zc varies inversely with r2.5

bp and aortic root diameter framingham
BP and Aortic Root Diameter (Framingham)

Vasan, et al. Circulation 1995

aortic dilatation and bp life study

Aortic Dilatation and BP (LIFE Study)

Bella, et al. Am J Cardiol 2002

pulse wave transmission and reflection
Pulse Wave Transmission and Reflection
  • There are forward-traveling and backward-traveling (reflected) waves in the arterial tree
  • An arterial pulse contour at any point along the arterial tree is the sum of the forward-traveling and backward-traveling pressure waves at that point.
determinants of central systolic pressure augmentation
Determinants of Central Systolic Pressure Augmentation
  • Timing of reflected wave return
    • Pulse wave velocity (principally arterial stiffness-related)
    • Location of reflecting site (varies physiologically)
  • Amplitude of reflected wave
    • Reflection coefficient (principally vasoconstriction-related)
age and reflected waves
Age and Reflected Waves

ELASTIC VESSELS STIFF VESSELS

PWV 8 M/SEC PWV 12 M/SEC

Systolic Augmentation Pressure

FORWARD-TRAVELING WAVE BACKWARD-TRAVELING WAVE ACTUAL (COMPOSITE) WAVE

PWV = pulse wave velocity. Modified from Asmar, R. Arterial Stiffness

functional dependency of refl ected waves on systemic hemodynamics
Functional Dependency of Reflected Waves on Systemic Hemodynamics

RADIAL

AP = 20

AP = 2

AP = - 8

CENTRAL

NORMAL NOREPINEPHRINE EPINEPHRINE

(HYPERTENSION)

systolic augmentation and cardiac work aging and hypertension
Systolic Augmentation and Cardiac Work: Aging and Hypertension

40

“Wasted” Cardiac Work

P

PP

30

Augmentation

index

(P/PP, %)

20

HT

10

NT

0

45

25

75

55

65

15

5

35

Age (years)

Adapted from Fleg/Kelly, Hypertension Primer, 1st Edition.

aging effects on pressure wave transmission and reflection
150

150

150

100

100

100

50

50

50

Aging Effects on Pressure Wave Transmission and Reflection

 Wave

Reflection

(mm Hg)

Age 68 years

(mm Hg)

Age 54 years

 Pulse Pressure

Ampli- fication

Age 24 years

(mm Hg)

Renal

artery

Femoral artery

Iliac artery

Thoracic

aorta

Abdominal aorta

Ascending aorta

Nichols WW, et al. Arterial Vasodilation. Philadelphia,1993;32.

pulse pressure amplification
Pulse Pressure Amplification

Progressive increase in vascular impedance (as arteries narrow

and become stiffer) causes pulse pressure amplification

  • Key issue:
  • Poor correlation between brachial BP and central BP
ish in the young healthy 18 y o cross country runner clinic bp 144 72 rx amlodipine
Radial tonometry

True PPA = 22 mmHg

AP = - 6 mmHg

Hemodynamics (Thoracic impedance)

HR 66 beats min-1

SV 124 ml

CO 8.2 L min-1

SVR 808 dyne sec cm-5

ISH in the YoungHealthy 18 y.o. cross-country runner; Clinic BP 144/72; Rx: amlodipine

Aorta 112/81

Radial134/80

implications for cuff brachial bp
Implications for Cuff (Brachial) BP
  • Inaccurate indicator of hypertension ?
  • Poor indicator of central systolic BP, cardiac load, and LVH ?
  • Poor indicator of renal and cerebral microcirculatory pulsatile loads and organ damage ?
  • Poor indicator of beneficial effects of antihypertensive drugs ?
conjunctival capillary rarefaction in early hypertension
SBP

PP

 CO

 FBF

SVR

NORMOTENSION BORDERLINE HTN

Sullivan JM, et al. Hypertension, 1983;5:844

Conjunctival Capillary Rarefactionin Early Hypertension
pulse pressure microalbuminuria and renal function
Pulse Pressure, Microalbuminuria, and Renal Function

Cross-section of non-diabetic men (677) and women (890), age 45-64

120

105

90

14

10

6

Urinary Albumin (g/min)

Cr clearance (ml/min/1.7m2)

30 55 80

30 55 80

Pulse pressure (mmHg)

Cirillo M. et al. The GUBBIO Study Collaborative Research Group. Kidney Int 2000;58:1211-8

systolic hypertension syndrome
Systolic Hypertension Syndrome
  • Change In
  • Hypertension
  • LVH
  • Diastolic dysfxn
  •  Stiffness
  • Effective Diameter
  •  Stiffness
  • PP Amplification

Compartment

HEART

CENTRAL ARTERIES

PERIPHERAL ARTERIES

Impact

Angina Heart Failure

 PP, SBP

 BPVariability

“Spurious ISH”

systolic hypertension syndrome59
Systolic Hypertension Syndrome

Change In

Hypertension

Constriction

Rarifaction

Impact

 SVR & MAP

Augmentation

Insulin resistance Salt-sensitivity Albuminuria,CKD Lacunar infarcts Dementia (?)

Compartment

ARTERIOLES

CAPILLARIES

systolic hypertension syndrome compensatory hemodynamic changes
HEART

CENTRAL VEINS CENTRAL ARTERIES

VENULES ARTERIOLES

CAPILLARIES

Systolic Hypertension Syndrome:Compensatory Hemodynamic Changes

LVH, Angina, Heart Failure

 Preload  Aortic stiffness

SBP

 Afterload

Venoconstriction SVR (Augmentation)

Rarefaction (Insulin resistance, Salt-sensitivity, Albuminuria,CKD, Lacunar infarcts, Dementia)

systolic pressure augmentation
Systolic Pressure Augmentation
  • In young normotensives with compliant arteries and slow pulse wave transmission, the reflected wave returns to the aortic root during late diastole, where it augments coronary blood flow with no effect on cardiac load.
  • With aging and hypertension, increased vascular stiffness and higher pulse wave velocity cause the reflected wave to return to the aortic root in late systole, where it augments systolic pressure and increases myocardial work.
ace inhibition and glomerular function in diabetic rats
ACE Inhibition and Glomerular Function in Diabetic Rats

MAP GFP

Diabetes 115 52

DM + Enalapril 9834

(-15%) (-32%)

Zatz, et al. J Clin Invest 1986;77:1925

slide63
Focal, Occlusive

Inflammatory

Endothelial dysfunction

Related to LDL cholesterol oxidation

“Inside-out”

Diffuse, Dilatory

Fibrotic (elastin breakdown, collagen increase)

Adventitial and medial hypertrophy

Related to age and BP

“Outside-in”

ATHERO- ARTERIO-SCLEROSIS SCLEROSIS (Increased vascular stiffness Decreased vascular compliance)

components of cardiac afterload64
Components of Cardiac Afterload

Late-systolic pressure augmentation (wave reflection)

Contractility/Aortic impedance (“ventricular-vascular coupling”)

Residual systemic (diastolic) pressure (SVR)

(DBP > Aortic impedance > Augmentation)

pulse pressure amplification66
Pulse Pressure Amplification

Progressive increase in vascular impedance (as arteries narrow

and become stiffer) causes pulse pressure amplification

  • Key issues:
  • Poor correlations between brachial BP and central BP
  • Incident wave properties vs. peak pressure
bp responses to monotherapy
0

10

20

30

40

50

60

70

BP Responses to Monotherapy

Thiazides

50–55%

Beta blockers

45–50%

ACE inhibitors

50–60%

40–60%

Calcium Antagonists

Alpha blockers

35–40%

Central agonists

30–35%

% Responders

Adapted from Neutel et al. Hosp Med. 1998;34:35–38, 41–43.

pseudotolerance to antihypertensive drugs
“Pseudotolerance” to Antihypertensive Drugs

SYSTEMIC MECHANISMS

Systemic BP defense mechanisms (SNS, RAAS) are activated by monotherapy with diuretics or vasodilator drugs. Concomitant “anti-neurohumoral” agents (ACE inhibitor, etc) often required .

RENAL MECHANISMS

Hypertensive nephrosclerosis promotes salt/water retention when renal perfusion pressure is reduced. Concomitant diuretic often required.

impact of pseudotolerance
Impact of Pseudotolerance
  • Pseudotolerance mechanisms limit the sustained effectiveness of any single-drug regimen
  • COMBINATION THERAPY IS UNAVOIDABLE !
slide70
Diastolic vs systolic hypertension
  • Prevention vs treatment
  • Compelling indications
  • Other high risk conditions
ukpds bp control reduces diabetes related deaths
UKPDS: BP Control Reduces Diabetes-related Deaths

5

p<0.0001

Hazardratio

1

17% decrease per 10 mmHg SBP

0

5

.

1

1

0

1

2

0

1

3

0

1

4

0

1

5

0

1

6

0

1

7

0

Mean systolic BP (mmHg)

Adler AI, et al. BMJ 2000;321: 412-19.

cardiac implications of excessive pulse wave reflection augmentation
Cardiac Implications of Excessive Pulse Wave Reflection-Augmentation

Increased central systolic BP

Increased left ventricular load

Concentric LVH

Increased ventricular stiffness

Diastolic dysfunction

Increased end-diastolic pressure

Overt heart failure

slide73
Pathogenesis and Consequences

of Hypertension

PATHOGENETIC HEMODYNAMIC DISEASE INTERACTIONS FACTORS FACTORS

ENVIRONMENTAL FACTORS (Stress, Drugs, etc)

CARDIO-VASCULAR DISEASE

INAPPROPRIATELY HIGH CO

NEUROHUMORAL HYPERACTIVITY (SNS, RAAS, etc)

AGING

METABOLIC ABNORMALITIES (Glucose, ROS, NO, etc)

INAPPROPRIATELY HIGH SVR

 SBP

NEPHRON LOSS

VASCULAR MALADAPTATIONS (Reactivity, Hypertrophy)

CENTRAL ARTERIAL STIFFNESS

END-STAGE RENAL DISEASE

SALT-WATER RETENTION (Nephron dysfunction)

jnc 7 compelling indication definition74
JNC 7 Compelling Indication: Definition

A high-risk condition associated with hypertension for which there is clinical trial evidence of a specific outcome benefit of a given class of antihypertensive drugs

ace and ace nep inhibitor effects on aortic impedance mitchell g izzo jl et al circulation 2002
ACE and ACE-NEP inhibitor effects on aortic impedance(Mitchell G, Izzo JL, et al. Circulation 2002)
ada goal bp for hypertension in diabetes 130 80 mm hg
Combination Therapy

“It is very clear that many people will require 3 or more drugs to achieve the recommended target.”

ACE inhibitors/ARBs

“All patients with diabetes and hypertension should be treated with a regimen that includes either an ACE inhibitor or an ARB.”

Which Combination?

“Achievement of the target BP goal with a regimen that does not produce burdensome side effects…is probably more important than the specific drug strategy.”

ADA Goal BP for Hypertension in Diabetes: <130/<80 mm Hg

- American Diabetes Association

American Diabetes Association. Diabetes Care. 2004;27(Supple 1):S65-S67.

ukpds bp control reduces diabetes related deaths77
UKPDS: BP Control Reduces Diabetes-related Deaths

5

p<0.0001

Hazardratio

1

17% decrease per 10 mmHg SBP

0

5

.

1

1

0

1

2

0

1

3

0

1

4

0

1

5

0

1

6

0

1

7

0

Mean systolic BP (mmHg)

Adler AI, et al. BMJ 2000;321: 412-19.

relative risk of new onset diabetes
Relative Risk of New Onset Diabetes

NOD = New-onset diabetes; BB = beta-blocker

Lancet. 1999;353:611-616; Lancet. 2003;362:759-766; JAMA. 2003;290:2805-2816; Lancet. 2000;356:366-372;

Lancet 2004;363:2022-2031; JAMA. 2002;288:2981-2997; N Engl J Med. 2000;342:145-153; J Hypertension. 2002;20:1879-1886; Am J Hypertens. 2003;16:544-548.

ace inhibition and glomerular function in diabetic rats79
ACE Inhibition and Glomerular Function in Diabetic Rats

MAP SNGFR GFP

Control 118 46 39

Diabetes 115 82* 52*

DM + Enalapril 98* 72* 34

Zatz, et al. J Clin Invest 1986;77:1925

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