TREATMENT OF COMPLICATED HYERTENSION Joseph L. Izzo Jr, MD Professor of Medicine, Pharmacology, and

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TREATMENT OF COMPLICATED HYERTENSIONJoseph L.
Izzo Jr, MDProfessor of Medicine,
Pharmacology, and ToxicologySUNY-Buffalo
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• Diastolic vs systolic hypertension
• Prevention vs treatment
• Compelling indications
• Other high risk conditions

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Hypertension Subtypes by Age (NHANES III
Untreated Hypertensives)
17
16
16
20
20
11
Frequency of hypertension subtypes in all
untreated hypertensives ()

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 200137 869-874.
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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
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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

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Pathogenesis of Systolic and Diastolic
Hypertension
SYSTOLIC HYPERTENSION
? Stroke Volume
? Central Artery Stiffness
? Arteriolar Constriction
DIASTOLIC HYPERTENSION
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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)
8
ACE and ACE-NEP Inhibitor Effects on Aortic
Impedance(Mitchell G, Izzo JL Jr, et al.
Circulation 2002, in press)
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• Diastolic vs systolic hypertension
• Prevention vs treatment
• Compelling indications
• Other high risk conditions

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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
0.75
CAPPP
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 200135813051315.
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Clinical Trialists View
Amount of BP lowering is more important than
choice of drug class in overall disease prevention
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JNC 7 Medication Algorithm
Initial Drug Choices
With Compelling Indications
Without Compelling Indications
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)
Stage 1 Hypertension(SBP 140159 or DBP 9099
mmHg) Thiazide-type diuretics for most. May
consider ACEI, ARB, BB, CCB, or combination
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 drugs until
goal BP is achieved.Consider consultation with
hypertension specialist.
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Why the discrepancies?

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

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

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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
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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
o o o o o o

O
O O
A B C D
HEART FAILURE (STAGE) POST-MI HIGH CAD RISK
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Components of Cardiac Afterload
Late-systolic pressure augmentation (wave
reflection)
Contractility/Aortic impedance (ventricular-vascu
lar coupling)
Residual systemic (diastolic) pressure (SVR)
(DBP Aortic impedance Augmentation)
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Age and Components of Cardiac Afterload
Augmentation Component
Younger
Older
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SEVERE HYPERTENSIVE LEFT VENTRICULAR HYPERTROPHY
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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
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Therapy for CHF
NYHA Class
Agent
II
I
IV
III
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.
199922bbV21-V29.
8
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JNC 7 Compelling Indications for Individual
Drug Classes (o Updated)
Initial Therapy Options TZ BB
ACE ARB CCB AA
Compelling Indication
Basis
DIABETES CHRONIC KIDNEY DISEASE RECURRENT
STROKE
NKF-ADA Guideline, UKPDS, ALLHAT

? O O
NKF Guideline, Captopril Trial, RENAAL, IDNT,
REIN, AASK
PROGRESS, MIRACLE
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MDRD Study Impact of BP Control

• Hebert, et al. Hypertension 301997.428-35

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Aggressive BP Goals Consensus Across Treatment
Guidelines
Organization Patient Type BP Goals (mm
Hg) ADA Diabetes American 1 g/24
h DM, CKD 300 mg/d or
200 mg/g creatinine), diabetes Proteinuria (protein to creatinine
ratio Consider even 500-1000 mg/g) lower
than CVD SBPdamage, or associated clinical conditions
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
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ACEI in Diabetic Renal Disease
Overall Deaths Captopril 8/2074 Placebo
14/2027
Placebo SCr?1.5
Death Dialysis or Transplant ()
P.002 vs placebo (Scr?1.5 )
Captopril SCr?1.5
Placebo SCrCaptopril SCrYears of Follow Up
Lewis EJ et al. N Engl J Med 19933291456-1462.
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ESRD
RENAAL 10 Components
Risk Reduction 28
p0.002
P
with event
L
Doubling of Serum Creatinine
Risk Reduction 25
p0.006
Months
762
715
610
347
42
751
714
625
375
69
with event
ESRD or Death
Risk Reduction 20
p0.010
P
with event
L
Months
762
689
554
295
P ( CT)
36
L ( CT)
751
692
583
329
52
Months
762
715
610
347
42
751
714
625
375
69
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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
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Clinical Trials and Renal Outcomes Based on
Proteinuria Reduction
Progression of diabetic nephropathy/ESRD
No Protection
Protection

• Amlodipine (IDNT)
• Amlodipine (AASK)
• Isradipine (STENO)
• Nifedipine

• Captopril
• Ramipril (AASK/REIN)
• Losartan (RENAAL)
• Irbesartan (IDNT)

30-35 proteinuria
No proteinuria
ESRD End Stage Renal Disease
Lewis EJ et al. N Engl J Med. 19933291456-1462
Wright JT et al. JAMA. 2002 288(19)2421-2431
Ruggenenti P et al. Lancet. 1999354(9176)359-364
Brenner BM et al. N Engl J Med.
2001345(12)861-869 Lewis EJ et al. N Engl J
Med. 2001345(12)851-860 Norgaard K et al.
Blood Press.19932(4)301-308 Abbott K et al. J
Clin Pharmacol. 199636274-279.
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JNC 7 BP Thresholds and Goals for Initial Use
of 2-Drug Combinations

• Initial BP Goal BP
• (mmHg) (mmHg) Condition
• 160/100 kidney disease (CKD)
• 150/90 125 mg/dL
  x 2)
• CKD (eGFR 300
  mg/d)

20/10 mmHg above goal
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Probable dose-response relationships for BP and
albuminuria
BP
Albuminuria
Effect ?
l l l l
Log Dose ?
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Combination Therapy Is Usually Requiredto Reach
JNC Goals
Most patients with HTN will require 2 or more
agents to achieve goal of or CKD)
-JNC 7
SBP mm Hg
Trial
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 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. 200036646-661 ALLHAT
Officers. JAMA. 20022882981-2997 Hansson L et
al. Lancet. 19983511755-1762 Pepine CJ et al.
JAMA. 2003290(21)2805-2816 Wright JT et al.
Arch Intern Med. 20021621636-1643 UK
Prospective Diabetes Study Group. BMJ.
1998317703-713 Brenner BM et al. N Engl J
Med. 2001345(12)861-869 Sica DA, Bakris GL. J
Clin Hypertension. 20024(1)52-57.
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• Diastolic vs systolic hypertension
• Prevention vs treatment
• Compelling indications
• Other high risk conditions

35
Resistant hypertension

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

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Selected conditions associated with resistant
hypertension

• Non-adherence
• Sleep apnea
• Renal failure
• Interfering drugs

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TREATMENT OF COMPLICATED HYERTENSIONJoseph L.
Izzo Jr, MDProfessor of Medicine,
Pharmacology, and ToxicologySUNY-Buffalo
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Primary Composite Endpoint of LIFE Trial
Stratified by Time-varying Albuminuria
RAAS Blockade Treatment Benefit Seen at All
Albuminuria Baseline Levels
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. 2004221805-1811.
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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

40
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

41
Determinants of SBP and Afterload
Late-systolic pressure augmentation
Aortic impedance
Diastolic pressure
(DBP Aortic impedance Augmentation)
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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
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Central Arterial Stiffness and PPPathophysiology
Elastic vessels Inelastic
vessels
SYSTOLE
DIASTOLE
DIASTOLE
SYSTOLE
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.
198129520-524.
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Impedance and arterial radius
Impedance is the pulsatile equivalent of
resistance

• Characteristic aortic impedance
• Zc ? vEh/r5

E elastic modulus h wall thickness r
radius
Zc varies inversely with r2.5
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Age, Gender, PP and Aortic Root Diameter
(Framingham)
Vasan, et al. Circulation 1995
46
BP and Aortic Root Diameter (Framingham)
Vasan, et al. Circulation 1995
47
Aortic Dilatation and BP (LIFE Study)
Bella, et al. Am J Cardiol 2002
48
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.

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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)

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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
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Functional Dependency of Reflected Waves on
Systemic Hemodynamics
RADIAL
AP 20
AP 2
AP - 8
CENTRAL
NORMAL NOREPINEPHRINE EPINEPHRINE
(HYPERTENSION)
52
Systolic Augmentation and Cardiac Work Aging and
Hypertension
40
Wasted Cardiac Work
?P
PP
30
Augmentation index (?P/PP, )
20
HT
10
NT
0
25
45
75
15
65
55
5
35
Age (years)
Adapted from Fleg/Kelly, Hypertension Primer, 1st
Edition.
53
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,199332.
54
Aorta-brachial artery differences

• Aorta (carotid-femoral PWV)
• Stiffness increase with age
• Brachial artery (wall track)
• Diameter increases with age and hypertension
• Stiffness
• lower in hypertension
• No age-related increase

Heidjen-Speck, et al. Hypertension 200035637-42
55
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

56
ISH in the YoungHealthy 18 y.o. cross-country
runner Clinic BP 144/72 Rx amlodipine
Aorta 112/81
Radial134/80
57
Peripheral Pulse Wave Transmission

• Pulse pressure amplification (peak pressures,
  aorta to brachial) is diminished with age due to
  wave reflection
• Incident wave amplification continues
• Elastic characteristics of peripheral arteries
  are not related to central changes brachial
  artery compliance is not a surrogate for aortic
  compliance

58
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 ?

59
Conjunctival Capillary Rarefactionin Early
Hypertension
60
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 2000581211-8
61
Systolic Hypertension Syndrome

• Change In
• Hypertension
• LVH
• Diastolic dysfxn
• ? Stiffness
• Effective Diameter
• ? Stiffness
• PP Amplification

Compartment HEART CENTRAL ARTERIES PERIPHERA
L ARTERIES

• Impact
• Angina Heart Failure
• ? PP, ? SBP
• ? BP Variability
• Spurious ISH

62
Systolic Hypertension Syndrome

• Change In
• Hypertension
• Constriction
• Rarifaction

Impact ? SVR MAP ? Augmentation Insulin
resistance Salt-sensitivity Albuminuria, CKD
Lacunar infarcts Dementia (?)
Compartment ARTERIOLES CAPILLARIES
63
Systolic Hypertension SyndromeCompensatory
Hemodynamic Changes
LVH, Angina, Heart Failure
? Preload ? Aortic stiffness
?SBP
? Afterload
Venoconstriction ? SVR (Augmentation)
Rarefaction (Insulin resistance,
Salt-sensitivity, Albuminuria, CKD, Lacunar
infarcts, Dementia)
64
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.

65
ACE Inhibition and Glomerular Function in
Diabetic Rats
MAP GFP Diabetes 115 52 DM
Enalapril 98 34 (-15) (-32)
Zatz, et al. J Clin Invest 1986771925
66
ATHERO- ARTERIO- SCLEROSIS
SCLEROSIS (Increased vascular
stiffness Decreased vascular
compliance)

• 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

67
Components of Cardiac Afterload
Late-systolic pressure augmentation (wave
reflection)
Contractility/Aortic impedance (ventricular-vascu
lar coupling)
Residual systemic (diastolic) pressure (SVR)
(DBP Aortic impedance Augmentation)
68
Aortic Pressure-Flow Curves and Reflected Waves
69
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

70
BP Responses to Monotherapy
5055
Thiazides
4550
Beta blockers
5060
ACE inhibitors
4060
Calcium Antagonists
3540
Alpha blockers
3035
Central agonists
Responders
Adapted from Neutel et al. Hosp Med.
1998343538, 4143.
71
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.

72
Impact of Pseudotolerance

• Pseudotolerance mechanisms limit the sustained
  effectiveness of any single-drug regimen
• COMBINATION THERAPY IS UNAVOIDABLE !

73

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

74
UKPDS BP Control Reduces Diabetes-related Deaths
5
pHazard ratio
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 2000321 412-19.
75
Dependency of Augmentation Index (AI) on Systemic
Vascular Resistance (SVR)
Supine Handgrip
AI ()
Supine
Upright
Upright Bike
SVR (dyne.sec.cm-5)
76
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

77
(No Transcript)
78
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
79
ACE and ACE-NEP inhibitor effects on aortic
impedance(Mitchell G, Izzo JL, et al.
Circulation 2002)
80
ADA Goal BP for Hypertension in Diabetes

- American Diabetes Association
American Diabetes Association. Diabetes Care.
200427(Supple 1)S65-S67.
81
UKPDS BP Control Reduces Diabetes-related Deaths
5
pHazard ratio
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 2000321 412-19.
82
Relative Risk of New Onset Diabetes
NOD New-onset diabetes BB beta-blocker
Lancet. 1999353611-616 Lancet.
2003362759-766 JAMA. 20032902805-2816
Lancet. 2000356366-372 Lancet
20043632022-2031 JAMA. 20022882981-2997 N
Engl J Med. 2000342145-153 J Hypertension.
2002201879-1886 Am J Hypertens.
200316544-548.
83
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 1986771925