HTN & CHD

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??????S? ??? S??F?????? ??S?S
Athanasios J. Manolis MD
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Progression of Cardiovascular Disease Focus on
LVH
Smoking Dyslipidemia Diabetes
Systolic Dysfunction
MI
CHF
Death
Hypertension
Diastolic Dysfunction
LVH
Obesity Diabetes
Possible pathway of progression
Subclinical LV Dysfunction
Overt Failure
LV Remodeling
Years
months
(Adapted from Levy D. J Am Coll Cardiol 1993)
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Cardiovascular disease the leading cause of
death worldwide
Values are percentages of death rate.IHD
ischaemic heart disease COPD chronic
obstructive pulmonary disease HIV human
immunodeficiency virusCVD cardiovascular
disease
WHO The World Heart Report 1999, Nikkei Medical
1999, Japan Welfare Ministry 1997
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Lifestyles and characteristics associated with
increased risk of future coronary heart disease
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New cardiovascular risk factors

• Left ventricular hypertrophy (LVH)
• Hyperhomocysteinaemia
• Lipoprotein (a) excess
• Hypertriglyceridaemia
• Increased thrombogenicity and decreased
  fibrinolytic activity
• Oxidative stress
• Infectious agents
• Markers of inflammation, such as C-reactive
  protein

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Hypertension SyndromeIts More Than Just Blood
Pressure
DecreasedArterial Compliance
Endothelial Dysfunction
Obesity
Abnormal Glucose Metabolism
Abnormal Lipid Metabolism
Accelerated Atherogenesis
Neurohormonal Dysfunction
Hypertension
Renal-Function Changes
LV Hypertrophyand Dysfunction
Blood-Clotting Mechanism Changes
Abnormal Insulin Metabolism
Kannel WB. JAMA. 19962751571-1576. Weber MA et
al. J Hum Hypertens. 19915417-423. Dzau VJ et
al. J Cardiovasc Pharmacol. 199321(suppl
1)S1-S5.
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ESH Factors influencing prognosis
M, men W, women LDL, low-density lipoprotein
HDL, high-density lipoprotein LVMI, left
ventricular mass index IMT, intima-media
thickness. Lower levels of total and
LDL-cholesterol are known to delineate increased
risk, but they were not used in the stratification
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• Vascular diseaseand CAD in particularis the
  leading cause of death in the US and other
  Western nations
• By 2020, cardiovascular disease will become the
  most common cause of death worldwide
• Due to the high initial mortality of vascular
  disease, the target of clinical practice must be
  aggressive risk factor management

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Coronary Artery Disease (CAD)The Diagnosis
Often Comes Too Late
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Atherosclerosis Begins in Childhood

• (Adapted from Berenson et al.)

Berenson GS et al, N Engl J Med, 1998.
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Most Myocardial Infarctions Are Causedby
Low-Grade Stenoses
Pooled data from 4 studies Ambrose et al, 1988
Little et al, 1988 Nobuyoshi et al, 1991 and
Giroud et al, 1992.(Adapted from Falk et al.)
Falk E et al, Circulation, 1995.
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CAD Not Just a Lipid Disease

• Half of all MIs occur in normolipidemic patients
• SmokingAccounts for 200,000 cardiovascular
  deaths annually
• DiabetesAffects 16 million Americansand is
  growing
• HypertensionConfers as much risk for MI as
  smoking or dyslipidemia
• Systolic hypertension is an even greater
  indicator of CAD risk than diastolic hypertension

Braunwald E, N Engl J Med, 1997 Grundy SM et al,
Circulation, 1998 The Joint National Committee
on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure and the National
High Blood Pressure Education Program
Coordinating Committee, Arch Intern Med, 1997.
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Total Cholesterol Distribution CHD vs Non-CHD
Population
Framingham Heart Study26-Year Follow-up
No CHD
35 of CHD Occurs in People with TClt200 mg/dL
CHD
150
250
300
200
Total Cholesterol (mg/dL)
Castelli WP. Atherosclerosis. 1996124(suppl)S1-S
9. ?1996 Reprinted with permission from Elsevier
Science.
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Small Increases in Cholesterol Lead to Dramatic
Increases in CAD Death

• (Adapted from Neaton et al.)

Neaton JD et al, Arch Intern Med, 1992.
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Impact of High-Normal BP on CV Disease Risk in Men
High- normal
Normal
Cumulative Incidence ()
Optimal
Optimal lt120/80 mm Hg normal 120-129/80-84 mm
Hg high-normal 130-139/85-89 mm Hg. Vasan RS. N
Engl J Med. 20013451291-1297.
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Metabolic SyndromeNCEP ATP III Criteria

• Three or more of the following
• Abdominal obesitywaist male gt102 cm, female gt88
  cm
• Triglycerides ?150 mg/dL
• HDL cholesterolMale lt40 mg/dL, female lt50 mg/dL
• SBP ?130 mm Hg or DBP ? 85 mm Hg
• Fasting glucose ?110 mg/dL (IFG)

NCEPNational Cholesterol Education Program.ATP
IIIThird Report of NCEP Expert Panel on
Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults.
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Distribution of the components of the metabolic
syndrome in the population of the ATTICA Study
Panagiotakos D. et al. Am Heart J 2004
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Impact of Lifestyle Habits on the Prevalence of
the MS among Greek Adults from the ATTICA Study
Levels of anthropogenic, inflammation and
coagulation markers in pts with MS
Participants without MS Participants with MS
plt Apo A1 (mg/dL) 15826 14671
lt.001 ApoB (mg/dL0 10541 12328
lt.001 CRP 2.164.36 3.654.7
lt.001 LDL-C (mg/dL) 12337 13237 lt.
001 WBC (counts) 6.611.8 7.141.8
lt.001 Homocysteine (nmol/L) 12.25.3 13
.66.9 lt.001 Fibrinogen
(mg/dL) 315149 33873 lt.003 Serum
amyloid A (mg/dL) 58 5.957.5
lt.058 Lipoprotein-a (mg/dL) 19.828.9 17.65
22 lt.082 Oxidized LDL-C
(mg/dL) 63.230 63.732
lt.883
Panagiotakos D. et al. Am Heart J 2004
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Atherosclerosisa multifactorial disease
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• What is the current understanding of the
  atherosclerotic process?
• What is the role of endothelial dysfunction in
  atherosclerosis and hypertension?
• How do dyslipidemia and hypertension interact to
  exacerbate disease?

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Different stages of atherosclerotic
plaquedevelopment
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• What is the current understanding of the
  atherosclerotic process?
• What is the role of endothelial dysfunction in
  atherosclerosis and hypertension?
• How do dyslipidemia and hypertension interact to
  exacerbate disease?

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CVD Risk Factors and Endothelial Dysfunction
Dyslipidemia
Diabetes
Hypertension
Smoking
Endothelium
Dysfunction
Vasoconstriction
Cell adhesionand/or infiltration
Proliferation
Lipid accumulationand clearance
Dzau VJ. J Cardiovasc Pharmacol. 199015(Suppl
5)S59-S64.
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HTN, hemodynamic factor and atheroclerosis
HTN creates areas of low sear stress within
arteries
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• What is the current understanding of the
  atherosclerotic process?
• What is the role of endothelial dysfunction in
  atherosclerosis and hypertension?
• How do dyslipidemia and hypertension interact to
  exacerbate disease?

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CAD Risk Is Incremental

• (Adapted from Neaton et al.)

Neaton JD et al, Arch Intern Med, 1992.
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Interaction of Hypertension and Dyslipidemia and
Atherosclerotic Risk
Hypertension
Dyslipidemia
Endothelial dysfunction



? NO Synthesis
? Endothelin
Inflammation
Vasoconstriction Calciummobilization
? Vasoconstriction ? Thrombosis ?
Superoxide production
? Leukocyte adhesion ? Endothelial
permeability ? Foam cell formation ? T cell
activation
Adapted from Mason RP. Cerebrovasc Dis.
200316(Suppl 3)11-17.
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Role of Angiotensin II in the Progression of
Atherosclerosis
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Vulnerable plaqueKey role of the macrophage in
vascular wall inflammation
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Thrombosis of a Disrupted Atheroma, the Cause of
Most Acute Coronary Syndromes, Results from

• Weakening of the fibrous cap
• Thrombogenicity of the lipid core

Illustration courtesy of Michael J. Davies, M.D.
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Plaque Rupture with Thrombosis
Fibrous cap
Thrombus
1 mm
Lipid core
Illustration courtesy of Frederick J. Schoen,
M.D., Ph.D.
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CVD has the highest economic impact of all
diseases (15 of total healthcare costs)
Source www.hc-sc.gc.ca/hpb/lcdc/publicat/burden/b
urd1_e.html
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How to reduce the risk of plaque rupture
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Implications for Treatment
Statins
Dyslipidemia
Synergistic reductions in CV risk?
Synergistic increase in CV risk
Antihypertensives
Hypertension
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Lifestyle Modification
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Mechanism by Which Diet Potentially Influences
Risk of CHD
Intermediary Biological Mechanism Lipid Levels
Low-Density Lipoprotein Cholesterol
High-Density Lipoprotein Cholesterol
Triglycerides Lipoprotein(a) Blood
Pressure Thrombolic Tendency Cardiac
Rhythm Endothelial Function Systemic
Inflammation Insulin Sensitivity Oxidative
Stress Homocysteine Level
Risk of Coronary Heart Disease
Diet
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Food Pyramid Reflecting the Traditional Healthy
Mediterranean Diet
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Adherence to a Mediterranean Diet and Survival in
Greek Population Trichopoulou A. et al. N Engl J
Med 2003
Mediterranean Diet Score, Other Baseline
Characteristics and Mortality among 22.043 study
Participants
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Relative risk of outcome event
SBP difference between randomized groups (mmHg)
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Odds Ratio for CV Events and Systolic BP
Difference Recent and Older Trials
1.50
Recent trials
Older
Recent
ALLHAT/Dox
AASK L vs H
Older trials placebo
ATMH
ABCD/NT L vs H
1.25
EWPHE
ALLHAT/Aml
Older trials active
HEP
ALLHAT/Lis
HOPE
ALLHAT/Lis ?65
Plt.0001
HOT
ALLHAT/Lis Blacks
HOT M vs H
ANBP2
1.00
INSIGHT
CONVINCE
MIDAS/NICS/VHAS
DIABHYCAR
Odds Ratio (experimental/reference)
L vs H
ELSA
MRC
IDNT2
MRC2
LIFE/ALL
0.75
PART2/SCAT
LIFE/DM
PATS
NICOLE
PROGRESS/Per
PREVENT
PROGRESSION/Com
SCOPE
RCT70-80
0.50
RENAAL
SHEP
STONE
STOP 1
STOP2/CCBs
0.25
STOP2/ACEIs
Syst-China
Syst-Eur
UKPDS C vs A
Difference (reference minus experimental) in
Systolic BP (mm Hg)
UKPDS L vs H
Staessen et al. J Hypertens. 2003211055-1076.
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Superior Effect of New vs Conventional Drugs on
Markers of TOD (Intermediate End-Points)
LV hypertrophy Carotid artery IMT /
Atherosclerosis Arteriolar remodelling Urinary
protein excretion Endothelial dysfunction Arterial
stiffening Mild renal damage CA coronary content
ACEI / CA / ARB CA / ACEI ACEI / ARB / CA ACEI /
ARB CA / ACEI (?) / ARB (?) ? CA CA
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Where ACE Inhibitors Work
Sudden death
Angina
Ventricular arrhythmias
Atrial fibrillation
Hyperlipidemia
Cardiac rupture
Hypertrophic cardiomyopathy
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All-Cause Mortality
TRACEEchocardiographicEF 35
AIREClinical and/or radiographic signs of HF
SAVERadionuclideEF 40
Flather MD et al. Lancet. 20003551575-1581.
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Death and Major CV Events
TRACEEchocardiographicEF 35
AIREClinical and/or radiographic signs of HF
SAVERadionuclideEF 40
0.75
(0.67 0.83)
ACE-I (n 2995)
40
Placebo (n 2971)
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Events ()
0.73
0.80
20
(0.63 0.85)
(0.69 0.95)
10
n 460
n 355
n 324
n 391
n 1049
n 1244
0
Readmission for HF
Reinfarction
Death/MI or Readmission for HF
Odds ratio (95 CI).Flather MD et al. Lancet.
20003551575-1581.
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Repair of Coronary Arterioles After Treatment
with Perindopril in Hypertensive Heart Disease
Morphological and Haemodynamic changes before
and after treatment.
67


54
70
p lt 0,04 p lt 0.001
0

12
22


33
54

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PCA Periarteriolar collagen area TIC Total
Interstitial Collagen
Hypertension 2000
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EUROPA Aim of the study

To investigate whether long-term
administrationof the ACE inhibitor perindopril,
added tostandard therapy, leads to a reduction
ofcardiovascular events in low risk patients
withdocumented coronary disease
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EUROPA Primary endpoint
CV death, MI or cardiac arrest
Placebo
Perindopril
Years
Placebo annual event rate 2.4
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EUROPA Sub-groups analysis
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VALIANT Mortality by Treatment
0.3
0.25
0.2
Probabilityof Event
0.15
0.1
0.05
Valsartan vs Captopril HR 1.00 P 0.982
Valsartan Captopril vs Captopril HR 0.98 P
0.726
0
Months
0
6
12
18
24
30
36
Captopril 4909 4428 4241 4018 2635 1432 364

Valsartan 4909 4464 4272 4007 2648 1437 357
Valsartan Cap 4885 4414 4265 3994 2648 1435 382
Pfeffer MA et al. N Engl J Med.
20033491893-1906.
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LIFE Study ISH Subgroup Composite of CV Death,
Stroke, and MI
Unadjusted relative risk29 P0.02 Adjusted
relative risk reduction25 P0.06
18
16
14
12
10
Endpoint rate ()
8
6
Atenolol
4
Losartan
2
0
0
6
12
18
24
30
36
42
48
54
60
66
Study month
CVcardiovascular MImyocardial infarction
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LIFE Primary Composite Endpointin Subgroup
Patients without LVH (n662)
15
12,1
10
7,2

5
RR 45 p0.019
0
Atenolol n330
Losartan n332
Cornell Voltage lt 2400 and Sokolow-Lyon lt 24
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Where b-Blockers Work
Sudden death
Angina
Ventricular arrhythmias
Hypertension
Coronary artery disease
Myocardial infarction
LV dysfunction
Heart failure
Diabetes
Atrial fibrillation
Hyperlipidemia
Cardiac rupture
Pump failure
Hypertrophic cardiomyopathy
Mechanical death
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Beta-Blocker Trials InterveningWithin 24 Hours
of an Acute MI

• Study of Treatment Duration Effect on Effect
  on Patients Groups of therapy Mortality Reinfarc
  tion
• Göteborg 1,395 Placebo 3 ? 36 NS
  Study Metoprolol months (P 0.03)
• MIAMI 5,778 Placebo 3 NS NS
  Trial Metoprolol months
• ISIS-1 16,027 Placebo 1 ? 15 NS
  Trial Atenolol week (P lt 0.04)
• TIMI IIB 1,434 Immediate vs 12 NS NS
  Trial Late Metoprolol months

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Beta-Blocker Trials Intervening3 - 28 Days
Following an Acute MI

• Study of Treatment Average Effect on Effect
  on Patients Groups Follow-up Mortality Reinfarcti
  on
• Multicenter 3,038 Placebo 12 - 36 ? 39 ? 23
  International Practolol months (P lt 0.01) (P lt
  0.09)
• Norwegian 1,884 Placebo 17 ? 39 ? 28
  Trial Timolol months (P lt 0.001) (P lt 0.001)
• BHAT 3,837 Placebo 25 ? 26 NS
  Trial Propanolol months (P lt 0.005)
• Julian 1,458 Placebo 12 NS ? 35
  Post-MI Sotalol months (P 0.07)
• European 1,741 Placebo 12 ? risk ? risk
  Infarction Oxprenolol months
• Lopressor 3,395 Placebo 12 NS ------
  Intervention Metoprolol months

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CAPRICORN All-Cause Mortality
1
23 ? vs. placeboP 0.031
0.95
0.9
Carvedilol
Proportion Event-Free
0.85
0.8
Placebo
0.75
0.7
0
0.5
1
1.5
2
2.5
Years
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Where Statins Work
Sudden death
Angina
Ventricular arrhythmias
LV dysfunction
Heart failure
Atrial fibrillation
Hyperlipidemia
Cardiac rupture
Pump failure
Hypertrophic cardiomyopathy
Mechanical death
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Where Aspirin Works
Sudden death
Angina
Ventricular arrhythmias
Hypertension
Coronary artery disease
Myocardial infarction
LV dysfunction
Heart failure
Diabetes
Atrial fibrillation
Hyperlipidemia
Cardiac rupture
Pump failure
Hypertrophic cardiomyopathy
Mechanical death
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Association of Hypertension with Other CAD Risk
Factors Framingham Study
One 26
One 27
Two 25
Two 24
None 19
None 17
Three 22
Three 20
Four or more 8
Four or more 12
Men
Women
Kannel, Am J Hypertens 2000 13 3S-10S
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A study of RF for first MI in 52 countries and
over 27.000 subjects (INTER-HEART)
Mean age of MI was lower in men vs women by a
median of 9 yrs
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New DM in Antihypertensive Drugs Trials
CAPPP ACEI vs Conv
STOP-2 ACEI vs Conv
ALLHAT ACEI vs D
HOPE ACEI vs PL
STOP-2 CA vs Conv
STOP-2 ACEI vs CA
LIFE ARB vs BB
SCOPE ARB vs Conv
CHARM ARB vs PL
INVEST CA vs Conv
INSIGHT CA vs D
ALLHAT CA vs D
-2
-2
-4
-16
-14
-16
-20
-21
-23
-25
-30
-25
-34
-40
T, 2 yrs T, 4 yrs
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VALUE Incidence of New-onset Diabetes
23 Risk Reduction With Valsartan
18
P lt 0.0001
16
14
12
10
New-Onset Diabetes ( of patients in treatment
group)
16.4
8
13.1
6
4
2
0
Valsartan-based Regimen (n 7649)
Amlodipine-based Regimen (n 7596)
Julius S et al. Lancet. June 2004363.
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Patients on Combinations No of antihypertensive
drugs
RENAALReduction of Endpoints in NIDDM with
the Angiotensin II Antagonist Losartan IDNTIrbes
artan Diabetic Nephropathy Trial MAPátlagos
arteriális nyomás
UKPDSUnited Kingdom Prospective Diabetes
Study MDRDModification of Diet in Renal
Disease HOTHypertension Optimal
Treatment AASKAfrican American Study of Kidney
Disease
Bakris et al. Am J Kidney Dis. 200036646-661
Brenner et al. N Engl J Med. 2001345861-869 Le
wis et al. N Engl J Med. 2001345851-860.
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2003 ESH/ESC Guidelines
Diuretics
AT1-receptor blockers
ß-blockers
Calcium antagonists
?1-blockers
ACE inhibitors
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CAD Risk Factors Minimal and Optimal
Grundy SM, Circulation, 1999 American Heart
Association Consensus Panel, Circulation, 1995
The Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High
Blood Pressure and the National High Blood
Pressure Education Program Coordinating
Committee, Arch Intern Med, 1997.