Hypertension and The Heart

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Hypertension and The Heart
Vasilios Papademetriou, MD Professor of Medicine
(Cardiology) Georgetown University Director
Hypertension and Cardiovascular Research VAMC
Washington DC
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FDRs Final Picture (April 11, 1945)
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FDRs BP as recorded April 1944 at Bethesda Naval
Hospital
4
CV Complications of Untreated Hypertension
(N500)
50
50
45
40
35
30
Event rate ()
25
18
20
16
15
12
8
10
5
2
0
Renal Failure
Stroke
Enceph
MI
Angina
CHF
MI, myocardial infarction CHF, chronic heart
failure. Perera GA J. Chron Dis. 1955133-42.
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Progression From Hypertensionto Heart Failure
LVH
Obesity Diabetes
CHF
Hypertension
SmokingDyslipidemiaDiabetes
MI
Normal LV Structureand Function
LV Remodeling
Subclinical LV Dysfunction
Overt Heart Failure
LVH, left ventricular hypertrophy MI, myocardial
infarction CHF, chronic heart failure. Vasan RS
and Levy D. Arch Intern Med. 19961561789-1796.
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Cumulative Incidence of Heart Failure by Baseline
Hypertension Status
Stage 2
25
25
Men aged 60-69 y
Women aged 60-69 y
Stage 1
20
20
Cumulative Incidence()
15
Stage 2
15
Normotensive
10
Stage 1
10
Normotensive
5
5
0
0
2
4
6
8
10
12
14
16
2
4
6
8
10
12
14
16
40
Women aged 70-79 y
Stage 2
30
Cumulative Incidence()
20
Stage 1
10
Normotensive
0
2
4
6
8
10
12
14
Time (y)
Levy D et al. JAMA. 19962751557-1562.
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Population-Attributable Risks for Development of
CHF
Men
Women
AP5
AP5
DM6
HTN 39
DM12
HTN 59
LVH4
LVH5
VHD7
VHD8
MI34
MI12
Population-attributable risk defined as (100 x
prevalence x hazard ratio 1)/(prevalence x
hazard ratio 1 1)
CHF, chronic heart failure AP, angina pectoris
DM, diabetes mellitus LVH, left ventricular
hypertrophyVHD, valvular heart disease HTN,
hypertension MI, myocardial infarction. Levy D
et al. JAMA. 19962751557-1562.
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Effects of Hypertension on The Heart

• Left Ventricular Hypertrophy
• Vascular Disease
• -Atherosclerosis
• -Arteriosclerosis

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Prevalence of Systolic and Diastolic Dysfunction
by Age
60
50
40
of Population
30
20
10
0
EFlt50
EFlt40
Mild
Moderate
Severe
Diastolic Dysfunction
Systolic Dysfunction
Redfield MM et al. JAMA. 2003289194-202.
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SYSTOLIC AND DIASTOLIC HEART FAILURE

• LOW EF
• HIGH LV MASS
• MYOCYTE HYPERTOPHY
• INTERSTITIAL FIBROSIS
• ABNORM CALC HANDLING
• REDUCED CONTRACTILITY
• SLOWED RELAXATION
• DEPLETED PREL0AD RESERVE
• LARGE VOLUMES

• NORMAL EF
• HIGH LV MASS
• MYOCYTE HYPERTROPHY
• INTERSTITIAL FIBROSIS
• ABNORM CALC HANDLING
• REDUCED CONTRACTILITY
• SLOWED RELAXATION
• DEPLETED PRELOAD RESERVE
• SMALL VOLUMES

KONSTAM MA J OF CARDIAC FAILURE, 2003 VOL 9, No
1 1-3.
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Left Ventricular Hypertrophy

• Independent Predictor of
• Myocardial infarction
• Stroke
• Heart Failure
• Total Mortality
• Sudden Death

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LIFE Design Dosing
Titration to target blood pressure lt140 / lt90
mmHg
Losartan 100 mg HCTZ 12.5-25 mg others
Losartan 100 mg HCTZ 12.5 mg
Losartan 50 mg HCTZ 12.5 mg
Losartan 50 mg
Placebo
Atenolol 50 mg
Atenolol 50 mg HCTZ 12.5 mg
Atenolol 100 mg HCTZ 12.5 mg
Atenolol 100 mg HCTZ 12.5-25 mg others
Day ?14
Day ?7
Day 1
Mth 1
Mth 2
Mth 4
Mth 6
Yr 1
Yr 1.5
Yr 2
Yr 2.5
Yr 3
Yr 3.5
Yr 4
Yr 5
Other antihypertensives excluding ACEIs, AII
antagonists, beta-blockers. Dahlöf B et al Am J
Hypertens 199710705?713.
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LIFE Blood Pressure Results Follow-up
Atenolol 145.4 mmHg
Systolic
Losartan 144.1 mmHg
mmHg
Mean Arterial
Losartan 81.3 mmHg
Diastolic
Atenolol 80.9 mmHg
Study Month
B Dahlof et al. Lancet 2002359995-1003
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LIFE Fatal/Nonfatal Stroke
Intention-to-Treat
Study Month
B Dahlof et al. Lancet 2002359995-1003
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LIFE Fatal/Nonfatal Myocardial Infarction
Intention-to-Treat
Study Month
B Dahlof et al. Lancet 2002359995-1003
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LIFE Cardiovascular Mortality
Intention-to-Treat
Study Month
B Dahlof et al. Lancet 2002359995-1003
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LIFE Other Classified Endpoints
Favors Losartan
Favors Atenolol
Total Mortality
Hosp for AP
Hosp for HF
Revascularization
0
0.5
1
1.5
2
Hazard Ratio (95 CI)
23
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LVH Prevalence at Baseline and Annual Follow-Up
in LIFE
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HR 0.58, 95 CI 0.38-0.86 P-0.008
Hazard ratios represent risk reduction associated
with absence versus presence of LVH
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HR0.34, 95 CI 0.17-0.71 P-0.004
Hazard ratios represent risk reduction associated
with absence versus presence of LVH
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HR0.48, 95 CI 0.24-0.93 0.031
Hazard ratios represent risk reduction associated
with absence versus presence of LVH
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HR0.36, 95 CI 0.23-0.53 Plt0.001
Hazard ratios represent risk reduction associated
with absence versus presence of LVH
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LIFE Echo Substudy Change in LVMI
p0.021, adjusted for baseline LVMI and
baseline in-treatment BP
Change (g/m2)

Change from Baseline to Year in LIFE
Devereux RB et al. Am J Hypertens 20021515A
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Regression of Hypertensive LVH Results of 2000
Meta-Analysis
Plt0.09 vs ß-blockers
Plt0.05
LVM Regression ()
AII receptor Blockers
Diuretics
Beta- Blockers
Ca Blockers
ACE- Inhibitors
Schmieder et al J Am Coll Cardiol
200137261-262A
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CHARM Programme
3 component trials comparing candesartan to
placebo in patients with symptomatic heart failure
CHARM Added
CHARMPreserved
CHARMAlternative
n2028 LVEF 40ACE inhibitor intolerant
n2548 LVEF 40ACE inhibitor treated
n3025 LVEF gt40ACE inhibitor treated/not
treated
Primary outcome for each trial CV death or CHF
hospitalisation
Primary outcome for Overall Programme All-cause
death
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CHARM-Preserved Primary and secondary outcomes
Covariate adjustedp-value
p-value
Candesartan
Placebo
0.89
0.118
0.051
CV death, CHF hosp. 333 366 - CV death 170 170
- CHF hosp. 241 276 CV death, CHF
hosp, 365 399 MI CV death,CHF hosp, 388 429
MI, stroke CV death,CHF hosp, 460 497 MI,
stroke, revasc
0.99
0.918
0.635
0.85
0.072
0.047
0.90
0.126
0.051
0.88
0.078
0.037
0.91
0.123
0.13
0.8
1.0
1.2
candesartan better
Hazard ratio
placebo better
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Effects of Hypertension on The Heart

• Left Ventricular Hypertrophy
• Vascular Disease
• -Atherosclerosis
• -Arteriosclerosis

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

• Focal, Occlusive
• Inflammatory
• Endothelial dysfunction
• Related to LDL cholesterol oxidation
• Inside-out
• Sensitive to A II and other substances

• Diffuse, Dilatory
• Fibrotic (elastin breakdown, collagen increase)
• Adventitial and medial hypertrophy
• Related to age and BP
• Outside-in
• Sensitive to A II and other substances

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Integrated Perspective on CV Risk Factors and
Vascular Disease
Oxidative Stress Inflammation
Endothelial Dysfunction
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Unstable Plaque
Hemorrhaged microvessels
Plaque rupture
Thinning of fibrous cap
Ruptured plaque (coronary artery)
Ross R, N Engl J Med 340 (1999) Davies,
Circulation 94 (1996)
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BP and Risk of CHD Mortality
CHD, coronary heart disease. Multiple Risk Factor
Intervention Trial (MRFIT) n347,978 men without
previous myocardial infarction. Neaton JD et al.
In Hypertension Pathophysiology, Diagnosis, and
Management. 1995127-144.
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Stroke and IHD Mortality vs Usual Systolic BP by
Age
Mortality(Floating Absolute Risk and 95 CI)
IHDischemic heart diseaseProspective Studies
Collaboration. Lancet. 20023601903-1913.
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AGING AND ARTERIAL STIFFNESS PATHOPHYSIOLOGY
Young elastic vessels Old
inelastic vessels
SYSTOLE
DIASTOLE
DIASTOLE
SYSTOLE
STROKE VOLUME
STROKE VOLUME
)
(
AORTA
AORTA
RESISTANCE ARTERIOLES
RESISTANCE ARTERIOLES
Increased systolic
PRESSURE (FLOW)
PRESSURE (FLOW)
Decreased diastolic
Adapted from Izzo JL. J Am Geriatr Soc.
198129520-524.
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SBP DBP by Age Race/Ethnicity Gender (US
Population ?Age 18 Years, NHANES III)
Pulse pressure
Pulse pressure
Men, Age (y)
Women, Age (y)
Burt VI, et al. Hypertension. 199525305-313.
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Distribution of Hypertension Subtype in the
untreated Hypertensive Population in NHANES III
by Age
17
16
16
20
20
11
Frequency of hypertension subtypes in all
untreated hypertensives ()
lt40
40-49
50-59
60-69
70-79
80
Age (y)
Numbers at top of bars represent the overall
percentage distribution of untreated hypertension
by age. Franklin et al. Hypertension
200137 869-874.
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Relationship of SBP and DBP to risk for CHDThe
Framingham Heart Study
Adjusted for age, sex, and other risk factors
P probability for ? coefficients
3
2.5
SBP 170 mm Hg (P 0.01)
CHD hazard ratio
2
SBP 150 mm Hg (P 0.02)
1.5
SBP 130 mm Hg (P 0.06)
1
SBP 110 mm Hg (P 0.03)
0.5
60
70
80
90
100
110
DBP (mm Hg)
Mean age 61 years (range 50-79), n 1924

Franklin SS, et al. Circ. 1999100354.
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Effect of Systolic BP and Diastolic BP on CHD
Mortality MRFIT Screenees (N316,099)
Death rateper 10,000person-years
Diastolic BP (mm Hg)
Systolic BP (mm Hg)
Men aged 35 to 57 years followed up for a mean
of 12 years. Adapted from Neaton et al. Arch
Intern Med. 199215256-64.
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Hypertension A Major Risk Factor for CHF
Diastolic Dysfunction
LVH
Death
CHF
Hypertension
Systolic Dysfunction
MI
Subclinical Left Ventricular Dysfunction
Overt Heart Failure
Left Ventricular Remodeling
Time, decades
Time, months
Vasan RS, Levy D. Arch Intern Med.
19961561789-1796.
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Development of CHF
3.5
Active 112 of 6,914 Placebo 240 of 6,923 55 risk
reduction
3
plt.001
2.5
2
1.5
1.6
3.5
1
0.5
0
Active
Placebo
Moser, Herbert JACC 1996271214-28
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Risk Reduction of Heart Failure in Elderly
Hypertensives
Coops Warrender
STOP Hypertension
EWPHE
SHEP
0
-10
Risk reduction ()
-20
-30
-35
-40
-50
-51
-53
-54
-60
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FROM HYPERTENSION TO HEART FAILURE IN SHEP
about 85
HEART FAILURE
about 15
Kostis et al, JAMA 1997
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Fatal and Nonfatal HospitalizedHeart
FailureSHEP Study by Age Group
Age 60-69 y
Age 70-79 y
Age 80 y

Follow-Up (y)
Kostis et al. JAMA. 1997.
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Treatment of Hypertension and CVD Outcomes
Placebo Controlled Trials
Heart failure
Fatal/nonfatal strokes
Fatal/nonfatal CHD events
CVD deaths
0
-10
-20
-16
Risk reduction ()
-21
-30
-40
-38
-50
-52
-60
17 randomized, placebo-controlled trials (48,000
subjects)14 diuretic and 3 beta blocker based
trials. All differences are statistically
significant. CVD, cardiovascular disease CHD,
coronary heart disease. Herbert PR et al. Arch
Intern Med. 1993153578-581. Moser M, Herbert
PR. J Am Coll Cardiol. 1996271214-1218.
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There is no question that treatment of
Hypertension will prevent CV Complications

• Does it Matter How We Do it ?

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ACE/CCB Trials vs Beta-Blockers/Diuretics
Major cardiovascular events included stroke,
myocardial infarction, heart failure, or death
from any cardiovascular cause Adapted from
Blood Pressure Lowering Treatment Trialists
Collaboration. Lancet 20003561956-1964.
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CONVINCEHazard Ratios for Subgroups
No. of Events


COER-v
SOC
Favors COER-v Favors SOC ? ?
SOC Diuretic
181
165
?
SOC
-Blocker
183
200
-Blocker
USA

204
212
Canada
93
86
Western Europe
39
35
Other

28
32
JAMA. 2003.
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CONVINCECVD-Related 2 Endpoints
(No. of events)
Event COER-v SOC HR P value
1 or CVD Hosp 793 775 1.05 0.31
CVD Hospitalization
Angina 202 190 1.09 0.39
Revascularization 163 166 1.01 0.91
CHF 126 100 1.30 0.05
TIA 89 105 0.87 0.33
Renal Insufficiency 27 34 0.81 0.43
Acc HTN 22 18 1.26 0.37
JAMA. 2003.
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Randomized Designof ALLHAT
Amlodipine Chlorthalidone Doxazosin Lisinopril
High-risk hypertensive patients
Consent / Randomize (42,418)
Eligible for lipid-lowering
Not eligible for lipid-lowering
Consent / Randomize (10,355)
Pravastatin Usual care
Follow for CHD and other outcomes until death or
end of study (up to 8 yr).
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Cumulative Event Rates for the Primary Outcome
(Fatal CHD or Nonfatal MI) by ALLHAT Treatment
Group
RR (95 CI) p value
A/C 0.98 (0.90-1.07) 0.65
L/C 0.99 (0.91-1.08) 0.81
Chlorthalidone Amlodipine Lisinopril
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Heart Failure
Cumulative Event Rate
doxazosin
chlorthalidone
13,644 7,845
5,531 3,089
2,427 1,351
9,541 5,457
Years of follow-up
C 15,268 D 9,067
JAMA. 20002831967-1975.
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SBP Results by Treatment Group
Doxazosin
Chlorthalidone
BP (mmHg)
Months
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Heart Failure Subgroup Comparisons RR (95 CI)
Total
1.38 (1.25, 1.52)
Total
1.20 (1.09, 1.34)
Age lt 65
1.51 (1.25, 1.82)
Age lt 65
1.23 (1.01, 1.50)
Age gt 65
1.33 (1.18, 1.49)
Age gt 65
1.20 (1.06, 1.35)
Men
1.41 (1.24, 1.61)
Men
1.19 (1.03, 1.36)
Women
1.33 (1.14, 1.55)
Women
1.23 (1.05, 1.43)
Black
1.47 (1.24, 1.74)
Black
1.32 (1.11, 1.58)
Non-Black
1.33 (1.18, 1.51)
Non-Black
1.15 (1.01, 1.30)
Diabetic
1.42 (1.23, 1.64)
Diabetic
1.22 (1.05, 1.42)
Non-Diabetic
1.33 (1.16, 1.52)
Non-Diabetic
1.20 (1.04, 1.38)
0.50
1
2
0.50
1
2
Amlodipine Better Chlorthalidone Better
Lisinopril Better Chlorthalidone Better
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BP Results by Treatment Group
Chlorthalidone
Amlodipine
Lisinopril
BP (mmHg)
BP (mmHg)
Years
Compared to chlorthalidone SBP significantly
higher in the amlodipine group (1 mm Hg) and the
lisinopril group (2 mm Hg).
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BP-Lowering Treatment TrialistsComparisons of
different active treatments
BP Difference(mm Hg)
RR (95 CI)
Relative Risk
Stroke
Coronary Heart Disease
Heart Failure
0.5
1.0
2.0
FavorsFirst Listed
FavorsSecond Listed
Lancet. In press.
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BP-Lowering Treatment TrialistsComparisons of
different active treatments
BP Difference(mm Hg)
RR (95 CI)
Relative Risk
Major CV Events
CV Mortality
Total Mortality
0.5
1.0
2.0
FavorsFirst Listed
FavorsSecond Listed
Lancet. In press.
63
BP-Lowering Treatment Trialists Angiotensin
Receptor Blocker vs Other
Favors ARB
Favors Other


Outcome
RR (95 CI)
0.79 (0.69,0.90)
Stroke
0.96 (0.85,1.09)
CHD
Heart Failure
0.84 (0.72,0.97)
Major CV Events
0.90 (0.83,0.96)
CV Death
0.96 (0.85,1.08)
Total Mortality
0.94 (0.86,1.02)
0.5
1.0
2.0
Relative Risk
Lancet. In press.
64
BP-Lowering Treatment Trialists
Stroke
CHD
1.50
Relative Risk of Stroke
1.25
1.00
Relative Risk of CHD
0.75
0.50
0.25
Systolic Blood Pressure Difference Between
Randomised Groups (mm Hg)
Systolic Blood Pressure Difference Between
Randomised Groups (mm Hg)
Lancet. In press.
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Hypertension A Major Risk Factor for CHF
Diastolic Dysfunction
LVH
Death
CHF
Hypertension
Systolic Dysfunction
MI
Subclinical Left Ventricular Dysfunction
Overt Heart Failure
Left Ventricular Remodeling
Time, decades
Time, months
Vasan RS, Levy D. Arch Intern Med.
19961561789-1796.
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Prevention of Cardiac Complications of
Hypertension

• Its the Blood Pressure stupid
• Treat Blood Pressure to Goal
• Systolic BP Reduction is Probably more important
• Diuretic Trerapy is as good as any
• Calcium Channel Blockers/ Alfa Blockers seem to
  be less effective in preventing Heart Failure

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WORKING HARD, Right Tools?
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Science 3/01
Lancet 3/01