Hypertension and Cardiovascular Disease

1
Hypertension and Cardiovascular Disease

• Cardiology Organ System
• December 7, 2005
• Paul N. Hopkins, M.D., M.S.P.H.
• Cardiovascular Genetics
• University of Utah

2
Case History Hypertension in a Historical
Setting
Age SBP DBP Notes
39 Polio paralysis of both legs to the hips
53 136 78 High public office for 2 years
55 162 98 Dx of HTN
58 178 88
59 188 105
3
Age SBP DBP Notes
62.2 186 108 Hx Cough, short of breath, malaise. Cigarettes. 1-2 dry martinis qpm Vitals Pulse 72, temp 99 F, wt 188 lbs Fundi Occasional AV nicking Lungs Numerous rales CV Enlarged heart, systolic murmur at apex, loud S2 CXR Enlarged heart, engorged vessels ECG Inverted T in I and chest lead, ST depression in chest lead (new) Dx Possible LV failure, HTN, hypertensive heart disease Acute bronchitis Rx Bed rest 1-2 weeks, digitalis leaf 0.1 g qd Light diet, low salt, substitute KCl Gradual weight reduction, codeine for cough
4
Age SBP DBP Notes
62.3 218 120 Felt fine. Lungs clear. On 1800 Cal diet. Started on phenobarbital 0.25 grains bid. CXR decreased heart size, lungs cleared. Started potassium iodide 10 drops bid.
62.4 196 112 Episode of acute cholelithiasis during a vacation. Cleared spontaneously.
62.6 Travel to Hawaii and Alaska. Substernal chest pain during a speech. Wt. 173.
62.7 240 130 Travel to Quebec. Wt. 168. Increased phenobarbital to 0.5 grains tid.
62.8 210 112 Apex 3-4 cm left of MCL.
5
Age SBP DBP Notes
62.9 260 150 After swimming on vacation. Wt. 165. Decreased appetite.
63.1 In Yalta. Episode of pulsus alternans noted after disturbing conference. Travel to Egypt, Algiers. DCd phenobarbital.
63.2 170 88 On vacation in Warm Springs, Georgia. Looked good. Increased appetite.
63.2 240 130 Repeat BPs during vacation.
6
Age SBP DBP Notes
63.3 gt300 190 130 pm Sudden onset terrific occipital headache. Unconscious in 2 minutes. Pale, cold, diaphoretic. Right pupil widely dilated. Given papavarine and amyl nitrite.
240 120 245 pm Color improved
210 110 315 pm Right pupil widely dilated. Left pupil moderately dilated. Occasional spasms of rigidity. Markedly depressed respirations. Cyanotic.
331 pm Breathing suddenly stopped. No heart sounds. Adrenaline into heart muscle no result.
335 pm Pronounced dead (4-12-1945)
7
Classification of blood pressure

• Definitions
• Measurement

8
HypertensionAn Historical Perspective

• Traube (Berlin, 1856) - High BP Is Essential
• Thought required for blood to flow through
  thickened arteries.
• Believed needed for proper kidney function.
• Unchallenged for almost 80 years.
• Page (Cleveland, 1934) - High BP Is NOT Necessary
• Developed techniques to estimate renal blood flow
  in humans.
• Demonstrated that early antihypertensive measures
  were not detrimental to renal function.
• Radical sympathectomy without loss of renal
  function.

9
Blood Pressure Classification

• Based on the average of at least 4 properly taken
  seated measurements!
• Check both arms first and use the higher arm for
  each visit.
• 2 readings taken at each of 2 visits.
• Usually 1 week apart.
• Not taking antihypertensive drugs and not acutely
  ill or in pain.

10
Classification of BP for Adults Age 18 Years and
Older JNC 7 Guidelines
Category SBP DBP
Normal lt120 and lt80
Pre-hypertension 120-139 or 80-89
Stage 1 hypertension 140-159 or 90-99
Stage 2 hypertension 160 or 100
Chobanian AV, et al. JAMA 2003 2892560
11
Recommendations for Follow-up Based on Initial
Set of BP Measurements for Adults
Systolic Diastolic Follow-up Recommended
lt120 lt80 Encourage lifestyle modification. Recheck in 2 years
121-139 80-89 Lifestyle modification. Recheck in 1-2 years
140-159 90-99 Confirm within 1-2 months. Lifestyle modifications. Thiazide diuretics for most.
160-179 100-109 Evaluate and confirm within 1 month. Sooner for higher blood pressures. Two drugs for most.
180 110 Evaluate or refer to source of care immediately or within 1 week depending on clinical situation
12
Inaccurate Diagnosis

• Too few measurements
• Average 2 readings separated by 2 minutes.
• Too few visits
• 2 visits over several weeks after initial
  screening.
• Physical or emotional stress
• Rest 5 minutes
• Refrain from talking (raises systolic 10 mm Hg)
• No smoking or caffeine in the last 30 minutes.
• Dont count for classification if in pain.

13
Inaccurate Diagnosis

• Inappropriate cuff size
• Use correct cuff size. Bladder to encircle 80
  of the arm. Adequate width.
• Deflation too fast
• Deflate 2 mm Hg per heart beat.
• White coat hypertension
• Consider ambulatory BP monitoring.

14
Why does cuff size matter?
Cuff too small
15
Why does cuff size matter?
Cuff size adequate
16
Epidemiology of blood pressure

• Prevalence
• Associated risks

17
U.S. BLOOD PRESSURE DISTRIBUTION, ADULTS

• Classification BP Level Prevalence (millions)
• Normal lt 120/80 50 (90)
• Prehypertensive 120-139/80-89 21 (38)
• Hypertensive ? 140/90 29 (52)

Chobanian AV, JAMA 2003 2892560 Hajjar I,
JAMA 2003 290199
18
Prevalence of Hypertension () Result From
NHANES, 1999-2000
Age Males Females
18-34 9.3 2.1
35-44 16.5 15.3
45-54 32.2 30.0
55-64 43.6 52.7
65-74 59.6 70.0
75 68.1 84.0
Fields LE, et al. Hypertension 2004 44398
19
Prevalence of hypertension is increasing (NHANES
surveys)
Prevalence () Prevalence () Prevalence ()
1988 1991 1991-1994 1999-2000
Overall 25 25 29
Whites 26 26 29
Blacks 29 33 34
Hispanics 17 18 21
Age 60 58 60 65
Hajjar I, et al. JAMA 2003 290199
20
Lifetime risk of developing hypertension in
Framingham
Percent () with HTN Percent () with HTN
Time, years Women, Age 55 Men, Age 55
10 52 56
15 72 78
20 83 88
25 91 93
Free of HTN at baseline
Vasan RS, et al. JAMA 2002 2871003
21
Age and baseline blood pressure predict
progression to HTN
Vasan RS, et al. Lancet 2001 3581682
22
Global Mortality 2000 Impact of Hypertension and
Other Health Risk Factors
Ezzati et al. Lancet. 20023601347-1360.
23
HYPERTENSION AS A RISK FACTOR

• Relative risk of 2.0 4.0 for
• - CHD - Renal failure
• - CHF - Atrial fibrillation
• - Stroke - Dementia
• - PAD - Mild cognitive impairment
• JAMA 1999 281438 JAMA 1996 2751571 NEJM
  1996 33413

24
Blood Pressure and CHD - MRFIT
Diastolic
Systolic
Neaton JD. Arch Intern Med 1992 15256
25
Blood Pressure and CHD - MRFIT
Diastolic
Systolic
Neaton JD. Arch Intern Med 1992 15256
26
Ischemic Heart Disease Mortality vs Usual BP by
Age
Prospective Studies Collaboration. Lancet.
20023601903
27
CARDIOVASCULAR RISK AND USUAL BP

• Log-linear CVD death risk from 115/75 185/115
• ? 20/10 mm Hg 2X ? in CVD death
• ? 2/0 mm Hg 10 ? in stroke death
• 7 ? in CHD death

Prospective Studies Collaboration. Lancet.
20023601903
28
Effect of Systolic BP and Diastolic BP on CHD
Mortality MRFIT Screenees (N316,099)
Neaton and Wentworth. Arch Intern Med.
199215256-64. 
29
Blood Pressure and Risk of Hemorrhagic Stroke in
114,793 Korean Men
NOTE There was no effect of serum cholesterol
on risk of hemorrhagic stroke in this study.
Suh I, et al. Lancet 2001 357922
30
Consequences of Untreated Hypertension
Historical Data
Other
Stroke
-9 years
MI
-16.5 years
Years of Life Remaining at 35 Years Old
Uremia
CHF
Causes of Death in Malignant Hypertension (95
5-year mortality!)
Flaxman N. Ann Intern Med 1936 10748
31
Pathological consequences of high blood pressure

• Increased atherosclerosis
• Direct damage to arteries arterioles
• Arteriosclerosis
• Arteriolosclerosis

32
Age 35-44
Age 45-54
Age 55-64
Hopkins PN, Hunt SC. Genet Med 2003 5413
33
Hemodynamics and Lesion-Prone Sites
internal carotid

• Lesion-prone sites characterized by
• slow flow, eddies (not turbulence!)
• less elongated endothelial cells
• decrease NO production
• increased lipoprotein penetration
• more white cell adherence
• Coronary arteries are particularly prone. (Why?)

flow divider
external carotid
common carotid
34

• How does hypertension promote atherosclerosis?
• If not by turbulence then how?
• Clue atherosclerosis is not seen in the venous
  circulation. Must be related to pressure itself.

35
How Does Hypertension Promote Atherosclerosis?
Pressure-driven LDL convection in rabbit
thoracic aorta
20x ? LDL 10x ? albumin
Media
Intima
70 mm Hg
160 mm Hg
Curmi, et al. Circ Res 1990 661692
36
Hypertension damages arteries and arterioles

• Stage 1 2 pressures ? HYPERTROPHY of media
• Can protect against breakdown of blood-brain
  barrier.
• Stage 2 for prolonged periods or Stage 3 ?
  ARTERIOSCLEROSIS in arteries
• myointimal hyperplasia (proliferation of smooth
  muscle cells in the intima)
• in arteries - collagen replaces much of media,
  splitting of internal elastic membrane - makes
  older arteries stiff. May promote abdominal
  aortic aneurysm.

37
Hypertension damages arteries and arterioles

• Stage 2 for prolonged periods or Stage 3 ?
  ARTERIOLOSCLEROSIS in arterioles
• myointimal hyperplasia (proliferation of smooth
  muscle cells in the intima)
• increase in collagen and glycoproteins,
  accumulation of lipid (some from increased
  insudation from plasma). CAN LEAD TO LUMEN
  COMPROMISE.
• Severe HTN ? endothelial barrier breakdown,
  plasma fluids and proteins enter arteriole wall
  causing vascular edema, fibrin is deposited ?
  fibrinoid change, and ultimately fibrinoid
  necrosis ? organ ischemia and / or vessel rupture.

38
Pathological Consequences of Hypertension
(continued)

• Arteriolosclerosis by itself (without
  atherosclerosis!) can lead to
• In kidney glomerulosclerosis, nephrosclerosis,
  ? ischemia ? malignant hypertension.
• In brain ischemic changes (lacunar infarcts),
  dementia, Charcot-Bouchard aneurysms ? cerebral
  hemorrhage.
• In eye microvascular changes, eventual
  blindness.
• In heart hypertensive heart disease, CHF.

39
What causes hypertension?

• Several mechanisms and control systems
  understood.
• Can only rarely determine cause in any individual.

40
What causes hypertension?

• Franks Formula (BP CO x PVR)
• Analogous to Ohms Law
• (flow driving force / resistance)
• True by definition but provides little insight.
• Guyton Model
• Systems analysis approach based on years of
  careful empirical research (primarily in dogs).

41
Short-Term Pressure Natriuresis in Dogs
RBF
Na excretion
GFR
Majid DSA, Navar LG. Hypertension 1994 231040
42
33
Volume-Loading Hypertension in Dogs
4
40
5
Approximately 70 of the renal mass was removed
several weeks in advance. After day 0, isotonic
saline was continuously infused intravenously at
a rate about 5 times the normal salt intake.
38
-11
45
22.5
Guyton AC, In Laragh, Hypertension 1995
43
AII Modulates Pressure Natriuresis and Salt
Sensitivity of Arterial Pressure
500
Soduim intake(mEq/d)
300
AII (n 6) Control (n 6) ACE inhibition (n
6)
100
150
140
130
120
Mean arterial pressure (mm Hg)
110
100
90
80
70
1
3
5
7
9
29
27
25
23
21
19
17
15
13
11
Time (d)
Hall JE, et al. J Am Soc Nephrol.
199910S258-S265.
44
Hall JE. Am J Physiol 1999 277S174
45
(No Transcript)
46
Decreased number of nephrons may cause
hypertension
Keller G, et al. N Engl J Med 2003 348101
47
Decreased number of nephrons may cause
hypertension
Normotensive
Hypertensive
Keller G, et al. N Engl J Med 2003 348101
48
Rare Genetic Causes of Hypertension and
Hypotension

• Hypertension
• Glucocorticoid Remediable Aldosteronism (GRA)
• dominant
• Liddles Syndrome
• dominant
• Apparent Mineralocorticoid Excess (11
  ß-hydroxysteroid dehydrogenase deficiency)
• recessive
• Others
• Hypotension
• Bartter syndrome
• Others

Hopkins PN, Hunt SC. Genet Med 20035413
49
Common Gene Variants and Essential Hypertension

• Angiotensinogen (AGT)
• Linkage and association studies
• 235T (-6A) higher risk than 235M (-6G)
• Transgenic animal studies
• Local renal expression
• Human mechanistic studies
• a-Adducin
• G-protein ß3 subunit
• Others

Hopkins PN, Hunt SC. Genet Med 20035413
50
Secondary Hypertension (about 5 of all
hypertension)

• Renal Failure
• Renovascular Hypertension
• Hyperaldosteronism
• Pheochromocytoma
• Polycystic kidney disease
• Oral Contraceptives
• Sleep Apnea (some consider a risk factor for
  primary hypertension).

51
Renal Stenosis
A major cause of 2o HT
Decreased renal blood flow - ? renal BP - ?
renin release - ? angiotensin II aldosterone
- ? Na, water retention - ? systemic BP
52
Take Home Messages from Hypertension Mechanisms

• Hypertension etiology is exceedingly complex.
• The kidney provides the dominant mechanism for
  long-term blood pressure control.
• All monogenic forms of hypertension (and low
  blood pressure) identified affect renal sodium
  handling.
• Drug mechanisms of action may be more complex
  than usually presented.
• Treatment is largely empirical and evidence-based.

53
Treatment of Hypertension

• Lifestyle interventions
• Drugs
• Intervention trials

54
Lifestyle Modification The Foundation of
Treatment

• Weight reduction
• most effective non-drug intervention
• Reduced salt diet
• 50 of hypertensives are salt sensitive
• Exercise
• Must be regular 5 days/week, aerobic
• DASH
• 8 servings of fruits and vegetables each day
• Low fat dairy products
• Alcohol reduction

55
Central Fat Accumulation Predicts Incidence of
Hypertension in the Framingham Study
Garrison RJ, et al. Prev Med 1987 16235
56
LIFESTYLE MODIFICATION TO REDUCE BP
? BP (mm Hg) ? BP (mm Hg)
Modifications HTN Pre-HTN
Wt loss 10 lbs 7/6 5/7
DASH Diet (feeding study) 11.4/5.5 6/3
ETOH 2 d/day men 1 d/day women 3.9/2.4 3.6/1.8
? Dietary Na 1.8-2.4 gm/d 3.4/1.9 2.1/--
Exercise 120 min/wk 4.9/3.7 4.0/2.3
Whelton PK, et al. JAMA 2002 2881882
57
Pharmacologic Treatment

• Drug therapy will be covered in more detail in
  pharmacology lecture(s)
• Coexisting conditions that influence
  antihypertensive choice
• Congestive heart failure ACEI, ARB, thiazides,
  aldosterone inhibitor, some beta-blockers
• Diabetes/renal disease ACEI, ARB
• Angina beta-blockers, calcium channel blockers
• Post-MI beta-blocker
• Urinary retention, BPH alpha-blockers
• Migraine headaches some beta-blockers, calcium
  channel blockers, ACEIs, ARBs

58
Pharmacologic Treatment

• Numerous randomized controlled trials demonstrate
  CVD risk reduction with a variety of
  antihypertensive agents.
• Protects against stroke, coronary events, heart
  failure, progression of renal disease,
  progression to more severe hypertension, and
  all-cause mortality.

59
VA Cooperative Study in Male Patients with
Diastolic BP 115-129 mm Hg
Endpoint reached (followed up to 2 years) Placebo (n73) Treated (n70)
Death 4 0
Severe retinopathy (grade 3 / 4) 10 0
Stroke / TIA 4 1
MI / sudden Death 3 0
Congestive heart failure 4 0
Dissecting / ruptured AAA 3 0
Progressive HTN 4 0
Renal failure / rising creatinine 3 0
Other treatment failure 4 1
Total patients with any of above 27 2
HCTZ, reserpine, hydralazine
VA Cooperative Study Group. JAMA 1967 202116
60
Blood pressure reduction appears to be most
important factor in reducing CAD and stroke.
61
Diuretics and ?-Blockers as First-Line Treatment
in Older Patients Meta-Analysis of 10 Trials
(N16,164)
No. of Trials
OutcomeFirst Drug
Odds Ratio and95 CI
Cerebrovascular events Diuretics 8 ?-Blockers 2
Coronary heart disease Diuretics 8 ?-Blockers 2
Cardiovascular mortality Diuretics 7 ?-Blockers
2 All-cause mortality Diuretics 7 ?-Blockers 2
Messerli et al. JAMA. 19982791903-1907.
62
Blood Pressure Lowering Treatment Trialists
Collaboration Contributing Trials
Second cycle (n 162,341)
IDNT INSIGHT JMIC-B LIFE NICOLE NICS-EH NORDIL PAR
T-2 PREVENT PROGRESS
QUIET RENAAL SCAT SCOPE SHELL STOP-2 SYST-EUR UKPD
S-HDS VHAS
AASK ABCD (H) ABCD (N) ALLHAT ANBP2 CAPPP CONVINC
E ELSA HOPE HOT
Blood Pressure Lowering Treatment Trialists
Collaboration. Lancet. 20033621527-1535.
63
Results of Prospectively Designed Randomized
Blood Pressure-Lowering Trials
Stroke
CHD
Relative Risk of Stroke
1.50
1.25
1.00
Relative Risk of CHD
0.75
0.50
0.25
SBP Difference Between Randomized Groups (mm Hg)
SBP Difference Between Randomized Groups (mm Hg)
Conclusion larger reductions in blood
pressure produce larger reductions in risk.
Blood Pressure Lowering Treatment Trialists
Collaboration. Lancet. 20033621527
64
Results of Prospectively Designed Randomized
Blood Pressure-Lowering Trials
Comparisons with placebo
BP Difference(mm Hg)
Relative Risk
RR (95 CI)
Stroke
0.72 (0.64, 0.81)
ACEI vs placebo
-5/-2
0.62 (0.47, 0.82)
CCB vs placebo
-8/-4
0.77 (0.63, 0.95)
More vs less
-4/-3
Coronary Heart Disease
0.80 (0.73, 0.88)
ACEI vs placebo
-5/-2
CCB vs placebo
-8/-4
0.78 (0.62, 0.99)
More vs less
0.95 (0.81, 1.11)
-4/-3
Heart Failure
0.82 (0.69, 0.98)
ACEI vs placebo
-5/-2
CCB vs placebo
1.21 (0.93, 1.58)
-8/-4
More vs less
0.84 (0.59, 1.18)
-4/-3
0.5
1.0
2.0
FavorsFirst Listed
FavorsSecond Listed
Blood Pressure Lowering Treatment Trialists
Collaboration. Lancet. 20033621527-1535.
65
Results of Prospectively Designed Randomized
Blood Pressure-Lowering Trials
Comparisons of Different Active Treatments
BP Difference(mm Hg)
Relative Risk
RR (95 CI)
Stroke
1.09 (1.00, 1.18)
ACEI vs D/BB
2/0
0.93 (0.86, 1.00)
CCB vs D/BB
1/0
1.12 (1.01, 1.25)
ACEI vs CA
1/1
Coronary Heart Disease
0.98 (0.91, 1.05)
ACEI vs D/BB
2/0
CCB vs D/BB
1/0
1.01 (0.94, 1.08)
0.96 (0.88, 1.04)
ACEI vs CA
1/1
Heart Failure
1.07 (0.96, 1.19)
ACEI vs D/BB
2/0
CCB vs D/BB
1.33 (1.21, 1.47)
1/0
ACEI vs CCB
0.82 (0.73, 0.92)
1/1
0.5
1.0
2.0
FavorsFirst Listed
FavorsSecond Listed
Blood Pressure Lowering Treatment Trialists
Collaboration. Lancet. 20033621527-1535.
66
Why do ACEIs ARBs decrease onset of diabetes?

• Ang II may impair adipocyte proliferation
• Ang II may promote insulin resistance directly
• In part, mediated by generation of reactive
  oxygen species (ROS)

67
Sowers JR, et al. Am J Physiol Heart Circ
Physiol 2004 286H1597
68
Sowers JR, et al. Am J Physiol Heart Circ
Physiol 2004 286H1597
69
Sowers JR, et al. Am J Physiol Heart Circ
Physiol 2004 286H1597
70
Stroke risk reduction associated
epidemiologically with a long-term difference of
5-6 mm Hg DBP
Collins Brit. Med. Bull. 199450272
71
CHD risk reduction associated epidemiologically
with a long-term difference of 5-6mm Hg DBP
Collins Brit. Med. Bull. 199450272
72
What percent of CHD mortality in hypertensives
can be attributed to lipids?

• Using data from Selby JV. (JAMA 1991 2652079)
• 60 of 185 hypertensives had abnormal lipids
• Prevalence 32.4
• Relative risk 14.7 / 4.1 3.6
• Attributable risk 45.6
• Implies you would only decrease risk for CHD
  death by 54.4 of expected if you just normalized
  the blood pressure.
• This is a conservative estimate of the lipid
  effect