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Understanding the Neuronal Hormonal Mechanisms and End-Organ Protection
JEAN-BERNARD DURAND, M.D., FCCP, FACC
ASSOCIATE PROFESSOR OF MEDICINE
MEDICAL DIRECTOR CARDIOMYOPATHY SERVICES
UNIVERSITY OF TEXAS
M. D. ANDERSON CANCER CENTERHOUSTON, TEXAS
Jean-Bernard Durand, M.D.Presenter Disclosure Information
I will not discuss off label use and/or investigational use in my presentation.
I have the following financial relationships to disclose:
Employee of: University of Texas M. D. Anderson Cancer Center
Overview
• The renin –angiotensin system
• Defining effective RAS blockade
• Strategies for RAS blockade
• End-organ Protection provided by RAS blockade
Development of Antihypertensive Therapies
ANGIOTENSIN CONVERTING ENZYME INHIBITORS (ACEIs)
• MOA: Block conversion of angiotensin I (AG I ) to
angiotensin II ( AG II )
– AG II is a potent vasoconstrictor, and causes aldosterone
secretion
– Cause peripheral vasodilation TPR BP
ACEIs
• 1st LINE IN PATIENTS WITH CHF OR
DIABETES per JNC VI
Proteinuria in DM pts
– May stabilize renal function
• Also 1st Line Agents for CHF
ACEIsAgents
• Captopril ( Capoten )
• Enalapril ( Vasotec )
• Fosinopril ( Monopril )
• Lisinopril ( Prinivil, Zestril )
• Quinapril ( Accupril )
• Ramipril ( Altace )
Side Effects
• DRY COUGH: 80-90%
• 1st dose hypotension ( seen more
with captopril)
• Hyperkalemia
• Angioedema (rare)
• Renal dysfunction
ACEIs Dosage Range(mg/ day)
CommonDose
CaptoprilEnalaprilFosinoprilLisinoprilQuinaprilRamipril
25 – 150 mg5 – 40 mg10 – 40 mg5 – 40 mg5 – 80 mg5 – 20 mg
25 mg BID-TID10 mg BID
10-20 mg QD10-20 mg QD20-40 mg QD
5 mg QD
ARBSCandesartanIrbesartanLosartan
TelmisartanValsartan
4 – 32 mg150 – 300 mg25 – 100 mg20 – 80 mg80 – 320 mg
8 mg QD150 mg QD
50 mg QD-BID40 mg QD160 mg QD
ACEIs
Drug Interactions
• K+ sparing diuretics
• K+ supplements
ACEI effect:
– ASA / NSAIDs
– Sympathomimmetics
Contraindications
• Bilateral Renal artery
stenosis
• Pregnancy
Precautions
• Renal Insufficiency
ACEIsMonitoring Parameters
• BP
• Scr
• K+
• Angioedema
• Tolerance of dry cough
Special Considerations
• Post MI
• Prevent progression of
proteinuria in DM pts
• Improve insulin sensitivity
• No change in lipids
• No sexual dysfunction
ACEIs Counseling
• We are treating HTN to prevent MI and stroke!
• Stress adherence
• Side effects:
– DRY COUGH: will occur, usually with time
– May do some blood work to make sure kidneys working
properly
Physiology and Pathophysiology of the Renin Angiotensin System
Hypertension Is Associated With Vascular Damage Along the Entire CV Continuum
Adapted from Dzau V et al. Am Heart J. 1991;121:1244–1263.
Vascular Damage
Ventricular RemodelingTransmural MI
Atherosclerosis
Endothelial Dysfunction
Ventricular Dilatation
Heart Failure (HF)
End Stage CVDHypertension
Angiotensin II
Oxidative Stress
Renin inhibitorsRenin inhibitors
A-II receptor blockersA-II receptor blockers
Angiotensin IIAngiotensin II
ReninReninReninRenin
Converting enzymeConverting enzyme
AngiotensinAngiotensinreceptorsreceptors
AngiotensinAngiotensinreceptorsreceptors
AngiotensinogenAngiotensinogen
ACE inhibitorACE inhibitor
Angiotensin IAngiotensin I
Circulating(Liver)
Local(Tissue)
Non-renin pathways• t-PA• Cathepsin G• Tonin
Non-renin pathways• t-PA• Cathepsin G• Tonin
Non-ACE pathways• Chymase• CAGE• Cathepsin G
Non-ACE pathways• Chymase• CAGE• Cathepsin G
The Renin-Angiotensin System
Alternate Pathway
Ang II Plays a Central Role in Organ Damage
Adapted with permission from Givertz MM. Circulation. 2001;104:E14–E18.
Angiotensinogen Angiotensin I
Lungs
LiverRenin
ACEACEACEACE
BrainVasopressin secretion
Sympathetic activation Adrenal GlandAldosterone secretion
Blood VesselVasoconstriction
SMC hypertrophy
Superoxide generation
Endothelin secretion
Monocyte activation
Inflammatory cytokines
Reduced fibrinolysis
HeartCellular hypertrophy
Myocyte apoptosis
Myocardial fibrosis
Inflammatory cytokines
Coronary vasoconstriction
Positive inotropy
Proarrhythmia
KidneySodium and water retention
Efferent arteriolar vasoconstriction
Glomerular and intenstitial fibrosis
Angiotensin II
JNC 7 Blood Pressure Classification
Blood Pressure Classification Systolic Blood Pressure Diastolic Blood Pressure
Normal <120 <80
Prehypertension 120-139 80-90
Stage 1 hypertension 140-159 90-99
Stage 2 hypertension ≥160 ≥ 100
(mmHg)(mmHg)
Clin J Onco Nursing;2005:9(4);407-11
The Definition of “Uncontrolled Hypertension” varies in clinical practice
RAS and SNS Pathophysiology in Cardiac Disease Progression
ARB=angiotensin II receptor blocker; CAD=coronary artery disease; MI=myocardial infarction.
Reaven GM et al. N Engl J Med. 1996;334:374–381. Packer M. Prog Cardiovasc Dis. 1998;41:39–52.
Hypertension MI/CAD CHEMOTHERAPY
Injury to the Heart
Angiotensin I Norepinephrine
Mortality and disease progression
Angiotensin II
1-ReceptorsArrhythmia, sudden death,
vascular resistance, adverse lipid effects,
impaired renal blood flow, myocyte cell death,
hypertrophy, Na retention
2-Receptors
Arrhythmia, sudden death,potassium loss
1-ReceptorsArrhythmia,
myocyte cell death, hypertrophy, LVD
ACEinhibition
ARBNonselective -blockade with
1-blockade
Renin-angiotensinsystem (RAS) activation
Nonselective -blockade
Selective -blockade
Sympathetic nervous system(SNS) activation
ACC/AHA Staging System for Heart Failure
Stage Patient Description
High risk for developing heart failure (HF)
• Hypertension
• Coronary artery disease
• Diabetes mellitus
• Family history of cardiomyopathy
• Cardiotoxic chemotherapy
Asymptomatic HF
• Previous myocardial infarction
• Left ventricular systolic dysfunction
• Asymptomatic valvular disease
Symptomatic HF
• Known structural heart disease
• Shortness of breath and fatigue
• Reduced exercise tolerance
Refractory end-stage HF• Marked symptoms at rest despite maximal
medical therapy (eg, those who are recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions)
CC
AA
BB
CC
DD
Hunt SA, et al. Circulation 2000; 104:2996-3007.
ACC/AHA Guidelines for the Evaluation and the Management of Chronic Heart Failure in the Adult
ACE Inhibitor Therapy
Includes all the above listedRefractory end-stage HFD
ACE inhibition in all patients, unless contraindicated
Symptomatic HFC
ACE inhibition in patients with recent or remote history of myocardial infarction regardless of ejection fraction
ACE inhibition in patients with reduced ejection fraction, whether or not they have experienced a myocardial infarction
Asymptomatic HFB
ACE inhibition in patients with history of atherosclerotic vascular disease, diabetes mellitus, or hypertension and associated risk factors
High risk for developingheart failure (HF)
A
Guideline RecommendationStage
Hunt SA et al. J Am Coll Cardiol. 2001; 38:2101–2113.
ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult
Hunt SA et al. J Am Coll Cardiol. 2001; 38:2101–2113.
-Blockade TherapyStage Patient Description
A High risk for developing heart failure (HF)
For patients that are on combination therapy for hypertension (HTN), drugs that treat HTN and HF (eg, diuretics, ACE inhibitors, and -blockers) are preferred
B Asymptomatic HF Patients with a recent myocardial infarction, regardless of ejection fraction
Patients with a reduced ejection fraction, whether or not they have experienced a myocardial infarction
C Symptomatic HF In all stable patients, unless contraindicated. Patients should have no or minimal evidence of fluid retention and should not have required treatment recently with a intravenous positive inotropic agent
D Refractory end-stage HF Includes all the above listed
JNC 7: Antihypertensive Drug Classes for High-Risk Hypertensive Conditions
Recommended Drugs
*Chobanian AV et al. JAMA. 2003;289:2560–2572.
High-Risk Condition With Compelling Indication
Thiazide-Type
Diuretic -Blocker ACEI ARB CCBAldosterone Antagonist Clinical Trial Basis
HF • • • • •
ACC/AHA HF Guidelines, MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, Val-HeFT, RALES
Post-MI • • •ACA/AHA Post-MI Guidelines, BHAT, SAVE, CAPRICORN*, EPHESUS
High Coronary Disease Risk • • • •
ALLHAT, HOPE, ANBP2, LIFE, CONVINCE
Diabetes • • • • • NKF-ADA Guidelines, UKPDS, ALLHAT
Chronic Kidney Disease • •
NKF Guidelines, Captopril Trial, RENAAL, IDNT, REIN, AASK
Recurrent Stroke Prevention • • PROGRESS
Effect of Ramipril on Cardiovascular Events in Diabetic Patients: MICRO-HOPE
0 200 400 600 800 1,000 1,200 1,400 1,600 1,800
0.05
0.10
0.15
0.20
0.25
0
Primary Outcome*
Placebo
Ramipril
All-Cause Mortality
0 200 400 600 800 1,000 1,200 1,400 1,600 1,800
0.04
0.08
0.12
0.16
0
Stroke
5000 1,000 1,500 2,000
0
0.02
0.04
0.06
0.08MI
5000 1,000 1,500 2,000
0
0.04
0.08
0.12
0.16
HOPE Study Investigators. Lancet. 2000;355:253-259.
Cardiovascular Mortality
0
0.03
0.06
0.09
0. 12
5000 1,000 1,500 2,000
Duration of Follow-up (days)
Kap
lan
-Meie
r R
ate
s
*Primary outcome defined as development of MI, stroke, or CV death. Kaplan-Meier survival curves for 3,577 participants with diabetes.
GFRProteinuriaAldosterone releaseGlomerular sclerosis
A II AT1 Receptor
Atherosclerosis*VasoconstrictionVascular hypertrophyEndothelial dysfunction
LV hypertrophyFibrosisRemodelingApoptosis
Stroke
Death
*Preclinical data.LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate.
Hypertension
Heart FailureMI
Renal Failure
Angiotensin II Plays a Central Role in Organ Damage
Adapted from Willenheimer R, et al. Eur Heart J . 1999;20:997–1008; Dahlöf B. J Hum Hypertens. 1995;9(suppl 5):S37–S44; Daugherty A, et al. J Clin Invest. 2000;105:1605–1612; Fyhrquist F, et al. J Hum Hypertens. 1995;9(suppl 5):S19–S24;Booz GW, Baker KM. Heart Fail Rev. 1998;3:125–130; Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy.17th ed. Whitehouse Station, NJ: Merck Research Laboratories. 1999:1682–1704; Anderson S. Exp Nephrol . 1996;4(suppl 1):34–40;Fogo AB. Am J Kidney Dis. 2000;35:179–188.
*P < 0.001 vs placebo. Adapted with permission from Biollaz J, et al. J Cardiovasc Pharmacol. 1982;4:966–972.
Plasma A II levels increase with time, although plasma angiotensin-converting enzyme activity remained suppressed
Angiotensin II Escape With Long-term ACEI TherapyP
lasm
a A
CE
, n
mo
l/m
L/m
in
100806040
200
* * * * * * * *
30
20
10
0
Pla
sma
A I
I,
pg
/mL
*
Placebo 4h 24h 1 2 3 4 5 6
Hospital Months
ALLHAT Trial Design Antihypertensive and Lipid-lowering
Treatment to Prevent Heart Attack Trial (ALLHAT)
33,357 participants aged 55 years or older with HTN and at least 1 other CHD risk factor
Antihypertensive component: randomized, double-blind (no ARB studied)
Lipid-lowering component is unblinded Assessment of MI will rely on
centrally coded ECGALLHAT. JAMA. 2002;288:2981-2997.
ALLHAT Study Endpoints Antihypertensive Component • Primary endpoints:
CHD, non-fatal MI• Secondary endpoints:
All-cause mortality Combined CHD (CHD, revascularization,
hospitalized angina) Stroke LVH by ECG Renal disease
• Slope and reciprocal of serum creatinine• ESRD
• QOL, major costs of medical care ALLHAT. JAMA. 2002;288:2981-2997.
No. at RiskChlorthalidone
AmlodipineLisinopril
1447785768535
1382082188123
1310278437711
1136268246662
634038703832
295618781770
209215195
Time to Event, years
0
4
8
12
16
20
1 2 3 4 5 6 7
ChlorthalidoneAmlodipineLisinopril
1525590489054
* Fatal coronary heart disease event or non-fatal myocardial infarction.ALLHAT. JAMA. 2002;288:2981-2997.
Cu
mu
lati
ve E
ven
t R
ate
, %
ALLHAT Primary Outcome*No significant differences among the 3 treatment groups
ALLHAT Study ResultsPrimary Endpoint:• ALLHAT found no difference between the three treatment groups on the
primary endpoint of combined fatal coronary heart disease and non-fatal myocardial infarction.
Secondary Endpoints:• Secondary outcomes were similar for clorthalidone, and amlodipine,
except that a 38% higher for HF with a 6-year absolute risk difference of 2.5% was seen with amlodipine
• Secondary outcomes were also similar for chorthalidone and lisinopril, except that a 15% higher risk for stroke and a 10% higher risk for combined CVD was seen with lisinopril.
Author’s Conclusion:• Thiazide-type diuretics are superior in preventing 1 or more major forms
of CVD and are less expensive. They should be preferred for first-step antihypertensive therapy.ALLHAT. JAMA. 2002;288:2981-2997.
ALLHAT Key Messages
• More aggressive treatment of blood pressure is needed today. According to JNC VI, only 27% of hypertensive patients are treated to goal. In ALLHAT, despite the use of multiple medications, only 66% of patients were controlled to <140/90 mmHg.
• Multiple agents are required to achieve BP targets. Regardless of which agent was used, Initially, only 30% of patients in ALLHAT were controlled on monotherapy.
Six-Year Rate of Clinical Outcomes by ALLHAT High-Risk Treatment Group
Chlorthalidone Amlodipine Lisinopril
CHD* 11.5% 11.3% 11.4%
Heart Failure 7.7 10.2 8.7
Revascularization 9.2 10.0 10.2
Cancer 9.7 10.0 9.9
Stroke 5.6 5.4 6.3
GI Bleeding 8.8 8.0 9.6
All-cause mortality 17.3 16.8 17.2
•Primary outcome, consisting of 64-66 percent of nonfatal MI’s
Source: ALLTHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium-channel blocker vs diuretic.
JAMA 288:2981, 2002
Benefits of Lowering BP
Stroke incidence 35–40%
Myocardial infarction 20–25%
Heart failure 50%
Average Percent Reduction