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)

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*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

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30

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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.

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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