Sarver Heart Center Dedicated to research and the treatment of heart failure.
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Transcript of Sarver Heart Center Dedicated to research and the treatment of heart failure.
Sarver Heart Center
Dedicated to research and the treatment of heart failure
Heart FailureHeart Failure
Douglas Larson, Ph.D.Douglas Larson, Ph.D.Sarver Heart CenterSarver Heart Center
Heart FailureOutline
1. Overview
2. Historical aspects
3. Pathophysiology
4. Hemodynamic measurements
5. Neurohumoral Mechanisms
6. Therapeutics
Heart Failure• Heart failure is characterized by depressed
ventricular contractility and impaired relaxation
• Heart failure is a clinical syndrome with many causes
• Heart failure is defined as limited cardiac output to accomplish daily activities
• Heart failure leads to the accumulation of blood in the veins and lymphatics – affecting the lungs, liver, and kidneys.
Epidemiology of Heart Failure in the US
•More deaths from heart failure than from all forms of cancer combined
•4.7 million symptomatic patients; estimated 10 million in 2037
• Incidence: About 550,000 new cases/year
•Prevalence is 1% between the ages of 50 and 59, progressively increasing to >10% over age 80
3.5
4.7
10
0
2
4
6
8
10
12
1991 2000 2037*
Hea
rt F
ailu
re P
atie
nts
in U
S(M
illio
ns)
Heart Failure• Heart failure will affect one in four Americans
and all of these cases involve altered diastolic function (American Heart Assoc).
• Diastolic heart failure has recently been reported to have a mortality rate of 23% during a 3.1 year follow-up with optimized medical therapy (Jones,R.C. J Am Coll.Cardiol.2004).
Survival Curve- Heart Failure
50
100
75
0 52.5
YEARS
% S
urv
ival
DigitalisDiureticsACE inhibitorsBeta blockersSpironolactone
Heart Failure• Most striking, the mortality rate of heart
failure is only exceeded by that of pancreatic cancer (personal communication, Dr. Gregg Fonarow, UCLA).
• Today the heart failure DRG accounts for the highest hospital admission classification in the United States.
Heart Failure
Further Definition
Heart Failure
Systolic DiastolicEjection fraction < 30%
Ejection fraction > 30%
Cardiac Index < 2.4 L/m2
Normal ejection fraction is 60-70%
Heart Failure• Current systolic heart failure therapeutics
affect symptoms, appreciably prolong life expectancy, but are not curative.
• Current diastolic heart failure therapeutics affect symptoms however without reducing mortality rate.
• This suggests a failure in treating the underlying mechanisms.
Dev
elo
pm
ent
of
Hea
rt F
ailu
re• Initiators: Hypertension, aging,
myocardial infarction, viral infection, vavlular dysfunction, diabetes
• Compensatory: myocyte and extracellular matrix remodeling
• Decompensation phase: • Remodeled extracellular matrix collagen,
• Altered calcium cycling protein expression and function,
• Disordered cytoskeletal proteins, and
• Dilated cardiomyopathy (DCM)
Stage AHypertension
CADDiabetes mellitus
Cardiotoxins
Stage BPrevious MI
LV systolic dysfunctionAsymptomatic
valvular disease
Stage CKnown structural
diseaseShortness of breathReduced exercise
tolerance
Stage DSymptoms with
maximal medical therapy
ACC /AHA Guidelines for the Management of Chronic Heart FailureJACC 38;2101-2113:2001
Class NYHA Classification
Class I (Mild)
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea (shortness of breath).
Class II (Mild)
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea.
Class III (Moderate)
Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea.
Class IV (Severe)
Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency at rest. If any physical activity is undertaken, discomfort is increased.
Question
Heart failure will affect:A.1 in 1000 Americans
B.1 in 100 Americans
C.1 in 20 Americans
D.1 in 4 Americans
Answer
Heart failure will affect:A.1 in 1000 Americans
B.1 in 100 Americans
C.1 in 20 Americans
D.1 in 4 Americans
Heart FailureOutline
1. Overview
2. Historical aspects
3. Pathophysiology
4. Hemodynamic measurements
5. Neurohumoral Mechanisms
6. Therapeutics
Heart Failure
History:
Clinical observations. Two thousand years ago, Hippocratic Corpus first described heart failure patients with what may have been rheumatic valvular disease.
Heart FailureHistory:
Anatomic Pathology. Galen understood that heart failure was associated with enlargement of cardiac muscle but did not understand that the heart was for pumping blood.
Galen believed that the heart was to generate the vital spirit (pneuma) and this forestalled any understanding of the pathophysiology of heart failure for centuries.
Heart Failure
History: Circulatory Physiology. In 1628, William Harvey published De Motu Cordis that identified the failing cardiac pump with dyspnea and edema Flint in the middle of the nineteenth century recognized the progressive clinical deterioration and poor prognosis associated with ventricular dilation and was the first to suggest hypertrophy as an adaptive response to wall stress.
Heart Failure
History:
Cardiac Hemodynamics. In the early years of the twentieth century Starling of England and Wiggers of the United States were able to interpret the pressure and flow abnormalities associated with heart failure.
Heart FailureHistory:
Molecular Biology. A major change in the above paradigm is now occurring due to the unexpected and counter-intuitive adverse effects of inotropes such as dobutamine, phosphodiesterase inhibitors (milrinone), vasodilators including diltiazem and digitalis.
Heart Failure
History:Molecular Biology. Equally unexpected has been the long-term benefits of adrenergic receptor blockers.
These pharmacological experiences demonstrated that heart failure is not just an inotropic and lusitropic disorder.
Heart Failure
History:
Molecular Biology. Today, the major problem in heart failure is now recognized as altered gene expression and immunological mediation of disordered cell growth, and deterioration of the cardiac interstitium.
Question
Which of the following increases the life expectancy of heart failure patients?A. Dobutamine
B. Beta-blockers
C. Digitalis
D. Milrinone
Answer
Which of the following increases the life expectancy of heart failure patients?A. Dobutamine
B. Beta-blockers
C. Digitalis
D. Milrinone
Heart FailureOutline
1. Overview
2. Historical aspects
3. Pathophysiology
4. Hemodynamic measurements
5. Neurohumoral Mechanisms
6. Therapeutics
HEART FAILURE
Mismatch: inflow to output.
A
B
C
A
B
C
Arterial Pressure Tracing
Pressure-volume loops
Normal Restrictive Dilated
Volume
Pre
ssur
e
A
B
C
A
B
C
Arterial Pressure Tracing
Pressure-volume loops
Normal Diastolic HF Systolic HF
Volume
Pre
ssur
e
SVSV
Examples of Common Causes of Heart Failure
• Hypertension
• Aortic Valvular Stenosis
• Viral cardiomyopathy
• Infarction
• Senescence
• Thyrotoxicosis
• Idiopathic
Heart Failure
Etiology:
• Gene mutation
• Single:
• Duchenne’s Musclular Dystrophy
• Familial hypercholesterolemia (FH)
• Multiple
• Genotype
• Environmental
Myocardial infarction (MI)
• MI is recognized as a leading cause of systolic heart failure.
Heart FailureOutline
1. Overview
2. Historical aspects
3. Pathophysiology
4. Hemodynamic measurements
5. Neurohumoral Mechanisms
6. Therapeutics
TIME
Acuteevent
CompensatoryRemodeling
HeartFailure
Co
mp
rom
ised
he
mo
dyn
am
icF
unc
tion
Time Course of Heart Failure
Decompensated
Heart Failure
PRESSURE OVERLOAD
Heart Failure
VOLUME OVERLOAD
Normal Cardiomyocyte
Intercalated disk folding
Intercalated disk folding
Z-band slippage
Z-band slippage
QuestionDecompensated heart failure is:A. The primary event that occurs
subsequent to myocardial injury
B. Is related to myocyte slippage and cardiac dilation
C. Is reversible with beta-blockers
D. Is related to the remodeling of the ventricular geometry to optimize ventricular function.
AnswerDecompensated heart failure is:A. The primary event that occurs
subsequent to myocardial injury
B. Is related to myocyte slippage and cardiac dilation
C. Is reversible with beta-blockers
D. Is related to the remodeling of the ventricular geometry to optimize ventricular function.
Heart FailureOutline
1. Overview
2. Historical aspects
3. Pathophysiology
4. Hemodynamic measurements
5. Neurohumoral Mechanisms
6. Therapeutics
Sympathetic
Pathogenesis of congestive heart failure
• A number of compensatory mechanisms come into play during the development of chronic heart failure in the body's attempt to maintain perfusion pressure and increase cardiac output: • Augmented sympathetic activity
• Sodium and water retention
• Myocardial hypertrophy
• Ventricular dilatation
Specific Neurohumoral Mechanisms
• In most patients with congestive heart failure, the changes in the peripheral circulation (decreased cardiac output) is accompanied by activation of:
• renin-angiotensin system (RAS)
•sympathetic nervous system
•aldosterone.
RASDecrease blood pressureIncreased sympathetic activityDecreased extracellular volume
Juxtaglomerlular cells release renin
Angiotensinogen Angiotensin I Angiotensin II
ACE
Increases blood pressure - vasoconstrictionActs upon the adrenal cortex to release aldosteroneStimulates the release of vasopressin – fluid retentionFacilitates norepinephrine release from nerve endings
Ang II
• Treating hypertension and heart failure with ACE inhibitors (ACEi) and AII receptor antagonists (ARB) can be used to decrease arterial pressure, ventricular afterload, blood volume and hence ventricular preload, as well as inhibit and perhaps reverse cardiac and vascular hypertrophy and pathologic remodeling.
Angiotensin II (Ang II)
Mo
du
lati
on
of
the
RA
S
Sympathetic NS & Heart Failure
• Epinephrine: sympathetic CNS
1, vasoconstriction
2, negative feedback for NE
1, cardiac specific increased function
2, smooth muscle relaxation
• Norepinephrine: powerful stimulator is ATII.
mainly 1,2
*The heart failure state stimulates sympathetic
outflow thus adding to the Ang II effects.
Inotropicagents
Vasodilators
Diuretics
ACE inhibitors
Aldosteroneinhibitors
HF RX
Markers for Heart Failure diagnosis and Prognosis
Markers of Heart Failure• Neurohormonal
• Brain Natriuretic Peptide (BNP)
• Plasma Norepinephrine
• Myocyte Injury and Matrix Remodeling• Troponins
• Matrix metalloproteinases (MMP)
• PIIINP = Pro-Col III cleaved propeptide
• Inflammation• C-reactive protein, IL-6, TNF-• Soluble IL-2 receptor, CD40-CD154
Natriuretic Peptides (ANP and BNP)
BNP/
ANP versus BNP• The Atrial Natriuretic Peptide (ANP) is
highly stimulated during heart failure.• Constitutively secreted by the atria
• Brain Natriuretic Peptide (BNP) • Secreted by ventricles only during heart
failure.Therefore BNP serves as an important
marker of CHF
BNP
• Serum concentrations of BNP parallels the ejection fraction of the left ventricle.
• Therefore it has become a highly reliable serum marker of heart failure and therapeutic efficacy.
BNPandSurvival
Control and heart failurepatients
BNP
Clinica Chimca Acta 306;19-26:2001
BNP versus Ejection Fraction
BNP Levels
• <100 pg/mL no heart failure
• 100-500 pg/mL suggestive of heart failure
• >500 pg/mL high likely-hood of heart failure
BNP Levels
• Drug therapy for chronic heart failure has been reported to reduce plasma BNP levels.ACEi reduce 40%ARB reduce 10%-blockers reduce 60%Aldosterone blockers reduce 55%
Question
Which of the following BNP levels indicates decompensated heart failure?
A.78 pg/mL
B.159 pg/mL
C.373 pg/mL
D.885 pg/mL
Answer
Which of the following BNP levels indicates decompensated heart failure?
A.78 pg/mL
B.159 pg/mL
C.373 pg/mL
D.885 pg/mL
Heart FailureOutline
1. Overview
2. Historical aspects
3. Pathophysiology
4. Hemodynamic measurements
5. Neurohumoral Mechanisms
6. Therapeutics
HF Therapeutics
• Digitalis: increase inotropy • Dobutamine: increase inotropy • Milrinone: increase inotropy• Beta- blockers: decrease
sympathetic outflow• Diuretics – Lasix: diuresis, naturesis• Spironolactone: aldosterone blocker• ACEi and ARB: vasodilation • Nesiritide: diuresis, vasodilation
Heart Failure Therapies
Medical:• Carvedilol (Coreg) is an and blocker.
• Carvedilol is one of the most efficacious medical therapies for heart failure.
• With NYHA II and III patients, it does not significantly change the survival slope.
Effect of Carvedilol ( and blockade) on Progression in Mild or Moderate Heart Failure
1.0
0.8
0.6
00 50 100 150 200 250 300 350 400 0 50 100 150 200 400
MILD (NYHA II) MODERATE (NYHA III)
Carvedilol(n=232)
Carvedilol(n=133)
Placebo(n=134)
Placebo(n=145)
P=.008 P=.019Risk reduction48%
Risk reduction39%
Days Days
1.0
0.8
0.6
Eve
nt-
free
su
rviv
al
0
Nesiritide - Natrecor® • An i.v. recombinant BNP that induces:
• arterial & venous vasodilation,
• increases water and sodium excretion,
• lowers pulmonary capillary wedge pressure & systemic arterial pressures and
• increases cardiac output.
HF Therapeutics• Digitalis:
• Dobutamine: Increased mortality rate
• Milrinone:
• Beta- blockers: decrease heart rate
• Diuretics – Lasix: K+ depletion
• Spironolactone: Interaction w/ other Rx
• ACEi and ARB: Hypotension
• Nesiritide: Increase mortality rateby 80%
Heart Failure Therapies
Medical: NEW• Cardiac
Resynchronization Therapy (CRT) - resynchronizing the activity of the right and left ventricles in patients with heart failure and ventricular dysynchrony.
Heart Failure Therapies
Medical:• Do medical therapies modulate the
cause or survival?
• In general: ACE inhibitors, & blockers, and CRT help symptoms but only marginally prolong life.
IABP = very temporary
SURGERY
Coronary ArteryBypass Graft (CABG) –
Prolongs life
Heart Failure Therapies
SURGERY
Transplantation-Prolongs life~ 10 years
Heart Failure Therapies
VADS andTotal Artificial Heart –Prolongs life
Heart Failure Therapies
HEART FAILURE
• In general, none of these therapeutic approaches actually addresses the underlying mechanisms of heart failure!
• Thus our research is dedicated to defining pathways and techniques that may provide a therapeutic reversal of the heart failure condition.
Our research goal is to show that the immune status accounts for:
50
100
75
0 52.5
YEARS
% S
urv
ival
Survivors
Died
What factors account What factors account for these survivors versusfor these survivors versusthose who do not survive?those who do not survive?
Question
The two leading causes of heart failure are:
A.MI and alcoholic cardiomyopathy
B.Viral and idiopathic
C.Genetic and diabetes
D.Hypertension and aging
Answer
The two leading causes of heart failure are:
A.MI and alcoholic cardiomyopathy
B.Viral and idiopathic
C.Genetic and diabetes
D.Hypertension and aging
Thank You
Questions?Questions?
Adoptive Transfer II
Altered cardiac function can be adoptively transferred through lymphocytes.