Transcript Pathophysiology of Heart Failure by Dr. Sarma

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Healthy
New
Year
2010
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Heart Failure
Basics to Recent Advances
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Definition, Etiology
Epidemiology and
Pathophysiology
Floor Plan of This Talk
Introduction
Etiology
Diagnosis
Definitions
Patho
Physiology
Prognosis
Risk Scoring
Epidemiology
Clinical
features
Treatment &
Prevention
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“The very essence of cardiovascular
practice is early detection of Heart
Failure”
HF is a ‘BIG’ Subject
• It afflicts millions of people worldwide
• Has many diverse causes and risk factors
• Large number of Mega trials and literature
• High mortality; Several drugs and devices
• A paradigm shift in understanding & Rx.
• Extremely costly – huge no. of bed days
• Complicated by many co morbidities
• Truly multidisciplinary in its management
Detection of Heart Failure
About half of the patients with left ventricular
dysfunction had no symptoms and therefore
would be difficult to identify at this early stage
by clinical examination alone – underscoring the
need for echocardiography.
Framingham Heart Study has been the most
important longitudinal source of data on the
epidemiology of heart failure.
Why HF is increasing ?
• Almost any disease of heart can cause it
• More of HT, DM, MS, Obesity - ASCVD
• CAD - which is its commonest cause
• Better tools for diagnosis and availability
• Better detection and treatment of causes
• Better Rx. of RF, CAD, MI - PTCA, CABG
• Increasing longevity of the population
• HF is an aging process – longer life span
Important Points
• Chronic Heart Failure (CHF) can be caused by
any type of cardiac dysfunction
• Most commonly attributable to LV Dysfunction
• Rarely HF is due to isolated RV dysfunction
• Most common and best studied cause of CHF
is LV Systolic Dysfunction (LVSD)
• Normal Ejection Fraction Heart Failure (NEFHF)
is due to LV Diastolic Dysfunction – (HFPSF)
• It is difficult to diagnose and quantify.
Floor Plan of This Talk
Introduction
Etiology
Diagnosis
Definitions
Patho
Physiology
Prognosis
Risk Scoring
Epidemiology
Clinical
Features
Treatment &
Prevention
Definitions of Heart Failure
Heart failure is a clinical syndrome characterized
by decreased systemic perfusion, inadequate to
meet the body's metabolic demands as a result of
impaired cardiac pump function - Cleveland Clinic
A pathophysiologic state in which an abnormality
of cardiac function is responsible for failure of the
heart to pump blood at a rate commensurate with
metabolic requirements of the tissues -E Braunwald
Definition of HF
Physiological:
Inability of the heart to pump sufficient
oxygenated blood to the metabolizing tissues
despite an adequate filling pressure.
Working Clinical Definition:
Clinical syndrome consisting of symptoms such
as breathlessness, fatigue, and swelling of ankle
caused by cardiac dysfunction.
Types of Heart Failure
•
•
•
•
•
•
•
•
Chronic Heart Failure (CHF)
Acute Heart Failure (Cardiogenic Shock)
Systolic Failure (LVSD) – Reduced EFHF
Diastolic Heart Failure (LVDD) – NEFHF
Left Heart Failure (LVF)
Right Heart Failure (Congestive CCF)
Forward Failure and Backward Failure
High output failure -Thyrotoxic, Paget's,
Anemia, Pregnancy, A-V fistula
• Low output failure – 95% of HF is this
Floor Plan of This Talk
Introduction
Etiology
Diagnosis
Definitions
Patho
Physiology
Prognosis
Risk Scoring
Epidemiology
Clinical
Features
Treatment &
Prevention
Heart Failure – Some Statistics
• Affects 10% of people over 65 years
• Affects over 50% of people with 85+ years
• Approx 10% of patients with HF die each yr.
• It is the most common condition for which
patients 65 + require admission to hospital
• It is NOT a single disease – A syndrome
• Results from any cardiac disorder that impairs
the ability of the ventricles to fill with or eject
blood
Epidemiology of Heart Failure
Clinical criteria – Prevalence 1-2 %
Males > Females; in 65+ Prevalence 7%
50% of LVSD is asymptomatic
NEF HF varies from 15 to 50%
Incidence 0.2 to 0.3 %;  with age
Epidemiology of Heart Failure
• Age
• 5059
• 8089
• All ages
Men
8
66
7.4
Women
8
79
7.7
• Age
• 5059
• 8089
Incidence • All ages
Men
3
27
2.3
Women
2
22
1.4
Prevalence
Data from Framingham Heart Study per 1000 population
Incidence of Heart Failure
McKee PA et al. Framingham study; N Eng J Med 1971; 285: 1441-6
Ethnic Differences in HF
Sosin MD, et al. Eur J Heart Fail 2004;6:669-72
Age, MI and Heart Failure
Prevalence of Chronic AF in HF
181
92
9970
11062
11016
No in study
Cleland JG, et al. Heart Fail Rev 2002;7:229-42
Systolic Heart Failure
• LVSD – Left Ventricular Systolic Dysfunction
• Most common type of Heart Failure; 60-70%
• LV is usually dilated & enlarged.
• Fails to contract normally due to WMA, Ischemia
• Cannot pump sufficient blood to meet needs
• Normal ejection fraction (EF) is at least 50-55%
• In LVSD heart failure the EF is <40 -45%
• This carries a 10% mortality per annum
Diastolic Heart Failure
• Accounts for 20-40% of patients
• Ventricles are normal-sized with normal emptying
• But there is an impairment in the ability of the
ventricles to fill with blood during diastole.
• Because of stiff myocardium due to hypertrophy
• The heart fails to relax normally (relaxation poor)
• Generally older women
• Hypertension is the commonest cause
• This carries a 5-8% mortality per annum
Population Differences in DHF
McMurray JJ, et al. Lancet 2005;365:1877
Floor Plan of This Talk
Introduction
Etiology
Diagnosis
Definitions
Patho
Physiology
Prognosis
Risk Scoring
Epidemiology
Clinical
Features
Treatment &
Prevention
Causes of Heart Failure
1. Coronary Artery Disease (MI, IHD) (2/3 of cases)
2. Hypertension (common fore runner of LVSD, LVDD)
3. Diabetes Mellitus (via IHD, direct cardiomyopathy)
• Cardiomyopathy (DCM, HOCM, OCM, RCM)
• Valvular Heart Disease (MS, MR, AS, AR)
• Congenital Heart Disease (ASD, VSD)
• Arrhythmias (AF, Brady, Tachy, Heart Block, SSS)
• ‘High output’ failures (Anemia, hyperthyroidism, AV-F)
• Pericardial Disease (Constrictive, Effusion)
• Right Heart Failure (PHT, PE, Cor Pulmonale)
Drugs and Heart Failure
Many drugs may precipitate HF or cause its deteriorate
Sodium and water retention agents
• Glucocorticoids, androgens, estrogens, NSAIDs (dose
dependent), Aspirins, Alginates
Negative Inotropic agents
• Anti arrhythmics, NDHP CCBS-Diltiazem & Verapamil
• Non selective beta blockers especially in NYHA class IV
particularly when used in large doses
Cardio toxins: Anthracyclines – Anti tumour- doxorubicin
Decongestants, High sodium containing drugs
Precipitating Causes of HF
• Arrhythmias, especially atrial fibrillation
• Infections (especially pneumonia)
• AMI, Angina pectoris or recurrent MI
• Anemia, Alcohol excess, Pregnancy
• Iatrogenic - postoperative fluid replacement or
• Poor drug compliance in pts on treatment for HT
• Thyroid disorders—Thyrotoxicosis
• Use of steroids or NSAIDs
• Pulmonary embolism
BMJ Vol . 320, 22 Jan 2000
Changing Pattern of Etiology
McMurray J J, Stewart S Heart 2000;83:596-602
Major Risk Factors
HT
 PA
DM
CAD
Age
60+
Lipids
Weight
Waist
Tobacco
Ethnicity – Etiological factors
Etiological Factor
White European
Black
South Asian
+++
+
+++
Diabetes Mellitus
++
+++
+++
Hypertension
++
+++
+
Atrial Fibrillation
++
+
+
Dilated Myopathy
+
++
No data
Increasing age
+++
++
++
Access to care
NA
+
+
Ischemic Heart Disease
Sosin MD, et al. Eur J Heart Fail 2004;6:831-43
Cardiomyopathies
Dilated (congestive)
Hypertrophic (Obstructive)
Restrictive
Obliterative
Floor Plan of This Talk
Introduction
Etiology
Diagnosis
Definitions
Patho
Physiology
Prognosis
Risk Scoring
Epidemiology
Clinical
Features
Treatment &
Prevention
Pathophysiology of Heart Failure
Developments in our understanding of the
Pathophysiology of heart failure have been
essential for recent therapeutic advances
After MI, plasma concentration of norepinephrine
is of prognostic value in the early phase after MI
Natriuretic peptides are also shown to predict
outcome after MI – “The Leukocyte Count of HF”
Cardiac Output
CO = SV x HR
CO is cardiac output expressed in L/min
Normal Cardiac Output is 5 L/min
SV ( Stroke Volume) is volume of blood put out/beat
Pre load, After load and Contractility determine the SV
HR (Heart rate) - number of beats/minute (Chronotrop)
Normally SV = 70 ml/beat. HR = 70/mt; so
CO = 70 x 70 = 4,900 ml/mt or 5 L approximately
Important Concepts
• Contractility: Contractility is the intrinsic ability of
cardiac muscle to develop force for a given muscle
length. It is also referred to as inotropism.
• Pre load: Preload is the muscle (stretch) length prior to
contractility, and it is dependent of ventricular filling (or
LV end diastolic volume). This is in turn dependent on LV
end diastolic pressure and LA pressure. The most important
determining factor for pre load is venous return.
• After load: It is the tension (or the arterial pressure)
against which the ventricle must contract. After load for
the left ventricle is determined by aortic pressure which
in turn is dependent on peripheral arterial resistance.
LV Ejection Fraction (EF%)
LV EF% =
LV Diastolic Volume – LV Systolic Volume
LV Diastolic Volume
LV EF% =
(140 ml – 70 ml) = 70 ml
140 ml
X 100
LV-EF% = 50% (Normal 50 to 70%)
May go up to 90% with exercise
X 100
Mechanisms of Heart failure
Restricted Filling: MS, Restrict CM, Constr Pericarditis
 Pressure Load on Ventricle: HT, AS, PS, Coarctation
 Volume load on Ventricle: MR, AR, VSD, TR, PR
 Myocardial Contraction: CAD, DCM, Myocarditis
Arrhythmia: Severe Brady or Tachycardia, AF, HB
Frank-Starling Curves
Sustained LVDF Leads to
1
•Hemodynamic
2
•Autonomic
3
•Neuro hormonal
4
•Immunological
Complex Mechanisms in HF
• Heart Failure is multi system syndrome
– Abnormalities of cardiac and skeletal muscle
– Abnormal renal function
– Stimulation of sympathetic nervous system
– Complex pattern of neuro humoral changes
• Ventricular Remodeling
– Damage to the myocytes & extracellular matrix
– Changes in size, shape and function of LV
• Electrical instability – causing arrhythmias
• Systemic processes with sequelae in organs
Pathophysiology of HF
• Decreased cardiac output results in
–  End Diastolic Pressure (LVEDP), LVH, LVD
–  Pulmonary Capillary Wedge Pressure (PCWP)
– The development of pulmonary edema
• Activation of Neurohormonal Mechanism
– Renin-Angiotensin-Aldosterone- System (RAAS)
– Sympathetic Nervous System (SNS)
– Other circulating and paracrine effects
• Counter-regulatory systems
– Natriuretic Peptide System (BNP, pro BNP)
Understanding RAAS
From Liver
Angiotensinogen
Globular
protein
Renin JGA
Angiotensin I
Deca (10 AA)
peptide
ACE in
Lungs
Angiotensin II
Octa (8 AA)
peptide
Angiotensin II Receptors
ARBs
AT II
ALDO
AT1
AT2
? AT4
Harmful
Beneficial
? Role
AT II – Major Effector Hormone
RENIN
AGTNG
Non ACE
pathways
Vasoconstriction
ACE
AT-I (1-10)
AT-II (1-8)
 Sympathetic
ACE2
 Aldosterone
ACE2
AT-I (1- 7,9)
Pathological Effects of RAAS
AT II and Aldosterone Havoc
AT II is the key hormone Aldosterone Excess imp.
• Increased AT II
• Na and H2O retention
• Vasoconstriction
• Hypokalemia
• Myocyte hypertrophy
• Volume over load
• Myofibril fibrosis
• Pulmonary edema
•  Aldosterone release
• Peripheral edema
• Activation of NA
• Myocardial apoptosis
• Activation of ETH
• Myocardial fibrosis
• ED – NO,  Inflam.
• Increased after load
Harmful Effects of Angiotensin II
Heart
• Myocardial Hypertrophy
• Interstitial Fibrosis; Inotropic Effects
Coronaries
• ED with  NO; Coronary Constriction
• Oxidative Stress , Inflammation, Atheroma
Kidneys
• IG pressure , Proteinuria,  Na Reabsorb
• Glomerular Growth and Fibrosis,  ADH
Adrenals
• Increased Aldosterone
• Augments Sympathetic Nervous System
Coagulation
• Increased Fibrinogen
• Increased PAI-1, Platelet Aggregation
Adverse Effects of Aldosterone
Aldosterone
Glomerulosclerosis
LVH
Endothelial
MRA Cardiac
– Eplerenone
Interstitial Fibrosis
Fibrosis Dysfunction
Proteinuria Brand name:
LV Dysfunction
Eplirestat
Inflammation
Renal Failure
Heart Failure
Oxidative Stress
RAAS Axis and its Blockade
RAAS Blockade
AGTNG
• Renin
• Aliskiren
AT-I
AT-II
• ACE
• ACE-i
Bradykinin
• AT1R
• ARB
AT2 AT4
Vasoprotection
ALDO
• Renal
• MRA
as
Sympathetic Nervous System
 CO activates baroreceptors -  SNS
Effects of  Circulating Epinephrine & NE
– Increased Heart Rate
– Increased Blood Pressure
– Increased myocardial oxygen demand
– Toxic effects on myocardium – cell death
– Down regulation of 1 receptors in heart
– Decrease in parasympathetic activity
Effect of Norepinephrine in HF
Circulating Paracrine Effects
•  Production of Endothelin (ETH)
– A potent vasoconstrictor through ET1R
•  in Vasopressin (ADH) from pituitary
– Excess water retention and vasoconstriction
• Excess of Cytokines – TNF, IL-1 & IL-6
– Myocyte apoptosis and cardiac cachexia
•  in circulating Steroids and GH
Counter Regulatory System
Increased LVDP and LA pressure
LV and LA wall stretch
 Natriuretic Peptides
Natriuretic Peptides Hormones
ANP (NT-pro-ANP)
BNP (NT-pro-BNP)
The active peptide BNP offsets RAAS & SNS
Natriuresis, Vasodilatation
Adrenomedullin
Natriuretic Peptides in HF
B-Natriuretic Peptide (BNP)
RAAS
BNP
Pro BNP 108 AA
NT proBNP (76)
BNP
(32)
1-76 AA
77 -108 AA
Endothelium – The Endocrine Organ
Vasodilators
Vasoconstrictors
• NO, Bradykinin,
Prostacyclin, EDHF,
Serotonin, Histamine CNP,
Substance P
• AT-II, Endothelin, TXA2
AA, PGH2,
Inhibitors of SMCG
• PDGF, BFGF, ILGF
Endothelin, AT-II
• NO, Prostacyclin,
Bradykinin, Heparin, CNP,
TGF-
Promoters of SMCG
Promoters of Inflammation
Inflammation inhibitors - NO
• Superoxide, TNF-
ELCAM, ICAM, VCAM
Thrombolytic factors- t-tPA
Thrombotic Factors - PAI-1
Vaso Activity of Endothelins
BIG ET 39
21
ECE - Endothelin
Converting Enzyme
Endothelin 1
ETRA
Harmful
Endothelin 2
ETRB1
Helpful
Endothelin 3
ETRB2
Mixed
Endothelium, Heart, Renal Tubule, VSMC
AT-II, Catacholamines, Insulin, LDL, GF, Stress
Other Changes in HF
Peripheral Changes – Anorexia, IR, TNF, NE
Wasting,  Perfusion, Wt loss
Fatigue, Abnorm Metabolism
Atrial Ventricular Arrhythmias - AF
Structural, Neurohumoral
Ischemia, Electrolyte abnorm.
Co morbidities cause deterioration
CKD (eGFR<50%), HT, DM
Anemia, Valvular Disease, MI
Ventricular Remodeling
McKay RG, et al. Circulation 1986;74:693-702
Ventricular Remodeling
• After extensive MI - remodeling occurs
– Impaired cardiac contractility
– Neuro humoral activation leads to regional
eccentric and concentric hypertrophy of the
non-infarcted segment
– Regional thinning and dilation of infarct area
• Factors which affect remodeling are
– Large infarct, Anterior infarct, HT, Persistent
occlusion of the artery of the infarct area
McKay RG, et al. Circulation 1986;74:693-702
Cardiac Remodeling
Na and H2O retention,  Performance
Myocyte hypertrophy, death, fibrosis
Dilated and spherical ventricle, thinned
The Cardiovascular Continuum
AMI
CHD
Ischemia
LVSDF
HT
CMR RF
SHF
Important Events after MI
1
• Remodeling
2
• Stunning
3
• Hibernation
“Stunning” and “Hibernation”
• Myocardial “Stunning”
– Post ischemic dysfunction
– Delayed recovery of the myocardial function
despite restoration of coronary blood flow
– In the absence of irreversible damage
• Myocardial “Hibernation”
–
–
–
–
Persistent myocardial dysfunction at rest
Secondary to reduced myocardial perfusion
Function improves with revascularization
Cardiac myocytes remain viable in hibernation
“Stunning” and “Hibernation”
• Myocardial “Stunning” and “Hibernation”
– Viable myocardium retains responsiveness to
inotropic stimulation
– Can be identified by resting and stress echo,
thallium scintigraphy, PET, MR Imaging with
gadolinium
– Revascularization may improve the over all
ventricular function with beneficial effects
on symptoms and prognosis.
Thank You All
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Clinical Features, Staging
Investigations, Scoring
will follow