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Pathophysiology of Brain & Body
USSJJQ-20-3
Heart Failure
Introduction
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Heart function…
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pump sufficient blood to organs to…
furnish oxygen/substrates and remove metabolites…
thereby maintaining ‘steady-state’ (homeostasis)
Heart failure (HF)
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ventricular contraction compromised such that...
heart cannot meet demand or…
can only do so at raised ventricular pressure
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Increased workload & reduced cardiac reserve
A symptom complex rather than a single disease
Types
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Chronic - eg congestive heart failure (CHF)
Acute - eg myocardial infarct
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not usually classed as heart failure (different ICD code to HF)
CHF Incidence (USA)
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~ 5.3 million people in the USA (2006)
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estimated that similar number have unsuspected HF
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Circa 2% of the population has HF
75-80% of these > 65 years of age
Approx 660,000 new cases each year
likely to develop symptoms in the next 1-5 years
HF  3 million visits to the doctor  1 million
hospitalisations per year (2009)
CHF Burden (USA)
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Approx 57,000 deaths in 2009
A leading cause of hospitalisation for > 65 years old
The risk of death is 5 - 10% per year (mild symptoms),
30-40% (severe symptoms)
$25-40 billion on care of HF patients
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$8-15 billion on hospitalisations
~ $10,000 per admission (~1,000,000 admissions in 2005)
rest in medications, home health care, etc
does not include indirect costs (eg lost productivity)
Incidence of heart failure, by sex and age, 1995/96, Hillingdon
Cowie MR et al (1999) European Heart Journal 20: 421-428
Heart Failure
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Common, Deadly, Expensive, ‘Epidemic’
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Risk Factors
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Coronary Artery Disease, previous MI
Hypertension
Obesity
Diabetes, Dyslipidemia
Valvular disease; eg aortic valve stenosis
Drug/disease-induced myocardial dysfunction
Smoking
Congenital defects
Cardiac Output (CO) and Cardiac Reserve
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CO is the volume pumped per ventricle per min
CO = heart rate (HR) x stroke volume (SV)
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Cardiac reserve is the difference between
resting and maximal CO (5 L/min vs 30 L/min)
Eg CO (ml/min) = HR (75 beats/min) x SV (70
ml/beat)
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HR is the number of beats per minute
SV is the volume of blood pumped out by a ventricle
with each beat (SV = EDV – ESV)
= 5250 ml/min or 5.25 L/min
Low CO in HF essentially a problem with SV
CO = HR x SV : Control of Stroke Volume
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Preload – amount ventricles are stretched prior
to systole
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Contractility – cardiac cell contractile force due
to factors other than EDV
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set by End Diastolic Volume
Eg circulating epinephrine
Afterload – back pressure exerted by blood in
the large arteries leaving the heart
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Ie pressure against which ventricle is ‘pushing’
SV and Preload : Starling’s Law of the Heart
 The heart is a ‘demand
pump’
 It always attempts to
pump what returns to it
(Venous Return)
 Greater VR 
greater filling 
greater stretch 
greater force 
greater stroke vol 
greater CO
 Starling’s Law of the Heart
SV and Preload: Starling’s Law of the Heart
SV and Afterload
 Before it can actually pump
blood, the ventricle must
expend energy generating
a pressure > arterial
pressure
 ie > diastolic pressure
 Some of the work done by
the heart muscle is ‘wasted’
by not pumping blood
 during isolvolumetric
contraction
SV and Contractility
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Contractility is a change in contractile
strength independent of stretch/EDV
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↑ contractility  ↑ Stroke Volume
↑ in contractility comes from:
↑ sympathetic activity
 Hormones such as epinephrine
++ and some drugs
 Ca
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Law of Laplace: the physics of failure
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Wall tension in ventricle
reflects the minimum work the muscle must perform to just
shorten
T = P x r / 2H
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T = tension
P = pressure
r = radius
H = wall thickness
Can rearrange  P
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Raised preload
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= T x 2H
r
overfilling ventricles ↓ H, ↑ r
so ↑ T needed to generate same P needed to eject blood
Raised afterload
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↑ P needed to eject blood
So ↑ T needs to be produced, all other things equal
Categories of Heart Failure
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Chronic (CHF)
Acute (MI)
High output
Low output
Systolic
Diastolic
Right-side
Left-side
High/Low Output
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High output
Rare
 Excessive need for CO, even at rest
 Causes do not reflect inadequate heart
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Severe anaemia
 Hyperthyroidism
 Arteriovenous shunts (low resistance pathways)
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Low output
Most common
 Impaired pumping ability
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Eg ischaemic heart disease
Systolic
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Impaired ejection during systole
↓ in contractility & ejection fraction
Typical causes…
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Ischaemic Heart Disease (2/3rds of Sys HF),
cardiomyopathy
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Hypertension, valvular (eg aortic) stenosis
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Affect contractile activity
Cause pressure overload in ventricle
Results in ↓ ejection fraction
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Can be as low as 15% (normally 65%)
Causes ↑ in EDV, dilation, pressure
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Law of Laplace means this is not good! 
Diastolic
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Impaired filling during diastole
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Leads to congestive symptoms
Caused by…
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Myocardial hypertrophy (eg caused by hypertension)
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↑ ventricular wall thickness
Ischaemic Heart Disease
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Delayed ventricular relaxation
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Mitral valve stenosis
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↓ O2 so ↓ ATP (needed to pump Ca++ and break actomyosin)
Poor ventricular filling
Features
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Ventricular hypertrophy  abnormal remodelling
↓ chamber size
↓ventricular compliance
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‘stiffer’ chambers more difficult to fill
Right-sided
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Impaired pumping of blood to lungs
Leads to…
Damming of blood in systemic veins
 ↑ in systemic venous, r. atrial, r. vent. ED
pressures
 Fluid movement to interstitial spaces
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Oedema, especially lower regions
Backup in liver and portal vessels →
Impaired liver function
 Impaired digestion
 Ascites
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Weight gain through fluid retention
Left-sided
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Impaired pumping of blood to systemic
circ.
Leads to…
Damming of blood in pulmonary vessels
 ↑ in pulmonary, L. atrial, L. vent. ED
pressures
 Fluid movement to pulmonary interstitium
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Impaired gas exchange
 Cyanosis, shortness of breath
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Oedema
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Symptoms
Due to ↑venous/capillary pressure
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‘damming’ of blood and salt/water retention
Nocturia
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Return of fluid from interstitial spaces in tissues to
plasma when supine
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Dyspnea (shortness of breath): cardinal sign
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↑ diffusion distance due to pulmonary oedema
 Worse when lying down (↑ VR  pulm congestion)
 Especially at night (paroxsymal nocturnal dyspnea)
 Bronchospasm due to excess fluid (cardiac asthma)
Above arise from altered microcirculation fluid dynamics
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Cyanosis
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Bluish mucosal membranes/skin
↓ oxygenation in lungs + ↑ extraction in tissues
Physiological Response to HF
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Response to ↓ SV & ↓ CO
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↑ Sympathetic tone and (nor)epinephrine
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↑ heart rate and contractility
NE/E can ↑ TPR and, therefore, afterload
Na+ & H2O retention
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Via activation of RAS by ↓ RBF & ↓ BP
↑ SV by ↑ ventricular filling (Frank-Starling mechanism)
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Frank Starling mechanism
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CO can be normal at rest due to ↑ ED V & P
Exercise-induced ↑ in CO at high ED V & P
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Can be counter-productive by ↑ ‘volume load’ on heart
Can lead to pulmonary congestion/shortness of breath
Myocardial hypertrophy
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Like skeletal muscle, cardiac response to exercise
Can get abnormal remodelling of chamber → ↓ volume
Compensated vs Decompensated
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If physiological responses restore CO
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Compensated 
If physiological responses fail to restore CO
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Decompensated 
↑HR
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↑TPR
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↑ afterload
Na+ & H2O retention
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↓ diastolic filling time
Over-stretching of ventricles
Development of oedema
Further responses exacerbate the situation
Therapeutics
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Diuretics
Beta-adrenergic blockers
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Vasodilators
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Captopril, Enalopril
Angiotensin II receptor antagonists
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Nitrates (eg nitroglycerin)
ACE inhibitors
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Carvedilol
Losartan
Positive inotropic drugs
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Cardiac glycosides
Sympathomemetics
Phosphodiesterase inhibitors
Cardiac Contraction
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Only 10% of myocardial cell volume is
cytoplasm
Na + channels open for 1-2 msec
Slow Ca++ channels open and conc ↑
Contractile protein activation occurs
K+ channels open and K+ efflux restores RMP
Ca++ channels close
Ca++ conc returned to normal by Ca++ pumps
May wish to bolster contraction short-term but ‘unload’
heart long-term – a therapeutic tightrope!
Possible Interventions
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↑ Na+ influx
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↑ Ca++ loading of the SR
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Maintain Ca++ concentration
Inhibit K+ channels
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Greater Ca++ release
↓ Ca+ extrusion
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Larger depolarisation
Prolong depolarisation
↓ adrenergic stimulation
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‘unload’ the heart  recovery
Digitalis Glycosides
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Extracted from the foxglove plant
Effective range = 1.0 - 2.5 ng/ml
But toxic range = 1.5 ng/ml and up !
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↑ cytoplasmic Na+ conc
Inhibits Na+, K+-ATPase (sodium pump)
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arrhythmias
↓ gradient inhibits Na+ influx which is…
coupled to Ca++ efflux so…
increases Ca++ retention & loading in the SR
Relieves symptoms, but does not ↑ survival
Diuretics: reversing renal retention
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Drugs which ↑ Na+ & H2O excretion
↓ ECF volume, oedema
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‘Unload’ ventricular filling
Normally, < 1% filtered Na+ /H2O excreted
Filtered load is circa 600 g/day & 180 L/day
 Topologically, filtrate is external to body
+
+
 Reabsorption of Na is active, via Na pump
 Reabsorption of H2O is passive, no H2O
pump
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Relies on hydrostatic & osmotic forces
+
 By heart & Na pump
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Common Diuretics Types
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Loop diuretics
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Thiazides
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eg acetazolamide
Osmotic diuretics
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eg bendrofluazide
Carbonic anhydrase inhibitors
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eg frusemide
eg mannitol
K+ sparing
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eg spironolactone
Loop diuretics
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Eg: Frusemide/Furosemide
Most powerful diuretics
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Affect up to 20% filtered Na+ load excreted
Mode of Action
Thick (ascending) segment of loop of Henle
 Inhibit Na/K/2Cl carrier via Cl-binding site
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Misc
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venodilator action seen clinically in the
treatment of heart failure
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gives symptomatic relief occurring before the
onset of diuretic action
From Martinez-Maldonado, M, and Cordova, HR: Cellular and molecular aspects of the renal effects of diuretic
agents. Kidney Int. 1990, 38:632-641.
Loop Diuretics – unwanted effects
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↑ Na+ conc reaching the distal tubule
Results in ↑ loss of H+ and K+
Exchangers are driven more
 Hypokalaemia
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arrhythmias, convulsions
Metabolic alkalosis
Hypovolaemia
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low cardiac output