Heart failure

pathophys.org/heartfailure/

Definition
N Engl J Med. 2010 Jan 21;362(3):228-38
N Engl J Med. 2003 May 15;348(20):2007-18.
It is important to note that heart failure is not a diagnosis. Rather, it represents a constellation of signs and symptoms resulting
from the inability of the heart to pump blood forward at a sufficient rate to meet the metabolic demands of the body (forward
failure) or the ability to do so only if the cardiac filling pressures are abnormally high ( backward failure), or both. Often, it is the
final and most severe manifestation of almost any form of cardiac disease.
Extra-cardiac conditions resulting in inadequate tissue perfusion, such as severe hemorrhage, or increased metabolic
demands, such as in hyperthyroidism, can also cause the above definition to be met, but will not be addressed here.

Etiology
N Engl J Med. 2003 May 15;348(20):2007-18.
Am J Cardiol. 2005 May 2;95(9A):8B-13B.
Lilly, Pathophysiology of Heart Disease, 2007
Predominantly systolic dysfunction is seen in a majority of patients, while others exhibit mainly diastolic dysfunction.
Components of both can also be found.
Systolic dysfunction diminished ability to eject blood due to:
Impaired ventricular contractility : destruction or abnormal function of myocytes, fibrosis
Increased afterload increases resistance to flow
Diastolic dysfunction
Impaired ventricular relaxation
Impaired ventricular filling due to increased ventricular wall stiffness
This classification may help distinguish causes in terms of their impact on normal heart physiology, heart failure can also be
thought of clinically as right- versus left-sided heart failure.

Systolic and diastolic dysfunction leading to left- and right-sided heart failure
Left-sided heart failure

Right-sided heart failure

Systolic dysfunction
Impaired
ventricular
contractility

Myocardial infarction, or transient myocardial

ischemia

Myocardial infarction, or transient

myocardial ischemia

Chronic volume overload (mitral or aortic

regurgitation)

Chronic volume overload

(tricuspid or pulmonic
regurgitation)

Dilated cardiomyopathy (see cardiomyopathy

chapter for etiology of dilated cardiomyopathy)

Dilated cardiomyopathy

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Increased
afterload

Uncontrolled systemic hypertension

Aortic stenosis

Uncontrolled pulmonary
hypertension
Pulmonic stenosis
Chronic obstructive pulmonary
disease (COPD)
Interstitial lung disease
Acute respiratory distress
syndrome (ARDS)
Chronic lung infection or
bronchiectasis
Pulmonary embolism

Diastolic dysfunction
Impaired
ventricular
relaxation

Ventricular hypertrophy
Cardiomyopathy (hypertrophic or restrictive)
Transient myocardial ischemia

Impaired
ventricular filling

Mitral stenosis

Tricuspid stenosis

Pericardial constriction or tamponade

Pericardial constriction or
tamponade

NOTE: In contrast to the left ventricle, the right ventricle is thin-walled and highly compliant, and therefore adapts well to a wide
range of filling volumes when working against a low pulmonary vascular resistance. However, it is quite susceptible to failure
when there is a sudden increase in afterload, such as in left-sided heart failure (retrograde pressure transmission to the
pulmonary circulation). Consequently, the most common cause of right-sided heart failure is left-sided heart failure . Although
less common, isolated right heart failure does arise as a result of primary lung pathology and in such cases is referred to as
cor pulmonale.

Pathogenesis
Myocyte loss and/or dysfunction
In addition to global mechanical dysfunction in heart failure, another key player in this process may be dysfunction at a cellular
level.
Myocyte loss
Necrosis resulting from insults such as MI or exposure to cardiotoxic drugs
Apoptosis (programmed cell death) from elevated catecholamines, angiotensin II, inflammatory cytokines, and
mechanical strain from increased wall stress
Changes activated in expression of contractile proteins, ion channels, enzymes, receptors and secondary messengers
Reduced cellular ability to maintain calcium homeostasis
Changes in handling of high-energy phosphates

Compensatory mechanisms
These mechanisms attempt to maintain sufficient blood pressure to perfuse vital organs by compensating for the decrease in
cardiac output that occurs in heart failure.

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Frank-Starling mechanism
Frank-Starling relationship: Ventricular output increases in relation to preload, i.e. with a greater stretch of myocardial
fibers (larger diastolic volume), there will be a greater force of contraction generated
In heart failure, a decreased stroke volume results in reduced chamber emptying, with higher than normal diastolic
volume
This induces a greater stroke volume for the subsequent contraction to help empty the ventricle and preserve
forward cardiac output
However this mechanisms has limits, and at markedly elevated diastolic volumes, the stretch of myofibers becomes too
great and suboptimal for generating a strong contraction

Myocardial hypertrophy
Wall stress is often increased in heart failure due to either ventricular dilatation or the need to generate high systolic
pressures to overcome excessive afterload
Wall stress is estimated from LaPlaces relationship, in which the wall stress () is proportional to ventricular
pressure (P) and ventricular chamber radius (r), and inversely proportional to ventricular wall thickness (h)
In response to a sustained increase in pressure and chamber radius, hypertrophy of the
ventricular myocytes is stimulated
The increased mass of muscle fibers serves to maintain contractile force and counteract the
elevated ventricular wall stress
Eventually, the chamber may dilate out of proportion to wall thickness, resulting in excessive
hemodynamic burden on the contractile units, rapid deterioration of ventricular function and worsening of
symptomatology
Lowering wall stress as a way to slow the remodelling process is a common therapeutic target

Neuro-hormonal mechanisms
In the early stages of heart failure, these mechanisms help maintain a near normal perfusion to vital organs by increasing
systemic vascular resistance as a way to balance the fall in cardiac output (blood pressure (BP) = cardiac output (CO)
total peripheral resistance (TPR)). In addition, activation of neuro-hormonal mechanisms leads to salt and water retention
with a consequent increase in intravascular volume and preload, which maximizes stroke volume via the Frank-Starling
mechanism.
Renin-angiotensin-aldosterone system (RAAS): (See Nephrology for details of physiology ). The pathway leads to the
activation of angiotensin II.
Angiotensin II
Vasoconstriction: Increases TPR to maintain BP.
Increased intravascular volume to increase preload to raise the SV via Frank-Starling mechanism.
Angiotensin II does this by (i) stimulating thirst at hypothalamus and (ii) increasing aldosterone secretion at
adrenal cortex.
Aldosterone
Increased water retention via increased sodium resorption. This increases preload, in turn increasing the
SV

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Antidiuretic hormone (ADH, aka vasopressin)

Increased secretion thought to be induced by arterial baroreceptors (detecting decreased CO) and increased
angiotensin II levels.
Promotes water retention in the distal collecting tubule, in order to increase preload.

Adrenergic nervous system

Decreased CO results in decreased perfusion pressure sensed by baroreceptors in carotid sinus and the aortic arch.
Central and peripheral chemoreflex activation induces epinephrine, norepinephrine, and vasopressin release. This
results in an increased sympathetic outflow to heart and peripheral circulation, and decreased parasympathetic tone.
Increased HR and contractility directly increase cardiac output (CO = HR SV)
Peripheral vasoconstriction
Venous: Increases preload (venous return).
Arteriolar: Raises peripheral vascular resistance, to maintain BP.
Unfortunately, despite these compensatory mechanisms, there is progressive decline in the hearts ability to contract and relax
in the face of persistent hemodynamic challenges. Furthermore, chronic activation of the above mechanisms ultimately
becomes maladaptive and induces further worsening of cardiac performance.

Deleterious consequences of compensatory mechanisms

Continuous sympathetic activation results in downregulation of -adrenergic receptors with decreased sensitivity to
circulating catecholamines and less inotropic response.
Increased heart rate augments metabolic demands and can further reduce performance by increasing myocardial cell
death.
Increased circulating volume and preload ultimately overwhelm Frank-Starling mechanism and hearts ability to maintain
forward flow, resulting in worsening of lung vasculature congestion.
Increased total peripheral resistance results in higher afterload, impeding the left ventricles stroke volume and reducing
cardiac output.
Chronically elevated angiotensin II and aldosterone trigger production of cytokines, which activate macrophages an
stimulate fibroblasts resulting in adverse heart remodelling.

Exacerbating factors in compensated heart failure

Heart failure can be clinically silent (i.e. asymptomatic) if compensatory mechanisms are sufficient to balance the degree of
cardiac dysfunction, or alternatively if it is adequately managed medically. However, patients can become symptomatic, if
decompensation occurs.
Precipitants

Mechanism of exacerbation

Fever, infection, anemia,

tachyarrhythmia, hyperthyroidism

Increased metabolic demands: Inability to sufficiently increase cardiac output to

match disproportionately elevated demand of organ systems

Excessive salt content in diet,

excessive fluid administration,
renal failure

Increased circulating volume (preload): Promotes systemic and pulmonary

congestion as the heart is unable to accommodate a larger preload (Frank-Starling
mechanism overwhelmed)

Uncontrolled hypertension,
pulmonary embolism

Increased afterload: Increased resistance against which ventricle must pump with
consequent decrease in stroke volume

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Negative inotropic medications (blockers, calcium channel

blockers), ischemia

Impaired contractility: Reduced contractility impairs stroke volume and

consequently decreases cardiac output

Bradyarrhythmia

Direct drop in cardiac output (CO = HR SV)

Medical non-adherence

Multifactorial; e.g. if diuretics not taken adequately, can result in increased circulating
volume (as above)

Pathophysiology
Signs and
symptoms

Underlying mechanism

Left-sided heart failure

Symptoms
Shortness of breath

Increased pulmonary capillary oncotic pressure from left-sided backflow causes extravasation of
fluid into the pulmonary interstitium, which then leads to reduced pulmonary compliance and
increased airway resistance. There is also an increased ventilatory drive secondary to hypoxemia,
a consequence of increased pulmonary capillary pressures and ventilation/perfusion mismatch
due to inadequate CO.

Orthopnea

Redistribution of extravascular fluid from the periphery into dependent areas when supine (i.e.
lungs) exacerbates dyspnea as the ventricles cannot adapt to the acute increase in volume; this
results in increased pulmonary capillary pressure and worsening of interstitial pulmonary edema.

Paroxysmal
nocturnal dyspnea
Cough +/- frothy
blood-tinged sputum

Caused by pulmonary congestion. Rupture of engorged bronchial veins can lead to hemoptysis.

Confusion and/or
impaired memory

Manifestations of inadequate cerebral blood supply

Decreased urine
output

Decreased renal perfusion during the daytime can sometimes lead to acute kidney injury and
eventually renal failure.

Nocturia

At night when supine, blood flow is redistributed to the kidney, promoting perfusion and diuresis.

Signs
Pulmonary crackles

Opening of small airways that were closed by interstitial edema prior to inspiration; initially present
at lung bases where hydrostatic forces are greatest, but worsening pulmonary edema is
associated with crackles in higher lung fields

Cardiac asthma

Coarse ronchi and wheezing caused by compression of conduction airways by pulmonary

congestion

Accentuated P 2

Reflects increased pulmonary vascular pressures caused by elevated left-heart filling pressures

Mitral regurgitation
murmur

May be auscultated if dilation of the left ventricle has excessively stretched the mitral valve
annulus and spread the papillary muscles, preventing full closure of the mitral leaflets

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Pulsus alternans

May present as a sign of advanced ventricular dysfunction

Right-sided heart failure

Symptoms
Peripheral edema,
sacral edema,
ascites and/or
anasarca

Various manifestations of increased hydrostatic venous pressures

Hepatosplenomegaly
(+/- right upper
quadrant pain)

Portal and splenic circulation engorgement from inadequate right-sided forward flow

Anorexia/weight loss

Hepatic and intestinal congestion result in diminished appetite; there can also be occasional
impaired intestinal fat absorption, and more rarely, protein-wasting enteropathy; total metabolism
can also be increased secondary to increased myocardial oxygen consumption and excessive
work of breathing

Signs
Elevated JVP

Reflects elevated right-sided pressures and inadequate right-sided forward flow

Kussmaul sign

Paradoxical elevation of JVP with inspiration (as opposed to decrease) reflects increased right
atrial pressure

Palpable right
ventricular heave

Represents right ventricular enlargement and approximation of the chamber to the chest wall

Tricuspid
regurgitation murmur

May be auscultated if dilation of the right ventricle has excessively stretched the tricuspid valve
annulus and spread the papillary muscles, preventing full closure of the tricuspid leaflets

Right- or left-sided heart failure

Symptoms
Chest pain/pressure

Can occur as a result of primary myocardial ischemia from CAD or secondary to increased filling
pressures, poor cardiac output (with consequent poor coronary diastolic filling) or hypoxemia

Palpitations

Can be secondary to sinus tachycardia due to decompensated heart failure, or atrial/ventricular

tachyarrhythmias arising in dilated heart chambers

Chronic
fatigue/weakness

Likely a result of the chronic state of hypoxemia from inadequate oxygen delivery to peripheral
tissues, with generalized decreased muscle strength, decreased endurance and multi-organ
system dysfunction

Cachexia

In part due to poor appetite, along with increased metabolic demands of increased work of
breathing

Signs
S 3 gallop

Caused by abnormal filling of a dilated ventricle, often in systolic heart failure

S 4 gallop

Results from forceful contraction of the atria into a stiffened ventricle; common in diastolic
dysfunction

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Cardiomegaly

Chronically increased workload and excessive volume cause ventricular dilatation and hypertrophy

Treatment
Can J Cardiol. 2006 Jan;22(1):23-45.
Can J Cardiol. 2013 Feb;29(2):168-81
Principles: The main goal of therapy is first and foremost to identify and aim to correct any underlying conditions causing
heart failure. In an acute decompensation, the goal also includes eliminating acute precipitating causes that turned a
compensating heart failure state into a decompensated state. Symptomatic management and modulation of neurohormonal
mechanisms are also important therapeutic targets.

Chronic management

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Non-pharmacologic management
Lifestyle modification:
10% weight loss
Sodium < 2gm/day
Fluid restriction (<2L/day)
Smoking and drinking cessation

Pharmacologic management
-blockers: (Lancet. 1999 Jun 12;353(9169):2001-7, Lancet. 1999 Jan 2;353(9146):9-13. Lancet. 2003 Jul
5;362(9377):7-13)
Counteract the harmful effects of sympathetic nervous system activation, may also assist in preventing
tachyarrhythmias and myocardial ischemia
Of all beta blockers, only metoprolol succinate (MERIT-HF trial), carvedilol (COMET trial), and bisoprolol
(CIBIS-II trial) have demonstrated mortality benefit
COMET carvedilol superior to metoprolol reducing mortality in NYHA II+ & EF <35%
CIBIS II significant reduction in all-cause mortality and hospitalization in NYHA II+
ACE inhibitors (ACEi) / angiotensin receptor blockers (ARBs) : (N Engl J Med. 1992 Sep 3;327(10):685-91)
Counteract the activated mediators of the RAAS to prevent their deleterious consequences and ultimately
minimize cardiac remodelling
Enalapril shown to have significant morbidity and mortality benefit (SOLVD & CONSENSUS trials)
For patients unable to tolerate ACEi, both candesartan and valsartan have been studied and have been shown
to have mortality benefit (CHARM & V-HeFT trials) no added benefit to ACEi
Hydralazine + nitrates (N Engl J Med. 2004; 351:2049-2057)
Consider if patients unable to tolerate ACEi/ARBs or in African American patients with NYHA class III/IV
A-HEFT trial 40% reduction in mortality
Aldosterone antagonists (N Engl J Med. 2011 Jan 6;364(1):11-21, N Engl J Med. 1999 Sep 2;341(10):709-17.)
Aldosterone antagonist counteracts the harmful effects of aldosterone including salt retention, myocardial
hypertrophy and potassium excretion
Spironolactone: RALES trial 34% mortality benefit in patients with heart failure NYHA Class III+ (patients
already optimized on beta blocker and ACEi therapy)
Epleronone: EMPHASIS-HF trial 37% reduction in death from CV causes or hospitalization for HF NYHA Class
II+
Digoxin (N Engl J Med. 1997 Feb 20;336(8):525-33):
Enhances cardiac contractility, but also blunts the compensatory sympathetic drive by increasing the sensitivity of
baroreceptors, which decreases afterload
No mortality benefit; only decreased hospitalizations ( DIG trial)

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ICDs and cardiac resynchronization therapy (N Engl J Med. 2005 Jan 20;352 (3):225-37, N Engl J Med. 2009 Oct
1;361 (14):1329-38.):
Pacemaker-based approach to treat patients with a wide QRS complex
Purpose is to provide electromechanical coordination and improve ventricular synchrony in patients with severe
systolic dysfunction and significant intraventricular conduction defects such as left bundle-branch block
ICDs in patients with NYHA II/III HF & EF<35% significantly reduced mortality ( SCD-HEFT)
CRT, when further added to ICDs, reduces HF exacerbations by 41%. Similar benefits for ischemic and nonischemic cardiomyopathy as well as significant reduction in LV volume & EF improvement (MADIT-CRT)
Mechanical circulatory support (i.e. intra-aortic balloon pump, IABP)
An IABP deflates in diastole and inflates in systole to decrease impedance to LV ejection of blood and increase
coronary perfusion
Used in extreme cases of unstable hemodynamics
Diuretics
Mainstay of symptomatic congestion control; may help improve stroke volume by eliminating excessive circulating
volume and decreasing preload, therefore reducing backup of fluid into pulmonary interstitium and peripheral
tissues. Diuretics have not shown mortality benefit.

Acute decompensation
Cardiol Clin. 2012 Nov;30(4):665-71.
Can J Cardiol. 2008 Jul;24 Suppl B:9B-14B.
CMAJ. 2007 March 13; 176(6): 797805.
It is important to identify the precipitant of heart failure and treat as the HF episode is being treated.
Diuretics: Lasix (furosemide)
Helps eliminate excess fluid that the heart cannot accommodate (preload) and improve stroke volume, thereby
decreasing pulmonary and peripheral edema
Morphine:
Decreases preload by acting as a venodilator, and reduces sympathetic activation and consequently demand on
heart by procuring pain relief
Nitrates:
Decrease preload via venodilation, and improve oxygen delivery to the heart
Oxygen:
Oxygen +/- noninvasive ventilation preserve ventilator drive and maintaining blood oxygen saturation
Positioning:
Sit patient upright with legs dangling down to promote blood pooling in the lower extremities and decrease preload

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