The Cardiac Cycle

Video of the Cardiac Cycle and Anatomy

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This video describes the series of events that occur simultaneously on both sides of the heart.

The Cardiac Cycle

The cardiac cycle represents the hemodynamic and electric changes that occur in systole and diastole. It has many phases.

 Phases of the Cardiac Cycle

1. Isovolumetric ventricular contraction (a-b): This phase marks the beginning of systole and starts with the appearance of the QRS complex on the EKG and the closure of the AV valves at point (a). With all valves closed, the ventricle generates positive pressure without any change in its volume (isovolumetric) to overcome the semilunar valves resistance that open at point (b). This phase usually lasts for 6% of the cardiac cycle.
2. Rapid ejection (b-c): As the semilunar valves open at point (b), there is a rapid ejection of blood due to increased ventricular contractility. The arterial pressure increases until reaching its maximum at point (c). This phase usually lasts for 13% of the cardiac cycle.
3. Reduced ejection (c-d): This phase marks the beginning of ventricular repolarization as depicted by the onset of the T wave on the EKG. Repolarization leads to a rapid decline in ventricular pressures and hence the reduced rate of ejection. However, some forward flow of blood continues secondary to remnant kinetic energy from the previous phase. This phase usually lasts for 15% of the cardiac cycle.
4. Isovolumetric relaxation (d-e): When the ventricular pressures drop below the diastolic aortic and pulmonary pressures (80 mmHg and 10 mmHg respectively), the aortic and pulmonary valves close producing the second heart sound (point d). This marks the beginning of diastole. The ventricles generate negative pressure without changing their volume (isovolumetric) so that the ventricular pressure becomes lower than the atrial pressure. This phase usually lasts for 8% of the cardiac cycle.
5. Ventricular filling (e-a): As the AV valves open at point (e), ventricular filling starts. The initial rapid filling is mainly augmented by ventricular suction which results from ventricular untwisting and the return of each ventricular muscle fiber to its slack length. The ventricular pressure gradually increases until it equals the atrial pressure and the AV valves close (point a). This phase usually lasts for 44% of the cardiac cycle.
6. Atrial contraction: Finally, near the end of ventricular diastole, the atrial contraction contributes about 10% of the ventricular filling volume. This is represented by the P wave on the EKG of the following cycle. This phase usually lasts for 14% of the cardiac cycle.

Heart Sounds

Normal pressures in various chambers of the heart

The first heart sound (S1) represents closure of the atrioventricular (mitral and tricuspid) valves as the ventricular pressures exceed atrial pressures at the beginning of systole (point a). S1 is normally a single sound because mitral and tricuspid valve closure occurs almost simultaneously. Clinically, S1 corresponds to the pulse.

The second heart sound (S2) represents closure of the semilunar (aortic and pulmonary) valves (point d). S2 is normally split because the aortic valve (A2) closes before the pulmonary valve (P2). The closing pressure (the diastolic arterial pressure) on the left is 80 mmHg as compared to only 10 mmHg on the right. This higher closing pressure leads to earlier closure of the aortic valve. In addition, the more muscular and stiff "less compliant" left ventricle (LV) empties earlier than the right ventricle. The venous return to the right ventricle (RV) increases during inspiration due to negative intrathoracic pressure and P2 is even more delayed, so it is normal for the split of the second heart sound to widen during inspiration and to narrow during expiration. Clinically, this is more remarkable with slow heart rates.

The third heart sound (S3) represents a transition from rapid to slow ventricular filling in early diastole. S3 may be heard in normal children.

The fourth heart sound (S4) is an abnormal late diastolic sound caused by forcible atrial contraction in the presence of decreased ventricular compliance.    

Abnormally wide splitting of S2 may occur in:

a) RV volume overload, such as atrial septal defect (ASD) and anomalous pulmonary venous connection. In these cases, the split is usually wide and "fixed" with no difference between inspiration and expiration due to fixed RV volume (see ASD section)

b) RV outflow obstruction, such as pulmonary stenosis (PS)

c) Delayed RV depolarization such as complete right bundle branch block

Narrow splitting of S2 occurs in:

a) Pulmonary hypertension as the pulmonary valve closes earlier due to high pulmonary resistance

b) Mild to moderate aortic stenosis as the A2 is delayed

Single S2 may occur:

a) If one of the semilunar valves is missing, as in pulmonary or aortic valve atresia and truncus arteriosus

b) If both valves close simultaneously as in pulmonary hypertension with equal pulmonary and aortic arterial pressures

c) If both valves close simultaneously as in double outlet single ventricle or in large VSD with equal ventricular pressures

d) Posterior displacement of the pulmonary valve away from the chest wall as in d-TGA

Paradoxical splitting of S2 (P2 is heard before A2) occurs in:

a) Severe aortic stenosis

b) Left bundle branch block

In both conditions, the aortic valve (A2) closes after the pulmonary valve (P2). Since the respiration only affects P2, its effect in paradoxical splitting is the opposite of normal, i.e. inspiration causes narrow splitting while expiration causes wide splitting of S2.

Heart Murmurs

Murmurs are additional sounds generated by turbulent blood flow in the heart and blood vessels. Murmurs may be systolic, diastolic or continuous.

Grading of systolic mumers based on thier intensity

• I/VI: Barely audible
• II/VI: Faint but easily audible
• III/VI: Loud murmur without a palpable thrill
• IV/VI: Loud murmur with a palpable thrill
• V/VI: Very loud murmur heard with stethoscope lightly on chest
• VI/VI: Very loud murmur that can be heard without a stethoscope

Systolic murmurs are the most common types of murmurs in children and based on their timing within systole, they are classified into:

a) Systolic ejection murmurs (SEM, crescendo-decrescendo) result from turbulent blood flow due to obstruction (actual or relative) across the semilunar valves, outflow tracts or arteries. The murmur is heard shortly after S1 (pulse).   The intensity of the murmur increases as more blood flows across an obstruction and then decreases (crescendo-decrescendo or diamond shaped). Innocent murmurs are the most common cause of SEM (see below). Other causes include stenotic lesions (aortic and pulmonary stenosis, coarctation of the aorta, Tetralogy of Fallot (TOF)) or relative pulmonary stenosis due to increased flow from an ASD

 
Crescendo decrescendo murmur

b) Holosystolic (regurgitant) murmurs start at the beginning of S1 (pulse) and continue to S2. Examples: ventricular septal defect (VSD), mitral and tricuspid valve regurgitation.

  
Holosystolic murmur

c) Decrescendo systolic murmur is a subtype of holosystolic murmur that may be heard in patients with small VSDs. In the latter part of systole, the small VSD may close or become so small to not allow discernible flow through and the murmur is no longer audible.

 
Decrescendo murmur

Diastolic murmurs are usually abnormal, and may be early, mid or late diastolic.

• Early diastolic murmurs immediately follow S2. Examples: aortic and pulmonary regurgitation.
• Mid-diastolic murmurs (rumble) are due to increased flow (relative stenosis) through the mitral (VSD) or the tricuspid valves (ASD).
• Late diastolic murmurs are due to pathological narrowing of the atrioventricular (AV) valves. Example: rheumatic mitral stenosis. Tricuspid stenosis is very rare in children.

Continuous murmurs are heard during both systole and diastole. They occur when there is a constant shunt between a high and low pressure blood vessel. Examples: patent ductus arteriosus (PDA) and systemic arterio-venous fistulas. This may also occur in surgically placed shunts such as a Blalock-Tauussig (BT) shunt between the aorta and the pulmonary artery.

Innocent murmurs are common in children and have the following characteristics:

• Grade III or less in intensity
• An otherwise a normal cardiac examination and normal heart sounds
• No associated cardiac symptoms
• Change in intensity with body position (e.g. louder in supine position)

Summary of Heart Murmurs 

EKG Interpretation

S. Bhatia, MD, L. Yun, S. Munir, M.E. Gomez, MD A. Aly, MD, PhD

Before you read the EKG, look for:

• Patient age: as many values change with age
• Standardization: full standard is two large squares (1 mV, 10 mm) and half standard is one large square (0.5mV, 5 mm)
• Paper speed: the standard is 25 mm/sec, the faster the paper speed the slower the HR will look and vice versa

Basic EKG interpretation

1. Heart rate: The standard paper speed is 25 mm (5 large squares)/sec. This means that if the interval between two beats (R-R) is 5 large squares, the HR is 60 beat/min.

• The HR may be counted by simply dividing 300 by the number of the large squares between two heart beats (R-R).
• If the interval between two beats is one large square, the HR is 300 beat/min, 2 squares →150, 3 squares →100, 4 squares → 75, 5 squares → 60, 6 squares → 50 beat/min.

2. Rhythm: The cardiac myocytes have an inherent automaticity and can generate an electric impulse. The SA nodal cells have the fastest automaticity (pacemaker) and hence control the heart rate and rhythm. There are 4 levels of conductions and potential pacemakers in the heart from fastest to slowest: SA node → atria → AV node → ventricles. If the rhythm is not sinus, we have to determine the origin of the pacemaker and where the impulse is initiated.

• SA nodal rhythm (normal sinus rhythm) (NSR) (Figure 2)

1. The sinus node is located at the SVC/right atrial junction. Sinus rhythm requires ALL of the following 3 criteria:
1. One P wave preceding each QRS complex
2. All P waves should be uniform in shape
3. Normal P wave axis is in the left lower quadrant (0-90 degrees), i.e. upright in both lead I and aVF (unless there is dextrocardia)
2. The R-R interval in NSR does not have to be identical as it may change with breathing (sinus arrhythmia) (Figure 3.) The sinus arrhythmia is easier to appreciate with slower heart rates.
1. HR increases during inspiration due to:
• Increased venous return
• Increased sympathetic tone
2. HR decreases during expiration due to:
• Decreased venous return
• Increased parasympathetic tone

• Atrial rhythm (Figure 4)

1. Characterized by narrow QRS complexes preceded by P waves that do not fulfill one or more of the normal sinus rhythm (NSR) criteria mentioned earlier.
2. If the P wave morphology changes, this may indicate a multifocal origin which is called "wandering pacemaker".

• AV nodal or junctional rhythm (Figure 5)

1. Characterized by narrow QRS complexes that are not preceded by P waves.
2. An inverted P wave may be seen following the QRS due to retrograde conduction.

• Ventricular rhythm (Fgure 6)

1. Characterized by wide QRS complexes that are not preceded by P waves.

If the sinus node fails to initiate the impulse, an atrial focus will take over as the pacemaker, which is usually slower than the NSR. When the atrial focus fails, the AV node will take over. Subsequently, if the AV node fails, the ventricular focus, which is the slowest, will take over as a pacemaker. Each time the focus is downgraded, the heart rate becomes slower based on the inherent automaticity of the pacemaker.

3. Axis: Determine both P wave and QRS axes. The net summation of positive and negative deflection is used to determine the axis. Look for two perpendicular leads (usually lead I and aVF) to determine in which quadrant the axis is located.

a) If QRS is positive in lead I and positive in aVF, the axis is in the left lower quadrant (0-90 degrees), which is normal
b) If QRS is negative in lead I and positive in aVF, the axis is in the right lower quadrant (90-180 degrees). This represents right axis deviation which can be normal in children.
c) If QRS is positive in lead I and negative in lead aVF, the axis is in the left upper quadrant (-90- 0). This represents left axis deviation.

d. If QRS is negative in lead I and negative in lead aVF, the axis is called indeterminate. Precordial leads may determine if it is an extreme right or left axis deviation.

a) P wave: Represents atrial depolarization. Normally it is 2.5 mm wide and 2.5 mm high.

• Tall P waves = right atrial enlargement (RAE)
• Wide P waves = left atrial enlargement (LAE)
• Wide and tall or bi-peaked P waves = bi-atrial enlargement (BAE).

b) PR interval represents a delay in conduction in the AV node. It varies with age and heart rate and is usually <0.2 sec at any age.

c) QRS duration: Represents ventricular depolarization. Normally 2 small squares or 0.08 sec.

• Wide QRS may indicate:
1. Ventricular contractions
2. Bundle branch block
3. Pre-excitation (Wolff-Parkinson White syndrome)

d) QT interval (measured from the beginning of Q to the end of T wave) represents both ventricular depolarization and repolarization

• QTc is the QT interval corrected for the heart rate. QTc=QT (in seconds)/square root of preceding RR interval (in seconds).
• See causes of long QT syndrome below.

a) Right ventricular hypertrophy (RVH):

1. Voltage criteria (tall R in V1 and deep S in V6>95% for age) (see table below)
2. Right axis deviation
3. rSR' in V1 with a tall R' (> 10 mm)
4. qR pattern in V1;
5. Upright T wave in V1 > 1 week of age
• Newborns have upright T wave in V1
• T wave normally becomes inverted during the first week of life
• Upright T wave beyond the first week of life is a strong indicator of RVH
• T wave remains inverted in V1 throughout early childhood
• T wave becomes upright in V1 in late childhood and early adolescence and is no longer diagnostic of RVH
• ~75% of adults have upright T wave in V1

b) Left ventricular hypertrophy (LVH): Criteria are not as well defined as RVH

1. Voltage criteria (tall R in V6 and deep S in V1);
2. Left axis deviation;
3. Strain pattern in left precordial leads (inverted T waves in V5 and V6)

6. Bundle Branch Block (delay in conduction in either the right or left bundle of His)

Incomplete right bundle branch block (iRBBB, RV conduction delay/ RV volume overload)

1. Narrow QRS complexes
2. RSR' only in V1
3. Does not qualify for RVH criteria

Complete right bundle branch block

1. Wide QRS complexes in all leads preceded by P waves
2. rSR' in V1
3. Terminal slurring (widening of QRS) is positive in V1 and negative in V6

Complete left bundle branch block

1. Wide QRS complexes in all leads preceded by P waves
2. rSR' only in V6
3. Terminal slurring (widening of QRS) is positive in V6 and negative in V1

Arrhythmias

Arrhythmias are defined as disturbances in heart rate and/or conduction. Arrhythmias result from abnormal impulse formation, abnormal impulse conduction, or both. Arrhythmias may occur in children with normal hearts and/or may be associated with CHD, medications or electrolyte disturbances.

Types of Arrrhyhimias

Bradyarrhythmias

Sinus bradycardia

The normal range of heart rate depends on the age of the individual, ranging from 120-160 beat/min in the newborn to 60-80 beat/min in the adult. Trained athletes may normally have sinus bradycardia due to increased vagal tone. Pathological sinus bradycardia is usually secondary to an underlying condition such as hypothyroidism or medications such as beta-blockers.

Asymptomatic physiologic sinus bradycardia requires no treatment. In symptomatic bradycardia, the underlying cause should be treated and a pacemaker placement may be considered if there is no response to medical therapy.

Atrioventricular Block:defect of conduction in the AV node

First degree AV block

This indicates prolongation of the PR interval more than 95th percentile for age and heart rate. At any age, PR interval > 0.2 seconds is considered prolonged.

Causes include:

• Impairment in the AV node conduction caused by increased vagal tone
• AV nodal ischemia
• Drugs such as digoxin and beta-blockers

It is usually reversible and does not require any treatment. First degree AV block could be one of the cardiac manifestations of rheumatic fever.

Second degree AV block

This is secondary to an intermittent failure of conduction through the AV node so that some P waves are not followed by QRS complexes.

Mobitz type I (Wenckebach) is a gradual prolongation of the PR interval until there is a P wave that is not conducted (not followed by a QRS complex). It is usually benign and may be seen in the presence of increased vagal tone, during sleep or in trained athletes.  

Mobitz type II is sudden loss of AV conduction (two or more P waves before QRS complexes). It is more serious as it may progress to a complete AV block. Implantation of a pacemaker may be considered in symptomatic patients.  

Third degree (complete) AV block (atrioventricular dissociation)

Complete AV block represents complete atrioventricular dissociation with no correlation between the atrial and ventricular electrical activity. The ventricular rate is significantly slower than the atrial rate. A pacemaker placement is warranted in symptomatic patients. This condition may be seen in infants born to mothers with systemic lupus erythematosus (SLE).

Tachyarrhythmias

Sinus tachycardia:

Sinus tachycardia is characterized by narrow fast QRS complexes that are preceded by normal P waves. Sinus tachycardia may be a physiologic response to exercise, anxiety, fever, hypovolemia, hypoxemia or hyperthyroidism. A good rule of thumb to remember for fever is 1 degree Celsius increase in temperature accounts for ~10 b/min increase in HR. Maximum physiologic HR is 220 bpm age in years.

Premature atrial complexes (PAC's)

PAC's represent an early atrial electrical activity outside the SA node. PAC's may appear in one of three forms:

1. Premature P wave followed by a narrow QRS complex (conducted PAC)
2. Premature P wave not followed by a QRS complex (non-conducted PAC)
3. Premature P wave followed by wide QRS complex (conducted PAC with aberrancy i.e. bundle branch block)

PAC's are commonly seen in infants and usually disappear with increasing age. It is usually benign and needs no treatment.

Supraventricular Tachycardia (SVT)

SVT is characterized by a narrow QRS complex tachycardia with a heart rate of 250-350 beat/min. It is commonly seen in children with normal hearts but may be associated with some CHD such as Ebstein anomaly. SVT may be caused by an accessory pathway between the atria and the ventricles or by a reentry circuit within the AV node. In infants, SVT presents with poor feeding, irritability, sweating and respiratory distress. Prolonged SVT may lead to CHF due to coronary insufficiency.

Compensated SVT should be treated promptly with vagal maneuvers such as application of ice to the face. If this is unsuccessful, then adenosine should be administered intravenously. Children with uncompensated SVT should undergo cardioversion. Wolff Parkinson White (WPW) syndrome is an example of pre-excitation due to an accessory pathway between the atria and ventricles. It is characterized by short PR intervals, delta waves, and wide QRS complexes.

Ventricular arrhythmias

Ventricular arrhythmias are characterized by wide QRS complexes that are not preceded by P waves, and abnormal T waves. The symptoms depend on the heart rate and are usually due to poor ventricular filling. This is a potentially serious dysrhythmia and synchronized cardioversion is commonly indicated.

Premature ventricular contractions (PVC's)

PVC's are early, wide QRS complexes that are not preceded by P waves. Isolated unifocal PVC's originate from the same spot in the ventricles and have a uniform morphology. They are usually benign in nature and disappear as the heart rate increase with exercise. On the other hand, multifocal PVC's have different morphology as they originate from different foci in the ventricles. They usually occur in diseased myocardium and their frequency often increases with exercise.

Ventricular tachycardia (VT)

VT is a rapid, wide QRS-complex tachycardia with a heart rate 150-250 beat/min. It is a serious condition that may result from drug toxicity (digoxin), myocarditis or severe metabolic derangement. It should be treated promptly with synchronized DC cardioversion if the patient is hemodynamically unstable. Stable VT may be treated with IV lidocaine infusion. Oral amiodarone may be used for outpatient management.

Ventricular Fibrillation (VF)

VF is a serious and terminal cardiac rhythm characterized by irregular, wide bizarre shaped QRS complexes. It needs urgent treatment with unsynchronized DC cardioversion.

 Long QT Syndrome (LQTS)

The QT interval represents both ventricular depolarization and repolarization. The QT interval varies with heart rate. The faster the heart rate, the shorter the QT interval. The corrected QT (QTc) interval is calculated by dividing the measured QT in seconds by the square root of the preceding R-R interval in seconds. A corrected QT greater than 0.46 seconds is considered prolonged. In normal neonates, the QTc may be 0.50 seconds in the first few days of life.

LQTS is an inherited condition characterized by syncope, seizures, palpitations or even sudden death. There are four different classes of patients with LQTS:

1. Jervell and Lange-Nielsen syndrome, which is inherited in an autosomal recessive fashion and is commonly associated with sensorineural deafness
2. Romano-Ward syndrome, which is inherited in an autosomal dominant fashion and is not associated with deafness
3. The QT interval may be prolonged beyond the neonatal period by certain drugs (Table 2), toxins and electrolyte imbalance
4. Sporadic cases of LQTS have also been reported

Table 2: Common drugs which may cause QT prolongation

Pathophysiology

Congenital long QT syndrome may be caused by an imbalance of the sympathetic innervation in the heart especially the stellate ganglion or derangements in the cardiac ion flow, resulting in prolongation of the action potential. During the latter phase of the action potential, the myocardium is very excitable and may develop arrhythmia if stimulated electrically or mechanically. If a PVC occurs during this phase of the action potential (R on T phenomenon), a delayed after-depolarization develops in the form of a specific polymorphic ventricular arrhythmia (Torsades de pointes).

No discernable P waves, wide QRS complexes twisting around isoelectric axis
Dianosis: Torsades de pointes

Clinical

Most patients are asymptomatic. Symptomatic patients present with episodic dizziness, palpitations, syncope, seizures, and/or cardiac arrest. Patients with long QT syndrome can develop Torsades de pointes, bradyarrhythmias, or AV block. This can be triggered by exercise, emotions or loud noises.

Making the Diagnosis

1. Clinical history.
2. Family history of arrhythmia or sudden cardiac death.
3. QTc> 0.46 second (beyond the neonatal period), bradycardia, second degree AVB, multiform PVCs and T wave changes (T wave alternans, bifid T wave or biphasic T wave).
4. Further testing: Holter or event monitors, stress test and other electrophysiologic studies.

Management

LQTS is a serious condition. The risk factors for sudden death include long QT > 0.55 seconds, family history of sudden death, bradycardia for age, and a prior history of symptoms. Any medications that may cause QT prolongation should be discontinued.

Treatment is aimed at preventing conversion to other possibly fatal arrhythmias. Beta-blockers are the mainstays of medical management. An implanted cardioverter-defibrillator (ICD) is often used as a nonpharmacological treatment. Other treatment modalities include permanent dual chamber pacemaker and left cardiac sympathetic denervation.   

Embryology

Snigdha Bhatia MBBS, Saef Munir, Ashraf Aly, MD

Early Development

• Development of the heart starts during the 3rd week of gestation and is completed by the 9th week.
• A single tube is formed with a venous and an arterial end.
• The heart tube has five distinct areas (going from up to down- Truncus arteriosus, Bulbus cordis, Primitive Ventricle, Primitive Atrium and the Sinus Venosus) (Figure 1A).
• Cardiac looping begins around the 22nd day of intra-uterine life. It results from elongation of the cardiac tube while both ends of the tube are fixed.
• Left-right polarity is established when the primitive ventricle is bent into a loop that moves anteriorly and to the right. At the same time, the caudal portion of the tube bends dorsally, cephalically, and to the left. (Figure 1B)
• By day 28, heart consists of the common atrium, common ventricle, and common outflow tract. (Figure 1C)
• During this time, blood is pumped from the distal end through the sinus venosus upwards to the truncus arteriosus.
• Development of the four chambered heart with two outflow tracts involves simultaneous formation of three septa that separate atria, truncus arteriosus, and ventricles.

Atrial Septation                                                                                                                                                                                  

• Primitive atrium is a single cavity. The primary atrial septum (septum primum) appears as a thin walled sagittal fold in the roof of the common atrium and grows down towards the endocardial cushions.
• The opening between the septum and the endocardial cushions is called foramen primum. (Figure 2A). Tissue resorption at the superior end of the septum primum results in formation of foramen secundum (Figure 2B), before the foramen primum is completely closed by the septum. This occurs between the 5th-6th week of embryonic life.
• Simultaneously, another enfolding appears in the roof of the common atrium to the right of the septum primum called septum secundum(Figure 2C). The inferior end of the septum secundum fuses with the lowermost part of septum primum and the endocardial cushion, causing complete separation of the two atria inferiorly (Figure 2D). Incomplete closure of the foramen secundum by the superior end of septum secundum results in formation of foramen ovale.
• Oxygenated blood coming from the inferior vena cava enters the left atrium and is preferentially directed to the right atrium through the foramen ovale by some primitive right atrial structures. This fetal inter-atrial communication (patent foramen ovale) normally closes after birth due to high left atrial pressure.

• Defects in the fusion of these structures leads to atrial septal defects (ASD) (Figure 3)                                  
• Primum ASD: Foramen primum remains open
• Incomplete fusion of the septum primum and the atrioventricular endocardial cushions.
• More common in Down syndrome due to disruptions in endocardial cushion development.
• Secundum ASD: Foramen secundum remains open
• Most common type of ASD
• Due to excessive resorption of the septum primum or interrupted septum secundum development.  
• Patent foramen ovale: incomplete fusion of the septum secundum and septum primum.
• Most patients are asymptomatic as opening remains functionally closed due to high left atrial pressures.
• Patients with PFO who are in a hypercoagulable state (i.e. pregnancy) are at increased risk for stroke during transient increase in right atrial pressure (i.e. Valsalva, childbirth, constipation). The increase in right atrial pressure may push emboli through the PFO to the systemic circulation.
• ASDs form a persistent shunt between left and right atria while PFOs are covered by a flap that may open and close intermittently.

Ventricular Septation

• The interventricular septum has three components- the muscular, inlet, and infundibular (outlet) septa.
• Muscular interventricular septum forms by proliferation of tissue upward towards the endocardial cushions from the apex of the heart.
• Membranous interventricular septum is formed by the downward growth of the aorticopulmonary septum towards the muscular interventricular septum and posterior-inferior proliferation of tissue from the endocardial cushions.
• Fusion of the membranous and muscular parts of the interventricular septum forms the complete interventricular septum.
• The infundibular septum is in continuation with the atrioventricular canal.
• Subsequent defects in the formation of these different components can lead to muscular, membranous and infundibular ventricular septal defects.  

Truncus Arteriosus Septation

• The bulbus cordis elongates and forms three parts- the proximal part forms the trabeculated portion of the right ventricle, the middle part forms conus cordis which is the outflow tract and the truncus arteriosus which forms the ascending aorta and pulmonary trunk.
• Truncus arteriosus undergoes two separate processes: septation and spiraling. There are two swellings along the truncus arteriosus- truncal swellings more distally and conal swellings proximally. The truncal swellings, similar in appearance to endocardial cushions, divide the lumen into the proximal ascending aorta and the pulmonary trunk. Fusion of the truncal and conal swellings establishes the right ventricular origin of the pulmonary trunk and left ventricular origin of the aorta. The aortopulmonary valves develop at the lines of fusion of truncal and conal swellings. (Figure 4)
• Spiralling of the septum allows the pulmonary trunk to cross anterior and to the left of the aorta.
• Failure of neural crest cells to migrate or disruptions to the aorticopulmonary septum leads to congenital heart disease
• Septation defects:
• Persistent truncus arteriosus: Failure of the aorticopulmonary septum to form
• Tetralogy of Fallot: anterior and cephalad deviation of the aorticopulmonary septum
• Double outlet right ventricle
• Spiraling defects:
• d-Transposition of the great vessels

Left-to-Right Shunts

The flow through the systemic and pulmonary circulations is normally balanced and equal in volume (Qp/Qs =1). The two circulations are placed in series with each other. The same volume of blood first makes its way through the systemic circulation, then the pulmonary circulation, then back to the systemic circulation, and so on.

Left to right shunts are characterized by a "back-leak" of blood from the systemic to the pulmonary circulation. This causes the pulmonary flow to be larger than the systemic flow (Qp/Qs >1). As a consequence, the pulmonary circulation carries not only the blood that entered the right atrium and right ventricle through the superior and inferior vena cava, but also the additional blood entering through a VSD, ASD, AVSD or PDA.   Blood volume and/or pressure in the pulmonary circulation become abnormally high. If the shunt is significant, there is progressive damage to the pulmonary vasculature and gradual development of irreversible pulmonary hypertension. The pressure in the pulmonary circuit may ultimately exceed the systemic pressure causing reversal of blood flow from the right side of the circulation to the left (Eisenmenger syndrome). This may take as short as 1-2 years in a large VSD, AVSD, or PDA, or as long as a few decades as in ASD.

Lesions resulting in left-to-right shunts include:

• Ventricular septal defect (VSD)
• Patent ductus arteriosus (PDA)
• Atrial septal defect (ASD)
• Atrioventricular defect (AVSD)

In small (restrictive) VSD and PDA, the direction and magnitude of the shunt depends on the pressure difference across the shunt. In large VSD and PDA, the direction and magnitude of the shunt depends on the relative resistance in the pulmonary and systemic circuits.

In ASD, the magnitude of the shunt depends largely on relative ventricular compliance (elasticity).

AVSD is a mix between ASD and VSD depending on the predominant lesion.

The defect size is determined by comparing its diameter with the aortic annulus. A small defect is less than 1/3 of the aortic annulus. A moderate sized defect is 1/3 to 2/3, and a large defect is >2/3 the size of the aortic valve annulus.

Ventricular Septal Defects (VSD)

Isolated ventricular septal defects (VSDs) constitute 25-30% of all congenital heart diseases (CHD) in children. VSD may be present in 50% of CHDs such as in Tetralogy of Fallot, double outlet right ventricle, truncus arteriosus and others.

Types

1. Membranous
2. Muscular
3. Inlet (usually a part of AV canal defect)
4. Outlet (Supra-cristal, sub-arterial)

Anatomy

Approximately 70% of all VSDs are present in the membranous portion of the inter-ventricular septum, about 20% are in the muscular portion, and the remaining defects are at either the inlet or the outlet portions of the ventricular septum. The inlet VSD is usually a part of atrioventricular septal (AV canal) defect. The outlet (supra-cristal) VSD is more common (about 20%) in the oriental population (or East Asian population). 

A ventricular septal defect

Pathophysiology

With a small sized VSD, "restrictive VSD," the direction and magnitude of the shunt depends on the size of the VSD and the pressure gradient between the left and right ventricles. The restrictive nature of the VSD maintains the pressure gradient between the two ventricles.

With a large VSD, the hole is not restrictive and the pressure in both ventricles is almost equal. The direction and magnitude of the shunt depend on the relative difference between the pulmonary and the systemic vascular resistances. In fetal life, the pulmonary resistance is higher than the systemic resistance. As the lungs expand with the first breath, the pulmonary resistance drops significantly and the pulmonary flow increases. The pulmonary resistance continues to decrease until reaching the normal adult ratio of 1:10 by 4-8 weeks (see figure).

 Prolonged large left-to-right shunt leads to gradual increase in the pulmonary pressure and pulmonary hypertension eventually develops. As the pressure difference between the systemic and pulmonary systems decreases, the flow across the shunt also decreases. If the pulmonary vascular resistance exceeds the systemic vascular resistance, the direction of the shunt reverses and cyanosis develops (Eisenmenger syndrome). This may develop within two years in otherwise healthy kids and within one year in patients with Down's syndrome.

The drop in pulmonary vascular pressure/resistance and the increase in pulmonary blood flow after birth

Clinical Presentations

Children with a small VSD are usually asymptomatic. An incidentally discovered holosystolic or decrescendo heart murmur is the most common presentation. The murmur is commonly discovered shortly after birth as the pulmonary vascular resistance drops and the pressure difference between the two ventricles becomes remarkable. The intensity of the murmur is inversely proportional to the size of the VSD because of the increased turbulence and flow velocity produced by a smaller defect. A thrill may be palpable in some cases. The defect may be small enough to almost close at the end of a systolic decrescendo murmur.

An infant with a large VSD may be asymptomatic in the first few days/weeks of life until the pulmonary vascular resistance drops. As the pulmonary resistance decreases, the left-to-right shunt increases. The right ventricle is thus subjected to high pressure and becomes hypertrophied while the left atrium and left ventricle receive more volume and become dilated. The right atrium is not usually affected. Congestive heart failure (CHF) may develop and presents as tachycardia, tachypnea, exertional dyspnea, breathlessness and sweating during feeding.   The child's growth is also often delayed because of poor caloric intake. In some infants, especially those with Down's syndrome, the pulmonary vascular resistance may not significantly drop. These infants may not develop CHF but are at increased risk of developing pulmonary hypertension. They may need earlier surgical intervention to prevent worsening of pulmonary hypertension and the early development of Eisenmenger syndrome.

Making the Diagnosis

• Pulmonary hypertension diminishes the pulmonary blood flow and makes CHF unlikely (honeymoon before the development of Eisenmenger syndrome).
• Cardiomegaly and hepatomegaly may be present if CHF is present.
• Chest radiographs may show cardiomegaly and increased pulmonary vascularity.
• EKG reflects the hemodynamic status and may show RVH, left atrial enlargement and left ventricular enlargement, (the EKG is not very sensitive in differentiating LVH from LV dilation). The right atrium is usually unaffected.
• Echocardiogram shows the location, type and size of the VSD. It can also estimate the pressure gradient across the VSD. The hemodynamic effects of VSD on different chambers can be elucidated. It is also important to look for aortic insufficiency (especially in membranous and supra-cristal VSD) which may indicate an early damage to the aortic valve.
• Cardiac catheterization is rarely needed but could measure the pulmonary pressure/resistance and help to determine the reactivity (and hence operability) of the pulmonary vasculature in case of pulmonary hypertension

Natural History

While more than half of small and medium sized VSDs close spontaneously, only about 10% of large VSDs close spontaneously. The muscular VSD closes by muscle in-growth. The membranous VSD closes by the neighboring tricuspid valve leaflet tissue. This forms an aneurysm that gradually gets endothelialized. Both inlet and supra-cristal (outlet) VSDs are unlikely to close spontaneously. In unoperated patients with large VSD, Eisenmenger syndrome may develop within two years but may develop as early as one year in Down syndrome patients. This could be attributed to the decreased vascular/alveolar density and increased secretion of endostatin in Down syndrome patients.

Management

Asymptomatic children with a small or medium sized VSD need only supportive care, with the expectation that the VSD will close in the first few years of life. If CHF develops, treatment consists of diuretics, afterload reducing agents such as ACE inhibitors, and possibly digoxin. Heart failure in left-to-right shunts is due to volume overload to the pulmonary circulation. This is in contrast to adults with myocardial infarction in which heart failure is due to pump dysfunction. In adults with heart failure, digoxin is used to enhance pump function.   However, if digoxin is used in treatment of CHF due to left-to-right shunt, it works primarily for its cholinergic effect to decrease the heart rate. Fluid restriction should be avoided as it reduces the caloric intake and delays growth. 

Oxygen therapy should also be avoided. It is a pulmonary vasodilator and a systemic vasoconstrictor that would worsen the left-to-right shunt and CHF symptoms. Patients with persistent CHF or those who are developing pulmonary hypertension require surgical closure of the VSD. If a patient is not a suitable candidate for surgery, pulmonary artery banding should be considered until surgery can be done (usually within the first year of life). Recently trans-catheter techniques have been used to close VSDs (especially the muscular VSDs).  

Patent Ductus Arteriosus (PDA)

Anatomy

The ductus arteriosus, formed from the embryonic 6th aortic arch, connects the aorta to the pulmonary artery. It normally closes within a few days after birth. A high oxygen tension and a decrease in endogenous prostaglandins are important factors in inducing ductal closure. For the same reason, prostaglandin synthetase inhibitors, such as indomethacin, are effective in inducing ductal closure and are commonly used in the neonatal period, especially in preterm infants.

Patent Ductus Arteriosus 

Pathophysiology

Failure of closure of the ductus arteriosus leads to hemodynamic changes similar to those seen in VSD. The direction and extent of the shunt in the PDA depends on the size of the PDA and the relative systemic and pulmonary vascular resistances.

Clinical Presentations

PDA is more common in females, premature infants, patients with Down Syndrome and congenital rubella syndrome. The symptoms are similar to those found in VSD and depend on the size of the shunt and direction of flow. While a small PDA is usually asymptomatic, a large PDA with significant left-to-right shunt may lead to CHF and eventually pulmonary hypertension.

Making the Diagnosis

• In older children, PDA classically produces a continuous or "machinery" murmur due to flow across the shunt throughout the cardiac cycle. In newborn infants, especially those born prematurely, the murmur may be heard only during systole because the higher pulmonary arterial pressure diminishes flow during diastole.
• An apical mid-diastolic murmur may be heard because of increased flow through the mitral valve (relative mitral stenosis). This usually signifies a large PDA and is often associated with CHF.
• Wide pulse pressure indicates a large left-to-right shunt due to a sudden drop in diastolic pressure.
• In a small PDA, the EKG is usually normal. In a large PDA, the EKG will demonstrate right ventricular hypertrophy, left ventricular enlargement, and left atrial enlargement, due to volume overload.
• Chest radiographs may show increased pulmonary vascularity and cardiomegaly due to left atrial and left ventricular enlargement. The heart size might be normal if the shunt is small.

Natural history and management

Small and moderate sized PDA often close spontaneously especially, in full term infants. PDA in premature infants may need indomethacin treatment (in the first 2-4 weeks of life) or surgical ligation. Transcatheter device closure of PDA is commonly used in older children.

Atrial Septal Defects (ASDs)

Anatomy

Atrial septal defects involve many different parts of the atrial septum. The septum secundum defect is the most common and comprises 6-10% of all CHD. It is located in the fossa ovalis, in the location of the foramen ovale. The primum septal defect is considered a partial form of atrioventricular septal defect. The other "less common" types of ASDs are the sinus venosus and the unroofing of the coronary sinus.

Secundum Atrial Septal Defect

Pathophysiology

Since the pressure difference between the two atria is small, no turbulence is generated by the flow across the ASD. In moderate to large ASDs, the direction and magnitude of the shunt across the ASD depends on the relative right and left ventricular compliances. In early infancy, the right ventricular compliance is low and the shunt across the ASD is small. As the right ventricular compliance increases, the left-to-right shunt increases. If the right ventricular compliance decreases, later in life, the shunt decreases. The shunt may eventually reverse if the patient develops pulmonary hypertension and Eisenmenger syndrome. This usually takes a few decades to develop.

Clinical Presentation

ASD is usually asymptomatic and typically presents with a heart murmur in preschool age. CHF rarely develops in patients with a large ASD. Right atrial stretch may cause atrial arrhythmias. Prolonged volume overload of the lungs eventually causes pulmonary hypertension, which may take 4 to 5 decades to develop.

Making the Diagnosis

• No murmur develops due to the flow across the ASD since there is only a minimal pressure gradient between the two atria and no turbulence is generated.
• A systolic ejection murmur may be heard in the pulmonary area due to increased flow across the pulmonary valve (relative pulmonary stenosis).
• A mid-diastolic murmur may be heard at the lower left sternal border due to increased flow across the tricuspid valve. This murmur is rarely heard because the tricuspid valve annulus is bigger than the pulmonary valve annulus. A tricuspid valve murmur indicates that the patient is in CHF due to a large left-to-right shunt.
• A wide splitting of S2 is due to delayed closure of P2 secondary to increased flow across the pulmonary valve.
• The splitting of S2 is "fixed" and does not vary with respiration.   This is due to diminished effects of respiratory cycle on the right ventricular volume. In inspiration, the venous return to the right atrium increases and impedes the left-to-right shunt across the ASD. In expiration, the venous return to the right atrium decreases and the shunt across the ASD increases. In both cases, the volume of blood in the right ventricle is increased and remains unchanged in both inspiration and expiration.
• EKG may demonstrate right atrial enlargement, right ventricular conduction delay (incomplete right bundle branch block), right ventricular dilation, and right axis deviation.
• Chest radiograph shows increased pulmonary vascularity, right atrial and right ventricular enlargement.
• Echo cardiogram is diagnostic

Management

Most patients with ASD are asymptomatic and no specific medical management is necessary. Medical management (as in VSD) may be needed if CHF is present. Trans-catheter closure is the preferred method of closing the secundum ASDs. Surgical closure may be needed in patients with a large secundum ASD could not be closed by a trans-catheter device. Other tytpes of ADS are unlikely to close spontaneously and may need surgical closure.

Atrioventricular Defect (AVSD)

Atrioventricular Septal Defect

AVSD occurs in 2% of all CHD and is more prevalent in patients with Down Syndrome. Forty percent of children with Down syndrome have CHD and 40 % of the defects are forms of AVSD

Anatomy

Atrioventricular septal defect is also known as endocardial cushion defect (ECD) and atrioventricular canal (AVC). It consists of a variety of defects in the endocardial cushions which form the lower part of the atrial septum, upper part (inlet) of the ventricular septum, and the medial parts of the AV valves.

There are 4 possible types:

a) Partial AVSD (primum ASD) consists of a defect in the lower part of the atrial septum and is usually associated with a cleft in the anterior mitral leaflet causing mitral insufficiency. The ventricular septum is usually intact.

b) Complete AVSD has a defect that extends from the lower part of the atrial septum to the upper part (inlet) of the ventricular septum. The mitral and tricuspid valves lose their anchor points in the ventricular septum and are instead attached to each other, forming a common AV valve that overhangs the ventricular septum.

c) Intermediate AVSD is similar to the complete AVSD but has two AV valves with a primum ASD and a large inlet VSD.

d) Transitional AVSD is similar to the intermediate AVSD but the VSD is small. 

Pathophysiology

The pathophysiology depends on the predominant lesion (atrial vs ventricular). There is a left-to-right shunt at the atrial level due to increased relative right ventricular compliance leading to right atrial enlargement. Left atrial enlargement occurs because of mitral insufficiency secondary to the mitral valve cleft. There is a varying degree of pulmonary hypertension as the pulmonary vasculature is exposed to excess blood volume at higher pressures. Pulmonary hypertension may develop in the first two years in normal patients and in the first year in patients with Down's syndrome.

Clinical Presentations

The clinical presentation of AVSD is variable and depends on the size of the defect and the degree of the left-to-right shunt. Patients with complete AVSD usually present with congestive heart failure in the first few weeks of life, while those with partial AVSD (primum ASD) may be completely asymptomatic.

Symptoms of CHF include poor feeding, shortness of breath, diaphoresis during feeding, and poor weight gain. Mild cyanosis may rarely develop because of right to left shunt due to increased pulmonary resistance or due to preferential streaming of the venous blood from the IVC to the left atrium.

Making the Diagnosis

• Physical findings are variable and depend on the presence or the absence of congestive heart failure. The precordium may be hyper-dynamic and the cardiac apex may be displaced inferiorly and to the left.
• The auscultatory findings are also variable and may include a systolic ejection murmur due to increased flow through the pulmonary valve with wide and fixed splitting of S2 as in ASD. A loud, single S2 indicates pulmonary hypertension.
• Additional auscultatory findings include a mid-diastolic murmur at the lower left sternal border due to increased flow through the tricuspid valve, apical holosystolic murmur radiating to the left axilla due to mitral insufficiency, and a holosystolic murmur of VSD.
• EKG is characterized by left superior axis deviation due to inferior and posterior displacement of the AV node (anatomical). It may also show right ventricular hypertrophy (due to increased pressure), right atrial enlargement, and LVH. A prolonged PR interval (first degree heart block), probably due to abnormal AV node conduction, may be present.
• Chest radiograph shows varying degrees of cardiomegaly and increased pulmonary vascularity.
• Echocardiography is useful in demonstrating the anatomical lesions and associated abnormalities. It is essential to assess the integrity of the AV valves. 

Left superior QRS axis deviation (negative in avF) and right ventricular hypertrophy in AVSD

Management

CHF, if present, is managed with diuretics, ACE inhibitors, and occasionally digoxin. A high caloric-density formula should be used with no fluid restriction.

Almost all patients with AVSD will need surgery. The timing of surgery depends on the size of the patient, the presence of CHF, response to medical management, and the presence or absence of pulmonary hypertension. In asymptomatic patients with partial AVSD, surgery may be delayed until preschool age. Corrective surgery is usually performed in symptomatic patients with intractable CHF in the first few months of life. Even in patients who respond to medical management, the presence of Down Syndrome necessitates early surgery to prevent the development of pulmonary hypertension. If surgery cannot be performed in a symptomatic patient, pulmonary arterial banding may help limit the pulmonary blood flow until surgical repair is possible.

Quick Checks

Obstructive Cardiac Lesions

This section deals primarily with ventricular outflow tract obstructive lesions. Congenital mitral and tricuspid valve stenosis are relatively rare in children, thus will be not discussed.

Outflow tract obstruction leads to an increase in the pressure proximal to the lesion and secondary myocardial hypertrophy. Turbulent flow across the obstruction produces an ejection systolic murmur. Myocardial hypertrophy leads to increased oxygen consumption with decreased exercise tolerance and possible myocardial ischemia and fibrosis. Ventricular dilatation is not a usual response to obstruction, and if present suggests ventricular failure.

Children with mild or moderate obstructive lesions usually have few symptoms. Children with severe obstruction may have low cardiac output symptoms. Newborns with severe obstruction are often PDA dependent to bypass the obstruction.

Pulmonary Stenosis (PS)

Anatomy

Pulmonary stenosis can be valvular, subvalvular (infundibular), or supravalvular.  

• The valvular PS is the most common form.
• Infundibular PS is usually associated with VSD as in Tetralogy of Fallot.
• Supravalvular PS is rare and may be associated with congenital rubella or Williams syndrome. It may occur as a complication of a previous arterial switch surgery.
• Peripheral pulmonary artery stenosis may result from congenital rubella or associated Alagille or Noonan syndromes.

Clinical Presentations

Patients with mild or moderate PS are usually asymptomatic. Severe PS may present with decreased cardiac output symptoms such as exertional dyspnea and subsequently symptoms of congestive cardiac failure.

Making the Diagnosis

• The physical findings depend on the severity of the obstruction.
• A right ventricular tap and a systolic thrill may be present at the upper left sternal border (ULSB).
• An ejection systolic murmur is heard best at the ULSB radiating to the back. Wide (and variable) splitting of S2 is commonly present. An ejection systolic click indicates valvular stenosis with post-stenotic dilation of the main pulmonary artery.
• Hepatomegaly may be present if CHF develops.
• The EKG is normal in mild PS. RVH and right axis deviation are usually present in moderate or severe cases. Right atrial enlargement indicates elevated right ventricular filling pressure. Severe PS may cause RV strain pattern (deep inverted T wave and ST segment depression) in right precordial leads. Newborns with critical PS may show LVH because of hypoplastic RV and large LV.
• Chest radiograph usually shows normal heart size with a prominent pulmonary artery segment because of post-stenotic dilatation. Cardiomegaly indicates CHF.
• Echocardiography demonstrates the level and degree of stenosis and the presence of PDA.

Management

Balloon valvuloplasty may be done to relieve the valvular obstruction in moderate or severe cases. Surgery is indicated in supravalvular and subvalvular PS or if valvuloplasty is unsuccessful. Infants with critical PS need PGE1 to maintain the ductal patency before intervention.

Aortic Stenosis (AS)

Anatomy

Aortic stenosis may be valvular, supravalvular or subvalvular.

• Supravalvular AS may be associated with Williams syndrome and after arterial switch procedure for D-TGA.
• A discrete fibrous ring, or membrane, may cause subvalvular obstruction.
• Bicuspid aortic valve is a common cause of AS in patients with Turner Syndrome.

Clinical Presentation

Aortic stenosis is more common in males. Children with mild or moderate AS are usually asymptomatic. Severe AS may be accompanied by exertional chest pain, decreased exercise tolerance or episodes of syncope. Infants with critical AS may present with CHF early in life.

Making the Diagnosis

•  Patients with AS are usually acyanotic unless critical AS is present.
• The pulse pressure may be narrow in severe AS. Patients with supravalvular AS may have higher BP in the right arm than the left due to preferential streaming (Coanda effect) to the right subclavian artery.
• A systolic thrill may be palpable at the URSB or the supra-sternal notch and radiates to the carotid arteries.
• A systolic ejection murmur is heard at the ULSB and URSB and radiates to the carotid arteries.
• An early diastolic murmur may indicate the development of aortic insufficiency.
• A newborn with critical AS who presents with CHF and poor peripheral pulses may have a faint murmur or no murmur at all.
• "Elfin facies" associated with mental retardation and personality changes suggest Williams syndrome and supravalvular AS.
• EKG is usually normal in mild AS. LVH indicates moderate or severe AS and may be associated with a strain pattern (inverted T waves in left precordial leads).
• Chest radiograph usually shows normal heart size. A prominent aortic knob indicates post-stenotic dilation in valvular AS. Cardiomegaly, if present, indicates severe or critical AS associated with CHF.
• Echocardiography is useful in determining the type and the severity of the lesion.
• Cardiac catheterization is rarely needed for diagnosis.

Management

Mild or moderate AS requires only supportive care. Severe valvular AS can be treated by balloon valvuloplasty. Subvalvular and supravalvular aortic stenosis are not amenable to balloon valvuloplasty and may need surgical intervention.

PGE1 infusion is essential to maintain the ductal patency in neonates with critical AS.

Surgery may involve simple valvotomy or valve replacement with a prosthesis or homograft. Another alternative is the Ross autograft procedure; the patient's normal pulmonary valve is excised, placed in the aortic position and a homograft replaces the pulmonary valve.

Coarctation of the Aorta

Coarctation of the aorta is usually congenital, but may be acquired as in Takayasu arteritis. It may also be associated with Turner or Williams syndromes, and with other CHD such as bicuspid aortic valve, VSD, or double outlet right ventricle.

Anatomy

Congenital coarctation is almost always juxta-ductal (opposite to the ductus arteriosus), and may be either discrete or tubular

Coarctation of the Aorta

Pathophysiology

Coarctation of the aorta causes mechanical obstruction of blood flow from the left ventricle. The pressure proximal to the coarctation is usually elevated. Collateral vessels may develop to bypass the obstruction; the most common collaterals are the internal mammary and the intercostal arteries. LVH develops in response to the elevated pressure proximal to the coarctation.

Clinical Presentation

Most patients with coarctation are asymptomatic. Some patients may present with symptoms of either upper extremity hypertension (headaches, blurred vision or frequent nosebleeds) or symptoms of reduced blood flow to the lower extremities (exercise induced claudication). In infancy, severe coarctation may present with CHF as the ductus arteriosus closes. If it is not diagnosed and treated promptly, acidosis, shock and death may occur.

Making the Diagnosis

• The hallmarks of coarctation of the aorta are weak, delayed, or absent femoral pulses and a systolic pressure in the lower extremity that is lower than in the upper extremity by >10 mmHg.
• A prominent left ventricular impulse or heave is commonly palpated.
• A systolic ejection click is heard if there is a bicuspid aortic valve.
• A systolic ejection murmur is usually present at the ULSB and the left subscapular region.
• In older children with unrepaired coarctation, continuous murmurs may be heard over the back and chest due to collateral blood flow.
• The EKG varies according to age. RVH is the rule in infancy and LVH develops by the second or third year of life.
• Chest radiograph in neonates with severe coarctation shows severe cardiomegaly and pulmonary edema. Older children may have the "inverted E or 3" sign which is the ascending aortic knob and the post-stenotic dilation. Rib notching from dilated collateral vessels may be present in children more than five years of age.
• Echocardiography is helpful in delineating the lesion. Magnetic resonance angiography (MRA) or CT angiography may also helpful in making the diagnosis. Cardiac catheterization is rarely needed.

Management

In asymptomatic patients without hypertension, elective surgery or angioplasty is recommended at 18 to 24 months of age. The presence of significant hypertension or CHF in infancy indicates the need for early repair. Neonates with CHF may also need medical management including PGE1 to keep the ductus arteriosus open.

Quick Checks

Cyanosis

L. Yun, S. Munir, M.E. Gomez, MD A. Aly, MD, PhD

Definition

Cyanosis is a blue discoloration of the skin and/or mucous membranes. It is due to the presence of greater than 3 g/dL of reduced or deoxygenated Hb (Hb) in the blood. It is important to note that cyanosis is dependent on the absolute concentration of reduced Hb. Cyanosis can be clinically appreciated when the O₂ saturation is < 85%.

Effect of Hb level on Cyanosis

At a normal Hb level of 15 g/dL, the presence of 3 g/dL of reduced Hb results in 20% desaturation. Therefore, cyanosis is visible when O₂ saturation is approximately ~80%. The lower the Hb level, the lower the O₂ saturation needed before cyanosis can be appreciated.  

• If the patient has Hb level 21 g/dL, the presence of 3 g/dL of reduced Hb leads to about 15% desaturation (3g/dL per 21 g/dL = 15%). Cyanosis is thus visible when O₂ saturation is reduced to 85%.
• Conversely, at a Hb level of 10 g/dL such as in anemia, the presence of 3 g/dL of reduced Hb results in about 30% desaturation (3g/dL per 10 g/dL = 30%) and cyanosis does not appear until O2 saturation is ~70% . By the time cyanosis is noted in a severely anemic patient, the concentration of Hb is markedly reduced and the patient is usually very sick.

Effect of Fetal Hb on Cyanosis

Fetal Hb (HbF) is the main oxygen carrier protein in the human fetus during the last 7 months of pregnancy and persists during the first 6 months after birth. HbF has a single amino acid substitution (histidine to serine) at the 2,3-bisphosphoglycerate (2,3-BPG) binding site, which results in a higher affinity for oxygen than seen in adult Hb. The partial pressure of oxygen (PaO2) at which HbF is 50% saturated (P50) is lower than in adult Hb.

Infants with a higher proportion of HbF may have a greater reduction in oxygenation before cyanosis is clinically apparent. For example, in infants who have mostly adult Hb, central cyanosis (arterial saturation 75% to 85%) will be observed when the PaO2 falls below 50 mmHg. In contrast, in infants with mostly HbF, central cyanosis may not be observed until the PaO2 drops well below 40 mmHg.

Causes of Neonatal Cyanosis

1. Respiratory system disorders are the most common causes of cyanosis in neonates and should be ruled out first
• Airway obstruction - choanal atresia, micrognathia, laryngomalacia
• Pulmonary pathology and V/Q mismatch - pneumonia, pulmonary hypoplasia, persistent pulmonary hypertension (PPHN)
2. Central nervous system disorders cause depression of respiratory drive
• Neonatal encephalopathy, seizures, intracranial hemorrhage
3. Hematologic disorders
• Methemoglobinemia results from the oxidation of Hb molecules from the normal ferrous to the abnormal ferric state. Patients may appear cyanotic without respiratory distress and have a decreased O₂ saturation with normal PaO2.
• Polycythemia may cause peripheral cyanosis due to decreased perfusion secondary to hyperviscosity
4. Cardiovascular disorders
• Cyanotic congenital heart disease (CCHD): 6 T's
1. d-transposition of the great arteries (d-TGA)
2. Tetralogy of Fallot
3. Truncus Arteriosus
4. Total Anomalous Pulmonary Venous Connection
5. Tricuspid Atresia
6. (The) Hypoplastic Left Heart Syndrome
• Eisenmenger Syndrome: pulmonary hypertension with reversal of a L-to-R shunt

Refer to the section on "Cyanotic Cardiac Lesions" for more detail

Evaluation of Neonatal Cyanosis

Types of Cyanosis:

1. Central Cyanosis
• Seen in the tongue and mucous membranes
• Cause: desaturation of the arterial blood
• Treatment: dependent on the underlying cause
2. Peripheral Cyanosis (acrocyanosis, perioral cyanosis)
• Seen in the tips of fingers, toes and around the lips
• Cause: peripheral vasoconstriction (common in patients with Down syndrome due to vasomotor instability); patient will have normal arterial O₂ saturation
• Treatment: reassurance, rewarming of extremities
3. Differential Cyanosis
• Cyanosis seen only in the lower part of the body
• Causes:
• interrupted aortic arch or critical coarctation of the aorta in the presence of a patent ductus arteriosus (PDA) due to right to left shunt to the lower part of the body (Figure A)
• Moderate coarctation in the absence of PDA may also cause a variable degree of differential cyanosis due to hypoperfusion (Figure B)
• Pulmonary hypertension with a super-systemic pulmonary pressure causing a right to left shunt across a patent ductus arteriosus

1. Reverse Differential Cyanosis
• Cyanosis seen only in the upper part of the body
• Causes:
• d-TGA with PDA and severe coarctation of the aorta or interrupted aortic arch (Figure C)
• The deoxygenated blood flows from the right ventricle through the aorta to the upper part of the body  cyanosis
• Lower part of the body is perfused with oxygenated blood from the left ventricle, passing through the pulmonary artery and PDA.
• d-TGA with PDA and suprasystemic pulmonary HTN (Figure D)
• The deoxygenated blood flows from the right ventricle through the aorta to the upper part of the body  cyanosis
• Suprasystemic pulmonary pressure shunts oxygenated blood through the PDA to the lower part of the body.  

Hyperoxia Test

The hyperoxia test is used to help differentiate between cardiac and noncardiac causes of cyanosis. The PaO₂ is measured in the right radial artery (preductal) on room air and after 10 minutes of 100% oxygen supplementation. The hyperoxia test is interpreted as shown in Figure E. Failure to increase O₂ saturation and PaO₂ raises the suspicion for cyanotic heart disease. In severe forms of lung disease or PPHN, the PaO₂ may not increase with the hyperoxia challenge. This test has limited utility in facilities with access to echocardiography but it may guide decision-making for the necessity of prostaglandin infusion.

Role of Critical Congenital Heart Disease (CCHD) Screening in the Cyanotic Neonate:

In CCHD pulse oximetry screening, preductal (right upper extremity) saturations are compared with post-ductal saturations (lower extremity). A failed screening is when:

1. Oxygen saturation value is less than 90%
2. Oxygen saturation is less than 95% in the right hand and foot on 3 measurements, each separated by an hour
3. Difference between pre- and post-ductal saturations is greater than 3% on 3 measurements, each separated by 1 hour

CCHD Screening is effective in early identification in the following 7 primary screening targets:

1. Hypoplastic Lleft Hheart Syndrome
2. Pulmonary Atresia with an iIntact sSeptum
3. Tetralogy of Fallot
4. Total aAnomalous pPulmonary vVenous cConnection
5. d-TGA
6. Tricuspid Aatresia
7. Truncus aArteriosus

CCHD screening is less sensitive in detecting cardiac lesions that may not present with early hypoxemia. These infants may pass the CCHD screen and be discharged after an unremarkable and brief birth hospitalization.

The secondary screening targets of the CCHD screen are as follows:

1. Coarctation of the aorta
2. Double outlet right ventricle
3. Ebstein's Anomaly of the tricuspid valve
4. Interrupted Aortic Arch
5. Single ventricle

Special Considerations for Eisenmenger Syndrome:

In Eisenmenger syndrome is , i.e.a reversal of L R shunt due to pulmonary hypertension  cyanosis. The following cascade may occur:

Chronic hypoxemia → polycythemia → immature and less malleable RBCs (micro-spherocytes) due to relative iron deficiency → microvascular occlusion → stroke

Patients with chronic cyanosis due to Eisenmenger syndrome may require special management:

• Adequate hydration
• Iron supplementation  production of mature malleable RBC's
• Oxygen supplementation
• Aspirin

They may eventually require pulmonary vasodilators and phosphodiesterase inhibitors, endothelial receptor blockers or even heart-lung transplantation. 

References:

• Dasgupta, S., Bhargava, V., Huff, M., Jiwani, A. K., & Aly, A. M. (2016). Evaluation of The Cyanotic Newborn: Part I—A Neonatologist's Perspective. NeoReviews, 17(10), e598-e604.

Cyanotic Cardiac Lesions

D-Transposition of the Great Arteries (D-TGA)

Anatomy

In D-transposition of the great arteries (D-TGA), the aorta is positioned anterior and to the right of the pulmonary artery (instead of the normal right posterior relationship). The aorta is connected to the right ventricle and the pulmonary artery is connected to the left ventricle. 

D=dextro, meaning 'right'

Although D-TGA is not the most common cyanotic CHD, it is the most common cardiac cause of neonatal cyanosis. It is more common in male infants of diabetic mothers who are usually large for gestational age (happy chubby blue boy).

D-TGA

Pathophysiology

The blood runs in two parallel circulations (rather than the normal series circulation). This situation is incompatible with life unless there is mixing between the two circulations. The mixing may occur at the atrial level (ASD or PFO), ventricular level (VSD) or at the arterial level (PDA). The atrial level communication is the most important as a bidirectional shunt can easily be produced due to the low pressure difference between the two atria as compared to the ventricles or the great arteries.

Clinical Presentation

The physical examination is usually benign except for severe cyanosis and a single loud S2_.

Making the Diagnosis

• EKG usually shows right axis deviation and right ventricular hypertrophy (RVH).
• CXR may show the characteristic egg on a string appearance (the great arteries lose their normal criss-cross relationship and the thymus may be hypoplastic).
• Echocardiogram is diagnostic of D-TGA. Echo is also important for identifying sites of communications between the two circulations and in delineating the coronary artery anatomy which is important in the surgical repair.
• Cardiac catheterization may be needed to perform atrial septostomy, (which could also be done under echo guidance) to allow mixing at the atrial level.

x-ray showing an egg on a string of D-TGA

Management

Medical management includes starting PGE1 to keep the ductus arteriosus open and treatment of metabolic acidosis if present.

Surgical repair options include:

Arterial switch (Jatene) procedure in which the great arteries are switched back to the corresponding ventricle and the coronary arteries are reimplanted in the neo-aorta.

D-TGA after arterial switch surgery

Atrial switch (Senning or Mustard) procedure involves redirecting the blood flow at the atrial level so the pulmonary venous blood is baffled to the right ventricle (systemic ventricle) and the systemic venous blood is directed to the left ventricle (pulmonary ventricle). It is a less favorable surgery because of its numerous complications.

Atrial Switch Procedure

Persistent Truncus Arteriosus (TA)

Truncus arteriosus is sometimes associated with DiGeorge syndrome (deletion of chromosome 22q.11) which is characterized by hypocalcemia and reduced T-lymphocyte function. Extra-cardiac abnormalities are present in 25-40% of patients.

Anatomy

A single large trunk overrides a large VSD and gives rise to the coronary arteries, pulmonary arteries, and the brachiocephalic arteries.

Truncus Arteriosus, with the main pulmonary artery arising from the common trunk

Pathophysiology

TA has a single ventricle physiology as the VSD is usually large (one ventricle pumps blood to both systemic and pulmonary circulations with complete mixing of blue and red blood). The truncal valve is frequently abnormal. In the neonatal period, the pulmonary vascular resistance is elevated and the pulmonary blood flow may be limited. This may cause mild and early cyanosis due to a right-to-left shunt. As the pulmonary vascular resistance drops, the pulmonary blood flow significantly increases causing CHF symptoms.    

Clinical Presentation

Physical Examination: mild cyanosis may be detected along with a wide pulse pressure and cardiomegaly. A single S2 (one semilunar valve) and a systolic ejection murmur due to increased flow through the truncal valve may be heard. An apical diastolic murmur may be heard due to increased flow through the mitral valve (relative mitral stenosis). An early diastolic murmur may indicate truncal valve insufficiency.

Making the Diagnosis

• EKG may show biventricular hypertrophy.
• CXR shows increased pulmonary vascular markings and prominent ascending aorta. It may also be suggestive of right aortic arch (25% of cases).
• Echo is diagnostic and shows associated cardiac anomalies.

Management

Medical management of CHF may be tried until surgical repair can be performed.

Surgical repair may include:

• Early surgical correction is preferred. The VSD is closed so that the LV is connected to the truncus and the pulmonary artery is detached from the truncus and is connected to the right ventricle via a conduit.
• If early surgical repair cannot be done, banding of the pulmonary artery is performed to limit the blood flow to the lung and to control CHF.  

Tetralogy of Fallot (TOF)

Tetralogy of Fallot is the most common cyanotic CHD (over 50% of all cases of cyanotic CHD; ~ 10% of all cases of CHD).

Anatomy

TOF has four abnormalities (hence the term 'tetralogy):

• Ventricular septal defect (mal-alignment)
• Overriding aorta
• Right ventricular outflow tract obstruction (RVOTO)
• Right ventricular hypertrophy (RVH)

Tetralogy of Fallot (TOF) with large mal-aligned VSD, overriding aorta,
right ventricular outflow tract obstruction and right ventricular hypertrophy

Pathophysiology

The VSD is nonrestrictive (both ventricles have equal pressures). The direction of the blood flow across the VSD depends on the relative systemic and right ventricular outflow tract (RVOT) resistances.

Clinical manifestations

TOF patients usually present with a heart murmur at birth with variable degree of cyanosis (depending on the degree of right ventricular outflow tract obstruction (RVOTO)). Many patients are completely acyanotic (pink TOF). There is a right ventricular tap at the left sternal border, systolic ejection murmur due to RVOTO, and single S2. The VSD is usually non-restrictive and does not produce a heart murmur. Clubbing of digits may be seen in untreated TOF with prolonged cyanosis.

Making the Diagnosis

• EKG: RAD, RVH
• Echocardiography is diagnostic; 25% of patients have right aortic arch and 5% have coronary artery anomalies
• CXR: 'Boot shaped' heart due to concave main pulmonary artery segment and upturned RV apex due to RVH

Chest X-ray showing boot shaped heart in Tetralogy of Fallot

Tet spells (hypercyanotic or hypoxic spells):

Tet spells are characterized by paroxysmal cyanosis, tachycardia, tachypnea and irritability. These spells are caused by reversal of the shunt across the VSD so the blood flows from the right to the left ventricle due to an increase in the RVOTO resistance. Initially, the systolic murmur gets louder and then diminishes as the RVOTO progresses to near complete obstruction. Tet spells are more common in the warm weather and in the morning hours when the systemic vascular resistance is low due to increased parasympathetic tone and decreased intravascular volume; a warm bath can have a similar effect. The RVOTO is worsened by increased catecholamine secretion due to irritability, hunger, or wet diapers.

Hypercyanotic spells need urgent treatment; if left untreated, metabolic acidosis, seizures, cerebrovascular accidents or even death may occur. The concept of treatment is to reverse the mechanism of the hypoxic spells. It is important to remove any source of irritation for the infant to decrease the catecholamine surge and worsening of the RVOTO.

While the mother is comforting the baby (nursing, bottle feeding), the baby is placed in a knee-to-chest position to increase systemic vascular resistance. Blow-by O2 is provided to enhance the oxygenation of blood and increase the systemic vascular resistance. If the spell continues, morphine sulphate (0.2 mg/kg) may be given intramuscularly to calm the patient and relax the obstruction of the RVOT. An IV line should be inserted and isotonic fluid boluses should be administered (and may be repeated) until the heart rate normalizes.

Acidosis should be treated with sodium bicarbonate. If the spell continues, vasoconstrictors such as phenylephrine may be tried. Intravenous beta blockers (propranolol or esmolol) may be used to decrease the cardiac contractility and, hence the RVOTO. Beta blockers also slow down the heart rate and therefore, enhance the coronary perfusion. If the spell continues despite all these measures, endotracheal intubation and general anesthesia are indicated in preparation for urgent surgical intervention.

Management

If the patient is pink and has never had a cyanotic spell, elective surgery is usually performed in the first few months of life by closing the VSD and relieving the RVOTO. If the patient is cyanotic or develops a cyanotic spell, intervention is necessary in the neonatal period. If neonatal repair cannot be done because of prematurity or an unstable medical condition, then a palliative shunt between the aorta or one of it's branches and the pulmonary artery is placed to bypass the RVOTO. The classic shunt is called Blalock-Taussig (BT) shunt.

Tetralogy of Fallot (TOF) with a BT shunt between the right subclavian and the right pulmonary arteries

Total Anomalous Pulmonary Venous Connection (TAPVC)

TAPVC accounts for about 1% of all CHD. It is also referred to as total anomalous pulmonary venous return (TAPVR), which is less accurate as the connection may be obstructed and there may be diminished or no pulmonary venous return. 

In TAPVC, the pulmonary veins connect to the right atrium or great veins (SVC or IVC) instead of connecting to the left atrium. An atrial communication is necessary to maintain life.

Pathophysiology

In the right atrium, both oxygenated and deoxygenated blood completely mix, and the mixture is then distributed to other cardiac chambers. The oxygen saturation is characteristically the same in all cardiac chambers. There are four different types of TAPVC:

• Supracardiac: The pulmonary veins connect via a vertical vein to the innominate vein and the SVC.
• Cardiac: The pulmonary veins connect to coronary sinus or the right atrium.
• Infracardiac: A common pulmonary vein crosses the diaphragm and connects to the portal vein, ductus venosus, hepatic vein or the IVC.
• Mixed type is a combination of the above.

Supracardiac type TAPVC with drainage of pulmonary veins into superior vena cava (SVC)
via vertical vein, which connects to the innominate vein and finally drains into SVC

Cardiac type of TAPVC with drainage of pulmonary veins directly into right atrium via coronary sinus

 
Infracardiac type TAPVC with drainage of pulmonary veins into inferior vena cava via hepatic vein

Clinical manifestations

The clinical manifestations depend on the presence or absence of obstruction to the pulmonary venous connection. If there is no obstruction, mild cyanosis, CHF and frequent pulmonary infection are the common manifestations. With obstruction, there is marked cyanosis, respiratory distress and pulmonary congestion.

Making the Diagnosis

• CXR shows pulmonary edema.
• Cardiomegaly with a "snowman" sign may be seen in supracardiac type.

Chest X-ray showing snowman sign of supracardiac TAPVC

Management

Medical management may be tried in patients with TAPVC without obstruction in the form of diuretics and correction of metabolic acidosis. PGE1 causes pulmonary vasodilatation and should be avoided as it may worsen the CHF. All patients with TAPVC will need surgical repair as soon as the diagnosis is made; this includes having the pulmonary veins re-implanted in the left atrium.

Tricuspid Atresia (TA)

 TA is a rare form of CHD (1% of all CHD). The RV is hypoplastic and an ASD is necessary for survival. If the ventricular septum is intact, the pulmonary valve would also be atretic. If a VSD is present, there will be a variable degree of hypoplasia of the pulmonary valve depending on the size of the VSD.

 TA is classified according to the presence or absence of VSD or TGA. In one fourth of the patients, there is a TGA. Patients with TA with normally related great vessels may be more cyanotic than those with TGA as the degree of cyanosis is inversely related to the volume of the pulmonary blood flow (Figures).

Tricuspid atresia with a restrictive VSD, pulmonary hypoplasia and normally related great arteries

Ticuspid atresia with a non-restrictive VSD and D-TGA

Clinical Presentation, EKG and, imaging

Patients with TA are cyanotic and have a single S2. A holosystolic murmur of VSD may be heard. A PDA murmur may also be heard.

EKG classically shows a left superior axis deviation (due to posterior and inferior displacement of AV node) and diminished RV forces. LVH may be present. Echo is usually diagnostic.

Left superior axis deviation and reduced right ventricular forces consistent with tricuspid atresia

Management

Management includes IV infusion of PGE-1 to maintain the ductal patency. CHF needs to be treated if present. Rashkind atrial septostomy may be needed if the ASD is restrictive. Patients with TGA and hypoplastic RV will need multi-stage single ventricle repair (see Fontan-type operation in HLHS).

Pulmonary Atresia with Intact Ventricular Septum (PA-IVS)

PA-IVS occurs in 2.5 % of patients with CHD.

There is no direct communication between the RV and the main pulmonary artery (MPA) as the pulmonary valve is atretic. The RV is usually hypoplastic. An atrial communication is needed for survival. The pulmonary blood flow is dependent on the patency of the ductus arteriosus.

Clinical Presentation, EKG, imaging

Clinically, patients are severely cyanotic and have respiratory distress. The S2 is single and a PDA murmur may be heard. EKG shows RAE, LVH and possibly RVH.

CXR usually shows reduced pulmonary vasculature.

Echo is diagnostic.

Management

• PGE-1 should be started to maintain the ductal patency.
• Cardiac catheterization is usually needed for the evaluation of the type of PA (membranous vs. muscular) and to detect the presence of coronary sinusoids.
• Balloon atrial septostomy may be performed in the cardiac cath lab.
• Perforation of a membranous atretic pulmonary valve (by radiofrequency) may be attempted.
• If the RV size is adequate, trans-annular patching across the pulmonary outflow may be done.
• In patients with RV dependent coronary circulation, RV decompression may lead to reversal of the coronary blood flow to the RV producing myocardial ischemia. In this case, a BT shunt is placed in preparation for a single ventricle repair.

Ebstein Anomaly of the Tricuspid Valve (EA)

Ebstein anomaly is a rare form of CHD (1%).

There is a downward displacement of the septal and posterior leaflets of the tricuspid valve into the RV cavity creating a large atrialized portion of the RV. The functional RV may be hypoplastic, dilated and thin-walled. There is usually an inter-atrial communication such as PFO or ASD. Ebstein anomaly may be associated with other CHD such as PS, TOF, pulmonary atresia or VSD.

Dysrhythmias, especially Wolff-Parkinson-White (WPW) and SVT are common.

Ebstein Anomaly of the tricuspid valve

Clinical Presentations, EKG, imaging

Infants may present with cyanosis which usually improves as the pulmonary vascular resistance drops. Older children usually present with dyspnea, fatigue and palpitations (SVT). A quadruple rhythm may be audible in addition to a holosystolic murmur at the left lower sternal border due to tricuspid insufficiency. A mid-diastolic murmur due to relative tricuspid stenosis may be heard at the same location. EKG is characterized by massive right atrial enlargement (RAE), RBBB and sometimes first degree AV block or WPW. CXR shows cardiomegaly due to RAE. Echocardiogram is diagnostic. The degree of TR and the size of the RV should be determined.

Management

Medical management is recommended in mild forms. This includes management of CHF and treatment of dysrhythmias. Oxygen supplementation is helpful early in life as it decreases the pulmonary vascular resistance. PGE-1 may be needed to maintain the ductal patency in severe cases. Surgery is required for severe forms and involves reconstruction or replacement of the tricuspid valve and closure of the ASD. If the RV is severely hypoplastic, a single ventricle repair (Fontan procedure) may be necessary.

Hypoplastic Left Heart Syndrome (HLHS)

Hypoplastic Left Heart Syndrome (HLHS) occurs in about 1% of CHD and involves hypoplasia or atresia of the left sided structures including the LA, mitral valve, LV, aortic valve and ascending aorta. A shunt at the atrial level (ASD or PFO) is necessary for survival. A PDA is essential for providing blood supply in a retrograde direction to the transverse and ascending aorta to provide blood to the neck vessels and coronary arteries.

Hypoplastic left heart with a non-restrictive ASD and a PDA

Pathophysiology

There is an obligatory L to R shunt at the atrial level. Both pulmonary and systemic venous blood completely mix in the RA. The RV pumps blood to both systemic and pulmonary circulations. Initially, both resistances are nearly equal and the blood is distributed equally to the pulmonary and systemic circulations. As the pulmonary vascular resistance drops in the first few days of life, more blood flows to the lungs causing pulmonary congestion, reduced systemic flow causing tissue hypoxemia, metabolic acidosis, shock, or even death.

Clinical Presentations

Neonates with HLHS usually present with one of three clinical scenarios:

• Respiratory distress due to pulmonary congestion (CHF) as the pulmonary vascular resistance drops in the first few days of life
• Shock as the ductus arteriosus constricts or
• Cyanosis which is usually mild due to excessive pulmonary flow. Severe cyanosis is uncommon and may indicate inadequate inter-atrial communication or persistent pulmonary hypertension.

A systolic ejection murmur may be heard at the ULSB due to increased flow through the pulmonary valve. A holosystolic murmur due to tricuspid insufficiency may be heard at the LLSB. S2 is usually loud and single. The peripheral pulses may be weak and the skin may be mottled due to poor tissue perfusion.

Making the Diagnosis

• This condition can be diagnosed prenatally as early as 16 weeks of gestation.
• EKG: EKG findings are nonspecific and may show poor progression of LV forces and myocardial ischemic changes.
• Echocardiography is diagnostic and also helps to determine the size of the inter-atrial communication, the patency of the ductus arteriosus, RV function and the presence of tricuspid insufficiency.
• CXR shows cardiomegaly, pulmonary venous congestion and pulmonary edema.
• Cardiac catheterization is rarely necessary for diagnosis but may urgently be needed to perform balloon atrial septostomy if the ASD is restrictive.

Management

Medical management:

• PGE-1 should be started to maintain the ductal patency.
• Avoid oxygen supplementation because it causes pulmonary vasodilatation and lowers the PVR, which makes pulmonary congestion and CHF worse. This may also compromise the systemic blood flow as oxygen is a systemic vasoconstrictor.
• Avoid administration of excessive IV fluids as most of the fluid will go to the lungs, worsening the CHF symptoms.
• Also avoid high doses of inotropic agents as this causes systemic vasoconstriction and increases the SVR. This may accentuate tissue hypo-perfusion and metabolic acidosis. It also increases the myocardial oxygen demand by increasing the contractility.

Surgical management: both multi-stage palliative surgery and heart transplantation have comparable outcomes.

Norwood procedure

Modified Norwood procedure with a Sano shunt between the right ventricle and the pulmonary artery bifurcation 

The first stage (Norwood procedure) is performed in the neonatal period and involves division of the MPA and ligation of the ductus arteriosus, removal of the atrial septum and reconstruction of a new ascending aorta using the proximal MPA and the ascending aorta. A BT shunt made from Gore-Tex^® is placed between the innominate artery and the right pulmonary artery to supply blood to both lungs. Because there is complete mixing of blood in the RV, the oxygen saturation is usually in the low 80's%.

Bidirectional Glenn procedure

The second stage is called bi-directional Glenn or hemi-Fontan procedure and is usually performed at 6 months of age. The SVC is connected to the right pulmonary artery and the BT shunt is removed. The systemic venous blood from the SVC is the only source of pulmonary circulation. The IVC venous blood mixes with the pulmonary venous blood in the RV. The systemic saturation is usually in the mid to high 80's%.

Modified Fontan procedure

The third stage is the Fontan procedure which is usually performed at 18-24 months of age. It involves connecting the IVC to the right pulmonary artery. After this procedure, both systemic and pulmonary circulations are separated. The systemic venous blood from the SVC and IVC passively flows to both lungs via the pulmonary arteries. The RV acts as the systemic ventricle. The oxygen saturation is usually in the low to mid 90% (as there is still some mixing from the coronary venous blood via the coronary sinus).

The Fontan procedure has many complications including an increase in systemic venous pressure, development of chylothorax, and diaphragmatic and vocal cord paralysis. Other complications include atrial tachy-arrhythmias, sick sinus syndrome, and protein-losing enteropathy.

Quick Check

Cardiomyopathies, Myocarditis and Inflammatory Disorders

Cardiomyopathies

Cardiomyopathy is defined as a structural or functional abnormality of the myocardium that is not secondary to structural heart disease, hypertension, or pulmonary vascular disease. Cardiomyopathies are usually classified as follows:

• Dilated cardiomyopathy (DCM) - in which the left ventricle is dilated and has poor systolic function.
• Hypertrophic obstructive cardiomyopathy (HOCM) - also known as idiopathic hypertrophic sub aortic stenosis. HOCM is characterized by ventricular hypertrophy (usually asymmetric) with normal systolic function but abnormal diastolic function.
• Restrictive cardiomyopathy - which is characterized by primary diastolic dysfunction, normal ventricular size and dilated atria.

Dilated cardiomyopathy

This is the most common cause of cardiomyopathy in children. It may be secondary to myocarditis, coronary artery disease, and many other conditions. In familial cases, an autosomal dominant transmission is the most frequent pattern of inheritance. Autosomal recessive, X-linked and mitochondrial inheritance have also been described.

Pathology

The heart in dilated cardiomyopathy is globular and is grossly dilated. The myocardium is pale and mottled, and the endocardium is thin. Histologically, there is myocyte hypertrophy and degeneration as well as interstitial fibrosis. This is compared to myocarditis, in which there is myocyte necrosis and lymphocytic infiltration.

Pathophysiology

Systolic dysfunction is manifested by decreased shortening and ejection fractions which leads to increased end-diastolic volume and pressure. The blood flow to kidneys is diminished with resultant salt and water retention and worsening of CHF. Myocardial fibrosis may lead to ventricular arrhythmias secondary to the development of reentry circuits in the ventricles.

Clinical Presentation

CHF signs and symptoms develop as the cardiac output decreases. These include decreased exercise tolerance and dyspnea with exertion. Infants present with poor feeding, diaphoresis during feeding, and failure to thrive. Palpitation and syncope are sometimes the earliest presentation of DCM.

Making the Diagnosis

• The condition needs to be differentiated from acute myocarditis (see below).

• The patient usually has tachycardia and tachypnea. The skin may be pale and cold. The peripheral pulses are weak and the blood pressure is in the low normal range with a narrow pulse pressure.
• Breath sounds may be diminished with rales and signs of respiratory distress. Cardiac examination reveals muffled heart sounds, gallop rhythm and possibly mitral regurgitation murmur. Hepatomegaly and other signs of venous congestion may be present.
• Chest radiograph reveals dilatation of the left ventricle and atrium. Pulmonary edema and pleural effusion may be seen.
• There may be atelectasis of the left lower lobe from compression of the left main bronchus by the dilated LA. The EKG shows nonspecific-T change as evidence of ventricular hypertrophy and atrial enlargement.
• Atrial and ventricular arrhythmias are common.
• Echocardiography shows decreased shortening fraction (the percentage of decrease in LV dimensions between diastole and systole.) The origin of the coronary arteries should be delineated to rule out coronary anomalies. Pericardial effusion may be present. Cardiac catheterization and myocardial biopsy are useful in confirming the diagnosis and evaluating the patient for potential cardiac transplantation.
• Urine examination for organic acids is important to exclude metabolic disorders. Blood studies should also be obtained for abnormalities in lactate, calcium, magnesium, carnitine, pyruvate, blood urea nitrogen (BUN) and serum electrolytes. Molecular genetic analysis for dystrophin mutations could be diagnostic in some cases.

Management

If cardiac decompensation is present, intravenous inotropic agents, such as dobutamine and dopamine (in renal doses), may be useful. Amrinone and milrinone also have positive inotropic effect and also reduce the afterload. When the patient is clinically stable, oral digoxin, ACE inhibitors and B-blockers (carvedilol) may be started. Diuretic therapy is useful for removing excess fluid. Patients with acute and severe decompensation may require ventricular assist devices or extracorporeal membrane oxygenation. Heart transplantation may be considered if all other measures fail.

Constrictive Pericarditis

Constrictive pericarditis occurs when a scarred, thickened, and calcified pericardium impairs cardiac filling.   The pathophysiological hallmark of pericardial constriction is equalization of the end-diastolic pressures in all four cardiac chambers. This occurs because the filling is determined by the limited pericardial volume, not the compliance of the chambers themselves.

Initial ventricular filling occurs rapidly in early diastole as blood moves from the atria to the ventricles without much change in the total cardiac volume. However, once the pericardial constraining volume is reached, diastolic filling stops abruptly. The stiff pericardium also isolates the cardiac chambers from respiratory changes in intrathoracic pressures, resulting in Kussmaul's sign.

Clinical Presentation

Patients with pericardial constriction typically present with manifestations of elevated systemic venous pressures and low cardiac output. Typically, there will be marked jugular venous distension, hepatic congestion, ascites, and peripheral edema. The limited cardiac output typically presents as exercise intolerance. Patients with pericardial constriction are much more likely to have left-sided or bilateral pleural effusions.

Making the Diagnosis

• The normal inspiratory drop in jugular venous distention may be replaced by a rise in venous pressure (Kussmaul's sign).
• The classic auscultatory finding of pericardial constriction is a pericardial knock. This occurs as a high-pitched sound early in diastole when there is sudden cessation of rapid ventricular diastolic filling.  
• Pericardial calcification seen on the lateral plane chest x-ray is suggestive of pericardial constriction.
• Most patients with pericardial constriction have a thickened pericardium (>2 mm) that can be imaged by echocardiography, CT, and MRI.
• Doppler echocardiography is important in the evaluation of patients with suspected pericardial constriction. The echocardiogram may demonstrate pericardial thickening and calcification. However, increased pericardial thickness can be missed on a transthoracic echocardiogram. Transesophageal echocardiography is more sensitive and accurate in determining pericardial thickness. Doppler echocardiography frequently demonstrates restricted filling of both ventricles.

Management

• In some patients with acute onset pericardial constriction, the symptoms and constrictive features may resolve with medical therapy alone. Medical management includes the use of anti-inflammatory agents, colchicine, and/or steroids.
• In more chronic pericardial constriction, definitive treatment is surgical pericardial decortication with resection of both the visceral and parietal pericardium.

Restrictive Cardiomyopathy

Restrictive cardiomyopathy (RCM) is a rare form of myocardial disease that is characterized by restrictive filling of the ventricles. In this disease the contractile function of the heart and wall thicknesses are usually normal, but the filling phase of the heart is abnormal. This occurs because the cardiac muscle is stiff and poorly compliant and does not allow ventricular filling. This inability to relax and fill with blood results in a backup of blood into the atria. RCM is the least common in children, accounting for 2.5-5% of the diagnosed cardiomyopathies. The average age of diagnosis is 5 to 6 years old and it appears to affect girls somewhat more often than boys. There is a family history of cardiomyopathy in approximately 30% of cases. In most cases the cause of the disease is unknown (idiopathic), although a genetic cause is suspected in most cases of pediatric RCM.

Clinical Presentation

Children with RCM frequently have a history of repeated lung infections. Referral to a cardiologist occurs when symptoms of heart failure are reported or cardiomegaly is seen on a chest x-ray. In approximately 10% of cases, syncope, may be the first symptom. Sudden death may also be the initial presentation in some patients. 

Making the Diagnosis

• The diagnosis of RCM is difficult to establish early in the clinical course due to the lack of symptoms.
• Therefore, in many cases, the diagnosis is made only after presentation with symptoms such as decreased exercise tolerance, new heart sound (gallop), syncope, or chest pain with exercise.
• EKG may demonstrate abnormally large electrical forces from enlargement of the atria.
• An echocardiogram may show marked enlargement of the atria, normal sized ventricles, and normal heart function. In more advanced disease states, pulmonary artery pressures may be increased.
• Cardiac catheterization is rarely needed to confirm the diagnosis. The pressure measurements often show significantly elevated pressures during diastole and varying degrees of increased pulmonary artery pressures in the absence of any other structural heart disease.
• Myocardial biopsy is rarely needed to confirm the diagnosis.
• Since childhood RCM is often genetic, once this diagnosis is established, it is important to screen other family members.

 Management

• Diuretics, beta-blockers and occasionally, afterload reducing agents.
• In children with RCM, there is a risk of clots forming inside the heart possibly leading to a stroke. Anticoagulation medications, are often used in these situations. These include aspirin, dipyridamole, warfarin, heparin, and enoxaparin.

Myocarditis

Myocarditis is an inflammation of cardiac myocytes associated with necrosis and degeneration.

Infection with Coxsackie B virus or adenovirus is the most common cause of myocarditis. Many other viruses, as well as bacterial infections, mycoplasma, fungi, protozoa, spirochetes and rickettsia have also been reported to cause myocarditis.

Clinical Presentation

The common presentation is a history of a recent viral infection followed by the development of signs and symptoms of CHF.

Making the Diagnosis

• The patient may have tachycardia and other signs of overt CHF.
• Chest radiography demonstrates cardiomegaly and pulmonary venous congestion. Evidence of pneumonitis may be present.
• The EKG may show sinus tachycardia, premature ventricular contractions or supraventricular tachycardia. Low voltage QRS and inverted T waves are common.
• Echocardiography and cardiac catheterization with biopsy may be necessary to differentiate myocarditis from dilated cardiomyopathy. Viral culture and viral titers may be helpful in making the diagnosis.

Management

Acutely sick patients require intravenous inotropic agents and diuretics until they can be transitioned to oral digoxin, afterload reducing agents and diuretics. The use of anti-inflammatory and immunosuppressive therapy is still controversial.  

Hypertrophic Obstructive Cardiomyopathy

Hypertrophic obstructive cardiomyopathy (HOCM) is the most common cause of sudden death in the young. The most important predictors of sudden death are a family history of sudden death and recurrent syncope. Mortality in children with HOCM is twice as high as adults. The condition is usually progressive and the symptoms depend on the age and mode of presentation.

HOCM is an inherited disorder of the cardiac muscle characterized by a hypertrophied, non-dilated left ventricle. The condition is associated with abnormal relaxation of the LV and sometimes with outflow tract obstruction. The mode of inheritance is most often autosomal dominant with variable penetrance and several genetic defects have been described.

Pathology

The hallmark of HOCM is left ventricular hypertrophy (LVH) which is characteristically asymmetric with more involvement of the ventricular septum. This asymmetric septal hypertrophy often produces sub-aortic obstruction that is exaggerated by systolic anterior movement (SAM) of the anterior mitral valve leaflet and its apposition to the bulging septum. Histologically, there is extensive myocardial fiber disarray. The myocardial cells are disorganized and are separated by loose connective tissue. The coronary arteries sometimes run within the myocardium (intramural) and show increased intimal and medial thickening causing luminal narrowing.

Clinical Presentation

Affected individuals may be asymptomatic, may have recurrent exertional dyspnea, chest pain or syncope. The condition may be recognized only after sudden death has occurred. Infants may present with CHF and the diagnosis is often missed.

Making the Diagnosis

• Beyond infancy, a heart murmur may be the mode of presentation.
• A prominent "a" wave in the jugular venous pulse may be present because of diastolic dysfunction.
• A systolic ejection murmur may be present due to LV outflow tract obstruction (LVOTO). The murmur is intensified by maneuvers that decrease the LV volume and increase the systolic anterior movement of the mitral valve leaflet such as standing or performing the Valsalva maneuver. Its intensity decreases by squatting or assuming a supine position. These maneuvers have the opposite effect of an aortic stenosis murmur.
• EKG changes are variable and may show LVH with a strain pattern (inverted T waves in the left precordial leads).   Chest radiography may be normal or have evidence of cardiomegaly. MRI and radionuclide studies are helpful in making the diagnosis and assessing systolic and diastolic functions.
• Echocardiography is the most important imaging study for the diagnosis of HOCM and allows an assessment of the pattern and degree of hypertrophy, the extent of LVOTO as well as the systolic anterior movement (SAM) of the anterior mitral leaflet.

Management

Beta-blockers are helpful in the medical management by reducing the contractility and the heart rate; thereby prolonging the diastolic time. However, these agents have no effect on the degree of LVOTO obstruction or sudden death. Digoxin, other inotropic agents, and ACE inhibitors are contraindicated in HOCM as they worsen the obstruction, though they may have a role in the end-stage dilated thin-walled HOCM hearts with impaired LV systolic function. Diuretics are also usually contraindicated as they reduce the preload and enhance the LVOTO.

Surgical myomectomy may be needed to relieve the LV obstruction. Alcohol ablation of the septal perforating coronary arteries can produce a controlled infarction and relieves the sub-aortic obstruction. There is also a role for a pacemaker or implantable defibrillator (ICD).

Patients with HOCM should avoid strenuous exercise and their families should undergo genetic counseling.

Heart Failure

Definition

• Heart failure is described as a syndrome of inadequate cardiac output to maintain end organ perfusion.   It could be due systolic or diastolic dysfunction. Patients with left to right shunts develop congestive heart failure (CHF) because of excessive volume overload to the lungs with a normal cardiac function.

Compensatory Mechanisms

• Catecholamine surge by the sympathetic nervous system that leads to tachycardia and increased myocardial contractility to increase the cardiac output.  

• Salt and water retention through activation of the renin-angiotensin-aldosterone system (RAAS) to increase the intravascular volume and enhance the end organ perfusion.  

Etiology

Clinical features

1. Neonates/infants:
• Respiratory distress, tachypnea and tachycardia
• Diaphoresis with feeding and poor weight gain
• Deceased urine output
• Hepatomegaly
2. Children/adolescents:
• Dyspnea on exertion, tachypnea and tachycardia
• Hepatomegaly and edema of extremities
• Cough
• Pallor

Diagnosis

1. Blood work:
• CBC (may show anemia) and thrombocytosis in case of Kawasaki disease
• CMP (look for elevated LFT's and BUN/Cr, may have elevated Na and low K secondary to activation of RAAS)
• Troponin I (only useful if concerned about acute ischemic injury)
• CK-MB (non-specific marker of cardiac injury)
• BNP/NTproBNP (see discussion below)
• Lactate (if concerned about low cardiac output)
2. Imaging:
• CXR (cardiomegaly, pulmonary edema)
• Echocardiogram (evaluate cardiac structure/function and coronary arteries)
• Cardiac MRI (done in cases of myocarditis/cardiomyopathies for risk stratification)

Utility of biomarkers in CHF

The ideal biomarker would have the following properties:

1. Specific for the myocardium
2. Is released in quantities sufficient to be detected by an assay with sufficient sensitivity and specificity to distinguish between healthy and disease states
3. A relationship can be determined between the serum level of the biomarker and the clinical severity of the disease state
4. Can provide diagnostic and prognostic information

• The prototype biomarker is Brain Natriuretic Peptide (BNP)
• BNP and its inactive processed product, N-terminal-pro-BNP (NTproBNP), are released from ventricular myocardium in response to increased myocardial fiber stretch
• BNP and NTproBNP have different biochemical properties, are measured by different assays
• NTproBNP has a longer half-life in plasma than BNP; therefore, NTproBNP levels are generally higher than BNP and display less variability

Management of CHF

1. Diuretics:

• Reduce symptoms of volume overload such as dyspnea, orthopnea, peripheral edema, hepatomegaly
• Loop diuretics (furosemide, bumetanide) are typically used as first-line agents, with thiazide diuretics (chlorothiazide, metolazone) added for refractory fluid retention
• Frequent monitoring of serum electrolytes is necessary, particularly if diuretics are used in combination with ACE inhibitors and/or digoxin 

2. ACE inhibitors/Angiotensin Receptor Blockers (ARBs):

• Afterload reduction of the left ventricle through systemic vasodilation has been a basic therapeutic premise of heart failure
• ACE inhibitors effect systemic vasodilation through blockade of ACE which converts angiotensin I into angiotensin II
• ARBs produce similar effects by blocking the angiotensin receptors

3. Beta-Blockers:

• Beta-blockers are widely used in chronic heart failure
• Beta-blockers improve left ventricular function, heart failure symptoms, and survival in adults
• Potential mechanisms of include up regulation of beta-adrenergic receptors, decreased stimulation of other neuro-hormonal systems, antiarrhythmic effects, coronary vasodilation, negative chronotropic effects, antioxidant effects, and improved myocardial energetics

4. Aldosterone receptor antagonists:

• The aldosterone receptor antagonists such as spironolactone prevent aldosterone from exerting adverse compensatory downstream mechanisms that are activated in chronic heart failure, many of which involve sodium and extracellular fluid retention
• Evidence also indicates that chronic aldosterone receptor stimulation leads to adverse remodeling such as myocardial scarring/fibrosis, ventricular dilation, and ventricular dysfunction
• Spironolactone is generally well tolerated in children, although hyperkalemia is a common side effect necessitating careful monitoring of serum electrolytes
• Gynecomastia can occur in males (up to 10%) and may be irreversible

5. Digoxin:

• Digoxin is a cardiac glycoside, which exerts positive inotropic effects on the heart by increasing sarcoplasmic calcium concentrations by inhibition of the sodium-potassium ATPase pump of the myocardial cellular membrane
• Digoxin also counteracts the adverse neuro-hormonal milieu of chronic heart failure by increasing vagal tone and sympatholytic effects, decreasing plasma norepinephrine levels, and possibly antagonism of aldosterone
• Digoxin is currently indicated for chronic heart failure in adults for patients who remain symptomatic despite adherence to guideline-directed medical therapy

6. Inotropes:

• Inotropes are frequently used in the inpatient setting to improve ventricular function or augment cardiac output in patients with exacerbations of chronic heart failure
• At present, there are no oral agents with inotropic properties, apart from digoxin, available in the United States
• In some situations, continuous inotropic therapy may be used as part of a palliative care strategy or as a bridge to more definitive treatment such as ventricular assist device or heart transplantation

7. Interventional catheterization:

• These procedures may be used for myocardial biopsy and to evaluate the cardiac hemodynamics  
• Interventional balloon valvuloplasty may be needed for critical aortic or pulmonary stenosis

8. Surgery:

• It is often the definitive treatment of heart failure if it is secondary to structural heart diseases

Chest Pain

Chest pain is a frequent complaint in children, with the highest incidence in the early teenage years. Musculoskeletal structures of the chest wall are the common culprits; cardiac reasons are rarely the cause but should always be considered.

Causes of chest pain in children

• Nonspecific (idiopathic) chest pain is the most common. It is described as a sharp, localized, non-radiating chest pain that lasts for a nonspecific period of time (few seconds to a few hours). It may be exacerbated by deep breathing and by pressure on the chest. The costochondral junctions are not tender to palpation.
• Costochondritis usually presents as unilateral chest pain involving a few costochondral junctions; these are tender to deep palpation.
• Pericarditis causes severe chest pain that often intensifies when the patient lies down in a supine position and lessens when the patient leans forward. The EKG may show ST segment elevation and PR depression. The patient is usually very sick and has other symptoms of inflammation.
• Herpes zoster chest pain is severe and is frequently associated with a typical skin eruption that has a specific dermatomal distribution.
• Pneumothorax causes abrupt severe chest pain.
• Other noncardiac causes of chest pain in children include pneumonia, bronchitis, sickle cell crisis, trauma, muscle strain and asthma.
• Cardiac causes of chest pain in children include hypertrophic cardiomyopathy, aortic stenosis, pericarditis, arrhythmias, mitral valve prolapse and coronary insufficiency. The causes of coronary insufficiency include Kawasaki disease, Williams syndrome, anomalous origin of the coronary arteries and coronary arterio-venous fistulas.

Evaluation of chest pain in children

A good history, including a family history, may help exclude serious causes of chest pain. Benign chest pain is not associated with other symptoms. Chest pain with exercise should raise the suspicion of potentially serious causes and warrants further investigations especially if associated with lightheadedness or presyncope. Exercise induced asthma should also be suspected.

An EKG should be done for any patient with chest pain. Further investigations, including echocardiography or other imaging modalities depend on the history and physical examination. An exercise stress test may be done if the chest pain is associated with physical activities.

Management

The management is directed to the underlying cause. Musculoskeletal chest pain and costochondritis are managed by reassurance and non-steroidal anti-inflammatory medications. Exercise induced asthma is managed with bronchodilators. Cardiac causes of chest pain are managed according to the specific etiology. 

Quick Check

Kawasaki Disease (Mucocutaneous Lymph Node Syndrome)

Kawasaki Disease (KD) is an acute multi-system immune-mediated vasculitis of unknown etiology. It usually presents in infancy and early childhood with 85% of those affected are less than 5 years of age. KD is the leading cause of acquired heart disease in children in the US. In untreated KD patients, the incidence of coronary artery aneurysm ranges from 15-25%.   Myocardial infarction from thrombotic occlusion of the coronary arteries is the principle cause of death. KD is more common in patients of Asian descent. The prognosis depends on the extent of the cardiac involvement and the promptness of medical treatment.

Pathogenesis

The etiology of KD is unknown. The inflammation in KD involves small to medium-sized arteries, including the coronary arteries. The extent of the coronary artery involvement is the critical factor that determines morbidity and mortality. Investigators propose that mediators such as tumor necrosis factor (TNF), interleukin (IL)-1B, interferon (INF) and IL-6 produced by activated T-cells and macrophages promote vascular injury. The earliest pathological change reported in the vessel wall is subendothelial accumulation of T-cells, mononuclear cells, macrophages and monocytes.

Clinical presentation

KD is divided into three phases.

• The acute phase begins with the onset of a high fever without an apparent source that may last for 1-2 weeks.   Acute myocardial infarction may occur during the acute phase due to vasculitis and perivasculitis.
• In the subacute phase, which may last for 2-4 weeks, the fever subsides. Desquamation of the skin and coronary artery aneurysms may appear in this phase. The platelet count increases and may rise above 106 per mm3.   Other acute phase reactants such as ESR and CRP are usually elevated.
• During the convalescent phase, the symptoms resolve and the platelet count and ESR return to normal, usually within 6-8 weeks following onset of the illness.  

Making the Diagnosis

According to U.S. and Japanese guidelines, Kawasaki Disease is a clinical diagnosis.

Classic KD is diagnosed by the following criteria:

• Fever of unknown origin lasting for at least 5 days, in addition to four of the following criteria:

• Bilateral conjunctivitis which is non-purulent
• Changes of the oral cavity and lips: cracked and erythematous lips, strawberry tongue
• Changes in the extremities (erythema of the hands and feet, desquamation of the skin of the fingers and toes in the 2^nd and 3^rd weeks)
• Polymorphous rash: maculopapular, erythema multiforme-like or scarlatiniform rash, involving extremities, trunk, and perineal regions
• Cervical lymphadenopathy (> 1.5 cm in diameter) that is commonly unilateral

• Alternative diagnostic criteria : Fever for at least five days and two or three of the clinical features or coronary artery abnormalities on transthoracic echocardiography

• Supplementary laboratory criteria (not required for diagnosis):

• Anemia
• Cerebrospinal fluid pleocytosis
• Elevated C-reactive protein and erythrocyte sedimentation rate
• Elevated liver enzyme levels
• Hypoalbuminemia < 3.0 g/dl
• Hyponatremia
• Platelets > 450 per mm³ after first week
• Sterile pyuria
• White blood cell count > 15,000/uL

• Incomplete (Atypical Kawasaki Disease)

In some cases, patients do not fulfill the classic criteria for Kawasaki disease and are classified as having incomplete (atypical) disease.   Incomplete disease is more common in younger infants and older children and should be suspected when patients have a fever for at least five days with only two or three of the principal clinical features. As a result, it is important to consider the diagnosis of Kawasaki disease and the possible need for echocardiography in all children who have an unexplained fever lasting at least seven days with laboratory evidence of systemic inflammation .

Figure demonstrating a suggested algorithm for the management of suspected Kawasaki Disease

Other clinical signs:

• Tachycardia and gallop rhythm (secondary to myocarditis) may occur.                                                                
• Pericardial effusion, aortic regurgitation, and mitral regurgitation may be seen.
• EKG shows mild abnormalities consistent with myocarditis such as arrhythmias, prolonged PR and QT intervals and nonspecific ST segment changes.
• Echo may show pericardial effusion, LV dilation, mitral insufficiency and/or decreased systolic function. Follow up echo should be done in 3-5 weeks. The need for further echocardiograms is determined by the presence or absence of coronary involvement.
• Coronary angiography should not be done in the acute phase but may be needed later on to evaluate the extent of the coronary involvement.
• Stress test may be needed in teenagers who had a history of previous coronary involvement before participating in competitive sports

Management (Figure):

Early detection of KD and prompt treatment reduce mortality below 1%. Baseline echocardiogram should be performed as soon as the diagnosis is made. The table below helps to stratify the risk of patients with KD and helps determine follow up testing.

1.Treatment of Acute Disease:

1. A single IVIG (2 g/kg).
2. High dose aspirin 80-100 mg/kg/day in 4 doses for at least 48-72 hours after cessation of fever; low dose should continue at 3-5 mg/kg/ day for 6-8 weeks until the acute phase reactants normalize and a repeat echo is negative for coronary involvement.          
3. Corticosteroids – not well established though some studies have shown shorter duration of symptoms and decreased severity of coronary involvement
4. Pentoxifylline "an inhibitor of TNF-alpha RNA transcription" has been shown to be effective as adjunctive therapy but its true role in treatment is yet to be determined.
5. Children should be vaccinated against varicella and influenza and the physician should be contacted immediately if the child has been exposed to the wild type of the virus.
6. Measles and varicella vaccines should be avoided for 11 months following administration of high dose IVIG.

2. Treatment of Refractory Disease:

1. Failure of IVIG therapy occurs in up to 10% of patients with KD and is defined as persistence of fever more than 36 hours after treatment with IVIG.
2. Even with high dose IVIG ~ 5% of patient may develop coronary dilation (ectasia) and ~ 1% may develop coronary aneurysms.
3. Retreatment
   1. A second dose of IVIG is recommended (2 g/kg).
   2. Pulse methylprednisolone 30 mg/kg for 2-3 hours administered once daily for 1-3 days (one study states that treatment should be monitored with CRP levels).
   3. Abciximab may be considered in cases where large aneurysms are present in the acute and subacute phase.
   4. Patients with moderate sized aneurysms are treated with aspirin in combination with other antiplatelet agents such as clopidogrel (Plavix) or dipyridamole (Persantine).
   5. A combination of aspirin and LMWH or warfarin may be used in thrombosis prophylaxis and treatment.
   6. Cardiac catheterization is recommended for patients with angina pains or ischemic changes on a stress test. It may be used as a diagnostic and interventional tool.
   7. Surgical intervention may be considered for significant ischemia/stenosis that is not amenable to catheterization.

3. Follow up of KD

1. Aneurysms need to be followed with serial echocardiograms until they completely subside.
2. Exercise stress test may be considered in select patients.  
3. Patients with regression of the coronary aneurysms remain at risk for stenosis because the affected area may be less compliant.
4. Patients with coronary involvement without aneurysm development may still be at higher risk for altered lipid metabolism and early development of atherosclerosis.
5. Risk stratification (see Table below)

References

American Academy of Pediatrics.

Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Statement for Health Professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics 114 (6) December 2004, pp. 1708-1733 (doi:10.1542/peds.2004-2182)

Sanchez-Manubens J, Bou R, Anton J. Diagnosis and classification of Kawasaki Disease. Journal of Autoimmunity. 48-49 (2014) 113-117

Infective Endocarditis

Infective endocarditis (IE) is an inflammation of the endothelial lining of the heart muscle, valves and great vessels. The valves have a particularly high propensity for infection due to the lack of blood supply and limited access to immune cells. IE is relatively rare in children. It has an estimated annual incidence of 3 to 9 cases per 100,000 persons in industrialized countries. The highest rates are observed among patients with prosthetic valves, intracardiac devices, unrepaired cyanotic congenital heart diseases, or a history of infective endocarditis. About 50% of cases of infective endocarditis develop in patients with no known history of valve disease. Other risk factors include chronic rheumatic heart disease (which now accounts for <10% of cases in industrialized countries), age-related degenerative valvular lesions, hemodialysis, and coexisting conditions such as diabetes, human immunodeficiency viral infection, and intravenous drug use.

Pathogenesis

Bacteremia and the presence of endothelial damage are important factors in the pathogenesis of IE. Cyanosis and polycythemia, if present, increase the viscosity of the blood and further enhance the likelihood of developing IE. Foreign materials such as prosthetic valves or shunts also significantly increase the risk for developing IE. It is not surprising that cyanotic CHD with an artificial shunt or prosthetic valves constitutes the highest risk for IE.

Neonatal endocarditis frequently occurs on the right side of the heart and is associated with disruption of endocardium or valvular endothelial tissue by catheter-induced trauma in hospitalized infants. Premature neonates often experience transient episodes of bacteremia from trauma to the skin and mucous membranes, vigorous endotracheal suctioning, parenteral hyperalimentation, or placement of umbilical or peripheral venous catheters. The combination of endothelial damage and bacteremia is critical for the induction of IE.

Pathology

Vegetations develop at the site of endothelial damage, which is usually located at the lower pressure side of the lesion i.e. in the right ventricle in patients with VSD and on the atrial surface of the mitral valve with mitral insufficiency.

 After bacteria adhere to the damaged endothelium, platelets and fibrin are deposited over the organisms, leading to the formation of a vegetation. The organisms trapped within the vegetation are protected from phagocytic cells and other host defense mechanisms.

Microbiology

Viridans group streptococcus, enterococci and S. aureus are responsible for most cases of IE. Streptococcus pneumoniae, coagulase negative staphylococcus, gram negative bacilli and fungi may also cause IE. The type of pathogens depends on the following factors: i) whether the valve is a native or a prosthetic valve, ii) patient age and iii) source of infection.

The blood cultures may be negative in patients who have already received antibiotics or in patients who have IE caused by fastidious microorganisms such as petronella species, brucella species,  Coxiella burnetii, bacteria in the HACEK group (haemophilus species,  actinomycetemcomitans, Cardiobacterium hominis,   Eikenella corrodens and  Kingella kingae), and  Tropheryma whipplei. In these cases, serologic testing, blood polymerase chain reaction (PCR) assay and highly specialized microbiologic techniques may lead to the identification of the pathogen in up to 60% of cases.

Clinical presentation

Persistent or recurrent low grade fever is the most common symptom of IE. Other symptoms are nonspecific and include malaise, myalgia, arthralgia, anorexia, night sweats and headaches. Splenomegaly can be found in 15-50% of patients with IE. A new or changing murmur indicates valvular involvement.

The classic peripheral manifestations of IE are rarely seen nowadays. These include petechiae, splinter hemorrhages (hemorrhages in the nail beds), Osler nodules (small, tender nodules on the pads of fingers and toes), Janeway lesions (painless hemorrhages on palms and soles), and Roth spots (hemorrhages in the retina with a white center).

Making the Diagnosis

• The above signs and symptoms in a patient with underlying CHD following transient bacteremia should raise the suspicion of IE.
• In the absence of prior antimicrobial therapy, positive blood cultures are found in >90% of patients.
• Other supporting laboratory evidence includes anemia, leukocytosis with a left shift, positive rheumatoid factor, hematuria and elevated ESR/CRP.
• The finding of vegetations on echocardiography is confirmatory. However, since IE is a clinical diagnosis, a negative echocardiogram does not rule out IE and treatment should not be delayed if there is strong clinical suspicion of IE. The Duke Criteria helps in making the diagnosis of IE.

 The Duke Criteria for diagnosis of infective endocarditis: Requires 2 major + 1 minor OR 1 major + 3 minor OR 5 minor criteria for diagnosis 

 ^*Viridans streptococci, Streptococcus bovis and HACEK group OR Staph aureus/enterococci in the absence of a primary focus and persistently positive blood Cx defined as 2 blood Cx drawn 12 hours apart

^#Positive echocardiogram for vegetations OR new valvular regurgitation

Management

The management of IE includes 4-6 weeks of high dose IV antibiotics. The choice of antibiotics depends on the organism isolated and the results of antibiotic sensitivity testing. Initial empiric therapy may be based on the table below. Surgical intervention may be necessary if vegetations are causing obstruction, or if there is significant malfunction of a prosthetic valve.

Antimicrobial prophylaxis: (2007 AHA guidelines)

Antimicrobial prophylaxis is indicated in patients undergoing dental procedures who have:

1. A prosthetic heart valve
2. A history of IE
3. A heart transplant with abnormal heart valve function
4. CHD only under the following conditions:

a) Unrepaired cyanotic CHD including those with palliative shunts and conduits,
b) Completely repaired CHD with a prosthetic material or device during the first 6 months after the procedure
c) Repaired CHD with a residual defect

Antibiotics are NOT recommended for patients who have procedures involving the reproductive, urinary or gastrointestinal tract.

References

Prevention of Infective Endocarditis. 2007 Guidelines From the American Heart Association. Circulation.116:1736-1754.

Ferrieri, P, et al.   Unique Features of Infective Endocarditis in Childhood. Circulation. 2002;105:2115. Scientific statement from American Heart Association

Hoen B, Duval X. Clinical practice. Infective endocarditis. N Engl J Med. 2013 Apr 11;368(15):1425-33

Rheumatic Fever (ARF)

Acute rheumatic fever (ARF) is an inflammation of the heart, skin, joints and/or brain which develops after infection with Group A streptococci, such as "strep" throat, or scarlet fever. Although the incidence of ARF has declined in Europe and North America over the past 4 to 6 decades, the disease remains one of the most important causes of cardiovascular morbidity and mortality in the developing countries that are home to the majority of the world's population. There is a 2-3 weeks delay between the strep infection and the development of ARF. Less than 3% of those with untreated strep infection may develop ARF. Most of the affected patients are between six and fifteen years of age.

Pathology

Group A streptococcal (GAS) infection of the pharynx is usually the precipitating cause of rheumatic fever. During epidemics over a half a century ago, as many as 3% of untreated acute streptococcal sore throats were followed by rheumatic fever; in endemic infections, the incidence of rheumatic fever is substantially less. Appropriate antibiotic treatment of streptococcal pharyngitis prevents acute rheumatic fever in most cases. Unfortunately, at least one third of episodes of acute rheumatic fever result from inapparent streptococcal infections. In addition, some symptomatic patients may not seek appropriate medical care. Among the most widely accepted concepts in support of an autoimmune hypothesis involving the GAS was the observation by Stollerman. He noted a correlation between outbreaks of GAS upper respiratory tract infections associated with a relatively limited number of M-protein types which were followed by outbreaks of rheumatic fever. Subsequent reports demonstrated that only a limited number of specific M-types (M-5, M-6, M-18) were isolated during rheumatic fever outbreaks. These findings supported the concept of antigenic mimicry. In ARF, antibodies against the M antigen found in the streptococcal cell wall cross react with cardiac myosin causing carditis.

Prevention of rheumatic fever requires adequate therapy for GAS pharyngitis. In selecting a regimen for the treatment of GAS pharyngitis, physicians should consider various factors, including bacteriologic and clinical efficacy, ease of adherence to the recommended regimen (frequency of daily administration, duration of therapy, and palatability), cost, spectrum of activity of the selected agent, and the potential side effects.

Clinical presentation

Signs and symptoms of rheumatic fever include fever, migratory arthritis in large joints, abdominal pain, erythema marginatum (a ring-shaped rash located on trunk and upper parts of arms and legs), Sydenham chorea, subcutaneous nodules, epistaxis, shortness of breath and chest pain.

Making the diagnosis

According to Jones Criteria, there must be evidence of previous streptococcal infection.

Any of the following may serve as evidence of GAS infection:

1. Increased or rising ASO titer or other streptococcal antibody such as Anti DNAase B
2. A positive throat Cx for GAS
3. A positive rapid test for GAS

Major Criteria:

• Polyarthritis. This is the most common manifestation of ARF, usually involves large joints, and is migratory in nature. It responds dramatically to high-dose salicylates.
• Carditis. Occurring in ~50% of patients with ARF, carditis presents with tachycardia out of proportion to the fever.   A heart murmur of mitral or aortic insufficiency indicates valvulitis. Pericarditis may present with chest pain, friction rub, pericardial effusion and EKG changes. Signs of CHF may be present. Recent recommendations require echocardiography to be performed in all cases of suspected ARF. It may be performed to assess the presence of carditis in the absence of auscultatory findings in certain high risk populations. As per the AHA, specific Doppler criteria for valvulitis are: i) MR seen in ≥ 2 views, jet length ≥ 2 cm, peak velocity > 3m/s, pan-systolic and ii) AR, seen in ≥ 2 views, jet length ≥ 1 cm, peak velocity > 3 m/s, pan-diastolic.
• Chorea. Sydenham chorea occurs in about 15% of patients with ARF and is more common in prepubertal girls. It is characterized by emotional lability, personality changes, poor motor coordination and the classic purposeless spontaneous movements. It is also characterized by hyperextension of the fingers (spooning) and irregular contractions of the muscles of the hands (milkmaid's grip). It usually resolves within 2-4 weeks. This may be the only manifestation of rheumatic fever and may occur in isolation and is considered pathognomonic for rheumatic fever.
• Erythema marginatum. It is an uncommon sign of ARF and presents as a truncal rash that is non pruritic and serpiginous with well-defined borders.
• Subcutaneous nodules. The least common signs of ARF; these are found on the extensor surfaces of the extremities or along the spine. The nodules are usually small, non-tender, and freely mobile.

Minor Criteria:

• Fever > 38.5 C
• ESR > 30 mm/hr or CRP > 3 mg/dl
• Prolonged PR interval on EKG (unless carditis is a major criteria)
• Polyarthalgia

 For ARF diagnosis, 2 major OR one major + two minor criteria are needed.

Management Principles:

• Treatment of the group A streptococcal infection

General treatment of the acute episode:

• Anti-inflammatory agents are used to control the arthritis, fever, and other acute symptoms. Salicylates are the preferred agents, although other nonsteroidal agents are probably equally efficacious. Steroids are also effective but should be reserved for patients in whom salicylates fail. None of these anti-inflammatory agents have been shown to reduce the risk of subsequent rheumatic heart disease.
• Bed rest is a traditional part of ARF therapy and is especially important in those with carditis. Patients are typically advised to rest through the acute illness and to then gradually increase activity; some clinicians monitor the patient's ESR and restart activity only as it normalizes .
• Intravenous immunoglobulin has not been shown to reduce the risk of rheumatic heart disease or to substantially improve the clinical course.
• Chorea is usually managed conservatively in a quiet non-stimulatory environment. Valproic acid is the preferred agent if sedation is needed. Intravenous immunoglobulin, steroids, and plasmapheresis have all been used successfully in refractory chorea, although conclusive evidence of their efficacy is limited.

Cardiac management:

• Bed rest is essential in patients with cardiac involvement. Carditis resulting in heart failure is treated with conventional measures. Diuretics are the mainstay of therapy. Close monitoring is needed for development of arrhythmias in patients with active myocarditis.

Prevention

Patients with a documented history of ARF should receive antibiotic prophylaxis until the age of 21 or for a minimum of five years if there is no cardiac involvement. Patients with valvular abnormalities should receive lifetime prophylaxis.   Prophylaxis consists of monthly injections of benzathine penicillin; alternatively, twice daily oral penicillin V may be used. Oral sulfadiazine may be used for patients with penicillin allergy, but it is not as effective as penicillin.

Prevention of Rheumatic Fever and Diagnosis and Treatment of Acute Streptococcal Pharyngitis: A Scientific Statement From the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research: Endorsed by the American Academy of Pediatrics, 2004.

Bach DS. Revised Jones Criteria for Acute Rheumatic Fever ACC, May 2015

Quick Checks - Kawasaki Disease, Endocarditis, Rheumatic fever

References and Resources

2007 Guidelines From the American Heart Association.

Abbreviations for CardiologyChapter

American Academy of Pediatrics

Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease:

Scientific statement from American Heart Association

Resources by Chapter Authors  

Evaluation of the Cyanotic Newborn: Part1 - A Neonatologist's Perspective UTMB password required

Evaluation of the Cyanotic Newborn: Part2 - A Cardiologist's Perspective UTMB password required