Chapter 12: Congenital Heart Disorders

Question 1

What is a congenital heart disease?

Answer 1

Congenital heart disease is a general term used to describe abnormalities of the heart or great
vessels that are present from birth.

Question 2

Where does most congenital disorders arise from ?

Answer 2

Most such disorders arise from faulty embryogenesis during gestational weeks 3 through 8, when major cardiovascular structures form and begin to
function.

Question 3

The most severe anomalies are incompatible with intrauterine survival.

Question 4

Congenital heart defects compatible with embryologic maturation and birth generally affect individual
chambers or discrete regions of the heart, with the remainder of the heart developing relatively
normally.

Examples are infants born with a defect in :

Answer 4

• septation (“hole in the heart”),
• such as atrial septal defect (ASD) or a ventricular septal defect (VSD),
• stenotic valvular lesions, or with
• abnormalities in the coronary arteries.

Question 5

Some forms of congenital heart disease produce
clinically important manifestations soon after birth, which are frequently brought on by the
change from fetal to postnatal circulatory patterns (with reliance on the lungs for oxygenation birth, rather than the placenta as in intrauterine life).

Approximately half of congenital
cardiovascular malformations are diagnosed in the first year of life, but some mild forms may
not become evident until adulthood (e.g., ASD).

Question 6

With an incidence of approximately 1% (estimates range from 4 to 50 per 1000 live births),

• *congenital cardiovascular** defects are among the most prevalent malformations and are the
• *most common type of heart disease among children**. [24]

T or F

Answer 6

True

The incidence is higher in premature
infants and in stillborns

Question 7

TABLE 12-2 – Frequencies of Congenital Cardiac Malformations

in desceding order

Answer 7

• Ventricular septal defect : 42%
• Atrial septal defect: 10%
• Pulmonary stenosis :8 %
• Patent ductus arteriosus: 7%
• Tetralogy of Fallot
• Coarctation of the aorta
• Atrioventricular septal defect
• Aortic stenosis
• Transposition of the great arteries
• Truncus arteriosus
• Total anomalous pulmonary venous connection
• Tricuspid atresia

Question 8

The number of individuals who have survived with congenital heart disease into adulthood is
increasing rapidly and is presently estimated at nearly 1 million individuals in the United States. [25]

Many of those with congenital heart disease have benefited greatly from rapid advances in the surgical and interventional repair of various structural heart defects.

Nevertheless, such repairs may not restore the heart to normal; in such instances, patients may
suffer from arrhythmias or ventricular dysfunction, and require additional surgery. [26] Other
factors that impact the long-term outcome include risks associated with the use of prosthetic
materials and devices, [27] such as substitute valves or myocardial patches, and maternal risks
associated with childbearing.

Question 9

The diverse malformations seen in congenital heart disease are caused by errors that occur
during cardiac development; thus, a brief review how the heart normally forms is in order before
discussing the specific defects

Question 10

Suffice it to say that the earliest cardiac precursors originate in ________________

Answer 10

lateral
mesoderm

Question 11

Suffice it to say that the earliest cardiac precursors originate in lateral
mesoderm and move to the mid-line in two migratory waves to create a crescent of cells
consisting of the first and second heart fields by about _____________

Answer 11

day 15 of development

Question 12

Suffice it to say that the earliest cardiac precursors originate in lateral
mesoderm and move to the mid-line in two migratory waves to create a crescent of cells
consisting of the______________ by about day 15 of development

Answer 12

first and second heart fields

Question 13

Each
heart field is marked by the expression of different sets of genes; for example, the first heart
field expresses the transcription factors ________

Answer 13

TBX5 and Hand1,

Question 14

Each
heart field is marked by the expression of different sets of genes; whereas the second heart field
expresses the transcription factor ______________

Answer 14

Hand2 and fibroblast growth factor-10.

Question 15

Both first and second fields contain
multipotent progenitor cells that can produce all of the major cell types of the heart;
endocardium, myocardium, and smooth muscle cells.

As an aside, there is considerable interest
in the therapeutic potential of such early cardiac progenitors, which could conceivably be used
to regenerate portions of the adult heart that are damaged or otherwise dysfunctional.

Question 16

Answer 16

FIGURE 12-3 Human cardiac development, emphasizing the three sources of cells.

• A, Day 15. First heart field (FHF) cells (shown in red) form a crescent shape in the anterior embryo with second heart field (SHF) cells (shown in yellow) near the FHF.
• B, Day 21. SHF cells lie dorsal to the straight heart tube and begin to migrate (arrows) into the anterior and posterior ends of the tube to form the right ventricle (RV), conotruncus (CT), and part of the atria (A).
• C, Day 28. Following rightward looping of the heart tube, cardiac neural crest cells (shown in
  blue) also migrate (arrow) into the outflow tract from the neural folds to septate the outflow
  tract and pattern the bilaterally symmetric aortic arch arteries (III, IV, and VI).
• D, Day 50. Septation of the ventricles, atria, and atrioventricular valves (AVV) results in the
  appropriately configured four-chambered heart. Ao, aorta; AS, aortic sac; DA, ductus
  arteriosus; LA, left atrium; LCA, left carotid artery; LSCA, left subclavian artery; LV, left
  ventricle; PA, pulmonary artery; RA, right atrium; RCA, right carotid artery; RSCA, right
  subclavian artery; V, ventricle.

Question 17

Even at this very early stage of development, each heart field is destined to give rise to particular portions of the heart.

Cells derived from the first heart field mainly give rise to _________,

Answer 17

the left ventricle

Question 18

Even at this very early stage of development, each heart field is destined to give rise to particular portions of the heart.

Cells derived from the second heart field give rise to the what?

Answer 18

• outflow tract,
• right ventricle,
• and most of the atria.

Question 19

What happens by day 20 in the development of heart?

Answer 19

By day 20, the initial cell crescent develops into a beating tube, which loops to the right

Question 20

When do the heart chambers begin to form?

Answer 20

begins to form the heart chambers by day 28

Question 21

Aside from the start of formation of the heart chambers on day 28, what else are the critical events that occur?

Answer 21

Around this time, two
other critical events occur:

• (1) cells derived from the neural crest migrate into the outflow tract, where they participate in the septation of the outflow tract and the formation of the aortic arches; and
• (2) the extracellular matrix (ECM) underlying the future atrioventricular canal and outflow tract enlarges to produce swellings known as endocardial cushions

This process
depends on the delamination of a subset of endocardial cells, which invade the ECM and
subsequently proliferate and differentiate into the mesenchymal cells that are responsible for
valve development.

Question 22

What happens by day 50 in the development of the heart?

Answer 22

By day 50, further septation of the ventricles, atria, and atrioventricular valves produces the four chambered heart.

Question 23

The proper orchestration of these remarkable transformations in the development of the heart depends on a network of transcription factors that are regulated by a number of signaling pathways, particularly the

Answer 23

• Wnt,
• VEGF,
• bone morphogenetic factor,
• TGF-β,
• fibroblast growth factor,
• and Notch pathways.

Question 24

Because a heart is a mechanical organ, what else play an important role in its development aside from the growth factors and genes?

Answer 24

It should also be remembered that the heart is a mechanical organ that is exposed to flowing blood from its earliest stages of development.

It is likely that hemodynamic forces play an
important role in cardiac development,just as theyinfluence adaptations in the adult heart such
as hypertrophy and dilation.

Question 25

How does micro-RNAs play critical roles in cardiac development?

Answer 25

In addition, specific micro-RNAs play critical roles in cardiac development by **coordinating patterns and levels of transcription factor expression**

Question 26

``` Many of the genetic defects that affect heart development are \_\_\_\_\_\_\_\_\_\_\_\_\_ that cause partial loss of function in one or another required factor, which are often transcription factors (discussed below). ```

Answer 26

autosomal dominant mutations Thus, even relatively minor changes in the activity of one of the many factors necessary for normal development can lead to defects in the final product, the fully developed heart. It can be imagined (but is unproved) that transient environmental stresses during the first trimester of pregnancy that alter the activity of these same genes might give rise to defects resembling those produced by inherited mutations.

Question 27

The main known causes of congenital heart disease consist of **:**

Answer 27

* **sporadic genetic abnormalities,** which can take the form of **single gene mutations,** * **small chromosomal deletions**, * and **additions or deletions of whole chromosomes (trisomies and monosomies).**

Question 28

In the case of single gene mutations, the affected genes encode proteins belonging to several different functional classes Many of these mutations affect genes encoding \_\_\_\_\_\_\_ that are required for normal heart development

Answer 28

transcription factors Since the affected patients are **heterozygous for these mutations,** it follows that a **50% reduction in the activity of these factors**is probably**sufficient to derange cardiac development.**

Question 29

What is the reason behind as to why mutations in any one of several genes produce similar defects?

Answer 29

Some of the affected transcription factors **appear to work together in large protein complexes,** providing an **explanation for why mutations in any one of several genes produce similar defects** For example, **GATA4, TBX5, and NKX2-5,** three transcription factors that are mutated in some patients with **atrial and ventricular septal defects**, all bind to one another and co-regulate the expression of target genes that are required for the **proper development of the heart. Of further interest, GATA4 and TBX20 are also mutated in rare forms of adult-onset cardiomyopathy (discussed later), indicating that they are not only important developmentally but are also needed to maintain the function of the postnatal heart.**

Question 30

TABLE 12-3 -- Selected Examples of Genetic Causes of Congenital Heart Disease Non-syndromic

Answer 30

* NKX2–5 * GATA-4 [\*] * TBX20 [\*]

Question 31

**TABLE 12-3 -- Selected Examples of Genetic Causes of Congenital Heart Disease** Syndromic

Answer 31

* TBX5 * TBX1 * JAG1, NOTCH2 * Fibrillin

Question 32

TABLE 12-3 -- Selected Examples of Genetic Causes of Congenital Heart Disease Non-syndromic affected gene: NKX2–5

Answer 32

Normal Function: **Transcription** Congenital Cardiac Disease : **ASD, VSD, conduction defects**

Question 33

TABLE 12-3 -- Selected Examples of Genetic Causes of Congenital Heart Disease Non-syndromic affected gene: GATA-4

Answer 33

Normal Function :Transcription factor Congenital Cardiac Disease: ASD, VSD

Question 34

TABLE 12-3 -- Selected Examples of Genetic Causes of Congenital Heart Disease Non-syndromic affected gene: **TBX20 [\*]**

Answer 34

Normal Function:**Transcription factor** Congenital Cardiac Disease: **ASD, VSD, valve abnormalities**

Question 35

TABLE 12-3 -- Selected Examples of Genetic Causes of Congenital Heart Disease Syndromic affected gene: TBX5

Answer 35

* Normal Function: **Transcription factor** * Syndrome Name:**Holt-Oram​** * Congenital Cardiac Disease: **ASD, VSD, Conduction defects**

Question 36

TABLE 12-3 -- Selected Examples of Genetic Causes of Congenital Heart Disease Syndromic affected gene: **TBX1**

Answer 36

* Normal Function: **Transcription factor** * Syndrome Name: **DiGeorge** * Congenital Cardiac Disease: **Cardiac outflow tract defects**

Question 37

TABLE 12-3 -- Selected Examples of Genetic Causes of Congenital Heart Disease Syndromic affected gene: **JAG1, NOTCH2**

Answer 37

* Normal Function: **Notch signaling** * Syndrome Name: **Alagille** * Congenital Cardiac Disease: **Pulmonary artery stenosis, Tetralogy of Fallot**

Question 38

TABLE 12-3 -- Selected Examples of Genetic Causes of Congenital Heart Disease Syndromic affected gene:**Fibrillin**

Answer 38

* Normal Function: **Structural protein** * Syndrome Name: **Marfan** * Congenital Cardiac Disease: **Aortic aneurysm**

Question 39

TABLE 12-3 -- Selected Examples of Genetic Causes of Congenital Heart Disease Syndromic affected gene:Fibrillin

Answer 39

* Normal Function: **Structural protein** * Syndrome Name: **Marfan** * Congenital Cardiac Disease: **Aortic aneurysm**

Question 40

Associated with adult-onset cardiomyopathy. ASD, atrial septal defect; VSD, ventricular septal defect

Answer 40

* **GATA-4** * **TBX20**

Question 41

Other single gene mutations associated with congenital heart disease affect proteins within signaling pathways or that have structural roles. Mutations in genes encoding various components of the **Notch pathway**, such as \_\_\_\_\_\_\_\_**,** are associated with a **number of different congenital heart defects,** including **bicuspid aortic valve (NOTCH1, discussed later) and Tetralogy of Fallot (JAGGED1 and NOTCH2).**

Answer 41

J**AGGED1, NOTCH1, and NOTCH2**

Question 42

As you will recall from Chapter 11 , **fibrillin** mutations underlie **what syndrome?**

Answer 42

**Marfan syndrome**, which is associated with valvular defects and aortic aneurysms. Although fibrillin was initially described as a structural protein, it is also an important negative regulator of **TGFβ signaling,** and **hyperactive TGFβ** signaling is at least partially responsible for the cardiovascular abnormalities in **Marfan syndrome.**

Question 43

A notable example of a small chromosomal lesion that causes congenital heart disease is deletion of \_\_\_\_\_\_\_\_\_, which is **found in up to 50% of patients with DiGeorge** syndrome. s.

Answer 43

chromosome 22q11.2 In this syndrome the fourth branchial arch and the derivatives of the **third and fourth pharyngeal pouches,** which contribute to the formation of the thymus, parathyroids, and heart, develop abnormally. One candidate gene in the deleted region is **TBX1,** which encodes a transcription factor that regulates the **expansion of cardiac progenitors in the second heart field.** Other important genetic causes of **congenital heart disease** include chromosomal aneuplodies, particularly **Turner syndrome (monosomy X) and trisomies 13, 18, and 21.** [31] Indeed, the most common genetic cause of congenital heart disease is trisomy 21 (Down syndrome), [32] in which about 40% of patients have one or more heart defects, most often affecting structures derived from the endocardial cushions (e.g., the atrioventricular septae and valves). The mechanisms by which aneuploidy leads to congenital heart defects remain largely unknown, but are likely to involve the dysregulated expression of multiple gene

Question 44

Beyond these known associations, more subtle forms of genetic variation probably also contribute to congenital heart disease. This assertion is based in part on the recognition that first-degree relatives of affected patients are at increased risk for congenital heart defects compared to the general population . For example, a child of a father with a VSD has a risk of 2%; if the VSD occurred in the mother, the risk to her offspring is 6% to 10%. ***Despite these genetic clues, it must be acknowledged that our understanding of the mechanisms that lead to heart defects remains rudimentary.*** Most affected patients have no identifiable genetic risk factor, and even in those that do, the nature and severity of the defect are highly variable. As a result, it is thought that environmental factors, alone or in combination with genetic factors, also contribute to congenital heart disease and in some cases may be the primary cause. Examples of known exposures that are associated with heart defects include congenital rubella infection, gestational diabetes, and exposure to teratogens (including some therapeutic drugs). [33] There is also great interest in identifying nutritional factors that may modify risk. For instance, intake of multivitamin supplements containing folate may reduce the risk of congenital heart defects

Question 45

What is the most common genetic cause of congenital heart disease\_\_\_\_\_\_\_\_\_\_ in which about **40% of patients have one or more heart defects,** most often affecting structures derived from the endocardial cushions (**e.g., the atrioventricular septae and valves).**

Answer 45

Indeed, the most common genetic cause of congenital heart disease is **trisomy 21 (Down** **syndrome**), [32] in which about 40% of patients have one or more heart defects, most often affecting structures derived from the endocardial cushions (e.g., the atrioventricular septae and valves).

Question 46

The mechanisms by which aneuploidy leads to congenital heart defects remain largely unknown, but are likely to involve the dysregulated expression of multiple genes.

Question 47

The varied structural anomalies in congenital heart disease fall primarily into three major categories:

Answer 47

* Malformations causing a **left-to-right shunt** * Malformations causing a **right-to-left shunt** * Malformations causing an **obstruction.**

Question 48

What is a **shunt?**

Answer 48

A shunt is an **abnormal communication** **between chambers or blood vessels.** Abnormal channels permit the flow of blood down pressure gradients from the left (systemic) side to the right (pulmonary) side of the circulation or vice versa

Question 49

What is the cyanotic congenital heart disease?

Answer 49

When blood from the right side of the circulation flows directly into the left side **(right-to-left shunt)**, **hypoxemia and cyanosis (a dusky blueness of the skin and mucous membranes)**result**because of the admixture of poorly oxygenated venous blood with systemic arterial blood**(called**cyanotic congenital heart disease).**

Question 50

What are the most important congenital causes of R to L shunts?

Answer 50

The most important congenital causes of right-to-left shunts are: * tetralogy of Fallot, * transposition of the great arteries, * persistent truncus arteriosus, * tricuspid atresia, and * total anomalous pulmonary venous connection.

Question 51

Aside from R to L shunts what else can cause cyanosis?

Answer 51

Moreover, with right-to-left shunts, emboli arising in peripheral veins can bypass the lungs and directly enter the systemic circulation **(paradoxical embolism);** brain infarction and abscess are potential consequences.

Question 52

What happens when there is severe, long-standing cyanosis?

Answer 52

Severe, long-standing cyanosis also causes **clubbing of the tips of the fingers and toes (called hypertrophic** **osteoarthropathy**) and **polycythemia.**

Question 53

What is hypertrophic osteoarthropathy?

Answer 53

clubbing of the tips of the fingers and toes (called hypertrophic osteoarthropathy)

Question 54

In contrast, **left-to-right shunts (such as ASD, VSD, and patent ductus arteriosus)** increase pulmonary blood flow and are initially associated with cyanosis. T or F

Answer 54

FALSE In contrast, **left-to-right shunts (such as ASD, VSD, and patent ductus arteriosus) *increase pulmonary blood flow***and**are not initially associated with cyanosis.**

Question 55

What happens when there is left to right shunt?

Answer 55

leftto-right shunts * **raise both flow volume**s and **pressures** in the normally low-pressure, * **low-resistance pulmonary circulation**, which can lead to right ventricular hypertrophy and * atherosclerosis of the pulmonary * vasculature.

Question 56

In left to right shunt what response first?

Answer 56

The **muscular pulmonary arteries (\<1 mm diameter) first respond to increased pressure and flow by undergoing medial hypertrophy and vasoconstriction,*****which maintains relatively normal distal pulmonary capillary and venous pressures***, and**prevents pulmonary edema.** Prolonged pulmonary arterial vasoconstriction, however, stimulates the proliferation of the vascular wall cells and the **consequent development of irreversible obstructive intimal lesions analogous to the arteriolar changes seen in systemic hypertension** ( Chapter 11 ). Eventually, pulmonary vascular resistance approaches systemic levels, thereby producing a new right-to-left shunt that introduces unoxygenated blood into the systemic circulation (late cyanotic congenital heart disease, or Eisenmenger syndrome).

Question 57

What is late cyanotic congenital heart disease, or Eisenmenger syndrome ?

Answer 57

pulmonary vascular resistance approaches systemic levels, thereby **producing a new right-to-left shunt that introduces unoxygenated blood into the systemic circulation**

Question 58

Once irreversible pulmonary hypertension develops, the structural defects of congenital heart disease are considered irreparable. T or F

Answer 58

True The secondary pulmonary vascular changes can eventually lead to the patient's death. This **provides the rationale for early intervention, either surgical or nonsurgical, in those with left-to-right shunts**

Question 59

What is the rationale for early intervention either surgical or nonsurgical, in those with left to right shunts?

Answer 59

The **secondary pulmonary vascular changes can** **eventually lead to the patient's death**. This provides the rationale for early intervention, either surgical or nonsurgical, in those with left-to-right shunts

Question 60

Can developmental anomalies of the heart produce obstructive congenital disease? T or F

Answer 60

True Some developmental anomalies of the heart (**e.g., coarctation of the aorta, aortic valvular** **stenosis, and pulmonary valvular stenosis)** produce abnormal narrowing of chambers, valves, or blood vessels and therefore are called **obstructive congenital heart disease.**

Question 61

What is obstructive congenital heart disease?

Answer 61

* *Some developmental anomalies of the heart (*e.g., coarctation of the aorta, aortic valvular*** * **stenosis, and pulmonary valvular stenosis***) produce **abnormal narrowing of chambers, valves,** * *or blood vessels and therefore are called obstructive congenital heart disease.**

Question 62

What is an atresia?

Answer 62

A **complete** **obstruction** is called an atresia.

Question 63

Is is possible to have a shunt and an obstruction?

Answer 63

In some disorders (e.g., Tetralogy of Fallot), an obstruction (pulmonary stenosis) and a shunt (right-to-left through a VSD) are both present.

Question 64

Can some defects induce a decrease in the volume and muscle mass of cardiac chamber? T or F

Answer 64

True The altered hemodynamics of congenital heart disease usually cause cardiac dilation or hypertrophy (or both). However, **some defects induce a decrease in the volume and muscle mass of a cardiac chamber; this is called hypo-plasia if it occurs before birth and atrophy if it develops postnatally.**