Pulmonary Hypertension in Congenital Heart Disease

Summary

Over the past 40 years, significant advances have been made in the diagnosis and management of congenital heart defects. Improvements in diagnostic and interventional cardiology, surgical technique, cardiopulmonary bypass and post-operative intensive care have all contributed to a reduction in mortality and morbidity. Despite these advances, pulmonary hypertension caused by congenital heart defects remains a significant problem in the immediate post- operative period, as well as long term. This article reviews the pathophysiology of pulmonary hypertension due to congenital heart disease and discusses the options available for the management of this condition.

Keywords

Cardiovascular system and disorders; Congenital abnormalities; Nitric oxide; Pulmonary hypertension

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PULMONARY ARTERIAL hypertension, defined as mean pulmonary artery pressure greater than 25mmHg after the first few weeks of life, is a recognised complication of congenital cardiac defects that are characterised by chronic left-to-right shunting (Lang et al 1982). Pulmonary hypertension can cause significant morbidity and occasional mortality. Advances in the treatment of pulmonary hypertension during the past decade have dramatically improved patient survival. Many of these advances are based on improved understanding of the vascular biology of the normal and hypertensive pulmonary circulations. This article describes current understanding of pathophysiology and management of pulmonary hypertension due to congenital cardiac defects.

Pathophysiology

There are four basic mechanisms that underlie pulmonary hypertension due to congenital cardiac disorders:

* Increased pulmonary vascular resistance (PVR).

* Increased pulmonary blood flow with normal PVR.

* A combination of increased PVR and increased blood flow.

* Increased pulmonary venous pressure.

In addition several factors peculiar to cardiopulmonary bypass may raise PVR after correction of congenital cardiac defects and predispose to pulmonary hypertension. These include microemboli, atelectasis, endothelial dysfunction, vasoconstriction, and adrenergic events (Jones et al 1981). Cardiac and non-cardiac causes of pulmonary hypertension in congenital cardiac disorders are listed in Box 1.

Effects of increased pulmonary vascular resistance Elevated PVR can result in significant morbidity. An increase in the workload or afterload of the right ventricle (RV) has the potential to cause RV dysfunction or failure and compromise cardiac output. The surgical patients at particular risk of significant RV dysfunction or failure in the presence of elevated PVR are neonates or young infants who require RV outflow reconstructions with a ventriculotomy. A sudden increase in PVR that results in low cardiac output from RV failure is termed a pulmonary hypertensive crisis (Lindberg et al 2002). Unless resolved quickly such an episode can escalate to a life- threatening event, for example, cardiac arrest. In patients with anatomic communications between pulmonary and systemic circulations, for example, atrial or ventricular septal defects (VSD), elevated PVR can generate a right-to-left shunt and cause severe hypoxaemia (Laussen and Rorh 2001). Patients with single ventricle anatomy who have undergone either a bi-directional Glenn shunt or Fontan procedure are particularly sensitive to increased PVR because they lack a ventricle to pump blood directly into the lungs.

Effects of increased pulmonary blood flow The resistance to blood flow through the lungs is primarily due to the anatomy of small blood vessels of the lung, that is, their diameter, number and length, but is also affected by blood viscosity. The diameter of these vessels is determined by the quantity and tone (degree of constriction) of smooth muscle cells in their walls, and by the presence of any anatomic changes that create narrowing of the vessel lumen. In the first 24 to 48 hours of life, PVR is often labile because of ongoing changes in the vasculature accompanying the transition from fetal life ( high PVR) to extrauterine life (low PVR), including closure of the ductus arteriosus (Heymann 1984). After three to four weeks of age, the tone of small lung vessels in infants with no cardiac or pulmonary disease is low, such that PVR is only about 20 per cent of the systemic vascular resistance (Laussen and Roth 2001). Much of this fall in PVR is due to vascular remodelling, with a reduction in the amount of smooth muscle in the walls of small lung vessels (Hall and Haworth 1992). It is during this period of falling PVR that infants with a large VSD or patent ductus arteriosus (PDA) typically develop signs and symptoms of congestive heart failure from increasing pulmonary-to-systemic flow ratio. These patients have pulmonary hypertension from increased pulmonary blood flow that is near or at systemic blood pressure in the setting of normal PVR.

BOX 1

Causes of pulmonary hypertension in congenital cardiac disorders

BOX 2

Classification of changes to the pulmonary arteries

Effects of increased pulmonary vascular resistance and increased blood flow If patients with a large, high-pressure left-to-right shunt do not undergo surgical repair or palliation in the first months or years of life, they are at significant risk of developing progressive, irreversible anatomic changes in lung vasculature resulting in pulmonary vascular obstructive disease (PVOD). These pathologic changes in pulmonary vasculature were described and graded by Heath and Edwards in 1958 (Box 2). In addition to a large VSD (or multiple VSDs) and a large PDA, the other lesions commonly associated with PVOD are complete common atrioventricular canal defect (especially in patients with trisomy 21), truncus arteriosus, transposition of the great arteries with a large VSD, and specific types of single ventricle defects with no obstruction to pulmonary blood flow (Laussen and Roth 2001). The physiologic result of this diffuse vascular obstruction is pulmonary hypertension; when advanced, PVOD can cause right-to-left shunting (that is, shunt flow reversal) and hypoxaemia. These patients have progressed from an initial state of high-pressure, high-volume pulmonary blood flow with normal PVR, through an intermediate state of high-pressure, high-volume pulmonary blood flow with elevated PVR, to an irreversible pathologic state of high-pressure, reduced-volume pulmonary blood flow with high PVR (Laussen and Roth 2001 ) as shown in Figure 1. Surgical repair of cardiac defect(s) in patients with hypoxaemia and high PVR often does not improve their pulmonary hypertension and is associated with a high post-operative mortality (Hopkins et al 1991).

Effects of increased pulmonary venous pressure Pulmonary hypertension is also seen in paediatric cardiac patients who have elevated pulmonary venous pressure. This mechanism of pulmonary hypertension occurs in newborns with pulmonary venous obstruction (for example, total anomalous pulmonary venous connection (TAPVC) with obstruction) or atrioventricular valve atresia in the pulmonary venous atrium plus an intact atrial septum (for example, single ventricle with mitral atresia and intact atrial septum). Urgent decompression of the hypertensive pulmonary veins or pulmonary venous atrium is required for survival in these patients (Laussen and Roth 2001).

Following decompression, pulmonary artery pressures typically begin falling within a few hours to a few days, because the pulmonary hypertension is due, at least in part, to discrete mechanical obstruction as opposed to a diffuse increase in vascular smooth muscle (Widlitz and Barst 2003). Older paediatric patients, who have pulmonary hypertension because of a left-sided obstructive lesion such as mitral valve stenosis, also tend to resolve their pulmonary hypertension with relief of the obstruction, although resolution can be delayed. PVOD rarely develops from pulmonary venous hypertension (Laussen and Roth 2001 ).

Risk factors

The risk of acquiring pulmonary arterial hypertension in congenital left-to-right shunts is multifactorial. The size of the shunt and subsequent blood flow is a significant risk factor for the development of pulmonary arterial hypertension (Granton and Rabinovitch 2002). For example, with small- to moderate-size VSDs only 3 per cent of patients develop pulmonary arterial hypertension (Kiddetal 1993). With larger defects (greater than 1.5cm in diameter), 50 per cent will be affected. The importance of the size of the defect supports the notion that the vascular injury results from a mechanical stretch injury to the endothelium and pulmonary vasculature from chronic high pulmonary blood flow. However, the type of defect also seems to be important.

FIGURE 1

Pathophysiology of pulmonary hypertension due to ventricular septal defect: oxygen saturations and cardiac pressures (mmHg)

For patients with large defects and nearly all patients with truncus arteriosus, approximately 50 per cent of patients with VSD, and only 10 per cent of those with atrial septal defects will develop Eisenmenger syndrome (Steele et al 1987). Even among patients with at\rial septal defects the incidence of pulmonary arterial hypertension differs.

Pulmonary arterial pressure and pulmonary vascular resistance are more commonly elevated in patients with sinus venosus defects than in secundum defects (26 per cent and 9 per cent for sinus venosus defects, versus 16 per cent and 4 per cent in secundum defects for pulmonary arterial pressure and PVR, respectively) (Vogel et al 1999). In addition the increase in pulmonary arterial hypertension occurs at a younger age in sinus venosus defects then in secundum defects (Vogel et al 1999). The factors outlined in Box 3 can affect the pulmonary vascular smooth muscle tone and alter PVR. Among these, it is important to recognise those that can be manipulated in the intensive care unit, because intervention to reduce PVR may improve patient recovery.

Role of the vascular endothelium The vascular endothelium is central to the development of vascular changes in pulmonary arterial hypertension. In patients with the disease, the endothelial surface of the pulmonary arteries appears ‘cable-like’, with cells that form deep twisted ridges (Rabinovitch et al 1986). As the disease advances, the endothelial surface develops a pattern with high ridges alternating with narrow, twisted, misshapen ridges. This contrasts with the appearance of a normal, thin-walled pulmonary artery. The abnormally contoured endothelium may be more likely to interact with marginating blood cells, resulting in the release of vasoconstrictor substances such as thromboxanes and smooth muscle mitogens (Rabinovitch 2000). Endothelial cells from these patients also demonstrate an increased density of microfilament bundles, suggesting an alteration in the cell’s cytoskeleton that may, in turn, alter endothelial integrity and permeability (Rabinovitch et al 1986).

BOX 3

Factors affecting pulmonary vascular resistance

Flow-related damage to the integrity and function of the endothelial cell may contribute or be central to the development of the observed smooth muscle hypertrophy and changes in extracellular matrix in pulmonary vasculature. Previous transmission electron microscopic evaluation of the subendothelium revealed fragmentation of elastin, suggesting that an elastolytic enzyme was altering the extracellular matrix, and perhaps stimulating the remodelling process (Rabinovitch et al 1986). Loss of the endothelial barrier function allows entry of factor(s) to the subendothelial space that promote abnormal smooth muscle cell growth and matrix protein synthesis, leading to hypertrophy of the arterial wall. Vascular endothelial growth factor (VEGF) is a key mediator of this vascular growth and differentiation. VEGF along with the other factors stimulates endothelial vascular elastase in smooth muscle cells (Granton and Rabinovitch 2002). Elastase, in turn, releases biologically active mitogens by degrading extracellular matrix proteoglycans that normally serve to bind these growth factors in an inactive form. Both fibroblast growth factor (FGF-2) and transforming growth factor (TGF-β) are released from proteoglycan storage sites by proteolytic enzymes such as elastases (Granton and Rabinovitch 2002). These growth factors can induce smooth muscle cell hypertrophy and proliferation and also stimulate connective tissue protein synthesis.

Immunohistochemical studies have also demonstrated an increase in the glycoproteins tenascin and fibronectin in the media and neointima (new intima in a vessel that has been affected by insult, injury or intervention) of hypertensive pulmonary arteries (Jones et al 1997). Tenascin is capable of amplifying the proliferative response to growth factors such as FGF, and is a necessary factor for endothelial growth factor-mediated smooth muscle cell proliferation (Jones and Rabinovitch 1996). Fibronectin can facilitate smooth muscle cell migration associated with neointimal formation in pulmonary arterial hypertension by inducing changes in cell shape (Granton and Rabinovitch 2002). The result of these processes is the observed hypertrophy of the arterial wall and neointimal formation causing occlusion of the lumen. Ongoing pressure and flow injury will perpetuate this response, and may directly promote elastin and collagen synthesis in the extracellular matrix.

Abnormalities in vasoconstriction Patients with flow-related pulmonary arterial hypertension share abnormalities in vasomotor tone with those who have primary pulmonary arterial hypertension. Elevations of vasoconstrictors such as thromboxane and endothelin have been documented in these patients (Granton and Rabinovitch 2002). In addition to being a potent vasoconstrictor, endothelin is a smooth muscle cell mitogen (Granton and Rabinovitch 2002). Healthy lungs normally clear endothelin. However, in pulmonary arterial hypertension there appears to be increased production of endothelin across the pulmonary vasculature (Stewarteftf/1991). Consequently, endothelin may contribute to vasoconstriction and the progressive muscularisation of the pulmonary vasculature in pulmonary arterial hypertension. It is interesting that in patients undergoing repair of congenital cardiac defects, a reduction in endothelin levels has been demonstrated (Adatia and Haworth 1993).

A key factor in the regulation of vascular tone is nitric oxide, which via cyclic guanosine monophosphate (GMP), mediates vasodilation and stimulates angiogenesis and proliferation of endothelial cells. Nitric oxide is also important because it possesses antiplatelet effects and impairs neutrophil adhesion (Granton and Rabinovitch 2002). Patients with pulmonary arterial hypertension appear to have high urinary cyclic GMP concentrations. This correlates inversely with cardiac index and mixed venous oxygen saturation, and suggests that nitric oxide excretion increases in response to an increase in vascular tone. Several reports demonstrate increased nitric oxide levels in exhaled air from patients with pulmonary arterial hypertension (Granton and Rabinovitch 2002). However, controversy exists with respect to the concentration of nitric oxide synthase (the enzyme responsible for the production of nitric oxide) in patients with pulmonary arterial hypertension. Nitric oxide synthase exists in several isoforms – inducible, constitutive, and neuronal. It has been shown to be both increased and decreased in the pulmonary vasculature and plexiform lesions in patients with pulmonary arterial hypertension (Granton and Rabinovitch 2002).

Abnormalities in ion channels, which control the membrane potential of vascular smooth muscle cells, have also been implicated in the pathophysiology of pulmonary arterial hypertension (Michelakis and Weir 2001). Several potassium channel subtypes exist, and abnormalities in the expression of voltage-gated channels have been described in patients with primary pulmonary arterial hypertension (Granton and Rabinovitch 2002). Voltage-gated channels, when inhibited, lead to an accumulation of potassium in the cell, raise the resting membrane potential and cause depolarisation. Calcium then enters the cell and produces vasoconstriction. Patients with primary pulmonary arterial hypertension have decreased potassium currents, suggesting that the smooth muscle cells remain depolarised and the vessels constricted as a result of increased intracellular calcium levels (Granton and Rabinovitch 2002). In pulmonary artery smooth muscle cells from patients with primary pulmonary arterial hypertension, the expression (messenger ribonucleic acid level) of one of the voltage-gated potassium channels is reduced, resulting in increased pulmonary vascular tone (Granton and Rabinovitch 2002). A similar reduction in potassium channel activity in pulmonary smooth muscle cells exposed to serum from patients with pulmonary arterial hypertension secondary to congenital heart disease has been reported (Limsuwan et al 2001).

Management

The intensity of treatment that is appropriate for a patient with pulmonary hypertension depends on several factors, including the patient’s diagnosis, degree of cardiac and respiratory dysfunction, magnitude of elevation in PVR, likelihood of response to therapy and prognosis. For example, a pulmonary artery pressure of 40/25mmHg in a stable neonate with a systemic blood pressure of 70/45mmHg who has undergone repair of obstructed total anomalous pulmonary venous connection does not require aggressive treatment, because in these patients pulmonary hypertension is expected early after repair, is typically short-lived, and is unlikely to cause significant morbidity at this moderate level (Atz et al 1996). However, if a similar patient is haemodynamically unstable on large doses of intravenous inotropes and has pulmonary artery pressure at or near the systemic pressure, more aggressive manoeuvres to reduce PVR must be instituted.

Previously, the only successful treatment for patients with advanced pulmonary hypertension due to congenital cardiac defects leading to Eisenmenger syndrome (reversal of shunt) was lung (with simultaneous cardiac repair) or heart/lung transplantation. However, recent advances in understanding pulmonary arterial hypertension and the application of medical therapies used in primary pulmonary arterial hypertension to this group of patients have been beneficial. The therapies for management of pulmonary hypertension that result from congenital cardiac defects can broadly be classified into general therapies and directed medical therapies (Box 4).

General therapies There are several therapies for elevated PVR that while non-specific, appear to be generally effective. These include analgesia and sedation, along with the manipulation of mechanical ventilation, oxygen supplementation, and generation of an alkalosis. Pain control with fentanyl or morphine infusion and sedation with a short-acting (for example, midazolam) or long- acting (for example, lorazepa\m) benzodiazepine have been associated with reduced and less labile PVR in the postoperative period (Wessel 1993). Attention to adequate analgesia and sedation for stressful or invasive procedures such as endotracheal tube suctioning is particularly important for minimising acute increases in PVR.

Directed medical therapies Over the past decade there has been a significant advance in the treatment of primary pulmonary arterial hypertension. Therapy has progressed beyond anticoagulation and calcium channel blockers, which were successful in reducing pulmonary artery pressure in only a minority of patients and usually only for a short duration. Intravenous and inhaled prostanoids, nitric oxide, and endothelin inhibition, have been evaluated in patients with pulmonary arterial hypertension and show promise.

BOX 4

Therapeutic options for pulmonary hypertension

However, the majority of these agents have largely been studied in patients with primary pulmonary arterial hypertension, or secondary pulmonary arterial hypertension associated with scleroderma and related diseases (Klings and Farber 2001). Trials are under way to assess the efficacy of these agents in pulmonary hypertension due to congenital cardiac defects. The main limitation with these pharmacologie agents is that their vasodilatory effects are not specific to the pulmonary vasculature, so that vasodilation of the systemic vasculature and systemic hypotension may accompany reduction of pulmonary hypertension.

Inhaled nitric oxide Inhaled nitric oxide is currently the agent with most selectivity for vasodilating the pulmonary vasculature. It is attractive as a therapeutic agent, as it is a readily available gas that acts on the abluminal surface of the endothelium. It is metabolised by haemoglobin and, therefore, has an ultrashort half- life without demonstrable systemic haemodynamic effects.

Nitric oxide has been used successfully in patients with pulmonary hypertension of varied origin, such as primary pulmonary hypertension; persistent pulmonary hypertension of the newborn; congestive heart failure; intrinsic pulmonary disease, including pulmonary fibrosis, scleroderma and chronic obstructive pulmonary disease; acute respiratory distress syndrome; and a variety of corrected and uncorrected congenital heart lesions (Napoli and Loscalzo 2004).

The usefulness of inhaled nitric oxide for congenital heart disease patients with pulmonary hypertension has been documented in several populations (Atz and Wessel 1997). Following surgery nitric oxide reduces pulmonary hypertension in patients with obstructed TAPVC, mitral stenosis, large, pre-existing left-to-right shunts, Fontan physiology, and pulmonary hypertensive crises related to cardiopulmonary bypass.

The main difficulties relating to the use of nitric oxide stem from the difficulty in administering the gas, the need for pulsed delivery systems and tanks, as well as the cost. The chief concerns for the use of inhaled nitric oxide include the generation of methemoglobin following the reaction of nitric oxide with haemoglobin, the generation of nitrogen dioxide (NO^sub 2^) when NO and O2 combine, and the possibility in some patients of ‘rebound’ pulmonary hypertension – an acute increase in pulmonary arterial pressure when nitric oxide is discontinued (Atz et al 1996).

Prostaglandins Based on the initial hypothesis that pulmonary arterial hypertension is characterised by an imbalance between vasodilators and vasoconstrictors, prostaglandins have been evaluated and demonstrated to be efficacious in patients with primary pulmonary arterial hypertension, pulmonary arterial hypertension due to scleroderma (Christman et al 1992), as well as pulmonary arterial hypertension due to congenital cardiac defects (Muller et al 2003). The benefits of prostaglandins in treatment of the disease may be due to effects beyond their vasodilator properties. To this end prostaglandins have been shown to have effects on platelet function, and may inhibit the proliferation of pulmonary arterial smooth muscle cells (Clapp et al 2002).

As prostaglandin-mediated vasodilation is non-selective, it may lead to both pulmonary arterial and systemic hypotension. In patients with right-to-left shunts, reductions in systemic blood pressure may worsen the degree of intracardiac shunting and hypoxaemia.

The application of prostaglandin therapy is limited by the stability of the drug. Epoprostenol, a prostaglandin analogue, is an unstable compound and must be administered via continuous infusion, kept away from light, and kept cool. Another limitation is the development of tachyphylaxis – the decrease in pharmacological response during repeated or continued administration of a substance. Patients generally require intermittent increases in the dose of medication, leading to an increase in cost and inconvenience. This agent also produces significant side effects such as jaw pain, flushing, bone pain, nausea, vomiting, diarrhoea, and more serious complications such as indwelling catheter infections or discontinuation of therapy, which may lead to sudden death (Granton and Rabinovitch 2002).

Based on these limitations, more stable analogues have been evaluated, but are not yet licensed for clinical use in the UK. One of these, Uniprost (UT-15) may be preferred, as it is a more stable analogue, has a longer half-life, and may be administered via subcutaneous infusion. However, the administration route has resulted in significant site pain owing to irritation from the drug (Granton and Rabinovitch 2002). An oral form of prostaglandin (Baraprost) has been evaluated in a small series of patients and appeared promising (Dandel and Hetzer 2003). These observations remain to be confirmed in larger clinical trials.

Aerosolised formulations of prostaglandins, for example, iloprost, with selective pulmonary vasodilator activity have also been used successfully in patients with acute lung injury, primary pulmonary arterial hypertension, and after repair of congenital heart disease (Zwissler et al 1995). The main limitation in the use of these agents is their relatively short half-life, necessitating frequent inhalation (every three to four hours), and the development of similar side effects that characterise the systemic delivery such as flushing and jaw pain. The long-term benefits of this therapy need to be prospectively evaluated in patients with congenital cardiac disease.

Endothelin inhibitors It is unclear whether or not an abnormality in the pulmonary clearance of endothelin is a cause or consequence of pulmonary hypertension. However, a recent study of a non- selective endothelin inhibitor in patients with primary and secondary forms of the disease lends support to the notion that endothelin contributes to the progression of pulmonary arterial hypertension.

Bosentan – a non-selective endothelin inhibitor – is an oral dual endothelin receptor antagonist approved for use in functional class III to IV pulmonary arterial hypertension. In two placebo- controlled trials, patients receiving bosentan showed improved functional class, six-minute walk distance and haemodynamics over a 12-to 16-week period (Chin and Channick 2004). Follow-up data over three years have shown few deteriorations, with the majority of patients maintaining their response to bosentan alone.

Investigations exploring the use of bosentan as an add-on agent to intravenous (IV) epoprostenol in those with the most severe disease are ongoing. Bosentan may also have antifibrotic properties and its use in pulmonary fibrosis is being explored (Chin and Channick 2004). Ease of administration of bosentan with twice-daily oral dosing will provide many patients with pulmonary hypertension an option for treatment without the risks and discomforts of continuous IV medication (Chin and Channick 2004).

Phosphodiesterase type-5 inhibitors Sildenafil (Viagra(TM)) is a selective phosphodiesterase type-5 inhibitor. Phosphodiesterase type- 5 breaks down cyclic GMP. Sildenafil produces acute and relatively selective pulmonary vasodilation (Schulze-Neick et al 2003) and acts synergistically with nitric oxide (Atz et al 2002). Preliminary reports suggest that sildenafil may have useful effects in pulmonary hypertension particularly in attenuating rebound effects after discontinuing inhaled nitric oxide and in the chronic therapy of pulmonary hypertension (Ravishankar et al 2003). Sildenafil is well tolerated and available as an oral preparation, which makes it particularly attractive in patients with pulmonary hypertension whose symptoms do not warrant a continuous IV infusion. In two studies from India, sildenafil was used in children and young adults with pulmonary hypertension with a significant improvement in the six-minute walk test at three months and six months (Ra vishankar et al 2003).

A randomised controlled trial demonstrated that IV sildenafil augments the pulmonary vasodilator effects of inhaled nitric oxide in infants early after cardiac surgery. However, sildenafil produces systemic hypotension and impaired oxygenation, which is not improved by inhaled nitric oxide (Stocker et al 2003).

Evolving therapies Alternative therapies have been proposed based on experimental animal models. Elastase inhibitors that are bioavailable after oral administration have successfully induced regression in an advanced and fatal form of pulmonary hypertension in experimental rats induced by the toxin monocrotaline (Granton and Rabinovitch 2002). Gene therapy strategies could also be applied. Although adenoviral or retroviral vector-based systems are effective in delivering the genes, the long-term use of these vectors is limited by the development of inflammation in the target organ. To avoid this problem, cell-based methods of gene transfer are being developed (Campbell et al 1999).

Conclusion

Progress in the understanding of the pathophysiology of pulmonary arterial hyperte\nsion, and the emergence of newer pharmacologic therapies provide new hope for patients with Eisenmenger physiology and other patients with lesser degrees of pulmonary hypertension due to congenital heart disease. The treatment of patients earlier in the disease process may arrest the progression of the vascular injury and circumvent or delay the need for transplantation. A systematic evaluation of these strategies, alone or in combination, through randomised controlled trials in patients with pulmonary hypertension due to congenital cardiac defects is needed to validate their safety and efficacy

GLOSSARY OF CONGENITAL CARDIAC DISORDERS

Atrial septal defect (ASD)

In this condition, an opening exists between the two upper chambers of the heart that allows some blood from the left atrium (blood that has already been to the lungs) to return via the hole to the right atrium instead of flowing through the left ventricle, out the aorta, and to the body.

Bi-directional Glenn shunt/cavo-pulmonary anastamosis

The bi-directional Glenn shunt is performed by connecting the superior vena cava (SVC) to the right branch of the pulmonary artery using fine sutures, and dividing or tying up the pulmonary artery. Venous blood from the head and upper limbs will pass directly to the lungs, bypassing the right ventricle. The venous blood from the lower half of the body will continue to enter the heart.

Ductus arteriosus

The ductus arteriosus, in utero, connects the proximal left pulmonary artery to the descending aorta, just distal to the left subclavian artery. Failure of closure at birth represents a congenital malformation – patent or persistent ductus arteriosus, which is usually an isolated lesion.

Eisenmenger syndrome

Eisenmenger syndrome is defined as pulmonary vascular obstructive disease that develops as a consequence of a large pre-existing left- to-right shunt such that pulmonary artery pressures approach systemic levels and the direction of the flow becomes bi- directional or right-to-left. Congenital heart defects can lead to Eisenmenger syndrome.

Fontan operation/procedure

The Fontan operation is a palliative procedure for patients with a functionally or anatomically single ventricle.

Single ventricles

Patients with single ventricles either have an ‘anatomically’ single ventricle made up of a single pouch of indeterminate origin or, more commonly, have a ‘functionally’ single ventricle with one well-formed ventricle accompanied by a second underdeveloped or rudimentary ventricle.

Transposition of the great arteries

The large arteries, which should be taking deoxygenated blood from the heart to the lungs, and oxygenated blood from the heart to the body, are round the wrong way. Deoxygenated blood returns to the body, and oxygenated blood from the lungs is directed back into the lungs.

Truncus arteriosus

This is a complex malformation where only one artery arises from the heart and forms the aorta and pulmonary artery. Surgery for this condition is usually required early in life.

Ventricular septal defect (VSD)

In this condition, an opening exists between the two lower chambers of the heart and allows some blood that has returned from the lungs and has been pumped into the left ventricle to flow to the right ventricle through the hole (instead of being pumped into the aorta). Because the heart becomes over-worked, it may become enlarged.

Raja SG, Basu D (2005) Pulmonary hypertension in congenital heart disease. Nursing Standard. 19, 50, 41-49. Date of acceptance: January 25 2005.

References

Adatia I, Haworth SG (1993) Circulating endothelin in children with congenital heart disease. British Heart Journal. 69, 3, 233- 236.

Atz AM, Wessel DL (1997) Inhaled nitric oxide in the neonate with cardiac disease. Seminars in Perinatology. 21, 5, 441-455.

Atz A, Adatia I, Wessel DL (1996) Rebound pulmonary hypertension after inhalation of nitric oxide. Annals of Thoracic Surgery. 62, 6, 1759-1764.

Atz AM, Lefler AK, Fairbrother DL, Uber WE, Bradley SM (2002) Sildenafil augments the effect of inhaled nitric oxide for postoperative pulmonary hypertensive crises. Journal of Thoracic and Cardiovascular Surgery. 124, 3, 628-629.

Campbell AI, Kuliszewski MA, Steward DJ (1999) Cell-based gene transfer to the pulmonary vasculature: endothelial nitric oxide synthase overexpression inhibits monocrotaline-induced pulmonary hypertension. American Journal of Respiratory Cell and Molecular Biology. 21, 5, 567-575.

Chin K, Channick R (2004) Bosentan. Expert Review of Cardiovascular Therapy. 2, 2, 175-182.

Christman BW, McPherson CD, Newman JH et al (1992) An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. New England Journal of Medicine. 327, 2, 70- 75.

Clapp LH, Finney P, Turcato S, Tran S, Rubin LJ, Tinker A (2002) Differential effects of stable prostacyclin analogs on smooth muscle proliferation and cyclic AMP generation in human pulmonary artery. American Journal of Respiratory Cell and Molecular Biology. 26, 2,194-201.

Dandel M, Hetzer R (2003) Clinical value of prostacyclin and its analogs in the management of pulmonary arterial hypertension. Current Vascular Pharmacology. 1, 2, 171-181.

Granton JT, Rabinovitch M (2002) Pulmonary arterial hypertension in congenital heart disease. Cardiology Clinics. 20, 3, 441-457

Hall SM, Haworth SG (1992) Onset and evolution of pulmonary vascular disease in young children: abnormal postnatal remodelling studied in lung biopsies. Journal of Pathology. 166, 2, 183-191

Heath D, Edwards JE (1958) The pathology of hypertensive pulmonary vascular disease; a description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation. 18, 4 Pt 1, 533- 547.

Heymann MA (1984) Control of the pulmonary circulation in the perinatal period. Journal of Developmental Physiology. 6, 3, 281- 290.

Hopkins RA, Bull C, Haworth SG, de Levai MR, Stark J (1991) Pulmonary hypertensive crises following surgery for congenital heart defects in young children. European Journal of Cardiothoracic Surgery. 5, 12, 628-634.

Jones PL, Rabinovitch M (1996) Tenascin-C is induced with progressive pulmonary vascular disease in rats and is functionally related to increased smooth muscle cell proliferation. Circulation Research. 79, 6, 1131-1142.

Jones OD, Shore DF, Rigby ML et al (1981) The use of tolazoline hydrochloride as a pulmonary vasodilator in potentially fatal episodes of pulmonary vasoconstriction after cardiac surgery in children. Circulation. 64,2 Pt 2, II134-139.

Jones PL, Cowan KN, Rabinovitch M (1997) Tenascin-C, proliferation and subendothelial fibronectin in progressive pulmonary vascular disease. American Journal of Pathology. 150, 4, 1349-1360.

Kidd L, Driscoll DJ, Gersony WM et al (1993) Second natural history study of congenital Heart defects. Results of treatment of patients with ventricular septal defects. Circulation. 87, 2 Suppl, 138-151.

Klings ES, Farber HW (2001) Current management of primary pulmonary hypertension. Drugs. 61, 13, 1945-1956.

Lang P, Chipman CW, Siden H, Williams RG, Norwood WI, Castaneda AR (1982) Early assessment of hemodyriamic status after repair of tetralogy of Fallot: a comparison of 24 hour (intensive care unit) and 1 year postoperative data in 98 patients. American Journal of Cardiology. 50, 4, 795-799.

Laussen PC, Roth SJ (2001) Pediatric cardiac intensive care issues. In Thys DM, Hillel Z, Schwartz AJ (Eds) Textbook of Cardiothorocic Anesthesiology. McGraw-Hill, New York NY, 1069-1105.

Limsuwan A, Platoshyn O, Yu Y, Rubin LJ, Rothman A, Yuan JX (2001) Inhibition of KW channel activity in human pulmonary artery smooth muscle cells by serum from patients with pulmonary hypertension secondary to congenital heart disease. Pediatric Research. 50, 1, 23-28.

Lindberg L, Olsson AK, Jogi P, Jonmarker C (2002) How common is severe pulmonary hypertension after pediatric cardiac surgery? Journal of Thoracic and Cardiovascular Surgery. 123, 6, 1155-1163.

Michelakis ED, Weir EK (2001) The pathobiology of pulmonary hypertension. Smooth muscle cells and ion channels. Clinics in Chest Medicine. 22, 3, 419-432.

Muller M, Scholz S, Kwapisz M, Akinturk H, Thul J, Hempelmann G (2003) Use of inhaled iloprost in a case of pulmonary hypertension during pediatric congenital heart surgery. Anesthesiology. 99, 3, 743-744.

Napoli C, Loscalzo J (2004) Nitric oxide and other novel therapies for pulmonary hypertension. Journal of Cardiovascular Pharmacology and Therapeutics. 9,111-8.

Rabinovitch M (2000) Pathobiology of pulmonary hypertension: impact on clinical management. Seminars in Thoracic and Cardiovascular Surgery Pediatric Cardiac Surgery Annual. 3, 1, 63- 81.

Rabinovitch M, Bothwell T, Hayakawa BN et al (1986) Pulmonary artery endothelial abnormalities in patients with congenital heart defects and pulmonary hypertension: a correlation of light with scanning electron microscopy and transmission electron microscopy. Laboratory Investigation. 55, 6, 632-653.

Ravishankar C, Tabbutt S, Wernovsky G (2003) Critical care in cardiovascular medicine. Current Opinion in Pediatrics. 15, 5, 443- 453.

Schulze-Neick I, Hartenstein P, Li J et al (2003) Intravenous sildenafil is a potent pulmonary vasodilator in children with congenital heart disease. Circulation. 108, Suppl 1, II167-173.

Steele PM, Fustei- V, Cohen M, Ritter DG, McGoon DC (1987) Isolated atrial septal defect with pulmonary vascular obstructive disease: long-term follow-up and prediction of outcome after surgical correction. Circulation. 76, 5, 1037-1042.

Stewart DJ, Levy RD, Cernacek P, Langleben D (1991) Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Annals of Internal Medicine. 114, 6, 464-469.

Stocker C, Penny DJ, Brizard CP, Cochrane AD, Soto R, Shekei- demian LS (2003) Intravenous sildenafil and inhaled nitric oxide: a randomised trial in infants after cardiacsurgery. Intensive Care Medicine. 29, 11, 1996-2003.

Vogel M, Berger F, Kramer A, Alexi-Meshkishvili V, Lange PE (1999) Incidence of secondary pulmonary hypertension in adults with atrial septal or sinus venosus defects. Heart. 82, 1, 30-33.

Wessel DL (1993) Hemodynamic responses to perioperative pain and stress in infants. Critical Care Medicine. 21, 9 Suppl, S361-362.

Widlitz A, Barst RJ (2003) Pulmonary arterial hypertension in children. European Respiratory Journal. 21, 1, 155-176.

Zwissler B, Rank N, Jaenicke U et al (1995) Selective pulmonary vasodilation by inhaled prostacyclin in a newborn with congenital heart disease and cardiopulmonary bypass. Anesthesiology. 82, 6, 1512-1516.

Authors

Shahzad G Raja is specialist registrar, Department of Paediatric Cardiac Surgery, Royal Hospital for Sick Children, Glasgow; Devika Basu is senior staff nurse, NICU, John Radcliffe Hospital, Oxford. Email: drrajashahzad@hotmail.com

Copyright RCN Publishing Company Ltd. Aug 24-Aug 30, 2005