Evaluation of Adults With Congenital Heart Disease

Preamble

Due to the dramatic progress of pediatric cardiology and heart surgery over the last decades, the majority of patients with congenital heart disease (CHD) can now reach adulthood, and the number of adult patients with CHD (ACHD) now exceed that of children. ¹ Despite the amazing results of pediatric cardiac surgery, most of the patients with ACHD cannot be considered cured, since residua are intrinsic to the surgery performed in childhood and often cause problems during adult life and may require timely reintervention. Patients with ACHD not only require careful long-term evaluation of the residua of their cardiac disease, but they might also present additional relevant topics (noncardiac comorbidities, the need of noncardiac surgery, and reproduction issues), making them a constantly growing population with very special needs. ² Thus, CHD is no longer a pediatric specialty. Appropriate specialist cardiologists may come from pediatric or adult cardiology as long as they have skills in echocardiography, cardiac catheterization, pacing, and electrophysiology in adults with special reference to CHD. ³ Specialists in ACHD also have to provide the understanding of the physiological changes in pregnancy, as well as the understanding of the psychosocial aspects of adolescence, and they need to have experience in lifestyle counseling for adolescents and adults with CHD. ⁴

Patient History, Assessment of Symptoms, and Functional Capacity

A comprehensive clinical evaluation is crucial in the diagnostic workup of patients with ACHD. The aim of examining patient history is to assess present and past symptoms as well as to search for any new event and/or changes in medication. The patient should be asked about his or her lifestyle in order to detect changes in daily activity and functional capacity.

There are profound differences in assessing the history in patients with ACHD compared to patients with acquired heart disease. First of all, patients with acquired heart disease are usually older, while the patients with ACHD are more often adolescents or young adults. This difference can result in a different approach of the patient to his or her disease, often involving the whole family who provided all the necessary care during childhood. Moreover, patients with acquired heart disease usually have a brief and clear cardiac history with clinical notes summarizing key problems and interventions performed, while patients with ACHD have long clinical notes, starting from birth. It is crucial to go through these notes accurately to understand whether they have been palliated or corrected and how, because most of the problems in adulthood are related to the specific cardiac surgery performed. Thus, a comprehensive knowledge of different interventions in different surgical eras is required. After a thorough analysis of the patient history from birth, the second step for a careful clinical evaluation is the assessment of present and past symptoms. This is of critical importance and can be particularly challenging in the population with ACHD. Indeed, patients with acquired disease can compare their new life with their previous one, and this is crucial in the way they report symptoms. Patients with ACHD, on the other hand, have made lifelong psychosocial adaptations on the basis of their congenital defects with respect to both physical and mental aspects and consider their situation as normal. Gratz et al ⁵ compared self-reported health-related quality of life with the objective of exercise performance in patients with CHD according to diagnosis. They evaluated more than 560 patients with different congenital defects with quality-of-life test and cardiopulmonary exercise test (CPET) and showed that self-estimated physical functioning poorly predicts actual exercise capacity. Indeed, peak oxygen uptake was significantly impaired in all diagnostic groups as compared to controls, depicting significant reduction in exercise capacity in all CHD groups. Diller et al ⁶ showed very clearly that patients with CHD have markedly depressed exercise capacity, even patients with minor defects, to an extent similar to that seen in noncongenital heart failure (HF). Secondly, and most important, they showed that impaired peak oxygen uptake predicts hospitalization and death over the following year even after accounting for age, gender, New York Heart Association (NYHA) class, laboratory parameters, and underlying cardiac lesions.

In conclusion, quality of life and functional capacity are key measures of the success of intervention in patients with CHD. Traditional exercise testing uses protocols that are largely designed for risk stratification of ischemic heart disease and are often not appropriate in this population. Cardiopulmonary exercise test, including assessment of objective exercise capacity (time and maximum oxygen uptake), ventilation efficiency (VE/VCO₂ slope), chronotropic and blood pressure response as well as exercise-induced arrhythmia, gives a broader evaluation of function and fitness and has end points that correlate well with morbidity and mortality. Cardiopulmonary exercise test should be used regularly in the follow-up of patients with ACHD to uncover deficits even if patients report satisfactory physical capabilities.

Clinical Examination

A detailed clinical examination plays a major role in the assessment and follow-up of unoperated, palliated, and repaired CHD. Comprehensive clinical examination should be performed with regard to any changes in auscultation findings or development of signs of HF. The relevant findings pertaining to specific lesions will not be treated in this review, but some general principles can be applied to all patients. While evaluating a patient with CHD for the first time, the specialist should look for syndromic features that can be obvious, inconspicuous, or unrecognized until adulthood and could require chromosomic mapping. The presence of characteristic facial or somatic features of an underlying syndrome may be a strong clue to the type of heart disease (eg, Williams, Noonan, and Down) at any age. Syndromic patients usually have comorbidities related to their syndromes, such as cognitive impairment, neurologic, or orthopedic disorders, which further complicates their management.

Thoracic scars are often present due to the surgery performed in infancy or later. A careful surveillance of chest wall scars is of particular importance in adults who do not always know or report the type of their surgical intervention. Scars can represent a psychological issue to the patient, especially when they are adolescents and can impact negatively on quality of life and acceptance of the disease in adult life.

Examination of the upper and lower limb peripheral pulses is important in CHD at any age. Delay, absence, or reduction of a pulse is an important clue to the presence of arterial obstruction and its site. Some palliative procedures (Blalock-Taussig shunt and interposition grafts) may affect either or both upper limb pulses. The pulse volume and character also provide important information regarding the severity of obstructive or regurgitant left heart disease. The jugular venous pressure examination may give several information (valvular disease, arrhythmias, pericardial constriction, etc). Cyanosis and nail clubbing can be found while they are extremely rare in non-CHD patients. Physical examination is followed by heart and lung auscultation. Cardiac and vascular malposition may significantly affect the appreciation of heart sounds and murmurs. The blood pressure measurement and pulse oximetry complete the clinical examination.

In conclusion, clinical examination in patients with ACHD presents some differences from patients with acquired heart disease and should be routinely performed together with blood pressure and oxygen saturation measurement.

Electrocardiography

Electrocardiography (ECG) should always be performed alongside clinical evaluation and each wave needs careful analysis. P wave reflects atrial depolarization. Peaked P waves consistent with right atrial overload is a usual finding in ACHD. Koyak et al ⁷ found nonsinus rhythm at ECG being significantly associated with the risk of sudden cardiac death (SCD). Atrial arrhythmias are a major concern in ACHD, they are very common after 20 years of age, reaching a cumulative incidence of 55% among patients with severe CHD after 65 years. ⁸ Indeed, Bouchardy et al conducted a population-based analysis of prevalence, lifetime risk, mortality, and morbidity associated with atrial arrhythmias in ACHD, finding a prevalence of 15%. The lifetime incidence increased steadily with age and was associated with a doubling of the risk of adverse events. Atrial flutter or fibrillation is associated with SCD in ACHD, especially in tetralogy of Fallot (ToF) or transposition of the great arteries (TGAs). ⁹ Sudden cardiac death is a prominent cause of death in ACHD (9% to 26%), ^10,11 and this association has been described earlier in patients with TGA but not in patients with ToF. ¹² Further studies are needed to clarify whether atrial arrhythmias are a surrogate marker for the risk of SCD or a consequence of ventricular dysfunction.

The PR interval represents atrioventricular (AV) conduction. First-degree AV block is commonly seen in patients with AV septal defects, and in older patients with atrial septal defect (ASD), Ebstein, and d-TGA. Preoperative abnormalities of AV conduction in the form of PR interval prolongation, second-degree AV block, and complete heart block persist after reparative cardiac surgery for congenitally corrected TGAs (ccTGAs). ¹³ In ccTGA, repair of a ventricular septal defect risks complete heart block because the nonpenetrating AV conduction bundle runs along the superior margin of the septal defect. Patients who escape intraoperative heart block are apparently not at risk for late postoperative heart block. ²

The QRS complex represents ventricular depolarization. Several studies underlined the importance of QRS duration in predicting SCD, and an association has been reported in patients with ToF, TGA, and Eisenmenger syndrome. ^{12 –14} In the study from Koyak et al, ⁷ QRS duration was significantly increased in SCD cases, but no association between QRS and SCD was demonstrated in patients with ToF and TGA. An association between fragmented QRS and right ventricle (RV) scarring and dysfunction assessed at cardiac magnetic resonance (CMR) was found in patients with ToF. ¹⁵

The QT interval represents electrical depolarization and repolarization of the ventricle. In a large multicenter case–control study, ⁷ including more than 25,000 adults with CHD, QT dispersion was found to be one of the clinical variables associated with SCD, with an odds ratio (OR) of 1.34 (per 10 millisecond increase; 95% confidence interval [CI] 1.22-1.63, P = .001) at univariate analysis and an OR of 1.22 (per 10 millisecond increase; 95% CI 1.22-1.48, P = .008) at multivariate analysis. Before this report, scarce data were available on QT dispersion in CHD. ¹⁶

In conclusion, careful ECG analysis plays a pivotal role in evaluating patients with ACHD, and ECG parameters should be recorded and compared from visit to visit. A comprehensive ECG evaluation can prompt the need to undergo 24 hours Holter monitoring, CPET for exercise-induced arrhythmias, and specialistic evaluation to decide whether to perform further testing, such as programmed atrial or ventricular stimulation. Arrhythmias are the major cause of death and hospitalization in patients with ACHD, and arrhythmic risk evaluation starts from ECG.

Echocardiography

Echocardiography is the first-line investigation in ACHD and presents several differences with echocardiography in acquired heart disease. An echocardiogram in ACHD should report information on the basic cardiac anatomy, venous return, connection of the atria and ventricles, and origin of the great arteries. Echocardiography in ACHD may be complicated by multiple factors; assessment of ventricular volumes and function may be complicated by geometry and regional dyssynchrony, particularly in systemic RVs or univentricular hearts. Doppler gradients may sometimes be misleading, particularly in right ventricular outflow tract obstruction and stenosis in series. Venous return and great arteries may be difficult to image in adults. Standard echocardiography is evolving and the new techniques (strain imaging, three-dimensional, etc) are finding application in CHD also.

Strain imaging is a novel method that has been developed to quantify regional myocardial function. The advantage of speckle tracking is that it is angle independent by virtue of its tracking along the myocardial wall rather than the ultrasound waves. The images are obtained at high frame rate and only one cardiac cycle is required. ¹⁷ Speckle tracking has been recently applied to CHD. Scherptong et al found ¹⁸ that RV longitudinal peak systolic strain may be a sensitive marker to detect early deterioration in RV function in adult patients with ToF. More recently, Chowdhury et al ¹⁹ found improvements in RV longitudinal strain and strain rate after percutaneous pulmonary valve implantation. It is well documented that global peak systolic longitudinal strain (GLS) in the systemic RV is significantly reduced compared with the systemic left ventricle or normal RV in control individuals. ²⁰ Moreover, GLS relates to adverse clinical outcome among these patients. ²¹ Lipczyńska et al ²² found that the systemic RV GLS is able to discriminate between patients with D-TGA after the atrial switch with, and those without, a CMR systemic RV EF of at least 45%. The authors also proposed a systemic RV GLS threshold value (−14.2%) that would define preserved systemic RV systolic function.

Real-time three-dimensional echocardiography (RT3DE) allows for accurate morphological characterization of CHD and complements two-dimensional echocardiography. RT3DE has been proven particularly useful in guiding interventional procedures. The images obtained are able to accurately portray the morphology, location, dimensions, and dynamic changes of atrial or septal defects. Specifically, RT3DE allows the user to measure defect size, rim size, left and right atrial occluder disc dimensions, and the distance between the left atrium and aorta which can help recognize appropriate candidates with secundum-type ASD for percutaneous closure. ²³ The RT3DE has also shown its usefulness in the detection and quantification of other anomalies. ²⁴

Although echocardiography still remains the first-line diagnostic tool, since it is a noninvasive, easily available, and low-cost technique, strategies for investigation of anatomy and physiology of CHD are changing rapidly. After a comprehensive echocardiographic evaluation, further noninvasive imaging or invasive assessment could be needed. Recently, there has been a shift from invasive studies to noninvasive protocols involving CMR and computed tomography that may overcome the issue of poor acoustic window.

In conclusion, echocardiography is the key imaging technique in ACHD and continues to evolve. Speckle tracking echocardiography (STE) and RT3DE offer promising imaging modalities and they are gaining a mainstream role in the world of echocardiography, including in CHD.

Main Clinical Issues in Population With ACHD

In our daily ACHD practice, clinical evaluation should be individualized in relation to the features of each patient’s anatomy, surgical repair, and presenting symptoms. However, the importance of complete standardized lesion-specific clinical protocols should be stressed, investigating all known risk factors specific for each cardiac disease, even if patients do not complain of symptoms. ²⁵ Although the prognosis for patients with ACHD is improving, significant cardiovascular problems still remain: HF, cyanosis, and pulmonary arterial hypertension (PAH) are among the most concerning issues that impact on quality of life, exercise capacity, morbidity, and mortality.

Heart Failure

Heart failure is a frequent problem in ACHD, because ventricles are exposed to abnormal loading conditions, surgical interventions, or electrical disturbance, which determine the clinical picture later in life. Heart failure is a clinical syndrome with many systemic clinical manifestations and it is one of the most frequent causes of reduced quality of life in population with ACHD. ²⁶

The pathophysiology of HF in ACHD is complex, multifactorial, and cannot be directly compared to HF in acquired heart diseases. ²⁷ The adult patients with CHD prone to congestive failure include those with long-standing volume load defects and those with a primary depression of myocardial function (eg, systemic RVs, ventricles damaged during surgery, or because of late treatment of ventricular overload). In particular, to better understand why, in patients with ACHD, the pathophysiology of cardiorespiratory dysfunction is so different from the failing “normal” circulation, we have to considerer some specific cardiac conditions.

First of all, we focus on CHDs which have a morphological RV as the systemic subaortic ventricle, such as D-TGA after atrial switch repair (Mustard or Senning operation) or ccTGA. In these CHDs, systolic dysfunction of the systemic ventricle is common, and HF is seen with older age, with RV myocardium intrinsically maladapted to perform as the systemic ventricle. However, the evidence for the RV myocardium being unable to support the systemic circulation is surprisingly weak. There is much more evidence to support tricuspid regurgitation as the key driver of progressive dysfunction. ²⁸ In these patients, relieving systemic AV valve regurgitation can positively alter the course of disease, especially when performed before the systemic RV ejection fraction declines. So, in clinical evaluation, it is important to try to understand the underlying mechanisms of ventricular decline, taking on the challenge of how to stem the progression of HF.

Congenital heart disease with “single-ventricle physiology” having undergone Fontan procedure is another particular setting of high risk for HF. In fact, elevation of the central venous pressure and reduced cardiac output are inevitable consequences of the Fontan circulation. ²⁹ Heart failure is seldom due to marked systolic dysfunction; indeed, it may result from a combination of diastolic dysfunction with increasing Fontan pressure, which leads to systemic venous congestion. In this condition, the most concerning problem is the “failing Fontan,” a multisystem disease with renal, pulmonary, and hepatic dysfunction, with high mortality rate.

Although patients with ACHD often do not report significant symptoms (82.4% NYHA class I or II in the single-ventricle and systemic RV population), clinical HF is documented in 22.2% of patients with D-TGA who have had a Mustard procedure, 32.3% of patients with ccTGA, and 40% of patients who have had a Fontan procedure, with symptomatic patients demonstrating a significant lower peak VO₂, systemic ventricular ejection fraction, and higher mortality rate. ³⁰

As concerns therapy, in general, ACHD specialists try to follow current treatment recommendations for HF; however, trials of proven HF therapies used in non-ACHD patients do not report the same significant treatment effects in the population with ACHD. Therefore, the few available data on HF treatment in patients with ACHD are not conclusive and are derived from small numbers. ³¹ For these reasons, ACHD-specific recommendations cannot be given in general, and treatment should be based on a clear understanding of the elements contributing to decompensation and addressing each of the treatable components.

Cyanosis

Central cyanosis refers to arterial oxygen desaturation resulting from the shunting or mixing of systemic venous blood into the arterial circulation. Cardiac defects that result in central cyanosis can be divided into 2 categories: those with increased pulmonary blood flow or those with decreased pulmonary blood flow. Cyanosis induces adaptive mechanisms to improve oxygen transport and delivery to the tissue, so secondary erythrocytosis is present in all patients with cyanosis, being the physiological response to chronic tissue hypoxia. However, cyanosis and secondary erythrocytosis imply a profound multiorgan involvement, which may cause symptoms of hyperviscosity syndrome (eg, headache, visual disturbances, and fatigue), bleeding and thrombotic diathesis, cerebrovascular accidents, arrhythmias, renal dysfunction, and infectious complications. Therefore, clinical presentation of patients with cyanosis is determined not only by underlying anatomy and pathophysiology but also by systemic complications of cyanosis. Right HF may be apparent in advanced stages. ³⁰

All patients with cyanosis should be carefully followed with lifelong visits every 6 to 12 months in specialized ACHD center. Particular attention should be paid to the underlying heart condition, symptoms of hyperviscosity, systemic complications of cyanosis, change in exercise tolerance, change in saturation levels, and prophylaxis against endocarditis. ³²

Pulmonary Arterial Hypertension and Eisenmenger Syndrome

Congenital heart disease with relevant systemic-to-pulmonary shunts, if not treated very early in the course of the disease, allows unrestricted pressure and volume overload of the pulmonary circulation and lead to the development of PAH. There are a multitude of very different clinical pictures of patients with PAH associated with CHD. However, four broad clinical phenotypes have recently been defined: Eisenmenger syndrome, PAH associated with moderate to large systemic-to-pulmonary shunts, PAH associated with small defects, and PAH after cardiac defect correction. ³³

The prevalence of PAH within the population having ACHD remains uncertain, with recent data suggesting a prevalence of over 10% for any PAH, but likely much lower for Eisenmenger syndrome. ³⁴

Most concerning is Eisenmenger syndrome, defined as pulmonary vascular obstructive disease that develops as a consequence of a large preexisting systemic-to-pulmonary shunt leading to a severe pulmonary vascular disease and PAH and resulting in a reversed pulmonary-to-systemic shunt. ³⁵ Eisenmenger syndrome is a multiorgan disorder with progressive deterioration over time. Physical examination reveals central cyanosis and clubbing of the nail beds; exercise intolerance is proportional to the degree of hypoxemia or cyanosis. Clinical presentation also includes hemoptysis, angina, syncope, arrhythmias, pulmonary thromboembolism, endocarditis, and right HF in advanced stages. In the absence of complications, these patients generally have a good functional capacity up to their third decade and thereafter usually experience a slowly progressive decline in their physical abilities. Congestive HF in patients with Eisenmenger syndrome usually occurs after 40 years of age. Right ventricular dysfunction, N-terminal of the prohormone brain natriuretic peptide (NTproBNP) serum levels, and progressive deterioration of exercise capacity, among others, are considered negative prognostic factors. ³⁶ The most common modes of death are sudden death and congestive HF. Pregnancy, perioperative mortality after noncardiac surgery, and infectious causes (brain abscesses and endocarditis) account for most of the remainder. ³⁰ In particular, pregnancy in patients with cyanosis results in significant maternal and fetal complications. Pregnancy is contraindicated in Eisenmenger syndrome.

Acquired Heart Disease in ACHD

In population with ACHD, there is an underlying defect characterized by abnormal anatomy, abnormal cardiovascular physiology, or abnormal myocardial substrate; therefore, the adverse impact of superimposed cardiovascular risk factors may well be amplified in this population who may also already be at risk for systemic ventricular dysfunction, rhythm disturbances, and HF.

In a recent study, in older patients (≥60 years of age) with CHD, coronary artery disease (CAD) as an acquired comorbidity emerged as a significant predictor of mortality in addition to the underlying CHD. ³⁷ This is of importance since it has been reported that the prevalence of significant CAD in patients with ACHD is similar to that in the general population. Furthermore, it has been shown that about 80% of patients with ACHD had at least one cardiovascular risk factor for atherosclerotic heart disease. ³⁸

Therefore, primary prevention, with a thorough assessment and approach to risk factor management, is imperative in this population as well as the fact that every physician taking care of this challenging patient group should be adequately trained in proper evaluation and treatment of CAD.