Adults with congenital heart disease (ACHD) are an expanding population who pose a significant challenge to the medical professionals who are caring for them. Although early surgery has transformed the outcome of these patients, it has not been curative. Exercise intolerance is a major problem for ACHD patients and significantly affects their quality of life. Physical limitation is common, even in patients with simple lesions, and is most severe in those with Eisenmenger syndrome, single ventricle physiology, or complex cardiac anatomy. Important systemic complications of the heart failure syndrome are also present, such as renal dysfunction hyponatremia, neurohormonal, and cytokine activation. Cardiopulmonary exercise testing provides a reliable tool for assessing the exercise capacity of ACHD patients and for risk stratification and has become part of the routine clinical assessment of these patients. Similarities in the pathophysiology of exercise intolerance in acquired heart failure and congenital heart disease suggest that established heart failure therapies, including rehabilitation and exercise training, might be beneficial to ACHD patients with exercise intolerance.
Heart Failure in Adults With Congenital Heart Disease
Heart failure is defined as a syndrome characterized by symptoms of exercise intolerance in the presence of any abnormality in the structure and/or function of the heart. All types of acquired or congenital heart disease, involving the myocardium, pericardium, endocardium, valves, or great vessels, can ultimately lead to the development of heart failure. In ACHD, heart failure is the ultimate expression of the sequelae and complications that ACHD patients often face even after “successful” repair of their primary defect.
Prevalence of Heart Failure in Adults with Congenital Heart Disease
Exercise intolerance is the mainstay of heart failure. It is common in this population, affecting more than one-third of patients in the Euro Heart Survey, a large registry of ACHD patients across Europe. Patients with cyanotic lesions and those with a univentricular circulation tend to be those with the highest prevalence of exercise intolerance, whereas patients with arterial switch for transposition of the great arteries and aortic coarctation are the least impaired. Within the cyanotic population, those with significant pulmonary arterial hypertension (Eisenmenger syndrome) tend to be most limited. Patients with the right ventricle in the systemic position as a result of congenitally corrected transposition of the great arteries or after atrial switch operation (Mustard or Senning procedure) for transposition of great arteries, also tend to be severely limited in their exercise capacity, especially after the third decade of life. As many as two-thirds of patients with congenitally corrected transposition of great arteries with major associated defects and prior open heart surgery suffer from congestive heart failure by age 45 years. Patients with univentricular circulation and a Fontan-type operation are also limited in their exercise capacity, especially in the presence of ventricular dysfunction, atrioventricular valve regurgitation, or a failing Fontan circulation. In a group of 188 patients with a systemic right ventricle or single ventricle, the prevalence of heart failure was high (22% in transposition of great arteries and atrial switch, 32% in congenitally corrected transposition, and 40% in Fontan-palliated patients). However, even patients with “simple” lesions, that is, late closure of atrial septal defects (ASDs), may present with reduced exercise capacity, albeit at a later stage (after the third to fourth decade of life).
Mechanisms of Heart Failure in Adult Congenital Heart Disease
Identification of the mechanisms responsible for exercise intolerance, both cardiac and extracardiac, is essential in the management of ACHD patients, because they can become targets for therapies.
Cardiac Causes of Exercise Intolerance in Adult Congenital Heart Disease
Ventricular Dysfunction
Cardiac dysfunction is the most obvious cause of exercise intolerance and heart failure in ACHD. A reduction in cardiac output may occur through a reduction in ventricular function (reduced stroke volume) or through inability to increase heart rate to meet demands. Myocardial dysfunction is common in ACHD and can be caused by ventricular overload, myocardial ischemia, and pericardial disease ( Fig. 7.1 ). It can also occur through the effects of medication, permanent pacing, and endothelial and neurohormonal activation.
Hemodynamic overload of one or both ventricles resulting from obstructive or regurgitant lesions, shunting, or pulmonary or systemic hypertension is common in ACHD. This overload is, by definition in ACHD, long standing, and can lead to severe ventricular dysfunction, as is found in patients with a systemic right ventricle 10 to 30 years after atrial switch repair of (d-)transposition of the great arteries or after the third decade of life in congenitally corrected (l-)transposition of the great arteries, and in patients with Fontan-type circulation. Right ventricular systolic dysfunction is common in patients with significant volume overload such as those with large ASDs or patients with tetralogy of Fallot and severe pulmonary regurgitation. Ventricular dysfunction can also result from repeated cardiac surgery, anomalous coronary circulation, and abnormal myocardial perfusion, as has been documented in patients after atrial or arterial switch repair for (d-)transposition of the great arteries. Ventricular-ventricular interaction is not uncommon in ACHD, with right-sided lesions often affecting the left ventricle and vice versa. Significant ventricular interaction is most pronounced in patients with Ebstein anomaly, in whom the left ventricle typically appears small, underfilled, and hypokinetic, almost “compressed” by the dilated right ventricular cavity.
Ventricular dysfunction may also be triggered or exacerbated by arrhythmias, permanent pacing, and medication. ACHD patients have an increased propensity for arrhythmias resulting from intrinsic abnormalities of the conduction system, long-standing hemodynamic overload, and scarring from reparative or palliative surgery. Arrhythmias can lead to significant hemodynamic compromise, especially in the presence of myocardial dysfunction, and can become life threatening, especially when fast or ventricular in origin. Even relatively slow supraventricular tachycardias may cause a reduction in cardiac output and exercise capacity through loss of atrioventricular synchrony, especially when long standing.
Diastolic dysfunction is also an important component of ACHD and can affect exercise capacity and ventricular response to overload. A significant number of patients after repair of tetralogy of Fallot present with restrictive right ventricular physiology, which is related to decreased predisposition to right ventricular dilation in the presence of significant pulmonary regurgitation. However, it is associated with low cardiac output and prolonged inotropic and volume support immediately after surgery in this population. In patients with a univentricular heart, the presence of a rudimentary chamber may affect the regional contractility of the dominant ventricle and affect relaxation and diastolic filling. Moreover, patients with diastolic dysfunction may also do worse following a Fontan-type procedure. However, evaluation of diastolic properties across the spectrum of cardiac anatomies is difficult because there are no established criteria for this population. Moreover, no data are available on the pharmacologic management of diastolic dysfunction in the ACHD population.
Acquired disease superimposed on the congenitally abnormal heart may also cause deterioration of myocardial dysfunction. Infective endocarditis, systemic hypertension, coronary atherosclerosis, myocarditis, alcohol or other substance abuse (ie, cocaine), and diabetes mellitus may all trigger or aggravate myocardial dysfunction in ACHD. Infective endocarditis, in particular, is not uncommon in ACHD, and can have devastating short- and long-term effects, especially in high-risk patients with multiple hemodynamic lesions and/or ventricular dysfunction.
The prevalence of significant coronary artery disease does not appear to be increased in ACHD patients. However, as this population ages, coronary artery disease should be considered when ventricular dysfunction is encountered, and traditional cardiovascular risk factors for coronary atherosclerosis should be addressed.
Chronotropic Incompetence
The chronotropic response to exercise is a major contributor to the increase in cardiac output, more so than the increase in myocardial contractility. Chronotropic incompetence may be defined as the inability to increase heart rate appropriate to the degree of effort and metabolic demands. Chronotropic incompetence is common in ACHD, was encountered in 62% of ACHD patients in one series, and can be a result of intrinsic abnormalities of the conduction system or be iatrogenic. In the ACHD population, chronotropic incompetence is related to the severity of exercise intolerance, plasma natriuretic peptide levels, and peak oxygen uptake. Chronotropic incompetence also has prognostic implications in patients with ischemic heart disease and is a strong predictor of mortality in ACHD patients, especially those with “complex” lesions, Fontan-type surgery, and repaired tetralogy of Fallot.
Medication such as beta-blockers, calcium channel blockers, and antiarrhythmics can have significant negative inotropic and chronotropic effects and can affect ventricular performance and exercise capacity. Medication can also unmask latent conduction system disease and lead to sinus node dysfunction, atrioventricular block, or chronotropic incompetence.
Permanent pacing can also affect cardiac output through chronotropic incompetence and ventricular dysfunction. ACHD patients with permanent pacemakers were, in fact, found to have significantly lower peak heart rates and a trend toward lower peak VO 2 levels compared with those without. Pacemaker therapy is often required in ACHD for atrioventricular block, common in patients with atrioventricular septal defects or corrected transposition of the great arteries and immediately after surgical repair of a ventricular septal defect or muscle bundle resection. Sinus node dysfunction requiring permanent pacing is also common after a Fontan operation or atrial switch repair for complete transposition of the great arteries. Dual-chamber pacemakers are most commonly used to avoid atrioventricular asynchrony, but this is not always possible in patients with complex anatomy. Moreover, despite advances in rate-responsive pacemakers, rate responsiveness at higher levels of exercise in younger patients may be inadequate to produce a sufficient increase in cardiac output. Right ventricular pacing can also cause ventricular asynchrony and in the noncongenital population has been shown to cause long-term left ventricular dysfunction and reduced exercise capacity. The development of sophisticated pacing technologies that encourage more intrinsic conduction, thus minimizing ventricular pacing, holds promise for ACHD patients.
Extracardiac Causes of Exercise Intolerance in Adult Congenital Heart Disease
Parenchymal and vascular lung disease are important contributors to exercise intolerance in ACHD. Subnormal forced vital capacity has been reported in patients with Ebstein anomaly, tetralogy of Fallot, corrected transposition of the great arteries, Fontan operation, and atrial repair of complete transposition of the great arteries, but even in patients with ASDs. Lung disease affects exercise capacity. Percent FEV 1 has, in fact, been shown to be a powerful predictor of exercise capacity in the ACHD population. Furthermore, lung dysfunction, which is common in ACHD patients, is a predictor of mortality. Prior surgery with lung scarring, atelectasis, chest deformities, diaphragmatic palsy, pulmonary vascular disease with loss of distensibility of the peripheral arteries, and significant cardiomegaly are possible mechanisms for the abnormal pulmonary function observed in ACHD.
Pulmonary Arterial Hypertension and Cyanosis
Patients with Eisenmenger physiology are by far the most symptomatic ACHD patients. Most are in New York Heart Association (NYHA) functional class II or higher at a median age of 28 suggesting a detrimental effect of cyanosis and pulmonary hypertension. Patients with complex univentricular anatomy are also highly symptomatic, especially in the presence of significant cyanosis.
Both cyanosis and pulmonary hypertension significantly affect exercise capacity and the ventilatory response to exercise. In unrepaired cyanotic patients with unrestricted defects, an increase in cardiac output is obtained through shunting, at the expense of further systemic desaturation. At the onset of exercise, oxygen consumption fails to increase because of the inability to sufficiently increase pulmonary blood flow. Ventilation increases abruptly and excessively, resulting in alveolar hyperventilation. Although ventilation is increased throughout exercise, ventilatory efficiency is significantly decreased. Pulmonary hypoperfusion, an increase in physiological dead space through right-to-left shunting and enhanced ventilatory reflex sensitivity are mechanisms contributing to the ventilatory inefficiency and the failure to meet oxygen requirements in ACHD patients with cyanosis and pulmonary arterial hypertension.
The effect of cyanosis on exercise capacity and ventilation is difficult to distinguish from that of pulmonary hypertension. Significant ventilatory inefficiency has also been described in patients with idiopathic pulmonary hypertension, in the absence of right-to-left shunting. Despite being “inefficient” and likely contributing to the early onset of dyspnea, the exaggerated ventilatory response to exercise in cyanotic ACHD patients appears appropriate from a “chemical” point of view because it succeeds in maintaining near-normal arterial partial pressure of carbon dioxide (PCO 2 ) and pH levels in the systemic circulation despite significant right-to-left shunting, at least during mild to moderate exertion.
Anemia and Iron Deficiency
In acquired heart failure, anemia relates to exercise capacity and is a predictor of outcome. Anemia results in reduced oxygen carrying capacity and a premature shift to anaerobic metabolism during exercise and can precipitate heart failure by affecting myocardial function and volume overload. Anemia in ACHD can occur as a complication of chronic anticoagulation, surgery or intervention, hemolysis because of prosthetic valves, intracardiac patches or endocarditis, or hemoptysis in patients with severe pulmonary arterial hypertension. Moreover, anemia can occur because of chronic renal failure or as anemia of chronic disease. Similar to acquired heart failure, anemia is associated with a higher risk of death in noncyanotic ACHD patients.
In cyanotic patients, anemia as conventionally defined is rare. Chronic hypoxia typically results in an increase in erythropoietin production and an isolated rise in the red blood cell count (secondary erythrocytosis), which augments the amount of oxygen delivered to the tissues. Relative anemia, that is, an inadequate rise in hemoglobin levels despite chronic cyanosis, can occur as a result of iron deficiency and can have important detrimental effects on exercise capacity. No universally accepted algorithm for the calculation of “appropriate” hemoglobin levels exists, and diagnosis of relative anemia is based on serum ferritin and transferrin saturation. Iron supplementation in these patients is associated with an improved exercise capacity and quality of life.
Quantification and Follow-Up of Exercise Intolerance
The first step in assessing exercise intolerance is quantification of its severity. This can be achieved by subjective (describing patients’ perception of their limitation) or objective means. The most commonly used scale for quantifying subjective limitation in ACHD is the NYHA classification (and the almost identical World Health Organization [WHO] classification for patients with pulmonary hypertension). This scale is preferred because it is familiar to adult cardiologists and is simple and easy to apply. When compared with objective measures of exercise capacity, the NYHA classification is able to stratify ACHD patients according to their exercise capacity, but overall tends to underestimate their degree of impairment. In fact, many asymptomatic (NYHA I) ACHD patients have dramatically lower objective exercise capacity compared to normal controls, which is similar to that of much older patients with acquired heart failure. It appears that ACHD patients tend to be less aware of their exercise limitation because it has occurred over several decades rather than abruptly, as occurs in acquired heart failure. This apparent unawareness of significant exercise limitation in many ACHD patients may impact the timing and type of therapeutic interventions, possibly supporting a “sooner rather than later” approach. In particular, patients with right-sided lesions, such as patients with severe pulmonary regurgitation after repair of tetralogy of Fallot, tend to remain asymptomatic or very mildly symptomatic for long periods, even in the presence of significant right ventricular dilation and dysfunction. It is, thus, important that objective means of assessment such as cardiopulmonary exercise testing be used for the routine clinical assessment of ACHD patients and aid in the decision making when considering elective surgery. Moreover, the NYHA class is not a tool for assessing quality of life, and is thus not a substitute for a quality-of-life questionnaire (eg, Cambridge Pulmonary Hypertension Outcome Review [CAMPHOR] or the more recently introduced emPHasis-10 score for patients with pulmonary arterial hypertension).
Objective Quantification of Exercise Capacity
Cardiopulmonary Exercise Testing
The best method for quantifying exercise tolerance in health and disease is cardiopulmonary exercise testing. It is a powerful tool for the objective assessment of the cardiovascular, respiratory, and muscular systems and has become part of the routine clinical assessment of ACHD patients. Incremental (ramp) protocols are used to assess functional and prognostic indices such as the peak oxygen consumption (peak VO 2 ), the VE/VCO 2 slope (the slope of the regression line between ventilation [VE] and rate of elimination of carbon dioxide [VCO 2 ]), the anaerobic threshold, and the heart rate and blood pressure response.
Peak VO 2 is the highest value of oxygen uptake recorded during maximal exercise testing and approximates the maximal aerobic power of an individual, ie, the upper limit of oxygen utilization by the body ( Fig. 7.2 ). It is usually expressed in mL/kg per minute and reflects the functional status of the pulmonary, cardiovascular, and muscular systems. In fact, during steady state, oxygen uptake from the lungs reflects the amount of oxygen consumed by the cells in the periphery. Peak VO 2 is the most reported exercise parameter because it is simple to interpret and carries prognostic power in acquired heart failure and ACHD. However, peak VO 2 can only be reliably estimated from maximal exercise tests and is limited by the ability and determination of a patient to exercise to exhaustion. Moreover, it can be prone to technical error and artifacts because it is derived from measurements that are recorded only during the last minute of exercise (peak).
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