Outline
Epidemiology, 363
Diagnosis, 363
Treatment, 366
Cardiac Resynchronization Therapy and Implantable Defibrillators in Adult Congenital Heart Disease, 368
Cardiac Resynchronization Therapy in Specific Populations, 369
Transplantation and Mechanical Support, 370
Exercise Training in CHD, 371
Specific Conditions, 372
Summary, 375
Adults with congenital heart disease (CHD) have multiple mechanisms placing them at risk for heart failure, leading one author to refer to CHD as “the original heart failure syndrome.” These mechanisms include chronic pressure and/or volume loading, inadequate myocardial preservation during prior surgeries, myocardial fibrosis, surgical injury to a coronary artery, and neurohormonal activation. The number of heart failure–related admissions for adult congenital heart disease (ACHD) patients has increased steadily and heart failure–related complications are the most common cause of death in these patients. However, ACHD patients are commonly excluded from heart failure clinical trials and there are few data to guide therapy in this growing population. Due to the increasing recognition of this problem, in 2016, the American Heart Association published two scientific statements focused on chronic heart failure and transplant and mechanical circulatory support in the CHD population. This chapter will discuss the growing number of ACHD patients at risk for heart failure, unique aspects of diagnostic testing and therapies in this group, and highlight several types of CHD at the highest risk for the development of heart failure.
Epidemiology
Due to tremendous advances in the diagnosis and management of CHD, there are now more adults than children alive with CHD; the prevalence of CHD is approximately 4/1000 adults. These advances have shifted mortality away from infants and towards adults living with CHD. The number of adults with CHD living in the United States is estimated to be at least 1.4 million, and at least 300,000 of these people have complex forms of CHD.
There is also an increased recognition of heart failure–related complications in ACHD patients, and certain centers have developed specialized ACHD-HF dedicated clinics. However, the reported prevalence of heart failure in ACHD patients is likely an underestimate due to challenges in making the diagnosis and the gaps in care for ACHD patients. The prevalence of heart failure is highest in patients with complex anatomy, including single ventricle physiology, transposition of the great arteries (TGA), tetralogy of Fallot (TOF), and pulmonary hypertension ( Fig. 27.1 ). Risk factors for the development of heart failure include high disease complexity, older age, more reoperations, and right ventricular dysfunction.
Heart failure is the leading cause of death in ACHD patients, particularly those with complex anatomy ( Fig. 27.2 ). In a cohort of 188 ACHD patients with a systemic right ventricle (RV) or single ventricle, 15-year mortality for symptomatic patients was much greater than those without symptoms (47.1% vs. 5%). Zomer reported that ACHD patients admitted for heart failure had a five-fold higher risk of mortality than patients who were not hospitalized (HR = 5.3; 95% CI 4.2–6.9). One- and three-year mortality after the first heart failure admission were 24% and 35%, respectively. In a single-center, retrospective study of almost 7000 adult patients with CHD with a median follow-up of over 9 years, the median age of death was 47 years, and the leading cause of death was heart failure. Additionally, heart failure in ACHD patients is associated with increased morbidities and health care resource utilization. In an analysis of the Nationwide Inpatient Sample (NIS), the number of heart failure–related admissions increased 82% from 1998 to 2005 in adults with CHD. More recently, a review of the 2007 NIS reported that heart failure accounted for 20% of the total ACHD admissions, and that heart failure–related hospitalizations were associated with a three-fold increased risk of death compared to non-heart-failure admissions.
Diagnosis
Heart failure symptoms in ACHD patients may manifest as systolic and/or diastolic dysfunction of a morphological left, right, or single ventricle. Other CHD patients may have normal ventricular function, but signs of end-organ dysfunction, such as the adult single ventricle patient with Fontan physiology, and significant liver disease.
The diagnosis of heart failure in ACHD patients is often challenging. Patients with CHD, having lived their lives with cardiac disease, may not detect subtle changes in their exercise capacity. By the time they notice symptoms, the extent of ventricular dysfunction and valve disease may be severe and irreversible. Compared to patients with acquired heart disease, patients with CHD are more likely to overestimate their functional capacity and underreport heart failure symptoms. Therefore, objective measures of ventricular function through imaging, exercise testing, and serum biomarkers can be helpful in these patients. Exercise testing can be useful to uncover early signs of heart failure, even in patients who report that they are asymptomatic ( Fig. 27.3 ). Patients with CHD and heart failure should be referred to a center with expertise in the care of these patients.
Imaging (see also Chapter 32 )
The imaging diagnosis of heart failure in ACHD patients may be challenging, and a multimodality approach is often utilized. The goals of diagnostic imaging in ACHD patients are to evaluate ventricular performance, identify anatomic and functional abnormalities, assess their severity, and provide information that informs clinical decisions. This includes identifying residual hemodynamic issues, such as valve dysfunction and shunts, and evaluating for pulmonary hypertension.
Echocardiography
Echocardiography remains the first-line modality in CHD imaging; however, acoustic windows are often poor in older patients and those with multiple prior cardiac surgeries. It is often challenging to visualize certain parts of the right heart, which limits assessment of RV size and function.
Assessment of ventricular size and function is important in the ACHD patient. Left ventricular (LV) function is most often calculated as the ejection fraction (EF) based on the biplane Simpson or area–length method, both of which assume an ellipsoid shape of the ventricle. These methods are not applicable to the RV or single ventricle patient due to the nonellipsoid shape of the ventricle. There are various echocardiographic techniques that can be used to evaluate RV function. A normal RV fractional area change is >35%. Three-dimensional echocardiography may provide a more accurate and reproducible quantification of RV volumes and function. However, it underestimates RV volumes and may overestimate EF, which is a discrepancy that may increase as the ventricle enlarges.
Cardiac Magnetic Resonance Imaging
The role of CMR is steadily increasing in the ACHD population and CMR has become the gold standard for quantification of RV volumes and function. Phase-velocity imaging is utilized for the assessment of cardiac output and valvular regurgitation. An additional strength of CMR is the ability to characterize myocardial tissue abnormalities. Specifically, late gadolinium enhancement suggestive of myocardial fibrosis has been associated with adverse clinical outcomes in patients with repaired TOF, systemic RV, and Fontan procedures. Quantification of the extracellular volume fraction using the modified look–locker inversion recovery sequence may identify areas of more diffuse fibrosis. However, the clinical significance in ACHD patients is unknown.
Cardiopulmonary Exercise Testing
Cardiopulmonary exercise testing is a valuable tool in the assessment of ACHD patients at risk for heart failure. Objective testing is important in this population, as ACHD patients commonly overestimate their actual measured exercise capacity and are unaware of functional limitations. Cardiopulmonary exercise testing is predictive of morbidity and mortality in CHD patients. In a recent single-center experience of cardiopulmonary exercise testing in 1375 ACHD patients (age 33±13 years), decreased peak oxygen consumption (VO 2 ) and heart rate reserve were predictive of death over a median follow-up of 5.8 years. Additionally, an elevated minute ventilation/volume of carbon dioxide (VE/VCO 2 ) slope was associated with an increased risk of death in noncyanotic patients. Diller reported the results of objective exercise testing in 335 ACHD patients, and demonstrated that these patients, with a mean age of 33 years, had a similar distribution of heart failure symptoms and exercise capacity to a noncongenital heart failure population at a mean age of 49 years (see Fig. 27.3 ).
ACHD patients may have limited exercise capacity due to both cardiac and non-cardiac etiologies. Ventricular dysfunction (both systolic and diastolic) and electromechanical dyssynchrony are increasingly recognized in ACHD patients. Residual hemodynamic lesions are common in ACHD patients, as almost no one who undergoes CHD surgery is “cured.” Chronotropic incompetence is common in ACHD patients, often secondary to injury of the conduction system during surgery, intrinsic conduction abnormalities, or medications, and is associated with increased mortality. Adults with CHD may have noncardiac limitations to exercise capacity. Restrictive lung disease is very common in those who have undergone thoracotomies. Obstructive lung disease, diaphragmatic paralysis (due to phrenic nerve injury), liver dysfunction, skeletal muscle dysfunction, and hematological derangements can also limit exercise capacity.
One of the challenges in interpreting the results and prognostic significance of cardiopulmonary exercise testing in ACHD patients is that the group is very heterogeneous. Kempny has published age- and gender-specific reference values for peak VO 2 for groups of ACHD patients with various congenital heart conditions ( Fig. 27.4 ). ACHD patients have elevations in the VE to VCO 2 production slope, and this finding is an independent predictor of mortality. An elevated VE/VCO 2 slope may be in seen in repaired TOF patients, when there is abnormal pulmonary blood flow distribution due to branch pulmonary artery stenosis. However, an elevated VE/VCO 2 slope is not associated with increased mortality in single ventricle patients who have undergone a Fontan procedure, where the elevation in the slope is a consequence of nonpulsatile pulmonary blood flow. Additionally, Fontan patients commonly have a depressed oxygen pulse, even in the absence of ventricular dysfunction, indicating a failure of the Fontan to increase preload to the systemic ventricle during exercise.
Biomarkers (see also Chapter 33 )
ACHD patients with heart failure experience neurohormonal activation similar to those patients with heart failure from acquired heart disease. However, because of the diversity of CHD and the various mechanisms of heart failure in ACHD patients, there is no consistent association of individual serum biomarkers to outcomes, which can be generalized across all ACHD patients. Even asymptomatic ACHD patients may have significant neurohormonal activation, which demonstrates the occult nature of ventricular dysfunction in this group of patients. Over the past decade, multiple investigators have reported results of abnormal biomarkers in ACHD patients that have been associated with mortality. However, since natriuretic peptides are influenced by age, gender, and hypoxia, it is difficult to define normal levels for a diverse population of ACHD patients. N-terminal pro b-type natriuretic peptide (NT-proBNP) levels vary considerably by the type of underlying CHD, with the highest levels seen in patients with complex CHD such as Fontan physiology and systemic RV. Elevated NT-proBNP levels are predictive of adverse events across a broad range of congenital heart diagnoses. Patients with low levels have excellent clinical outcomes. Patients with high NT-proBNP have worse outcomes and can be further risk stratified by the level of high-sensitivity troponin-T and growth-differentiation factor 15.
The utility of serum biomarkers in patients with Fontan physiology remains uncertain. In these patients, symptoms of heart failure may occur despite normal systolic ventricular function and unremarkable biomarker values. BNP values have not been shown to correlate with ventricular systolic dysfunction in this group of patients. In one study of 106 Fontan patients, elevated BNP was found to be an independent predictor of Fontan failure and mortality in adulthood. Biomarkers also have not been effective as screening tools for Fontan-associated liver disease; FibroSure and hyaluronic acid levels are elevated in most patients with Fontan circulation, but the levels do not correlate with the degree of hepatic fibrosis.
Treatment
ACHD patients are commonly excluded from heart failure clinical trials and there are few data to guide therapy in this growing population. It may be tempting to simply extrapolate from established heart failure guidelines; however, this is dangerous because the mechanism of heart failure is often very different in ACHD than in the noncongenital population. For example, ACHD patients may have a systemic RV or a single ventricle. Additionally, ACHD patients are more likely to have a correctable anatomic abnormality causing heart failure—such as baffle obstruction, stenotic conduits—so standard medical therapy for heart failure may not be appropriate. Therefore the evaluation of new heart failure symptoms in an ACHD patient must be tailored to the patient’s anatomy and surgical repair. It should include evaluation for residual shunts, baffle stenosis, valvular or conduit dysfunction, and collateral vessels; each of these may be amenable to interventions. The effectiveness of medical therapy for heart failure in specific ACHD populations is discussed in more detail below.
All ACHD patients with new onset heart failure also should be evaluated for pulmonary vascular disease. In a population-based study of greater than 38,000 adults with CHD, subjects with pulmonary hypertension had a more than twofold higher risk of all-cause mortality and three-fold higher risk of heart failure and arrhythmias compared to those without pulmonary hypertension.
The treatment of heart failure in the ACHD patient also must address modifiable risk factors such as hypertension, diabetes, and obesity.
Potential therapies for heart failure in ACHD patients include medical therapies, device therapies, and surgical interventions, such as mechanical assist devices and transplantation. The existing data for medical therapies in ACHD patients are limited, as no adequately powered clinical trials have been performed. Individual studies focused on medical therapies will be discussed in the lesion-specific section below and are listed in Table 27.1 .
| Author | Year | Study design | Agent | N | Duration (months) | Endpoints | Results | ||
|---|---|---|---|---|---|---|---|---|---|
| Tetralogy of Fallot | |||||||||
| Norozi | 2007 | PDB-RCT | Bisoprolol | 33 | 6 | NT-proBNP, RVEF, LVEF | Negative | ||
| Babu-Nararyan | 2012 | PDB-RCT | Ramipril | 64 | 6 | RVEF | Negative | ||
| Bokma | 2017 | PDB-RCT | Losartan | 95 | 21 | RVEF, RV and LV volume, LVEF, VO 2 max, NT-proBNP, QOL | Negative for all predefined primary and secondary endpoints | ||
| Systemic RV | |||||||||
| Dore | 2005 | PDB-COT | Losartan | 29 | 3.5 | VO 2 max, RVEF, NT-proBNP | Negative | ||
| Giardini | 2007 | Prospective uncontrolled trial | Carvedilol | 8 | 12 | RVEF, LVEF, VO 2 max, exercise duration | Positive: In this very small uncontrolled trial, carvedilol led to improvements in biventricular size and function | ||
| Doughan | 2007 | Retrospective | Carvedilol or metoprolol | 60 | Retrospective | NYHA class, RV size | Positive: In this retrospective uncontrolled trial beta blockers led to improvement in NYHA class in patients with systemic right ventricle | ||
| Therrien | 2008 | PDB-RCT | Ramipril | 17 | 12 | RVEF, RVEDV | Negative | ||
| van der Bom | 2013 | PDB-RCT | Valsartan | 88 | 36 | Primary: RVEF Secondary: RVEDV, VO 2 max, QOL | Negative except for small benefit on RVEDV | ||
| Fontan | |||||||||
| Kouatli | 1997 | PDB-COT | Enalapril | 18 | 2.5 | VO 2 max, exercise duration | Negative | ||
| Giardini | 2008 | PDB-RCT | Sildenafil | 27 | Single dose | VO 2 max, cardiac output, pulmonary blood flow | Positive: Fontan patients who received a dose of sildenafil had an improvement in VO 2 max while patients who received a placebo did not | ||
| Goldberg | 2011 | PDB-COT | Sildenafil | 28 | 1.5 | Primary: VO 2 max Secondary: VE/VCO 2 slope | Negative for primary outcome; Sildenafil improved VE/VCO 2 slope, the secondary outcome | ||
| Hebert | 2014 | PDB-RCT | Bosentan | 65 | 3 | VO 2 max | Positive: Patients who received Bosentan had improvement in VO 2 max, exercise duration, and NYHA class while patients taking placebo did not | ||
| Rhodes | 2013 | PDB-RCT | Iloprost | 18 | Single dose | VO 2 max, O 2 pulse | Positive: Fontan patients who received a single dose of iloprost had improvement in VO 2 max and O 2 pulse while patients who took placebo had no improvement | ||
While the etiology and treatment options for heart failure are diverse in CHD, one proposed algorithm for evaluation and treatment is shown in Fig. 27.5 .
