Heart failure is a complex pathophysiology that generally involves many noncardiac organs and organ−organ interactions (Fig. 4.2). Furthermore, postoperative ACHD patients have unique complexities that may involve pulmonary, autonomic, myocardial, conduction, arterial, and renal dysfunction as described below.

The central nervous system controls the cardiovascular system through projecting sympathetic and parasympathetic nerves. In healthy adults, sympathetic and parasympathetic activities are well balanced. In non-ACHD HF patients, sympathetic dominance occurs because of diminished parasympathetic (vagus) nerve activity [11, 12]. This imbalance is usually proportional to HF severity and thus predicts prognosis. In healthy adults, low systemic blood pressure is sensed by the arterial baroreflex center, and HR increases through the suppression of vagal inputs (reduced vagal tone). Sympathetic dominance in HF can be detected by the high washout ratio of the norepinephrine analogue metaiodobenzylguanidine (MIBG) as measured by scintigraphy, which reflects the accelerated turnover of norepinephrine at sympathetic nerve terminals. These physical phenotypes of HF, low systemic blood pressure, high HR, loss of HR variability, and high washout ratio of MIBG usually parallel HF severity and predict poor prognosis [13]. Thus, assessing CANA status provides useful information on HF pathophysiology in typical non-ACHD patients.

However, the associations between CANA and HF severity differ in postoperative ACHD because of the inevitable damage to sympathetic nerves during cardiac surgery, which interrupts central nervous system signals to great vessels, conduction systems, and atrial and ventricular myocardia ([14], Fig. 4.3). The type and number of cardiac surgeries determine the degree of CANA abnormality. These abnormalities are mainly due to surgical denervation, and severe CANA abnormality can resemble that after cardiac transplantation. The effects of sinus node and ventricular myocardium denervation and damage are detailed below.

The etiologies of ventricular dysfunction include pressure overload due to outflow stenosis, volume overload due to valvular regurgitation and intra/extracardiac shunting, hypoxia before definitive repair, the intrinsic problem of RV myocardium as a systemic ventricle, ischemia due to coronary artery stenosis, tachycardia-induced dysfunction, and intra/interventricular dyssynchrony [5]. In addition, the restrictive changes of the ventricle due to pericardial adhesion and myocardial fibrosis have adverse influences on ventricular function and make HF pathophysiology more complex in postoperative ACHD patients [18, 19].

Pharmacological approaches have limited efficacy in the management of pressure and volume overload due to structural abnormalities; hence, surgical or catheter-based interventions may be required in some ACHD patients. Pulmonary valve replacement (PVR) is one of these interventions [20]; however, the optimal timing of this procedure is still debated. Late definitive repair may predispose cyanotic patients to a subclinical progression of myocardial fibrotic change due to long-standing hypoxia and volume overload [21]. Right ventricular and tricuspid valve (TV) functions should be carefully monitored in ACHD patients with RV as a systemic ventricle to assess suitability for anatomical tricuspid valve replacement.

The conventional anti-HF strategy using angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) and β blockers may be effective for dilated LV with systolic dysfunction in some ACHD patients with relative tachycardia. However, these strategies may be harmful in postoperative ACHD patients with sinus node dysfunction and ventricular restrictive physiology. Furthermore, the long-term efficacy of these conventional strategies is uncertain for subpulmonary ventricular systolic and diastolic dysfunctions. In these scenarios, atrial pacing with appropriate HR corresponding to HF severity may be effective, although finding the optimal HR may be challenging.

Cardiac resynchronized therapy (CRT) has been applied to postoperative ACHD HF patients with some efficacy [22]. The electrophysiological assessment of QRS duration or various imaging modalities may reveal ventricular dyssynchrony; however, a standard diagnostic method has not been established, especially for patients with non-LV as a systemic ventricle. CRT focusing on the longitudinal direction in systemic RV or the site opposite two-chamber dyssynchrony in Fontan circulation with unbalanced ventricles may be effective for some cases [23].

Right ventricular restrictive physiology characterized by end-diastolic forward flow in the main pulmonary artery is a pathophysiology unique to postoperative ACHD patients, especially repaired TF patients; however, the clinical significance is controversial [24, 25]. The restrictive pathophysiology is one phenotype of the RV diastolic dysfunction and may differ from other types of RV diastolic dysfunction characterized by other criteria, such as HF with preserved RV ejection fraction [18, 19], a more severe subtype of RV pathophysiology. Management strategies for these diastolic dysfunctions are not yet established as the strategies have not been established in HF with preserved LV ejection fraction.

Electrophysiological abnormalities are often associated with atrial and/or ventricular remodeling. The QRS duration reflects RV volume in postoperative TF and systemic ventricular volume in Fontan patients [26–29]. Fragmented QRS complex in adult patients with Ebstein anomaly is associated with risk of arrhythmia and with the severity of the anomaly [30]. The electropathophysiology and its relations with clinical profiles and management strategies are further described in Chap. 5.

In the general population, metabolic disorders and obesity lead to endothelial dysfunction, which increases the risk of arteriosclerosis. In turn, arteriosclerosis and hypertension are strong factors predisposing to HF. Arteriosclerosis and hypertension also contribute to HF in ACHD patients. In addition, stiffened dilated ascending aorta, histologically characterized by medial necrosis in the aortic wall, i.e., aortopathy, resembling that of Marfan syndrome, has been described in various types of ACHD, particularly TF [31]. The stiffened dilated aorta has adverse impacts on ventricular function by augmenting blood pressure reflection and decreasing diastolic pressure, i.e., greater pulse pressure, resulting in ventricular pressure overload with impaired coronary perfusion [32]. This may in turn reduce exercise capacity [33] and contribute to metabolic syndrome, obesity, hypertension, arteriosclerosis, and ultimately HF. As demonstrated in Marfan syndrome, ACEIs/ARBs may be beneficial by preventing further progression of aortopathy in some selected ACHD patients.

Renal dysfunction due to cardiovascular disease, termed cardiorenal syndrome, has a strong impact on cardiovascular prognosis [34]. ACHD patients are categorized as typical type II cardiorenal syndrome when chronic cardiac problems lead to renal dysfunction [35, 36]. Elevated central venous pressure (CVP) in ACHD patients with right-sided HF causes renal congestion, whereas low systemic blood pressure results in lower perfusion pressure in the kidney. This vicious interaction may be associated with poor cardiovascular prognosis [37].

Sinus node dysfunction with blunted HR response and stiffened arterial and venous vessels are frequently combined in postoperative ACHD patients [9, 38, 39]. As a result, all organs are perfused through stiffened great vessels by a cardiovascular system with a limited ability to homeostatically regulate cardiac output, especially during stress. For instance, dehydration by any cause may lead to prerenal failure because of impaired baroreflex function, sinus node dysfunction, and less compliant vessels.

Impaired exercise capacity is one of the cardinal features of chronic HF. The causes of this impairment are multifactorial [6]. Peak oxygen uptake (VO₂) during cardiopulmonary exercise testing (CPX) is the gold standard metric of exercise capacity. The following equations explain the major determinants of peak VO₂:

where, CO = cardiac output, AVO₂D = arteriovenous oxygen content difference, EDV = ventricular end-diastolic volume, EF = ventricular ejection fraction, HR = heart rate, Hb = hemoglobin level, SaO₂ = arterial oxygen saturation, SvO₂ = mixed venous oxygen saturation, AOP = arterial pressure, PAP = pulmonary pressure, Rs = systemic artery resistance, and Rp = pulmonary artery resistance. The parameters EDV•EF, HR, Hb, SaO₂, and SvO₂ reflect cardiac function, sinus node function and CANA, oxygen transport capacity, pulmonary gas exchange, and peripheral factors, including skeletal muscle metabolism, respectively. The resistance terms Rs and Rp reflect the endothelial function of the systemic and pulmonary arteries, respectively. In addition, ventricular morphology, the synchronicity of ventricular contraction, and AV valve function also have significant impacts on peak VO₂. Perioperative myocardial insults, such as fibrotic change and diastolic restriction due to pericardial adhesion and/or calcification, are major causes of ventricular diastolic dysfunction, leading to limited EDV and impaired exercise capacity [18]. Thoracic surgeries, including palliative operations, inevitably cause restrictive ventilatory impairment, which is one reason for ventilation/perfusion mismatch in the lung and for small tidal volume during exercise. Small tidal volume leading to rapid-and-shallow respiration also increases dead space ventilation during exercise, which is in part responsible for low SaO₂ in some ACHD patients. Oxygen is consumed mainly by skeletal muscle during exercise; therefore, deconditioning (disuse) atrophy of skeletal muscle is a major reason for low peak VO₂ in chronic diseases, including cardiovascular disease [40]. At the same time, reduced skeletal muscle bulk impairs muscle blood pumping, which normally plays a crucial role in preserving cardiac preload during exercise. Furthermore, a stiffened aorta adversely impacts ventricular function due to augmented reflex pressure and diminishes vascular volume reserve capacity, both of which may also reduce exercise capacity [33, 41, 42]. Reduced peak VO₂ is closely associated with poor prognosis in ACHD patients; therefore, interventions that increase exercise capacity, such as aerobic exercise training, may improve prognosis.

Biomarkers are important assessment tools for HF severity in ACHD patients [43]. The clinical significance of plasma natriuretic peptide (NP) levels, especially brain NP (BNP), has been most intensively studied and validated in some cases. However, the clinical utilities of other possible markers, such as catecholamines and renin–angiotensin–aldosterone system hormones, have not been as extensively examined. Plasma NP levels are already increased in asymptomatic ACHD patients with HF irrespective of whether RV is a subpulmonary or systemic ventricle. The determinants of elevated plasma NP include RV volume overload due to intracardiac shunting, pulmonary and/or AV valve regurgitation, RV dysfunction due to pressure overload, and hypoxia due to unrepaired complex lesions or Eisenmenger syndrome (ES). Plasma NP levels are frequently lower in postoperative ACHD patients than in adults with non-ACHD HF even if NYHA class is equivalent [9, 18, 44], and the cutoff value for prognosis is usually lower in postoperative ACHD patients because of the restrictive physiology. Nevertheless, the high levels of NP and catecholamine predict poor prognosis, including mortality in ACHD patients with NYHA class ≥ III [unrepaired, ES, and pulmonary hypertension (PH)] [45]. In particular, a progressive increase in plasma BNP during follow-up strongly predicts mortality [46, 47]. However, evidence for the prognostic efficacy of biomarkers is mainly based on studies including a relatively small number of ACHD patients with mild HF, mostly NYHA class ≥ II (repaired TGA or TF patients). These limitations weaken the associations between biomarker levels and cardiac function. However, in adult Fontan patients, the high plasma levels of NP and catecholamines are associated with poor prognosis [48, 49]. In addition, BNP reflects RV volume reduction after PVR and improved PH after medical treatment [50, 51]. Therefore, measuring plasma biomarkers can provide clinically useful information for assessing HF pathophysiology, especially in complex ACHD patients. Although the clinical significance of higher plasma NP for assessing ACHD patients with stretched atrial and/or ventricular myocardium (congestive HF) is well established, abnormally low NP may be a reflection of ventricular underfilling due to low cardiac output, for instance, from dehydration, which is also a critical pathophysiology. Thus, comprehensive HF assessment by multiple modalities, including physical examination, is mandatory for the care of ACHD patients.

The unique HF pathophysiology of ACHD characterized by surgery-related CANA abnormality and restrictive ventricular function is presented schematically in Fig. 4.4, together with a comparison of clinical variables among postoperative patients with CHD, those with dilated cardiomyopathy (DCM, no surgery), and healthy controls. The two patient groups are comparable in terms of systemic ventricular EF and functional capacity. However, they show distinct hemodynamics, CANA variables, and plasma BNP levels. Finally, HF pathophysiology is summarized in Fig. 4.5. Some of these pathophysiological features are, to some extent, applicable to the following specific postoperative ACHDs.

Dextro-TGA (d-TGA) is the most common cyanotic CHD followed by TOF. It is managed by atrial switch operation (Mustard/Senning procedure: venous switch operation [VSO]) or arterial switch operation (Jatene procedure). VSO contributed to the dramatically improved survival rate of d-TGA in the 1960s. However, long-term postoperative pathophysiology has emerged that includes RV dysfunction as well as TR and rhythm disturbance [26, 76, 77]. Congenitally corrected TGA (c-TGA) is a rare form of CHD with pathophysiology resembling that of d-TGA after VSO in which RV acts as a systemic ventricle and features RV dysfunction, TR, and arrhythmias [78]. Congenitally c-TGA patients frequently have combined lesions, such as pulmonary stenosis, ventricular septal defect, Ebstein anomaly, and AV block, all of which have significant negative impacts on prognosis.

The overall 40-year post-VSO survival rate is approximately 50%; however, the survival rate is approximately 70% if the patient survives the immediate postoperative period [76]. Although the impact of atrial switch procedure type, either Mustard or Senning, on mortality is still unclear, combined lesion(s), pulmonary stenosis, and ventricular septal defects increase mortality [76]. In adult c-TGA patients, the prevalence of clinical HF and moderate to severe RV dysfunction at 45 years of age is 25–30% for those without combined lesions and 60–70% for those with substantial combined lesions [78]. The possible etiologies of RV dysfunction include myocardial ischemia and infarction [79, 80] associated with reduced coronary flow reserve and the resulting limitation on exercise capacity as well as the single coronary physiology of RV [81, 82]. Systemic RV fibrosis is associated with ventricular dysfunction and poor prognosis [77], although the cause of RV fibrosis remains unclear. However, a causal relationship between RV dysfunction and TR has not been established.