Produção Nacional
Revisado por pares
Chronic Heart Failure in Congenital Heart Disease
2016; Lippincott Williams & Wilkins; Volume: 133; Issue: 8 Linguagem: Inglês
10.1161/cir.0000000000000352
ISSN1524-4539
AutoresKaren Stout, Craig S. Broberg, Wendy Book, Frank Cecchin, Jonathan M. Chen, Konstantinos Dimopoulos, Melanie D. Everitt, Michael Α. Gatzoulis, Louise Harris, Daphne T. Hsu, Jeffrey T. Kuvin, Yuk M. Law, Cindy M. Martin, Anne M. Murphy, Heather J. Ross, Gautam K. Singh, Thomas L. Spray,
Tópico(s)Cardiac Valve Diseases and Treatments
ResumoHomeCirculationVol. 133, No. 8Chronic Heart Failure in Congenital Heart Disease Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessResearch ArticlePDF/EPUBChronic Heart Failure in Congenital Heart DiseaseA Scientific Statement From the American Heart Association Karen K. Stout, MD, Chair Craig S. Broberg, MD, Co-Chair Wendy M. Book, MD Frank Cecchin, MD Jonathan M. Chen, MD Konstantinos Dimopoulos, MD, MSc Melanie D. Everitt, MD Michael Gatzoulis, MD, PhD Louise Harris, Daphne T. Hsu, MD, FAHA Jeffrey T. Kuvin, MD, FAHA Yuk Law, MD Cindy M. Martin, MD Anne M. Murphy, MD, FAHA Heather J. Ross, MD, MHSc Gautam Singh, and MD Thomas L. SprayMD, FAHAon behalf of the American Heart Association Council on Clinical Cardiology, Council on Functional Genomics and Translational Biology, and Council on Cardiovascular Radiology and Imaging Karen K. StoutKaren K. Stout , Craig S. BrobergCraig S. Broberg , Wendy M. BookWendy M. Book , Frank CecchinFrank Cecchin , Jonathan M. ChenJonathan M. Chen , Konstantinos DimopoulosKonstantinos Dimopoulos , Melanie D. EverittMelanie D. Everitt , Michael GatzoulisMichael Gatzoulis , Louise HarrisLouise Harris , Daphne T. HsuDaphne T. Hsu , Jeffrey T. KuvinJeffrey T. Kuvin , Yuk LawYuk Law , Cindy M. MartinCindy M. Martin , Anne M. MurphyAnne M. Murphy , Heather J. RossHeather J. Ross , Gautam SinghGautam Singh and Thomas L. SprayThomas L. Spray and on behalf of the American Heart Association Council on Clinical Cardiology, Council on Functional Genomics and Translational Biology, and Council on Cardiovascular Radiology and Imaging Originally published19 Jan 2016https://doi.org/10.1161/CIR.0000000000000352Circulation. 2016;133:770–801Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2016: Previous Version 1 Part I: General ConsiderationsIntroductionThe past 60 years have brought remarkable advancements in the diagnosis and treatment of congenital heart disease (CHD). Early diagnosis and improvements in cardiac surgery and interventional cardiology have resulted in unprecedented survival of patients with CHD, even those with the most complex lesions. Despite remarkable success in treatments, many interventions are palliative rather than curative, and patients often develop cardiac complications, including heart failure (HF). HF management in the setting of CHD is challenged by the wide range of ages at which HF occurs, the heterogeneity of the underlying anatomy and surgical repairs, the wide spectrum of HF causes, the lack of validated biomarkers for disease progression, the lack of reliable risk predictors or surrogate end points, and the paucity of evidence demonstrating treatment efficacy.The purposes of this statement are to review the literature pertaining to chronic HF in CHD and to elucidate important gaps in our knowledge, emphasizing the need for specific studies of HF mechanisms and improving outcomes for those with HF. In this document, the definition of CHD severity is the definition common in CHD documents, including the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines1 for the management of adults with CHD (Table 11–3). The definition of HF corresponds to that found in the multiple guidelines on diagnosis and management of HF. Although nuances and specific details may be controversial,4 the broad definition from the Heart Failure Society of America guidelines states the following: "In physiologic terms, HF is a syndrome characterized by either or both pulmonary and systemic venous congestion and/or inadequate peripheral oxygen delivery, at rest or during stress, caused by cardiac dysfunction."5 The definition of chronic HF in this document concurs with that of the European Society of Cardiology guidelines, which emphasize chronic HF (whether stable, progressively worsening, or decompensated) rather than acute HF. Although specific definitions of acute and chronic HF are not universally accepted, we focus here on chronic HF as a persistent syndrome that requires consideration of therapy to prevent progression, decompensation, or death.4Table 1. Classification of CHD DiagnosesGreat complexity Conduits, valved or nonvalved Cyanotic congenital heart (all forms) Double-outlet ventricle Eisenmenger syndrome Fontan procedure Mitral atresia SV (also called double inlet or outlet, common, or primitive) Pulmonary atresia (all forms) Pulmonary vascular obstructive disease TGA Tricuspid atresia Truncus arteriosus/hemitruncus Other abnormalities of atrioventricular or ventriculoarterial connection not included above (ie, crisscross heart, isomerism, heterotaxy syndromes, ventricular inversion)Moderately complex Aorto–left ventricular fistulas Anomalous pulmonary venous drainage, partial or total Atrioventricular septal defects (partial or complete) Coarctation of the aorta Ebstein anomaly Infundibular RV outflow obstruction of significance Ostium primum atrial septal defect Patent ductus arteriosus (not closed) Pulmonary valve regurgitation (moderate to severe) Pulmonary valve stenosis (moderate to severe) Sinus of Valsalva fistula/aneurysm Sinus venosus atrial septal defect Subvalvular or supravalvular aortic stenosis (except hypertrophic cardiomyopathy) TOF Ventricular septal defect with: Absent valve or valves Aortic regurgitation Coarctation of the aorta Mitral disease RV outflow tract obstruction Straddling tricuspid/mitral valve Subaortic stenosisSimple Native disease Isolated congenital aortic valve disease Isolated congenital mitral valve disease (eg, except parachute valve, cleft leaflet) Small atrial septal defect Isolated small ventricular septal defect (no associated lesions) Mild pulmonary stenosis Small patent ductus arteriosus Repaired conditions Previously ligated or occluded ductus arteriosus Repaired secundum or sinus venosus atrial septal defect without residua Repaired ventricular septal defect without residuaCHD indicates congenital heart disease; RV, right ventricular; SV, single ventricle; TGA, transposition of the great arteries; and TOF, tetralogy of Fallot.Data derived from Warnes et al1 and Connelly et al.2 Modified from Warnes et al3 with permission from the publisher. Copyright © 2001, American College of Cardiology.This document focuses on the mechanisms and treatment of myocardial dysfunction while recognizing that HF symptoms may be attributable to underlying hemodynamic abnormalities such as valve dysfunction, outflow obstruction, coronary abnormalities, or residual shunting. Therefore, all patients with CHD with HF symptoms should undergo a detailed hemodynamic assessment by CHD-experienced cardiologists for any reversible hemodynamic abnormalities and receive appropriately targeted interventions if possible. Treatment recommendations for HF caused by valve dysfunction or ischemic heart disease are addressed elsewhere in the respective ACC/AHA guidelines, including the 2008 guidelines on the care of the adult with CHD.1 Although this document focuses on HF treatment, palliative care should be considered a valuable and needed component of care in all patients with CHD and end-stage HF.6The content of this document covers the age spectrum of pediatric to adult patients with CHD and HF with input from both pediatric and adult cardiologists. However, the bulk of available literature focuses on adult patients, in whom there is a greater relative burden of HF, presumably reflecting the natural history of CHD. Thus, the majority of the discussion herein is more applicable to adults with CHD and HF, although, whenever possible, specific issues in pediatric patients are discussed.Some features of HF in CHD are common across diagnoses and are discussed in the general overview. However, special emphasis is given to topics with unique anatomic and physiological considerations, in particular patients in whom the right ventricle (RV) is more vulnerable, whether in the normal subpulmonic position or as the systemic ventricle, and patients with single-ventricle (SV) physiology. In addition, there are variations in pressure or volume loading of the left ventricle (LV) that are unique to CHD, which are discussed separately.OverviewIncidence of CHDStructural heart disease is the most common congenital disorder diagnosed in newborns, with birth prevalence reported to be 10 per 1000 live births,7,8 and registry studies have estimated an incidence between 3 and 20 per 1000 live births.9 The incidence of CHD based on birth prevalence may be an underestimate, however, because CHD is not necessarily apparent at birth, and the diagnosis may be made in childhood or adulthood. In fact, more than one quarter of CHD diagnoses are made after infancy.10Survival in Patients With CHDSurvival in children born with CHD has improved dramatically over the past several decades, in large part as a result of surgical advances for children with complex CHD. Survival of newborns with complex CHD now approaches 90%, and 96% of newborns with CHD who survive the first year of life remain alive at 16 years of age.10 Infant survival in the present era is significantly better than in prior decades but varies with CHD complexity; only 56% of newborns with heart defects of great complexity survive to 18 years of age.11 In an analysis, 76% of the deaths that occurred in patients with CHD who survived the first year of life occurred after 18 years of age.12 Adults with CHD are also living longer, with the overall median age at death increasing from 37 years in 2002 to 57 years in 2007.9 Even more striking is the change in mortality for patients with CHD of great complexity, in whom the median age at death has increased from 2 years before 1995 to almost 25 years currently13 (Figure 114).Download figureDownload PowerPointFigure 1. Prevalence/incidence of congenital heart disease (CHD). A and B, Prevalence of CHD in different age groups in 1985 and 2000 for all CHD (A) and severe CHD (B).14 Black bars indicate adults; gray bars are children. The y axis on the left is percent alive; the y axis on the right is number alive.Prevalence estimates of CHD and registry data indicate that there are >1 million adults with CHD in the United States and 1.2 million in Europe.7,14,15 Although the majority of these survivors have simple forms of CHD such as atrial and ventricular septal defects, a significant number have more complex CHD, including 10% with defects of great complexity (such as SV) and 30% with moderately complex CHD (such as conotruncal defects and atrioventricular septal defects).14Importance of HF in CHDThe impact of cumulative survival means that more patients are at risk for HF. Despite great success in the medical and surgical management of CHD, long-term survivors often have residual cardiac abnormalities, pulmonary abnormalities, or hepatic impairment caused by sequelae of cardiac dysfunction.16,17 HF is an important problem for this expanding population of older children and adults, although the prevalence of HF in children and adults with CHD is unknown. However, HF has been reported to develop during childhood in ≈5% of all patients with CHD and up to 10% to 20% of patients after the Fontan procedure.18–20 After the Fontan procedure, the prevalence of HF (variably defined) is nearly 50% by adulthood.21,22HF Mortality and Morbidity in CHDIn a population-based study, HF was the major cause of late death (>30 days) in children after pediatric cardiac surgery, contributing to 27% of the deaths and occurring at a median age of 5.2 years.23 HF also is the leading cause of death in adults with CHD, described in 26% of all deaths in a national registry of >8000 adults with CHD, with similar findings in other reports.20,24,25 One study demonstrated that adults with CHD admitted with HF had a 5-fold increase in mortality compared with those who were not admitted. This study showed 1- and 3-year mortality rates of 24% and 35% after a first HF admission.26In addition to decreased survival, adults with CHD face significant morbidity. The number of CHD hospitalizations increased 101% from 1998 to 2005, with rates 2 to 3 times higher than population norms. HF is a common reason for admission, although less common than arrhythmia.18–20 Further highlighting the severity of the problem, CHD was the leading indication for heart transplantation in the pediatric age group.27 In adulthood, because ischemic heart disease predominates, CHD was the indication for transplantation in only 3% of cases.28 This represents a small subset of the adults with end-stage HF caused by CHD. One explanation may be that decisions about referral or transplantation listing are influenced by the higher early mortality after transplantation reported in the CHD population.29HF Classification in CHDThe clinical presentation of the HF patient with CHD may vary significantly by defect or age. Patients with CHD can have classic symptoms of fatigue, dyspnea, and exercise intolerance but may manifest more subtle signs of malnutrition, growth failure, or cachexia.1,30 Patients with CHD have often adapted to their long-standing limitations; therefore, they may not report symptoms despite significant objective exercise impairment.31 Thus, application of general HF classifications such as the New York Heart Association (NYHA) categories or the modified Ross classification may underestimate the severity of disease, particularly in patients with complex or cyanotic CHD.32 The Warnes-Somerville classification was developed to describe limitations in adults with CHD, although it is not commonly used. None of the available HF classification grading scales (Table 233–36) have been validated in predicting outcomes.Table 2. Classification SystemsModified Ross HF Classification for ChildrenNYHA Functional ClassCanadian Cardiovascular Society Grading for Angina PectorisWarnes-Somerville Ability IndexSpecific Activity ScaleAsymptomaticPatients with cardiac disease but without resulting limitations of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.Ordinary physical activity such as walking and climbing stairs does not cause angina. Angina with strenuous or rapid prolonged exertion at work or recreation.Normal life; full-time work or school; can manage pregnancy.Patients can perform to completion any activity requiring ≥7 metabolic equivalents (eg, can carry 24 lb up 8 steps, do outdoor work [shovel snow, spade soil], and do recreational activities [skiing, basketball, squash, handball, jog/walk 5 mph]).Mild tachypnea or diaphoresis with feeding in infantsDyspnea on exertion in older childrenPatients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain.Slight limitation of ordinary activity. Walking or climbing stairs rapidly; walking uphill; walking or stair climbing after meals, in cold, in wind, or when under emotional stress; or only during the few hours after awakening. Walking >2 blocks on level ground and climbing >1 flight of ordinary stairs at a normal pace and in normal conditions.Able to do part-time work; life modified by symptoms.Patients can perform to completion any activity requiring ≤5 metabolic equivalents (eg, have sexual intercourse without stopping, garden, rake, weed, roller skate, dance fox trot, and walk at 4 mph on level ground), but cannot and do not perform to completion activities requiring ≥7 metabolic equivalents.Marked tachypnea or diaphoresis with feeding in infantsProlonged feeding times with growth failureMarked dyspnea on exertion in older childrenPatients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea, or anginal pain.Marked limitation of ordinary physical activity. Walking 1-2 blocks on level ground and climbing 1 flight in normal conditions.Unable to work; noticeable limitation of activities.Patients can perform to completion any activity requiring ≤2 metabolic equivalents (eg, shower without stopping, strip and make bed, clean windows, walk 2.5 mph, bowl, play golf, and dress without stopping), but cannot and do not perform to completion any activities requiring >5 metabolic equivalents.Symptoms such as tachypnea, retractions, grunting, or diaphoresis at restPatient with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased.Inability to carry on any physical activity without discomfort; anginal syndrome may be present at rest.Extreme limitation; dependent; almost housebound.Patients cannot or do not perform to completion activities requiring >2 metabolic equivalents. Cannot carry out activities listed above (specific activity scale III).HF indicates heart failure; and NYHA, New York Heart Association.Data derived from the New York Heart Association,33 Rosenthal et al,34 Campeau,35 and Goldman et al.36The ACC/AHA buidelines for the diagnosis and management of HF, updated in 2013, specifically excluded children and patients with CHD, valvular heart disease, and infiltrative cardiomyopathies.37–39 The staging system described in the guidelines recognizes risk factors for the development of HF, including hypertension, diabetes mellitus, and coronary atherosclerosis. If the A through D staging in the HF guidelines were extrapolated to CHD, the vast majority of asymptomatic patients with CHD would be categorized as at least stage B (Figure 2). However, there are few data to show that the medical or device therapies recommended for stages B through D are effective in patients with CHD of any age, thus applying all the recommendations may not optimally suit the CHD population. There is inadequate evidence that categorizing patients with CHD by this system enables management decisions or improves outcome. However, portions of the guidelines should apply to patients with CHD. The guidelines are clear that HF is a clinical diagnosis and that the presence of ventricular dysfunction or the result of any other single diagnostic test is not sufficient to make the diagnosis. This definition of HF as a clinical diagnosis not based solely on a diagnostic test also applies to patients with CHD. Recommendations in the HF guidelines on the control of acquired heart disease risk factors, weight management, and the need for routine health maintenance screening are also broadly applicable to patients with CHD.Download figureDownload PowerPointFigure 2. American Heart Association/American College of Cardiology congestive heart failure stages. Stages of the development of heart failure (HF) if applied to patients with adult congenital heart disease (CHD). Patients with adult CHD enter in stage B because structural heart disease is by definition present. Repair of hemodynamic lesions is the primary objective in patients with adult CHD, for both the treatment (stage C) but also the prevention (stage B) of HF. ACEi indicates angiotensin-converting enzyme inhibitor; AICD, automatic implantable cardioverter-defibrillator; ARB, angiotensin receptor blocker; BB, β-blocker; CRT-P, cardiac resynchronization therapy–pacemaker; ERA, endothelium-receptor antagonist; and PDE-5i, phosphodiesterase type 5 inhibitor.Potential Mechanisms of HF in CHDGeneral ConsiderationsClinical HF in CHD is multifactorial. An ineffective cardiovascular system in CHD, even after repair, can be the cumulative result of valvular abnormalities, shunts, flow obstruction, arrhythmia, or persistent anatomic defects such as an SV, as well as dysfunction of the myocardium itself. Likewise, myocardial dysfunction in CHD can be the result of hemodynamic derangements such as abnormal pressure or volume loading, ventricular hypertrophy, myocardial ischemia, or effects of prior cardiopulmonary bypass or ventriculotomy. Any of these may incite systolic or diastolic impairment (Table 3) and clinical manifestations such as arrhythmia or exercise intolerance. In addition, constriction as a consequence of prior surgery may cause HF symptoms. This section acknowledges these many causes but focuses on potential origins of myocardial dysfunction, a final common pathway in CHD.40 Much is unknown or speculative, based on extrapolation from other HF models, yet understanding specific mechanisms and pathways is vital to providing informed and effective treatment strategies.Table 3. Causes of HF in Patients With CHDVolume overload resulting from left-to-right shunt lesions and valvular regurgitationPressure overload resulting from valvular disease and other obstructive lesionsVentricular failure related to intrinsic myocardial dysfunctionPulmonary hypertension caused by CHD lesions, ventricular dysfunction, or comorbidities such as obstructive sleep apneaSystemic arterial hypertension resulting from coarctation, acquired renal disease, essential hypertension, or arteriosclerosisCoronary artery disease related to CHD, atherosclerosis, or comorbidities such as diabetes mellitusCyanosisIntractable atrial arrhythmiasCHD indicates congenital heart disease; and HF, heart failure.Myocardial ArchitectureThe myocardial architecture in CHD can exhibit disarray of ventricular myocardial fibers.41,42 This is especially the case for the RV. Development of the RV is controlled by a profile of transcriptional pathways different from that of the LV.43 The normal RV myocardium has only a superficial circumferential layer and deep longitudinal layer but does not have the middle layer of circular fibers that normally makes up more than half the wall thickness of a morphological LV.41 In an animal model of hypoplastic left heart syndrome (HLHS), abnormal RV and LV myocardial fiber orientation was noted prenatally, reflected in abnormal patterns of anisotropic RV and LV deformation.44 Different myofiber and connective tissue architecture has also been observed in patients with tricuspid atresia. Although hypothetical, it is plausible that these alterations impart a disadvantage to the myocardium and make it vulnerable to dysfunction, although to what extent is unknown.There is some evidence that LV noncompaction is more common in CHD. If pathological, this would pose an additional risk for the development of HF because of the abnormal myocardium characteristic of the disorder. Whether LV noncompaction is a concomitant genetic abnormality, a response to hemodynamic derangement, or a combination of these is not clear.45Abnormal PerfusionMany patients with CHD are cyanotic at birth, which can result in significant myocardial ischemia until repair or palliation. The early period of ischemia may not have a detectable impact on ventricular function in the short term but may jeopardize or preprogram the myocardium to more serious dysfunction later in life. In other cases, there may be a coronary flow–demand mismatch such as that which occurs in the systemic RV. Many studies demonstrated perfusion abnormalities in patients with a systemic RV in whom the typical coronary anatomy supplying the RV is insufficient for a hypertrophied, enlarged ventricle, although there are conflicting data on the frequency and clinical importance of these findings.46–51 Some conditions such as transposition of the great arteries (TGA) are associated with coronary anomalies that may subject the myocardium to prolonged ischemia or infarction either before or as a result of surgical repair.52,53 Myocardial perfusion assessed by positron emission tomography was often abnormal in those with Fontan repairs, congenitally corrected TGA (ccTGA), and dextro-looped TGA (dTGA) after an atrial switch procedure.54–56 Even in the absence of coronary arterial abnormalities, tissue ischemia may be present. High wall stress from increased afterload in conjunction with decreased coronary flow reserve was associated with myocardial hypoperfusion and supply-demand mismatch,57,58 the effects of which may only become manifest over decades.Neurohormonal ActivationThere is ample evidence from acquired heart disease that activation of cell signaling systems occurs in response to ischemia or abnormal cardiac distension from deranged pressure or volume loading.40 Activation of natriuretic peptides and the sympathoadrenergic system, endothelin, and renin-angiotensin-aldosterone system (RAAS) can be driven by any of these adverse conditions,59–63 which are ubiquitous in CHD. Although less is known about specific activation pathways in CHD, there is certainly growing evidence, mainly in the form of elevated biomarkers, to support similar activation in CHD. Brain natriuretic peptide (BNP) has been the most extensively documented biomarker, with elevated serum levels demonstrated in patients with poorer cardiovascular function or prognosis.64–67 Data on RAAS and sympathoadrenergic axes in CHD are limited but also suggest activation40,62 and argue in favor of HF pathways similar to those well studied in other models. However, studies in CHD are small with limited follow-up and, importantly, do not show uptitration of biomarkers in all individuals. Therefore, there is more to understand about the factors that govern neurohormonal activation than available biomarker evidence provides.Myocardial FibrosisOne downstream effect of neurohormonal and RAAS activation is alteration in collagen turnover by myofibroblasts, leading to detectable myocardial fibrosis. Some data suggest that an abnormal accumulation of fibrous tissue from an early stage may be an inherent part of some CHD defects in hearts exposed to ischemia and pressure and volume overload.68,69 For example, biopsy studies demonstrated fibrosis in young patients with tetralogy of Fallot (TOF) undergoing surgery.70 Ex vivo studies also demonstrated fibrosis in varying quantities. These postmortem studies were not performed in individuals who died of HF, and it may be that fibrosis burden in HF patients is greater.There has been interest in the presence and impact of myocardial fibrosis in CHD as detected by delayed enhancement after gadolinium injection during cardiac magnetic resonance imaging (MRI), a phenomenon referred to as late gadolinium enhancement (LGE). Gadolinium increases signal intensity of extracellular material in myocardium late after injection, which correlates with fibrosis. This method has been used to demonstrate macroscopic areas of fibrosis in several different CHD subgroups, including TOF (53%),71 systemic RV (61%),72 Eisenmenger syndrome (73%),73 and Fontan palliation (26%).74 Collectively, these studies demonstrate that the presence of LGE is associated with poorer functional class, lower ventricular systolic function, reduced exercise capacity, and arrhythmia, although the quantity of enhancement is often small and sparse (apart from less common large subendocardial infarcts or surgical scars).Microscopic fibrosis may be much more diffuse and abundant than the dense replacement fibrosis demonstrated by LGE. Patients studied with methods that quantify diffuse fibrosis using T1 mapping to measure the extracellular volume fraction, a marker of fibrosis, demonstrated significantly more fibrosis than healthy control subjects and more than the amount detected by LGE; the increased diffuse fibrosis correlated with ventricular enlargement and decreased ventricular systolic function.75 Such methods may help explain the time course and specific inciting causes of fibrosis across the CHD spectrum.There may be reasons other than pathological fibrosis for increased extracellular volume. Given the differences in extracellular architecture of the RV already discussed, the amount of extracellular matrix may be inherently different. Studies in TOF have shown increased volume density of endomysial collagen and remodeling of collagen matrix in the RV from birth.76 However, the density of endomysial collagen may be adaptable to conditions. A significant reduction in extracellular collagenous matrix has been seen in patients with HLHS compared with normal control subjects.77RemodelingIt is likely that adverse remodeling, the process by which an initial injury or stressor to the ventricle leads to progressive and predictable structural changes of the ventricle such as dilatation or hypertrophy, is another result of the adverse loading and structural conditions driving subcellular signals and cellular changes discussed above, although our understanding of these processes is based almost entirely on other forms of heart disease. Regardless of initial insult, remodeling certainly occurs and in itself can lead to progressive ventricular failure and deterioration.Fibrosis likely contributes to restriction and impairment of diastolic filling. The effect of RV restriction after TOF repair remains somewhat controversial, especially in patients with residual pulmonary regurgitation. In contrast to other patients with pulmonary valve regurgitation, patients with a stiff or restrictive RV manifest a smaller increase in end-diastolic volume and increased early filling. Under such circumstances, the RV acts as a conduit between right atrium and pulmonary artery (PA) in which forward flow into the PA during atrial contraction can be observed. In patients with pulmonary regurgitation, the effect of restrictive RV physiology remains unclear. Increased RV end-diastolic pressure can limit pulmonary regurgitant volume and result in less RV dilation and better exercise tolerance.78However, RV restriction is also
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