Diastolic Function in Children and in Children With Congenital Heart Disease

Introduction

Ventricular function is a major determinant of outcomes in children and adults with congenital and acquired heart disease. Evaluation of diastolic function in children, most commonly performed by echocardiography, is strongly linked to clinical outcomes and is therefore important to assess as it provides information with prognostic value. Yet, the clinical assessment of diastolic function, particularly in children, and particularly in those with congenital heart disease (CHD), remains a persistently challenging area. Intrinsic and extrinsic factors affect diastolic performance. Systolic ventricular function, atrial and ventricular compliance, ventricular filling pressures, pericardial constraint, dyssynchrony, ventricular-ventricular interactions, and vascular compliance may each have effects on overall ventricular diastolic performance. Noninvasive evaluation of diastolic function in infants and children is additionally influenced by several factors, including age, heart rate, and respiratory cycle variations. This chapter will discuss concepts in diastolic function in pediatric acquired and congenital heart disease and review continuing challenges and efforts regarding the assessment of diastolic performance in this population.

Normal Diastolic Function in Children and Developmental Aspects

The myocardium matures from the fetus through childhood to the young adult, and with this maturation comes changes in its diastolic properties and function. In the fetal myocardium, fetal cardiomyocytes grow by hyperplasia (replication), whereas mature cardiomyocytes grow only by hypertrophy. Energy metabolism differs in that lactate, not long-chain fatty acid, is the primary fuel of the fetal myocardium. Diastolic properties of the fetal myocardium are also significantly different in that myocardial relaxation in the fetus is reduced compared to mature myocardium due to differences in Ca ²⁺ handling. Likewise, stiffness is higher due to the larger proportion of noncontractile elements compared to the adult and extrinsic constraint by the pericardium and fluid-filled lungs. Hence the normal fetus, when examined by echocardiography, exhibits a reversed E/A ratio of atrioventricular inflow and tissue Doppler velocities ( Fig. 27.6 ). These would be interpreted as reflecting impaired relaxation if seen in a mature heart. While the influence of extrinsic compression changes dramatically with the newborn’s first breaths, the neonate continues to manifest fetal characteristics of reduced early diastolic filling and dominant atrial contribution. These patterns characterize the immature neonatal myocardium for the first few weeks to months after birth, before transitioning to the mature pattern of dominance of early ventricular filling manifested as dominant E and e′ wave velocities and lower atrial contribution, manifested as lower A and a′ wave velocities ( Figs. 27.7 ).

As the normal myocardium matures through childhood and into adolescence, the ventricle displays vigorous relaxation properties. These manifest as dominant early diastolic filling (dominant E and e′ waves), with little contribution left to atrial filling (see Fig. 27.7 B). Higher heart rates further contribute to this dynamic physiology. Thus the normal E/A ratio of children and adolescents is often higher than that of adults (and DT shorter) and would be considered to be in ranges indicative of restrictive physiology if judged by adult criteria.

Reference values for diastolic parameters, including tissue Doppler velocity and cardiac time interval parameters, established in sizable cohorts of healthy children, have been available for several years ( Tables 27.1, 27.2, and 27.3 ). In general, Doppler parameters linearly increase or decrease over childhood toward adult values at 18 years of age. It is important to note that the normal reference values published in 1998 from the Mayo Clinic database include children from 4 years of age and older, and other studies exclude infants or toddlers, so that overall, normal data from neonates, infants, and toddlers are limited. Inspection of the Mayo Clinic data also shows that confidence intervals become progressively wider as age decreases, introducing further uncertainty for assessment of diastolic function in the already more challenging younger age group.

Pathophysiology of Diastolic Dysfunction in Children With Congenital Heart Disease

Diastole is a complex process involving both active and passive components. Abnormalities of relaxation and early rapid filling are often manifested by changes in the rate of relaxation and the amount of early rapid filling. Diastolic dysfunction also is manifested by changes in chamber stiffness, which are traditionally thought to manifest in late diastole. Adverse changes within the myocardium are common in the pathophysiology of congenital and acquired heart disease affecting children, with increases in collagen content and altered extracellular matrix composition leading to altered chamber compliance.

The rate of pressure decline within the ventricular chamber can be determined by invasive methods. Impaired relaxation leads to a decreased rate of ventricular pressure decline. Lengthening of isovolumic relaxation time (IVRT) (defined as the time interval between aortic valve closure and mitral valve opening) is also characteristic of abnormal diastolic filling and can be evaluated noninvasively by M mode or pulse wave (PW) Doppler echocardiography. However, neither IVRT nor tau elucidates whether dysfunction occurs in active or passive relaxation, which act in concert to cause a fall in ventricular pressure and augment filling. As diastolic dysfunction progresses, increased ventricular end-diastolic pressure (EDP) further increases tau and pressure half-time (period of time for LV pressure to fall to 50% of its initial value during isovolumic relaxation), while concomitant changes in atrial compliance and filling pressure act to shorten IVRT duration.

Echocardiography, and in particular Doppler echocardiography, has been an essential noninvasive tool in the quantitative assessment of LV diastolic function. Abnormalities of ventricular compliance and relaxation can be demonstrated by changes in mitral inflow, pulmonary venous Doppler patterns, and tissue Doppler echocardiography as in adults. Because diastolic dysfunction may precede systolic dysfunction and is linked to clinical outcomes, assessment of diastolic function is important in the noninvasive characterization and evaluation of children with acquired and congenital heart disease.

In many children with CHD, in utero or early neonatal pathophysiology may lead to myocardial injury and fibrosis and diastolic dysfunction. An example is critical aortic stenosis and other left-sided obstructive lesions, where not only is there LV hypertrophy and underdevelopment that impede filling, but very commonly endocardial fibroelastosis and myocardial fibrosis, which create a noncompliant ventricle with restrictive filling. Mitral valve hypoplasia and structural abnormalities further impede the ability of the ventricles to fill adequately, and the common presence of an atrial septal defect (ASD) leads to left-to-right shunt at the atrial level and further reduction of LV preload. Hence the progression in the severity of diastolic dysfunction, from delayed relaxation to restrictive filling, typical of adult pathology, may not be applicable to many CHD lesions. Moreover, these abnormalities substantially impede assessment of diastolic function. In other instances, the degree of ventricular loading, over and above myocardial properties per se, is a major determinant of ventricular filling and hence diastolic performance. This will be detailed later, but a prototype example is the preload-restricted Fontan circulation.

Difficulties in Assessing Diastolic Function in Children and Applicability of Adult Guidelines

While the principles of the pathophysiology of diastolic dysfunction in children, including those with CHD, are similar to adults, the natural history, progression, and echocardiographic manifestations are often different. In many children with heart failure, heart rates are high, resulting in merging of the E and A waves. This complicates use of inflow Doppler to characterize diastolic function. Alterations in ventricular geometry and loading conditions are hallmarks of CHD and complicate the quantitative evaluation of diastolic function. Diastolic parameters, including tissue Doppler velocities and strain imaging, are significantly affected by loading conditions, making determination of diastolic dysfunction using these parameters alone very challenging in patients with CHD. Moreover, it is often difficult to apply a dry value from a normal reference to determine whether a given value in a patient is abnormal due to the wide range of normal values in children, changing values with age and heart rate, difficulties in application of adult guidelines to children, absence of guidelines on how to classify diastolic dysfunction in children, presence of often apparently conflicting echo criteria, lack of correlation of echo criteria with invasively measured reference parameters, and the infrequent presence of isolated delayed relaxation in children. Our group studied the applicability of adult guidelines to normal children and to those with dilated, hypertrophic, and restrictive cardiomyopathies. Although the adult guidelines have since been updated, our findings remain pertinent. We found that whether using absolute values or abnormal values based on normal pediatric reference data, adult criteria and algorithms were not applicable to children. We found that pediatric reference data successfully defined normal controls, but because of the wide range of normal values, diastolic dysfunction was classified in only a minority of patients with overt, and often severe, cardiomyopathy. Thus our results suggested that current echo criteria are not adequately applicable for the diagnosis and classification of diastolic dysfunction in pediatric cardiomyopathy (and by inference in complex CHD). Our results also showed that when diastolic dysfunction was diagnosed or suspected, discrepancies between diastolic parameters or diagnostic criteria within individual patients are common, adversely affecting interpretation of diastolic dysfunction, the grading thereof, and interobserver agreement. The classification of diastolic dysfunction in adults is based on a paradigm of progression of abnormalities along a continuum of increasing severity from normal, through delayed relaxation, evolving through a phase of pseudonormalization to a pattern of restrictive filling. However, our results showed that criteria consistent with isolated delayed relaxation are distinctly uncommon in children. Only seven hypertrophic cardiomyopathy (HCM) patients (6.4% of the population studied), mostly adolescents, presented with criteria consistent with isolated delayed relaxation, whereas no dilated cardiomyopathy (DCM) or RCM patients had sufficiently concordant criteria to classify delayed relaxation or pseudonormal filling. Of the parameters studied, e′ (especially septal e′), mitral E deceleration time, and left atrial (LA) volume indexed for body surface area seemed best to differentiate children with cardiomyopathy from controls. Yet, even these parameters were often discrepant in the individual child. The E/A ratio, a central parameter in adult paradigms, was not useful in the children studied. Whether the addition of RV systolic pressure, new to the most recent iteration of the American Society of Echocardiography (ASE) adult diastolic guidelines, will be useful in children remains to be studied. It is logical, especially in left-sided obstructive lesions or dysfunction, if there is no RV outflow or pulmonary obstruction. Other studies have mirrored our findings. In a review of 33 original articles, Cantinotti found that in many studies, sample sizes were limited, particularly in the neonatal age range. There was heterogeneity in the methodologies used to perform and normalize measurements and whether results were expressed as normalized by z scores, percentiles, or mean values. Although most studies adjusted measurements for age, classification by specific age subgroups varied, and few addressed the relationships of measurements to body size and heart rate. Although reference values were reproducible in older children, they varied significantly in neonates and infants. Thus, as detailed earlier, assessment of diastolic function remains particularly challenging in the youngest children due to lack of normal data, rapid changes with age, and low measurement reproducibility.

Adult-based guidelines aim to classify the severity of diastolic dysfunction and to assess filling pressures. The E/e′ ratio has become an integral component of adult guidelines to assess filling pressures. However, data suggest that this ratio, whether using the lateral mitral or septal E/e′, correlates poorly with invasively measured filling pressures in children. Similarly, in a group of children with RCM, perhaps the hallmark disease of diastolic dysfunction with elevated filling pressures, individual cutoffs for Doppler indices had poor sensitivity in identifying restrictive physiology. The results of these studies, similar to our findings in children with various types of cardiomyopathy, suggested that poor LV compliance is the typical characteristic of RCM in children, even in the presence of what appears to be normal early relaxation and early ventricular filling. Another investigation of pediatric and young adult patients with RCM, lateral a′ velocity, and pulmonary vein a-wave duration, parameters not included in the adult guidelines, predicted elevated LVEDP with over 80% sensitivity and specificity. However, even then, these measurements were only feasible in about half of the patients. Other parameters that are incorporated directly or indirectly in the adult guidelines, such as indexed LA volume and mitral A wave, correlated only moderately with LVEDP. In a study of 61 consecutive pediatric patients, including infants and children with various biventricular heart diseases, LV relaxation, chamber stiffness, and LVEDP were measured using a high-fidelity micromanometer catheter with simultaneous Doppler echocardiography. The E/e′ correlated only moderately with LVEDP with sensitivity of 0.71 and specificity of 0.93 to determine the presence of EDP above the 90th percentile (12.96 mmHg). The e′ and mitral DT correlated weakly with invasive indices of relaxation and stiffness. Similarly, in other studies in children with a biventricular circulation, traditional diastolic parameters did not correlate with LVEDP; only diastolic strain rate parameters correlated, and even then only moderately, with LVEDP. Assessment of filling pressures in children will be detailed further later in the chapter.

Echocardiographic Evaluation of Diastolic Function in Children

Echocardiography is the most commonly used tool to noninvasively assess diastolic dysfunction in children, especially for serial assessment. However, from the previous discussion, it is apparent that no single echo parameter is adequate in and of itself to diagnose the severity of diastolic function or quantify filling pressures in children, even in those with a biventricular circulation. At best, single parameters may be sufficiently sensitive to detect diastolic dysfunction, but not to quantify it. Thus it is imperative that a combination of Doppler echocardiographic parameters and clinical criteria is used. In children with restrictive cardiomyopathies, a combination of increased LA size, increased septal E/e′, lack of a mitral A wave, and the presence of a mid-diastolic L′ wave was noted to be useful. Likewise, in our study, a combination of reduced septal e′, decreased mitral E deceleration time, and increased LA volume indexed for body surface area seemed best to differentiate children with cardiomyopathies from controls.

Within these boundaries and limitations, review of individual echo parameters and the progression of diastolic dysfunction in adults is warranted as a basis to using echocardiographic parameters in combination and to their interpretation in children.

Mitral Inflow Doppler

Mitral inflow Doppler reflects the diastolic pressure gradient between the left atrium and the left ventricle (see Fig. 27.7 A). The early diastolic filling wave, or E wave, is the dominant diastolic wave in children and young adults and relates to the peak LA-to-LV pressure gradient at the onset of diastole (see Fig. 27.7 B). The DT of the mitral E wave reflects the period of time needed for equalization of LA and LV pressures. As such it is influenced by ventricular relaxation and filling pressures. The late diastolic filling wave, or A wave, represents the peak pressure gradient between the left atrium and the left ventricle in late diastole during atrial contraction. Beyond the first months of life, normal mitral inflow Doppler is characterized by a dominant E wave, a smaller A wave, and a ratio of E and A waves (E/A ratio) between 1 and 3. Normal durations of mitral DT and IVRT vary with age and have been reported in both pediatric and adult populations. As detailed earlier, mitral inflow Doppler velocities are affected not only by changes in LV diastolic function but also by age, altered loading conditions, heart rate, and changes in atrial and ventricular compliance. In the adult population, the earliest stage of LV diastolic dysfunction demonstrated by mitral inflow Doppler is abnormal relaxation. This Doppler pattern represents a mild decrease in the rate of LV relaxation with normal LA pressure. It is characterized by a reduced E wave velocity, increased A wave velocity, decreased E/A ratio less than 1, and a prolonged mitral DT and IVRT ( Fig. 27.8 ). However, as detailed earlier, this pattern is not commonly seen in isolation in children, outside of older children with HCM.

With increased LA pressure, the initial transmitral gradient between the left atrium and the left ventricle increases, producing a pseudonormalized mitral inflow Doppler pattern with increased E wave velocity and E/A ratio and normalized mitral DT and IVRT intervals. This pseudonormal Doppler pattern may be difficult to distinguish from normal mitral inflow Doppler. In older children and adolescents, maneuvers that decrease ventricular preload, such as the Valsalva maneuver, as well as additional evaluation of pulmonary venous inflow and tissue Doppler can help differentiate between pseudonormalized mitral inflow and more advanced LV diastolic dysfunction. However, the Valsalva maneuver may be difficult to perform and interpret in children and is not routinely used in pediatric labs to the extent it is in adults.

Further deterioration of ventricular diastolic function results in further increases in ventricular filling pressures with an additional increase in atrial pressure and a concomitant decrease in ventricular compliance resulting in restrictive ventricular filling. As in adults, the Doppler pattern of restrictive LV filling is characterized by additional increases in E wave velocity, reduction in A wave velocity, an increased E/A ratio, and significant shortening of mitral DT and IVRT.