Implications of Pediatric Renal, Endocrine, and Oncologic Disease

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16 Implications of Pediatric Renal, Endocrine, and Oncologic Disease

Brandy Hattendorf

Pediatric diseases of many different etiologies have cardiovascular implications. Those associated with renal, endocrine, and oncologic processes can directly or indirectly impact the cardiovascular system.

Renal

The cardiovascular complications of renal disease differ based on the etiology of the kidney disease. Cardiovascular morbidity and mortality continue to increase in association with renal disease. The most common renal diseases with cardiovascular effects include hypertension, glomerulonephritis, chronic renal failure, post-renal transplantation, and iron overload secondary to renal failure with hemodialysis.

Hypertension

• Arterial hypertension may reflect chronic kidney disease.

• Metabolic and hormonal factors in chronic renal disease contribute to the development of both hypertension and left ventricular hypertrophy (LVH).

• Hypertension is associated with LVH.

• Concentric hypertrophy is more common than eccentric hypertrophy.

• Volume overload contributes to hypertension in hemodialysis patients.
• LVH is an independent risk factor for coronary artery disease.
• Reduced compliance of the left ventricle (LV) secondary to LVH results in left ventricular diastolic dysfunction.

Key Points

• LVH reflects pressure and volume overload on the left ventricle.
• Concentric hypertrophy occurs in the presence of pressure overload with a stiff ventricle (Fig. 16-1).
• Eccentric LVH is more likely secondary to increased volume overload (eg., in hemodialysis patients).
• Diastolic function is worse in patients with LVH.
• Regression of LVH with normalization of left ventricular mass (LVM) can occur in patients after successful treatment with antihypertensive therapy.
image

Figure 16-1 Parasternal short axis view of concentric left ventricular hypertrophy.

Glomerulonephritis

• Glomerulonephritis may result in:

• LVH, right ventricular and septal hypertrophy.
• Dilated ventricles.
• Decreased ventricular contractility.
• Impairment in diastolic ventricular function.

Chronic Renal Failure

• Adolescents are at higher risk of cardiovascular events than younger children.

• Cardiac findings: cardiomyopathy (CM), arrhythmias, and cardiac arrest of unknown origin.

• African American race and female sex have been reported to be risk factors for cardiovascular disease in children and adolescents on dialysis.

Key Points

• LVH can develop even with mild to moderate chronic kidney disease.
• Impaired diastolic dysfunction may be seen in children with chronic kidney disease, on long-term dialysis, and after transplantation.

• Abnormalities in calcium-phosphate metabolism, particularly in dialysis patients, are associated with diastolic dysfunction.

• Increased incidence of valvular disease in those undergoing chronic dialysis:

• Age older than 14 years, female African American.
• Aortic valve (AV) and mitral valve (MV) disease are most often involved.
• Annular calcification.

Post-Kidney Transplantation

• Decreased systolic function, diastolic dysfunction, and increased LVM can persist even after transplantation.

Key Points

• The most common findings post-transplantation are:

• LVH.
• Left atrial enlargement.
• Left ventricular dilation.
• Systolic dysfunction.

Iron Overload Cardiomyopathy

• Myocardial injury due to excess iron deposition, which may occur in association with chronic renal failure/hemodialysis.

The Echo Exam: Step-by-Step Approach

Step 1: Evaluate Cardiac Size

• M-mode and two-dimensional (2D) assessment of cardiac dimensions.

• Assess for left ventricular dilation and/or LVH using measurements indexed to body surface area (BSA).
• Image using multiple planes including four-chamber (4C) and short axis views.

• Use indexed LVM to define LVH in pediatric patients (g/m2.7).

• Height should be measured (in meters).

• LVM equation is 0.8{1.04[(LVED + left ventricular posterior wall thickness + interventricular septal thickness)3 − LVED3]} + 0.6, where LVED is left ventricular end-diastolic dimension.
• LVM is then indexed to height to the exponential power of 2.7.

• For patients older than 9 years old: more than 40 g/m2.7 in girls and more than 45 g/m2.7 in boys is abnormal.

Key Points

• Height and weight measurements should be obtained at the time of the echocardiogram to ensure accuracy rather than relying on patient history.
• M-mode is performed from a parasternal long axis view just below the MV leaflets.
• Leading edge to leading edge technique in end-diastole is used to measure

• LVED.
• Left posterior wall thickness.
• Interventricular septal thickness.

• To evaluate LVM in patients younger than 9 years of age, percentile curves should be referenced.

Step 2: Evaluate Systolic Cardiac Function

• Obtain end-diastolic and end-systolic measurements and calculate left ventricular fractional shortening (FS) using M-mode.

• Parasternal short axis or long axis view at the level of the papillary muscles.

• FS greater than 38% = hyperdynamic.
• FS less than 28% = reduced systolic function.
• Use the modified Simpson’s (disk summation) method for calculating ejection fraction (EF) to estimate left ventricular end-diastolic and end-systolic volumes.

• Use the apical 4C and two-chamber (2C) views (Fig. 16-2).

image image image

Figures 16-2 The modified Simpson method (disk summation) can be used to calculate left ventricular volumes. It involves tracing the left ventricular endocardial border in apical 4-chamber and 2-chamber views using the disk summation method for calculating ejection fraction based on estimating left ventricular volume in systole and diastole, as illustrated in A and B. Application of the modified Simpson method using an apical 4-chamber view is demonstrated estimating left ventricular end-systolic (C) and end-diastolic (D) volumes. As seen in the echo images, this technique requires adequate delineation of the left ventricular endocardium.

Step 3: Evaluate Diastolic Cardiac Function

• Ventricular relaxation occurs during isovolumic relaxation.

• Recorded from an apical 4C view at the MV leaflet tips.
• Use pulsed wave (PW) Doppler with the signal aligned parallel to mitral flow.

• Normal mitral inflow Doppler pattern.

• Isovolumic relaxation: brief interval between AV closure and the onset of ventricular filling (isovolumic relaxation time [IVRT]).
• Blood rapidly fills the left atrium (LA) with opening of the MV (E wave).

• E velocity of early maximum filling velocity.
• Filling then slows (deceleration time): E peak to intersection of the slope with the zero baseline.

• Left atrial contraction causes another peak velocity (atrial velocity or A wave).

• Tissue Doppler imaging (TDI).

• TDI is obtained at the lateral margin of the MV annulus from an apical 4C view.
• Time interval from the end to the onset of the mitral annular velocity pattern during diastole.
• Measurements include (Fig. 16-3).

• Early diastolic annular velocity (E′).
• Diastolic velocity with atrial contraction (A′).
• Isovolumic contraction time (IVCT).
• IVRT.
• Ejection time (ET).
• Used as an adjunct for evaluation of diastolic function.
• Less dependent on preload.

• Normal variation is less than 20%.

• In children with normal diastolic function, the E wave is larger than the A wave, reflecting that ventricular filling occurs primarily in early diastole.
• A reduced E/A ratio may be seen with diastolic dysfunction in chronic renal disease.
• Increased HR results in shorter duration of diastole with an increased A wave and lower E/A ratio.
• Impaired relaxation is associated with a prolonged IVRT.
• Decreased compliance and increased filling pressures are associated with a shortened IVRT.
• Changes seen associated with LVH secondary to hypertension include:

• Mild left ventricular diastolic dysfunction.

• Impaired relaxation.
• Reduced early diastolic filling.
• Enhanced atrial contribution:

• Increased IVRT.
• Reduced E velocity.
• Increased A velocity.
• E/A ratio < 1.

• The myocardial performance index (MPI) or Tei index may be calculated to assess left ventricular dysfunction.

• MPI or Tei index = (IVRT + IVCT)/ET.
image

Figures 16-3 Example of tissue Doppler from the lateral mitral valve annulus samples from an apical window. Isovolumic contraction time (IVCT) is characterized by biphasic motion, first toward the apex and then away. During isovolumic relaxation time (IVRT), the IVCT motion is reversed, with motion initially away from the apex followed by motion toward the apex. There are usually two distinct apically directed peaks during diastole, one early in diastole (E′) and one following atrial contraction (A′).

(Adapted from Keane JF, Fyler DC, Lock JE. Nadas’ Pediatric Cardiology, 2nd ed. Philadelphia: Elsevier/Saunders, 2006; Figure 15-18).

Key Points

• An E/A ratio can be used to evaluate left ventricular diastolic function.
• In children and adolescents with normal left ventricular diastolic function, E > A.
• Factors affecting left ventricular diastolic function include:

• Preload.
• Left ventricular systolic function.
• Heart rate (HR).
• Age.
• Respiratory rate.

Step 4: Evaluate for Dyssynchrony

• Velocity vector imaging (VVI).

• Method for calculation of delay between any two cardiac wall segments.

• The endocardial border is traced in peak diastole using VVI software in the 4C and 2C views.
• Myocardial velocity is calculated for six ventricular segments, and local velocities are tracked by the VVI algorithm.

• Degree of dyssynchrony is quantified by comparing the regions (Fig. 16-4).

• Strain rate and strain imaging.

• Strain rate is measured by TDI as the velocity difference between two regions in the myocardium divided by the distance between the two regions.
• Quantifies myocardial deformation.
• Correlates with left ventricular contractility.

• Strain is measured by integrating strain rate over time.

• Measures the change in length corrected for the original length or fractional change from the original dimension.
• Identifies regional diastolic asynchrony (Fig. 16-5).
• Quantifies rate of myocardial deformation.

image

Figure 16-4 An example of velocity vector imaging (VVI) demonstrating dyssynchrony. With normal cardiac function, all vectors should be aimed toward each other in systole. The image on the left demonstrates the vectors, particularly in the basilar region, aimed in different directions. On the right of the VVI are graphic representations of standard deviation of time-to-peak velocity among different cardiac segments. These are consistent with the VVI, demonstrating that different segments of the heart reach peak velocity independently rather than simultaneously.

image

Figure 16-5 With normal cardiac function, there should be no significant difference in the time to peak strain. In this example of time to peak strain among six cardiac segments, significant dyssynchrony is noted with a maximum wall delay of 170 ms. Dyssynchrony in this patient stems from dyssynchronous motion of the lateral, posterior, and inferior segments.

Key Points

• Patients with CM have a greater degree of dyssynchrony.
• Strain imaging can detect myocardial dysfunction before the appearance of clinically significant global ventricular impairment.
• Useful in patients with systemic hypertension.

Step 5: Interrogate Cardiac Valves

• Use spectral and color flow Doppler for assessment of stenosis and regurgitation.

Key Point

• There is an increased incidence of valvular disease in patients undergoing chronic dialysis.

Endocrine

The most common endocrine diseases with cardiovascular effects include hypothyroidism, hyperthyroidism, and metabolic syndrome. A unique population in pediatrics are the infants born to diabetic mothers in whom significant congenital cardiac disease may develop, including both structural and prenatally acquired cardiac disease secondary to hyperinsulinemia.

Hypothyroidism

• Deficiency of thyroid hormone either from deficient production or a defect in the receptor, which may be congenital or acquired.
• Cardiovascular implications include

• Bradycardia.
• Cardiomegaly.
• Pericardial effusion.
• Hypertrophic cardiomyopathy (HCM).
• Asymmetrical hypertrophy.

Key Point

• Amiodarone used to treat arrhythmias may cause hypothyroidism.

Hyperthyroidism

• Results from excess production of thyroid hormones triiodothyronine, thyroxine, or both.
• May be congenital in infants of mothers with untreated Graves’ disease during pregnancy or acquired.

• Cardiovascular implications include tachycardia.

Key Point

• Hyperthyroidism results in an increased kinetic state with hyperdynamic ventricular contractility.

Metabolic Syndrome

• Findings include obesity, atherogenic dyslipidemia, elevated blood pressure, impaired glucose tolerance, a prothrombotic state, and proinflammatory state.
• Metabolic syndrome increases the risk of atherosclerotic cardiovascular disease.

Key Points

• Metabolic syndrome is present in 30% to 40% of overweight adolescents.
• Echocardiographic changes include:

• Concentric LVH.
• Increased LVM.

Maternal Diabetes

• Increased incidence of cardiac anomalies seen in children born to mothers with insulin-dependent diabetes mellitus.
• HCM is most commonly seen (Fig. 16-6).

• Risk of CM is 18 times the risk among offspring of mothers not affected.
• More commonly associated with septal hypertrophy.
• May cause left ventricular outflow tract obstruction (LVOTO).
• Usually regresses over time.
• Increased incidence of structural cardiac disease in children born to mothers with pregestational insulin-dependent diabetes mellitus.

• Risk is 3.2 times higher than the risk if maternal diabetes was not present.
• Structural lesions include ventricular septal defects (VSDs) and conotruncal lesions such as dextro transposition of the great vessels.

image

Figure 16-6 Parasternal long axis view demonstrating hypertrophic cardiomyopathy in an infant secondary to maternal diabetes exposure prenatally. Note the significant degree of septal hypertrophy that resulted in left ventricular outflow tract obstruction in this patient as well as obliteration of the left ventricular cavity in systole.

The Echo Exam: Step-by-Step Approach

Step 1: Evaluate Cardiac Dimensions

• Use M-mode and 2D assessment of cardiac dimensions.

Key Points

• Assess for left ventricular dilation and/or LVH using measurements indexed to BSA.
• Image using multiple planes including 4C and short axis views.

Step 2: Evaluate Cardiac Function

• Calculate the shortening fraction using M-mode or 2D measurements.
• Calculate the EF using a modified Simpson method or 5–6 area-length method.
• Evaluate for diastolic cardiac function including

• Evaluation of mitral inflow (E and A wave velocities).
• TDI.
• VVI.
• Strain rate and strain imaging.

Key Points

• FS and EF may be increased secondary to hyperkinetic state.
• Obtain a cardiac rhythm strip during echocardiography when possible to evaluate for tachycardia.

Step 3: Evaluate Cardiac Structure

• Infants born to diabetic mothers are at increased risk of congenital heart disease.
• A full anatomic study should be performed on patients with clinical concerns.

Key Points

• Fully interrogate the ventricular septum to evaluate for VSDs.
• Evaluate for structural lesions including conotruncal abnormalities and valvular lesions.

• The aortic arch should be completely interrogated including both PW Doppler and continuous wave (CW) Doppler evaluation.

• Obtain CW Doppler measurements of both outflow tracts.

• HCM is the most common cardiac disease seen in infants of diabetic mothers.
• LVOTO may be present in cases of significant HCM.

Step 4: Evaluate for Pericardial Effusion

• Image from subcostal, parasternal short axis, and 4C views (Fig. 16-7).
• Measure effusion during diastole.
• Perform a spectral Doppler evaluation of the MV and tricuspid valve (TV).
image

Figure 16-7 Subcostal 4C view demonstrating a large pericardial effusion (PE). Subcostal imaging is useful in identifying the location of the effusion for consideration of approach for percutaneous pericardiocentesis. In this image, the effusion is circumferential with a larger posterior pocket of fluid.

Key Points

• Expiratory right ventricular free wall collapse early in diastole can be a sign of tamponade.
• Expiratory right atrial collapse occurring in more than one third of the cardiac cycle indicates tamponade.
• Mitral inflow with more than 30% variation between inspiration and expiration is an indication of tamponade physiology (Fig. 16-8).
image

Figure 16-8 Spectral Doppler evaluation of the mitral valve inflow demonstrates more than 30% variation between inspiration and expiration, consistent with tamponade physiology.

Oncologic Disease

Chemotherapeutic agents and radiation are associated with the development of CMs.

• Dilated cardiomyopathy (DCM).
• Restrictive cardiomyopathy (RCM).
• Risk factors for CM:

• Therapy at younger than 4 years of age.
• Females.
• Mediastinal irradiation.
• Total cumulative dose; may be seen starting at a cumulative anthracycline dose of 400 to 600 mg/m2.

Key Points

• Anthracyclines.

• Doxorubicin (Adriamycin) for oncologic processes including acute lymphocytic leukemia may cause a chronic, dose-related CM with left ventricular dysfunction.

• Can occur 3 to 8 weeks after last dose of drug.
• Incidence is related to cumulative dose, age at the time of anthracycline therapy, and duration since completion of therapy.

• No safe dose.

Dilated Cardiomyopathy

• DCM is defined as an increased end-diastolic and/or end-systolic volume indexed to BSA in the presence of ventricular dysfunction (Fig. 16-9).
• Mitral regurgitation may be present.
• Decreased forward flow in the ascending aorta (Ao) by Doppler.
• Diastolic flow reversal can be seen in the descending aorta.
image

Figure 16-9 Apical 4C view demonstrating dilated cardiomyopathy with increased end-diastolic volume. The significant left ventricular dilation, which dwarfs the normal-size right ventricle, was accompanied by ventricular dysfunction in this patient.

Restrictive Cardiomyopathy

• The LA and right atrium (RA) may be markedly dilated at end-diastole and often exceed the size of the LV.
• The LV is normal in size with no appreciable LVH or dilation.
• Normal to near-normal left ventricular systolic function.
• Shortened mitral deceleration time (<150 ms) and becomes shorter with inspiration.
• May have mid-diastolic flow reversal across the MV.

The Echo Exam: Step-by-Step Approach

Step 1: Evaluate Cardiac Dimensions

• Use M-mode and 2D assessment of cardiac dimensions.

• Measurements should be indexed to BSA to assess for left ventricular dilation and/or LVH.
• Evaluate the RA and LA (qualitative assessment).

Key Points

• Marked atrial dilation will be present with RCM (Fig. 16-10).
• Image using multiple planes including 4C and short axis views.
image

Figure 16-10 Apical 4C view demonstrating a restrictive cardiomyopathy with massive dilation of the left and right atrium (LA and RA). In this case, atrial size exceeds that of the ventricles.

Step 2: Evaluate Cardiac Function

• Calculate the shortening fraction using M-mode or 2D measurements.
• Calculate the EF by a modified Simpson biplane method or 5–6 area-length method.
• Evaluate for diastolic cardiac function including

• Evaluation of mitral inflow (E and A wave velocities).
• TDI.
• VVI.
• Strain rate and strain imaging.

Key Points

• The FS and/or EF are reduced in a cardiomyopathic state.
• Diastolic evaluation may detect myocardial dysfunction before the appearance of clinically significant global ventricular impairment.
• Patients with CM have a greater degree of dyssynchrony.

Step 3: Evaluate for Pericardial Effusion

• Image from subcostal, parasternal short axis, and 4C views.
• Measure effusion during diastole.
• Perform a spectral Doppler evaluation of the MV and TV (Fig. 16-11).
image

Figure 16-11 Parasternal short axis view of a large PE.

Suggested Reading

1 Lopez L, Colan S, Frommelt P, et al. Recommendations for quantification methods during the performance of a pediatric echocardiogram: a report from the Pediatric Measurements Writing Group of the American Society of Echocardiography Pediatric and Congenital Heart Disease Council. J Am Soc Echocardiogr. 2010;23:465-495.

This is an excellent resource for recommendations for pediatric echocardiogram measurements including left ventricular size and function.

2 Khoury PR, Mitsnefes M, Daniels SR, et al. Age-specific reference intervals for indexed left ventricular mass in children. J Am Soc Echocardiogr. 2009;22:709-714.

Description of a standard method for indexing LVM in the pediatric population using height and age.

3 Ucar T, Tutar E, Yalcinkaya F, et al. Global left ventricular function by tissue Doppler imaging in pediatric dialysis patients. Pediatr Nephrol. 2008:779-785.

Summary of cardiac findings and methods for echocardiographic assessment in patients with chronic renal disease including use of the MPI.

4 Harkl AD, Cransberg K, Osch-Gevers MV, et al. Diastolic dysfunction in paediatric patients on peritoneal dialysis. Nephrol Dial Transplant. 2009;24:1987-1991.

This article examined the cardiovascular changes seen in pediatric renal patients on dialysis and after transplantation. Persistent changes were seen in function (both systolic and diastolic) as well as LVM even after renal transplantation.

5 Kupferman J, Paterno K, Mahgerefeh J, et al. Improvement of left ventricular mass with antihypertensive therapy in children with hypertension. Pediatr Nephrol. 2010;25:1513-1518.

6 Chavers BM, Shuling L, Collins AJ, et al. Cardiovascular disease in pediatric chronic dialysis patients. Kidney Int. 2002;62:648-653.

Summary of cardiovascular risk factors in pediatric dialysis patients describing an increased incidence of cardiovascular morbidity and mortality in African American, female, and adolescent patients.

7 Greenbaum LA, Warady BA, Furth SL. Current advances in chronic kidney disease in children: growth, cardiovascular, and neurocognitive risk factors. Semin Nephrol. 2009;29:425-434.

Comprehensive article sponsored by the National Institutes of Health reviewing the cardiovascular effects of renal disease and describing the development of LVH and diastolic dysfunction.

8 Friedberg MK, Silverman NH, Dubin AM, et al. Mechanical dyssynchrony in children with systolic dysfunction secondary to cardiomyopathy: a Doppler tissue and vector velocity imaging study. J Am Soc Echocardiogr. 2007;20:756-763.

Excellent article describing how to use TDI and VVI for the assessment of dyssynchrony in pediatric patients with CM. This article specifically examines mechanical dyssynchrony in these patients rather than electrical dyssynchrony for this subset of patients.

9 Lopez L. Advances in echocardiography. Curr Opin Pediatr. 2009;21:579-584.

Summary of echocardiographic assessment including strain imaging and its utility in the early assessment of cardiac dysfunction in renal and oncologic diseases in pediatric patients.

10 DiBonito P, Moio N, Scilla C, et al. Preclinical manifestations of organ damage associated with the metabolic syndrome and its factors in outpatient children. Atherosclerosis. 2010;213:611-615.

A description of the cardiovascular findings associated with metabolic syndrome including LVH.

11 Abu-Sulaiman RM, Subaih B. Congenital heart disease in infants of diabetic mothers: echocardiographic study. Pediatr Cardiol. 2004;25:137-140.

Summary of findings in infants of diabetic mothers including HCM and conotruncal defects.

12 Van der Pal HJ, van Dalen EC, Hauptmann M, et al. Cardiac function in 5-year survivors of childhood cancer. Arch Inter Med. 2010;170:1247-1255.

Summary of the predictors for development of cardiac dysfunction in cancer patients including dose, cardiac irradiation, and younger age at diagnosis.

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