Cardiac Failure

Introduction

Heart failure continues to be a worldwide health dilemma. Health care costs for children are higher owing to the need for surgical or catheter-based interventions for congenital heart disease¹. Even though more children with heart disease are surviving into adulthood, there is still considerable childhood morbidity and mortality as well as psychological stress for both the patient and family.

Understanding the pathophysiology of heart failure is equally as important as recognizing the cause and severity of heart failure. The classic definition of heart failure involves a scenario where the cardiac function is inadequate to meet the body’s need for energy². This definition brings to mind a dilated, poorly contracting heart. However, children with congenital heart disease often have normal heart function yet exhibit classic features of heart failure. A more comprehensive definition would include cardiac dysfunction as well as pressure and volume overload³. Moreover, the complex interactions between the diseased heart and feedback signaling from the body and circulation cannot be ignored³. Such compensatory processes help to mask symptoms early on but complications appear as these processes fail and ironically accelerate the disease. Heart failure is best approached as a systemic disease where the heart is treated and compensatory responses are subdued. The goal of this discussion is to review broad etiologies of heart failure and treatments to allow the practitioner to select targeted, diagnosis-based therapies.

Recognizing Heart Failure

Children may develop heart failure at any time in their lifespan. Heart failure is sometimes difficult to diagnose because clinical symptoms may be heterogeneous or non-specific (Table 1). Respiratory distress (tachypnea, retractions), hepatomegaly, exercise intolerance, and abnormal cardiac examinations are universal findings^2,3. However, age and genetic background create variability in the presentation. Infants are less likely to exhibit peripheral edema compared to older children. Children with trisomy or other chromosomal anomalies may be more ill-appearing compared to those without. Adding to the complexity are the numerous etiologies of pediatric heart failure each with their own unique signs and symptoms. Furthermore, the prevalence of common heart lesions appears to vary by demographics. In developed countries, infants with heart failure most likely have congenital heart disease whereas older children will develop acquired disease or cardiomyopathy (Table 2). In contrast, within less developed countries, nutritional deficits, anemia, infection, and rheumatic fever predominate⁴.

Heart failure is diagnosed using history, physical exam, and laboratory findings (Table 1). These diagnostic findings should also be used to rate the severity of heart failure as this dictates treatment decisions. Unlike adults, however, rating the severity of heart failure in children has been a challenge. In part, this is due to the variability in age, diagnosis, activity level, and physiology in children compared to adults². The New York Heart Association classification has not proven reliable in children. The original Ross scale is useful in infants from birth to 6 months of age but is not for older children². A modified (but non-validated) Ross scale⁵ can be used for older children (Table 3). Likewise, the New York University Pediatric Heart Failure Index is useful for all ages but is not validated congenital heart disease. The scale is a weighted, combination of scores that takes into account symptoms, signs, single ventricle disease, and current treatments. The result is a range of scores from zero (no heart failure) to 30 (severe heart failure, 9). The scale appears sensitive for tracking fluctuations in the severity of heart failure for a given individual such as pre- and post- cardiac intervention.

Table 1. Common Signs and Symptoms of Heart Failure

• Symptoms
• Shortness of breath at rest or with activity (feeding)
• Fatigue
• Edema
• Nausea, anorexia, poor growth or weight loss (catabolic state)
• Fussiness (infants)
• Signs
  • Tachycardia Tachypnea
  • Pulmonary rales (pulmonary congestion)
  • Pleural effusion (less common)
  • Jugular venous distension (older children)
  • Hepatomegaly
  • Facial or peripheral edema
  • Poor circulation or perfusion
• Cardiac findings
  • Murmur
  • Arrhythmia
  • Arm/leg blood pressure discrepancy (coarctation)
  • Loud P2 heart sound (pulmonary arterial or vascular hypertension)
  • Increased or shifted cardiac impulse (pressure or hypertrophy)
  • Gallop (diastolic dysfunction)
  • Muffled heart sounds (poor systolic function, large pericardial effusion)
  • Cardiomegaly
  • Abnormal EKG or Echocardiogram
  • Increased natriuretic peptide or troponin I

Table 2. Common Etiologies of Heart Failure Based Upon Age

• Fetus
  • Tachyarrhythmias and complete heart block
  • Severe anemia
  • Arteriovenous malformations
  • Twin-twin transfusion
• Premature infants
  • Patent ductus arteriosus
  • Volume overload
• Term infants
  • Congenital heart disease
    • 1st week of life: hypoplastic left heart syndrome, critical valve disease
    • 1-4 weeks of life: coarctation or other ductal dependent lesions
    • 4 weeks-4 months of life: large ventricular or atrial septal defects, endocardial cushion defect, anomalous coronaries
• Older children
  • Failed congenital heart palliation
  • Myocarditis/infection
  • Cardiomyopathy
  • Rheumatic heart disease
  • Arrhythmia

Table 3. Modified Ross Heart Failure Classification

• Class I
  • Asymptomatic
• Class II
  • Mild tachypnea or diaphoresis feeding in infants, normal growth
  • Dyspnea on moderate exertion in older children (1-10y age)
• Class III
  • Marked tachypnea or diaphoresis with feeding failure in infants
  • Prolonged feeding times with growth failure
  • Marked dyspnea with minimal exertion
• Class IV
  • Tachypnea, retractions, grunting, diaphoresis at rest

Heart Failure Pathophysiology

Once heart failure is recognized, the next step is to localize and describe the lesion or disease process. When localizing a cardiac process, one must determine whether the disease affects the left, right, or both ventricles. Right, and left heart diseases have distinct clinical characteristics whereas biventricular disease exhibits a combination of both.

Right Heart Failure - Ineffective forward flow of venous blood into the pulmonary circulation.

Right heart failure can result from pump dysfunction or obstruction to flow. This causes a backup of fluid in the body, resulting in swelling, edema, hepatomegaly, and jugular venous distension (older children, not infants). Ascites and pleural effusions are possible but uncommon. Examples include severe pulmonary hypertension or severe pulmonic stenosis.

Left Heart Failure - Ineffective forward flow of arterial blood into the systemic circulation.

Left heart failure also results from myocardial dysfunction or obstruction. Back up behind the left ventricle causes accumulation of fluid in the lungs leading to respiratory distress and poor cardiac output. Examples include cardiomyopathy or severe aortic stenosis.

Biventricular disease- Children would exhibit a combination of the above findings. Examples include cardiomyopathy or arteriovenous malformation.

Ventricular failure can be further divided into systolic and diastolic dysfunction. The former is characterized by a reduced ejection fraction and an enlarged ventricular chamber, the latter by increased resistance to filling. Both systolic and diastolic dysfunction may coexist (dilated cardiomyopathy) and one or both ventricles may be affected.

Systolic dysfunction- pump dysfunction

Cardiomyopathy

Arrhythmia

Severe valve or vascular obstruction (aortic stenosis, pulmonic stenosis, coarctation)

Severe systemic hypertension

Toxins/medications

Diastolic dysfunction- decreased compliance (stiffness)

Cardiac fibrosis or scarring

Hypertrophic cardiomyopathy

Pericardial effusion/Pericardial disease

Laboratory Assessment of Heart Failure

Laboratory testing helps to support a heart failure diagnosis. Chest x-rays may reveal cardiomegaly or pulmonary congestion and help to track responses to therapy. Echocardiograms may reveal the underlying cause and the degree of myocardial dysfunction. EKG’s assess rhythm disturbances or ischemia but are less helpful for other diagnoses. Biomarkers such as serum brain-type natriuretic peptide (BNP) are commonly used to assess the presence and severity of heart failure. In acute heart failure, a BNP level >500 pg/ml has a 90% predictive value for the presence of heart failure, and levels <100 pg/ml have a 90% predictive value for the absence of heart failure. Cardiac MRI can be used to distinguish between myocarditis and ischemic heart disease as well as assessing cardiac chamber size and function^3,5,6.

Echocardiography remains the gold standard assessment for left heart function in children. In general, an ejection fraction (EF) <50% is usually considered abnormal. An EF of 40-50% is considered mid-range dysfunction whereas and EF <35-40% is considered more severe. The latter EF range is the key range used pediatric therapeutic clinical trials and forms the basis for many treatment options used today. Echocardiography is less accurate at assessing right ventricular dysfunction whereas cardiac MRI can assess either ventricle. Diastolic dysfunction is usually an echo diagnosis. However, the criteria for children are less clear as a diastolic function also changes with age.^10,11,12,13 Newer echocardiography guidelines for the assessment of cardiac dysfunction are pending for 2016.

Treatment Approaches to Heart Failure Based Upon Cardiac Etiology

Expert panels have developed treatment guidelines based upon the weight of scientific evidence as well as clinical expertise.^4,5 It is helpful to divide patients into one of two groups based upon the presence or the absence of structural heart disease (Table 4).

1) Children with Structural Heart Disease:

In children with congenital heart disease, symptoms are usually a consequence of either intracardiac shunts (volume overload) or blood flow obstruction (pressure overload) or a combination of the two.

Volume overload- (excessive preload)

This group includes either moderate to the large left to right intracardiac shunting (septal defects) or moderate to severe heart valve insufficiency. In newborns with intracardiac shunts, symptoms usually become apparent within the first few months of life as pulmonary vascular resistance falls. The key finding is progressive respiratory distress. Infants have exacerbated symptoms during feeds during which excessive calories are expended resulting in poor weight gain. There is a rise in renin, aldosterone, brain natriuretic peptide (BNP), and cytokines. These factors appear to contribute to fluid retention, tachycardia, failure to thrive, and cardiac dilation^3,4,5,6.

The treatment goal for volume overload (Table 5) is pre-load reduction using loop diuretics (furosemide, 0.5- 2 mg/kg/dose PO Q6-12h) and aggressive nutritional therapy (120-130 kcal/kg/day). Thiazide diuretics can be co-administered with loop diuretics to obtain a synergistic effect (if a loop diuretic alone is ineffective). Digoxin (dose schedule varies by age) may be used in combination with the former agents but is rarely effective when used alone. Aldosterone antagonists are used in combination with the aforementioned therapies, as these agents appear to modulate certain aldosterone-mediated activities (myocardial fibrosis, remodeling, and free radical production).

Pressure overload- (excessive afterload)

Pressure overload is usually a result of severe semilunar valve disease or hypertension. In the most severe cases, the left ventricular cardiac output becomes compromised and the child may become acidotic and develop shock. Subendocardial ischemia may lead to myocardial dysfunction. Very little known about the expression of systemic modulators in pressure overload. It is not clear if BNP is a helpful marker in these cases^{3-6, 13}.

Treatment for pressure overload involves relief of obstruction and support of cardiac function (inotropes, and vasodilators such as Nipride or Milrinone- 0.3-1 mcg/kg/min).

Table 4. Pathophysiology of Heart Failure Based upon Lesion

• Presence of structural heart disease
  • Volume overload (usually no pump dysfunction)
    • Left to right shunting
      • Moderate to large ventricular septal defect
      • Large atrial septal defect
      • Large patent ductus arteriosus
    • Heart valve insufficiency
      • Semilunar valve insufficiency
      • Atrioventricular valve insufficiency
  • Pressure overload (possible pump dysfunction)
    • Left sided blood flow obstruction, aortic valve stenosis, coarctation
    • Right sided blood flow obstruction, pulmonary valve stenosis
    • Complex congenital heart disease, single ventricle physiology

• Absence of structural heart disease (pump dysfunction systolic and or diastolic)
  • Primary cardiomyopathy
    • Dilated
    • Hypertrophic
    • Restrictive
  • Secondary cardiomyopathy
    • Tachyarrhythmia
    • Drugs/toxins
    • Infectious/metabolic
    • Myocarditis

Table 5. Summary of Treatment Options for Pediatric Heart Failure Based upon Pathophysiology

I Heart Failure with congenital heart disease

• Volume overload
  • Diuretics (drug class)
    • Loop- Lasix (Furosemide)
    • Thiazide- Diuril, may be used in combination with Lasix if refractory to Lasix alone
    • Potassium sparing, aldosterone receptor antagonist, Spironolactone
• Digoxin (Digitalis) may have anti-sympathomimetic effects
• Surgical or catheter intervention for definitive therapy
• Pressure overload
  • Surgical or catheter intervention for definitive therapy
  • Inotropic support for cardiac dysfunction if present
  • Prostaglandin (newborns with ductal dependent disease)

II Heart Failure with no structural heart disease

• Systolic dysfunction
  • Digoxin, inotropic and anti-sympathomimetic effects
  • ACE inhibitors (Captopril, Enalapril), afterload reduction, blocks aspects or renin angiotensin system
  • Beta-blockers (Carvedilol, Metoprolol), anti-sympathomimetic effects
  • Mechanical support/transplantation
  • Anticoagulation (Salicylates), intracardiac thrombosis
  • IVIG (controversial treatment for myocarditis)
• Diastolic dysfunction
  • Beta blocker- improve ventricular filling, decrease afterload, arrhythmia control
  • Diuretics- decrease ventricular volume
  • ACE inhibitors- reduce neurohumoral activation
  • Transplantation
• Arrhythmia
  • Cardioversion (medical/electrical)

  Pacemaker

  Radiofrequency ablation

Complex heart disease-

Infants with complex congenital heart disease may present with combined volume and pressure overload (hypoplastic left heart syndrome). These infants are frequently cyanotic and are dependent upon the ductal arteriosus to sustain adequate pulmonary or systemic circulation. Consequently, prostaglandins (0.05-0.1 mcg/kg/min) are required. The judicious use of diuretics can help with pulmonary volume overload. Low dose inotropes (Dopamine 5-10 mcg/kg/min) and afterload reduction (Milrinone) may help support systolic perfusion while awaiting an intervention^{3-6, 13}.

2) Children without Structural Heart Disease, Examples include:
Rhythm disorders: complete heart block, supraventricular tachycardia, ventricular tachycardia

Systolic dysfunction, myocarditis, dilated cardiomyopathy/metabolic disease, malnutrition, ischemia

Diastolic dysfunction: hypertrophic or restrictive cardiomyopathy, pericardial disease

The goals of medical therapy include reductions in preload and afterload but also require enhancement of contractility and oxygen delivery (blood, iron supplements, oxygen).^{3-6, 13}.

How aggressive therapy should largely depend upon the severity of the presentation. Severe acute heart failure may present as a shock (hypotension, poor peripheral perfusion, thready pulse) decreased urine output. Fatigue, abdominal pain, nausea/vomiting, exercise intolerance, dizziness, or syncope are seen in older children. Renal and liver dysfunction may be present, as well as a decreased level of consciousness. Intensive care admission with advanced monitoring and/or mechanical support versus referral to an experienced heart failure center is advised^{3-6, 11.13}.

Initially, airway, breathing, and circulation should be supported. Oxygen could be provided for comfort (except with volume overload shunts that may increase pulmonary congestion). Initial laboratory testing may include blood culture; and empiric antibiotic therapy for infants along with a complete metabolic profile, lactate, BNP, and troponin I. Sedimentation rates or C-reactive proteins may help support a diagnosis of pericarditis or myocarditis. Mixed venous oxygen saturation (Sv02, normal 60-80%) are to assess cardiac output. Older children may require the placement of a central venous or pulmonary artery catheter to monitor venous pressure and cardiac output. Fluid balance should be followed daily until patients are stabilized^{3-6, 13}. Urine output, pulses, capillary refill, and perfusion are useful markers of hydration status.

Management of low cardiac output can be initiated by using a dopamine infusion of 5-10 mcg/kg/min and Milrinone (0.3-1 mcg/kg/min). Acidosis can be corrected with the administration of fluid and/or bicarbonate. Calcium should be replaced when hypocalcemia is documented. Diuresis is achieved with loop diuretics (furosemide) but additional diuretics such as thiazides with alternative targets of nephron function could also be added. Nitrates (nitroprusside) may be useful in patients with elevated pulmonary capillary wedge pressure and pulmonary congestion. Tachyarrhythmias, (usually supraventricular tachyarrhythmia) and complete heart block require prompt pharmacologic or electrical cardioversion.

What outpatient treatments are best to remain controversial? Afterload reduction (ACE inhibitor) is indicated in the presence of left ventricular dysfunction and left-sided regurgitant lesions. An angiotensin receptor blocker (ARB), such as losartan, may be used if ACE inhibitor side effects (rash, cough) are not tolerated^{3-6, 13}. Low-dose furosemide (1 mg/kg/dose PO bid) may be added to decrease pre-load and increased to 2 mg/kg/dose orally 3 times daily as needed. A second agent, such as Diuril or Metolazone, can be provided as intermittent doses to treat mild exacerbations. Electrolytes should be monitored (alkalosis, hyponatremia, hypokalemia) if multiple diuretics are used simultaneously for longer periods.

Digoxin is commonly used if systolic dysfunction is present and it may also decrease cardiac autonomic tone. Beta-blocker use is controversial but considered reasonable for left but not right ventricular systolic dysfunction (carvedilol, 3-6, 13).

Other Treatment Considerations for Heart Failure

Anemia

Anemia increases cardiac output and oxygen consumption. Correcting the iron status and or transfusions may result in clinically significant improvement¹⁵.

Nutrition

During infancy, enhanced caloric content (100-130 mg/kg/day) with or without nasogastric or gastrostomy feedings may be necessary^3-6.

Thrombus formation- severe systolic dysfunction

Aspirin (low dose) is used as prophylaxis although, with severe dysfunction, Warfarin may be considered^3-6.

Genetic testing

Genetic testing for cardiomyopathy can diagnose a cause in 50% of cases⁵. Early testing may lead to immediate treatment versus waiting for the disease to become clinically evident. This information is also useful for family planning.

Systemic Effects On the Cardiovascular System and End-Stage Heart Disease

Systemic Effects on the Cardiovascular System and End-Stage Heart disease

There many communications between the heart, circulation, and neuro-hormonal signaling pathways. These pathways, triggered by changes in hemodynamic status, modulate cardiac function (compensated heart failure). Such responses benefit when heart failure is transient but paradoxically become detrimental over time and contribute to end-stage heart disease^3-6. Consequently, these effects must be considered in the overall treatment plan.

• Sympathetic nervous system

  Increases in sympathetic tone lead to higher heart rates, greater myocardial contractility, and vasoconstriction to sustain tissue perfusion pressure. Sympathetic stimulation increases afterload (blood pressure), myocardial oxygen consumption, and promotes fibrosis. Calcium flux within the cardiomyocyte may also be altered which subsequently results in reduced contractility (decompensation). Helpful drugs include beta-blockers.

• The renin-angiotensin-aldosterone system

  These pathways cause vasoconstriction and renal retention of salt and water. This process may augment contractility early in heart failure initially. Over time, systemic and pulmonary venous congestion develops due to volume overload. Helpful drugs include ACE inhibitors and diuretics.

• Ventricular hypertrophy

  Cardiac hypertrophy is thought to relieve cardiac wall stress. However, unrestrained hypertrophy may result in myocardial cell death and fibrosis.

• Inflammation

  Increased wall stress of myocardial fibers may lead to the production of cytokines and free radicals. These substances may cause cell apoptosis, tissue necrosis, fibrosis, cardiac dilation, and cardiac dysfunction. Beta-blockers, aldosterone antagonists, and ACE inhibitors may help mitigate these responses.

End-Stage Heart Failure

When heart failure progresses to advanced states, medication may have a limited capacity to provide stabilization. Families can choose between palliative care or mechanical based therapies while awaiting cardiac transplant.

Cardiac resynchronization therapy

Cardiac resynchronization therapy (CRT) involves the use of biventricular pacing to improve ventricular function by optimizing the timing of right and left ventricular contraction. CRT may slow or reverse cardiac remodeling and improve the quality of life in adults. However, outcome data are somewhat limited in children¹⁶.

Enlarged, poorly functioning ventricles are prone to rhythm disturbances. Arrhythmias that are not amenable to medication control should be treated by radiofrequency ablation, pacemakers, or defibrillators⁵.

Mechanical support

Mechanical support is used in the treatment of acute heart failure or in chronic heart failure as a bridge to recovery or to a heart transplant. The choice of support therapy depends on the expected duration of use.

Extracorporeal membrane oxygenation (ECMO) therapy is for unstable patients. The duration of use is limited to days or weeks because of the risks of infection or bleeding. It is intended to provide acute temporary support as a bridge to recovery or transplantation^{17, 18}.

Ventricular assist devices (VAD) may be used to provide long-term ventricular support compared to ECMO. Certain devices are made for children and have graduated sizes to fit children from newborns to adolescents. In children, VADs are used most often as a bridge to transplant as opposed to destination (long-term) therapy^{17, 18}.

Future Therapies

The finding that adult stem cells have the capacity to differentiate various lineages (endothelial, mesenchymal, etc.) has lead investigators into the early stages using them as therapy for myocardial dysfunction. In one series, 9 pediatric patients were compassionately treated with intracoronary bone marrow-derived stem cells. There was an improvement in symptoms in five of the children and the therapy was overall well tolerated^{19, 20}.