The Heart in Kawasaki Disease

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Overview
Kawasaki disease, also known as lymph node syndrome, mucocutaneous node disease, infantile polyarteritis and Kawasaki syndrome, is a poorly understood self-limited vasculitis that affects many organs, including the skin and mucous membranes, lymph nodes, blood vessel walls, and the heart. It does not seem to be contagious. It was first described in 1967 by Dr. Tomisaku Kawasaki in Japan.

Epidemiology and Demographics
Approximately 80% of the patients with Kawasaki disease are less than 5 years of age. Kawasaki disease rarely affects children over eight years. The disease is observed more often among boys (>60%). While the disease is more prevalent among those of Asian ancestry, it has been reported in every racial and ethnic group. Again, while more that 8,000 cases of Kawasaki disease are diagnosed annually in Japan, there are still approximately 4,000 cases diagnosed annually in the United States. Given the nature of disease progression, the age related characteristics of Kawasaki disease and the need to call upon different specialists, an aged based subgroup classification may be helpful in understanding and managing the disease. As a result the approach to the disease is divided into the pediatric and adult forms below.

Pathophysiology
The causative agent of Kawasaki disease is still unknown. However, current etiological theories center primarily on immunological causes for the disease. Much research is being performed to discover a definitive toxin or antigenic substance, possibly a superantigen, that is the specific cause of the disease. An unknown virus may play a role as an inciting factor as well.

Cardiac Complications of Kawasaki Disease
The cardiac complications are, by far, the most important aspect of the disease. Kawasaki disease can cause vasculitic changes (inflammation of blood vessels) in the coronary arteries and subsequent coronary artery aneurysms. These aneurysms can lead to myocardial infarction (heart attack) even in young children. Overall, about 10–18% of children with Kawasaki disease develop coronary artery aneurysms, with much higher prevalence among patients who are not treated early in the course of illness. Kawasaki disease is the most common cause of acquired heart disease among children in the United States.

Pediatric form of Kawasaki disease
Cardiac involvement ranges from myocarditis and pericarditis with or without pericardial effusion in the acute stage, to the development of coronary artery aneurysms later in the course of disease.

Kawasaki Disease has four different clinical stages. Cardiac involvement might be present in every stage.

Stage 1: Acute febrile phase (days 1-11) of Kawasaki disease

 * Cardiac complications noted in the first stage include myocarditis and pericarditis. There is no special laboratory test. A mild-to-moderate normochromic anemia is observed in the acute stage along with an elevated white blood cell count with a left shift, and elevation of acute phase reactants are frequent.

Stage 2: Subacute phase (days 11-21) of Kawasaki disease

 * Aneurysm formation may occur during this stage.


 * Children are at greatest risk of sudden cardiac death during this phase. There is no special laboratory test. Platelet counts begin to rise in the second week and continue to rise during the third week. Abnormally elevated platelet counts (up to 2 million is reported) may be observed at this stage and high levels of acute phase reactants are remain.

Stage 3: Convalescent phase (days 21-60 of) Kawasaki disease
The most significant clinical finding that persists through convalescent phase is the presence of coronary artery aneurysms. The levels of platelets and other markers of inflammation begin to return to normal reference values (usually it may take 6-8 weeks to return the normal range).

Stage 4: Chronic phase of Kawasaki disease

 * This stage is only of clinical importance in patients who have developed cardiac complications.


 * It is significant throughout the rest of the patient's life because the aneurysm formed in childhood may rupture in adolescence age or adulthood.


 * In some cases of aneurysms rupturing in adult life, careful reviews of past medical histories have revealed febrile childhood illnesses of unknown etiology.

Symptoms
Cardiovascular manifestations can be prominent in the acute phase of Kawasaki disease and are the leading cause of long term morbidity and mortality. During this phase, the pericardium, myocardium, endocardium, valves, and coronary arteries all may be involved.

Physical Examination
Cardiac auscultation of the infant or child with Kawasaki disease in the acute phase often reveals a hyperdynamic precordium, tachycardia, a gallop rhythm, and an innocent flow murmur in the setting of anemia, fever, and depressed myocardial contractility secondary to myocarditis. Children with significant mitral regurgitation may have a pansystolic regurgitant murmur that is typical of this condition.

Occasionally, patients with Kawasaki disease and poor myocardial function may present with a low cardiac output or shock.

Electrocardiography
Electrocardiogram may indicate the presence of various conduction abnormalities such as prolonged PR interval and arrhythmias or nonspecific ST and T wave changes. A low but finite risk of acute myocardial infarction in pediatric group of patients with Kawasaki disease should always be kept in mind.

Chest Radiography
A chest radiograph should be obtained to assess baseline findings and to confirm clinical suspicion of congestive heart failure.

Echocardiography
Baseline echocardiographic examination is important and the study of choice in the acute stage of Kawasaki disease. Although the two-dimensional echocardiography is the gold standard in the early cardiac assessment of Kawasaki disease and in detecting coronary artery aneurysms of proximal right and left coronary arteries in children, more invasive methods are required in order to better visualize in detail the entire coronary artery system. Repeated echocardiographic examinations should be performed again in the second or third week and at one month after all other laboratory results have normalized. Echocardiographic examination at one year may be of benefit in excluding long term sequela.

Dobutamine stress echocardiography has shown to be a safe and sensible diagnostic modality in evaluating the outcome of coronary artery aneurysms, comparable to cardiac catheterization.

Cardiac Magnetic Resonance Angiography
Cardiac magnetic resonance angiography (MRA) is of value in identifying coronary artery aneurysms during the follow up period.

Multi Slice Computed Tomography (MSCT)
While the sensitivity of multislice CT may not be 100% in the detection of coronary artery stenoses, the multislice CT may have near 100% sensitivity in the detection of coronary artery aneurysms. The presence of coronary artery calcification may adversely impact the interpretation of multi-slice computed tomography.

Electron beam computed tomography (EBT)
Electron beam computed tomography (EBT) is a noninvasive tool that enables the early detection of myocardial ischemia progressing from endocardial to the epicardium.

Positron emission tomography (PET)
Positron emission tomography (PET) is a useful diagnostic tool in evaluating the coronary flow reserve in children with normal epicardial coronary arteries, addressing the risk of residual coronary damage in the absence of obvious epicardial coronary artery involvement

Management of Pediatric Patients with Kawasaki disease
Immediate venous access and continuous electrocardiographic monitoring of the heart rhythm are essential first line management in the emergency department. If ischemia is present, some patients may require cardiac catheterization and coronary angiography. Surgical revascularization and heart transplantations may also need to be undertaken.

Long term management including aspirin and/or additional antiplatelet/anticoagulant therapy and referral to a specialized cardiology center should be considered. Follow up evaluations should be performed by a pediatric cardiologist or a pediatric cardio-surgeon.

Prognosis in the Pediatric form of Kawasaki disease
Kawasaki disease has a mortality rate <1%. Patients with Kawasaki disease have an increased lifetime risk of myocardial ischemia, myocardial infarction and sudden cardiac death.

The Adult Form of Kawasaki disease
Kawasaki disease is rare in adults. The disease may have an atypical onset. Myocarditis occurs to some degree during the acute phase of Kawasaki disease but typically resolves completely and may or may not be associated with coronary artery involvement. Although, coronary artery aneurysms are observed 18–25% of pediatric patients, their frequency is lower (only 5%) in adult cases.

The most common location of aneurysms are the arterial bifurcations of the proximal coronary arteries. Coronary artery aneurysms in adults are associated with premature atherosclerosis and subsequent myocardial infarction. Although microscopic fibrosis may alter vessel mechanics over the long term, 50–75% of coronary artery aneurysms resolve without any intervention

Physical Examination
Clinical findings include an S3 (ventricular gallop) and/or S4 (atrial gallop) on cardiac auscultation.

Chest x-ray
Cardiomegaly may be present on the chest x-ray.

Electrocardiogram
Non-specific ST segment and T wave changes or low voltage may be present on the electrocardiogram.

Echocardiogram
A pericardial effusion and depressed left ventricular systolic function may be present on the echocardiogram.

Cardiac catheterization
Cardiac catheterization is recommended for further diagnosis if the patient develops ischemic symptoms or if stress testing reveals reversible ischemia.

Treatment
Coronary revascularization is recommended for patients with giant or multiple coronary artery aneurysms or significant caronary artery stenosis. Overall mortality is low for such operations, and target sites for grafting are easily accessible, since most coronary artery lesions occur in proximal segments with little distal involvement. In situ arterial grafts are usually preferred given their excellent ability to accommodate the patient's growth.

Prognosis in the Adult Form of Kawasaki disease
Although, none of these can predict aneurysmal development, the following are associated with an increased risk of coronary artery aneurysmal formation: a significant rise in body temperature, prolonged fever, prolonged erythrocyte sedimentation rate elevation, markedly elevated white blood cell count, anemia, and time (<1 year) since disease onset.

In some patients, coronary artery aneurysms may persist and become occlusive, therefore the risk of acute myocardial infarction and/or sudden cardiac death is increased.

Acute myocardial infarction can occur early or late after the acute phase of Kawasaki disease; therefore, patients should be counseled to avoid atherosclerotic risk factors, and the progress of these patients should be followed into adulthood.

The most important correlate of acute myocardial infarction and other chronic sequelae is size of coronary artery aneurysm. Giant coronary artery aneurysms have a poorer prognosis than the smaller ones. They do not regress and may result in ischemic heart disease. In later stages, affected arterial segments may become calcified, contain thrombus, or become stenotic.

According to a long-term study of coronary artery aneurysms in 1,215 patients with Kawasaki disease, the incidence of developing giant coronary artery aneurysms was 5% (in 64 patients). Further analysis of this subgroup revealed regression without complications in 5% (3 patients), occlusion or stenosis in 47% (30 patients), and acute myocardial infarction in 23% (15 patients).

Coronary artery lesions are dynamic in the late acute and early convalescent phases. The longer the aneurysms or stenotic lesions persist, the less likely they are to resolve. Therefore early diagnosis and prompt management are important. With an unknown reason lesions in the right and left coronary arteries appear to progress differently. Massive thrombosis of the coronary artery aneurysm is seen more frequently in the right coronary artery, usually within a year after disease onset. Progression of a local stenosis at the aneurysm inlet or outlet is seen more frequently in the left coronary artery in the year after symptom onset.

It is unclear whether resolution of coronary artery aneurysms represents true healing, permanent “filling in” by either intimal proliferation or thrombus organization, or arterial wall contraction after scar formation. Kurisu and colleagues showed that angiographically normal arterial segments at previously aneurysmal sites are less distensible. An intravascular ultrasound and coronary angiography guided study results have shown that, in patients with regression of coronary artery aneurysm, coronary arteries become stiffer and may exhibit both morphologic and functional abnormalities.

Years later, vascular damage that occurred during the acute phase of Kawasaki disease may lead to vascular abnormalities. It is unknown whether survivors whose coronary arteries were normal on their coronary angiograms after resolution of aneurysms are at increased risk for premature coronary artery atherosclerosis.

Using a Doppler guidewire, Hamaoka's group found abnormalities in flow dynamics and decreased flow reserve in intermediate and large coronary artery aneurysms, even those of mild-to-moderate severity.

Although some chronic coronary artery aneurysms in patients with Kawasaki disease are associated with stenosis of coronary arteries and abnormal perfusion and ventricular function in adjacent myocardium, Hijazi et. al. using (treadmill testing and technetium-99m sestamibi single-photon emission computed tomography) TMT-MIBI, found that most coronary arteries with aneurysm related territories have normal myocardial perfusion and function.