Abstract Cardiac involvement in systemic disease can be broadly divided into those conditions where the heart is involved in the disease process itself and those where a structural or functional cardiac abnormality is associated with other anomalies, usually in a recognizable syndrome Many of the conditions in the latter group have received attention in the sections of this book dealing with etiology and genetics They are not dealt with in this chapter, although they may be mentioned, or the discussion amplified, as necessary A vast number of systemic diseases, nonetheless, can involve the heart during childhood Cardiac aspects of the latter diseases are the focus of this chapter Keywords Cardiomyopathy; metabolic; neuromuscular; collagen synthesis; endocrine; energy metabolism; nutritional autoimmune disorders Cardiac involvement in systemic disease can broadly be divided into those conditions where the heart is involved in the disease process itself and those where a structural or functional cardiac abnormality is associated with other anomalies, usually in a recognizable syndrome Many of the conditions in the latter group have received attention in the sections of this book dealing with etiology and genetics They are not dealt with again here, although they may be mentioned or the discussion amplified as necessary A vast number of systemic diseases, nonetheless, can involve the heart during childhood Cardiac aspects of the latter diseases are the focus of this chapter Metabolic Disorders: Storage Diseases Glycogen Storage Diseases Glycogen Storage Disease Type I (Von Gierke Disease, Glucose 6-Phosphatase Deficiency [Type Ia], Glucose 6-Phosphatase Translocase Deficiency [Type Ib]) Von Gierke disease is an autosomal recessive disorder Clinical manifestations of type I glycogen storage disease are profound hypoglycemia associated with hyperlipidemia, hyperuricemia, and lactic acidosis It presents in childhood and primarily involves the liver, kidneys, and small intestinal mucosa Pulmonary hypertension in association with type Ia glycogen storage disease has been described; when present, the prognosis is very poor Postulated mechanisms include chronic stimulation of the smooth muscle of the pulmonary arterioles by the persistent hepatic metabolism of circulating catecholamines such as serotonin Indeed, serotonin levels have been shown to be markedly elevated in some patients with glycogen storage disease type I However, elevated serotonin levels alone do not appear to confer pulmonary vascular disease on these patients Rather, it is hypothesized that other mediating factors in concert with persistently elevated serotonin levels increase the risk for pulmonary vascular changes Gene therapies are being developed to treat glycogen storage disease type I and initial results appear promising.1–3 Glycogen Storage Disease Type II (Pompe Disease) Pompe disease is a generalized glycogen storage disease in which glycogen of normal structure accumulates in the myocardium, skeletal muscle, and liver The disease is progressive and is associated with deficiency of lysosomal α-1,4glucosidase There are four subtypes based on age at onset of clinical symptoms: infantile (classic Pompe disease), childhood, juvenile, and adult The age at onset correlates inversely with the measured activity of lysosomal α-1,4glucosidase in muscle cells or fibroblasts In the infantile form, which generally has more severe cardiac involvement than the forms with later onset, there is generalized accumulation of glycogen in the heart (including in the conduction tissues), in skeletal muscle (notably the tongue and diaphragm), and in the liver Central and peripheral neurons and smooth muscle are also affected The results are cardiomegaly, hepatomegaly, a thickened diaphragm, and macroglossia In the heart, the glycogen is deposited mainly in ventricular muscle There is gross thickening of the ventricular walls, with impairment of both diastolic and systolic performance The infants typically appear normal at birth, although cases of severe neonatal ventricular hypertrophy have been reported.4 The median age at onset of clinical symptoms is 1.6 months Muscle weakness and hypotonia along with loss of motor milestones are noted during the first 6 months of life, and signs of CHF become evident Although there is excess glycogen in the liver, hepatomegaly is not commonly present until heart failure is apparent The disease is progressive, and most affected babies die before the age of 1 year The clinical course may be complicated by arrhythmias Since patients with Pompe disease appear very sensitive to digoxin, this drug must be used with extreme caution Irritability and poor feeding often draw attention to the disease The cardiac physical signs are not characteristic, with variable murmurs being heard Unexplained cardiomegaly and CHF in a generally “floppy” baby should suggest the diagnosis.5 The chest radiograph may be normal at birth, but in all affected infants the heart becomes enlarged within a few weeks There is no specific pattern to the cardiac silhouette but rather a generalized smooth enlargement of the contour The characteristic electrocardiographic features are a short PR interval, wider than normal QRS complexes, and voltage evidence of left or biventricular hypertrophy, which can be severe (Fig 59.1) In addition, in the majority there are Q waves and inverted T waves in leads I, II, and the left chest leads.6 Electrophysiologic studies have shown a short A-H interval.7 Both M-mode and cross-sectional echocardiography demonstrate gross increase in the thickness of the ventricular free walls and the ventricular septum (Fig 59.2) Impaired diastolic filling is frequent,8 together with reduction of the rate and extent of systolic shortening Cardiac catheterization is rarely performed as it adds little to the diagnosis or management