It is known that some infants with anomalous origin of the left coronary artery from the pulmonary trunk present with paroxysmal angina on exertion. Others present with congestive heart failure, with predominant involvement of the left heart. Those who survived infancy may have dyspnoea, syncope, or exertional angina. Exercise related sudden death is also frequently reported.1 The association with hypertrophy of the left ventricle, however, is extremely rare. It is not clear whether the hypertrophy is a result of the evolvement of the collateral coronary system, or due to an additional pathological gene for hypertrophic obstructive cardiomyopathy. The hypertrophy may have served as a compensatory mechanism accounting for the atypical clinical presentation. In this report, we describe two patients with anomalous origin of the left coronary artery from the pulmonary artery with hypertrophic left ventricles, discussing the possible mechanisms for this association.
Reports of cases
Case 1
A 12-year-old girl of Arabic descent, the fifth child to second degree consanguinity parents, with no family history of heart disease, was born at term and was well and thriving until four months of age. At that time, she was admitted to the paediatric ward for acute gastroenteritis. She was referred for a cardiological assessment due to the finding of a harsh systolic murmur. On physical examination, she appeared well, and was in no distress. A systolic murmur was present, heard at the apex and left sternal border, which radiated to the left lower quadrant of her back. Good peripheral pulses were palpated, with no signs of congestive heart failure. No dysmorphic features were present. Cervical vertebral fusion and hemivertebra were noticed on a cervical roentgenogram. The electrocardiogram showed sinus rhythm, a QRS axis of 0 degree, and left ventricular hypertrophy with the pattern of left ventricular strain.
Echocardiographic interrogation demonstrated normal segmental connections, moderate mitral regurgitation with mitral valvar prolapse, and minimal myxomatous changes. Left ventricular dilation and concentric hypertrophy were present. An abnormally hypertrophic antero-lateral papillary muscle was found. A minute muscular ventricular septal defect was present, which had closed spontaneously, as documented on follow-up examinations. There was no obstruction to left ventricular outflow. Good global left ventricular function was demonstrated, with a fractional shortening of 42%. Verapamil was preferred over a beta blocker due to the presence of a mild hyper-reactive airway disease.
A metabolic work-up demonstrated normal amino and organic acids in the blood and urine. Electro-cardiography and echocardiography performed on both parents and siblings were normal. Genetic counselling for a possible association between her cardiomyopathy and vertebral anomaly was not sug-gestive of a known genetic syndrome. Aggravation of mitral regurgitation, with distinct features of mitral valvar prolapse, led to treatment with Captopril for afterload reduction at 51 months of age.
An irregular colour flow Doppler pattern of coronary arterial flow was noticed at the age of eight years. An electrocardiogram at this time showed inversion of the T waves in leads L1 and AVL, and an intraventricular conduction delay. A haemodynamic cardiac catheterization and coronary angiography were performed to define the coronary arterial flow. These showed that left ventricular end diastolic pressure was elevated to 16 millimetre of mercury, albeit without a pressure gradient between the left ventricle and the aorta. When contrast medium was injected in the aortic root, only the right coronary artery filled, but this also revealed a collateral system that supplied the territory of the left coronary artery in retrograde fashion, draining eventually through the main stem of the left coronary artery and thence to the pulmonary trunk. Selective injection of the right coronary artery confirmed the diagnosis of anomalous origin of the left coronary artery from the pulmonary trunk. Surgical correction was performed by re-implanting the abnormal arterial orifice to the aorta, resulting in good coronary arterial flow. The post-operative course was complicated by moderate pleural effusion, necessitating drainage and anti-inflammatory medication. A postoperative right phrenic palsy gradually improved. Verapamil was substituted for atenolol after resolution of her hyper-reactive airway disease. A regression of the left ventricular hypertrophy, and improvement in the mitral regurgitation, were then noted, as shown by measurements taken at her last visit at 12 years of age.
Case 2
A 21-year-old asymptomatic male of Ashkenazi descent had been referred for cardiological evaluation due to a systolic murmur at 14 years of age. His mother was known to have left ventricular hypertrophy secondary to long standing arterial hypertension. Physical examination was normal, except for a 2/6 systolic murmur heard along the left sternal border. An electrocardiogram showed sinus rhythm, left ventricular hypertrophy, and strain. Echocardiographic findings included moderate concentric left ventricular hypertrophy, with no obstruction to left ventricular outflow, minimal mitral regurgitation, and good global left ventricular function. A wide right coronary artery was seen. Atenolol treatment was initiated. Ergometry demonstrated inferolateral ischaemic changes that were supported by an echocardiographic Dubotamine stress test, which revealed a stress related reversible abnormality of left ventricular mural motion involving the infero-lateral segments. A Thallium stress test demonstrated lateral, apical and infero-lateral reversible ischaemia. Angiography was performed in order to investigate the coronary morphology and flow, which revealed a large right coronary artery filling the left coronary arterial system in retrograde fashion through an extensive network of collateral arteries. The contrast then spilled into the main stem of the left coronary artery and drained to the pulmonary trunk, confirming the diagnosis of anomalous origin of the left coronary artery from the pulmonary trunk. A normal recording of left ventricular diastolic pressure was obtained. The patient was referred for surgical correction, the left coronary artery being reimplanted to the posterior aspect of the pulmonary trunk, followed by creation of a conduit connecting it to the aorta. This established good coronary arterial flow. Global left ventricular hypertrophy was noted, and a mild post pericardiectomy syndrome ensued. Three months later, echocardiography showed a leak of 3 millimetres in size between the conduit to the pulmonary trunk, which was surgically corrected. A 24-hour routine Holter electrocardiogram recording showed short asymptomatic ventricular tachycardia, for which Amiodarone was given. Shortly after, Hashimoto thyroiditis with hypothyroidism was diagnosed, requiring treatment with Eltroxin and the discontinuation of Amiodarone. The patient remains asymptomatic on 100 milligram Atenolol per day. A follow-up Holter electrocardiogram recording was normal. There was no progression of myohypertrophy or stress-related arrhythmia on ergometry. The left ventricular dimensions regressed significantly following surgery.
Discussion
Patients with anomalous origin of the left coronary artery from the pulmonary trunk may present with stress related paroxysmal angina or congestive heart failure. The left heart is predominantly involved. Death is usually related to ischaemic heart disease, congestive heart failure, and arrhythmia. Those who survived infancy may have symptomatic ischaemic left ventricular dysfunction with mitral regurgitation, dyspnoea, syncope, and angina on exertion. Sudden death was frequently reported during exercise. If left untreated, more than nine-tenths will die within the first year of life.1 A wide range of pathologic changes have been described secondary to the anomalous coronary arterial flow, including endocardial and subendocardial fibrosis, infarction and fibrosis of the papillary muscles, patchy myocardial necrosis, left ventricular dilation, and aneurysmal formation.1
Our patients, and those described by colleagues and reviewed here, survived infancy into adolescence and adulthood, and some reached an elderly age without congestive heart failure. Most patients were asymptomatic. Of the patients reviewed, 8 were diagnosed with myocardial hypertrophy, while one had normal myocardial mass. Is this a coincidental occurrence of two rare diseases, namely the association of anomalous origin of the left coronary artery from the pulmonary trunk and hypertrophic obstructive cardiomyopathy, or is it a result of a pathophysiological pattern, caused by the anomalous coronary morphology leading to myohypertrophy?
Several hypotheses may be proposed to explain the myohypertrophy seen in these patients. Hypertrophy may be induced by altered intra-myocardial wall stress.2 A resemblance between the morphology of the fetal heart and the hypertrophic heart has been described. The resemblance of certain features of the embryonic myocardium to that seen in hypertrophic obstructive cardiomyopathy suggests that it might reflect an arrest in maturation of the normal architecture. It is argued that an abnormal perfusion might trigger these changes. The developing myocardium responds to linear stress of the contraction by the development of a linear alignment of myofibrils. This in turn, leads to the linear alignment found in the bundles of adjacent myocytes. Inability to normalize wall stress might lead to local hypertrophy and myocytic disarray, leading to further inequalities of stress.2
Another theory for the development of myocardial hypertrophy associates ischemia to a decrease in transport of calcium by the sarcoplasmic reticulum. Such an abnormality of transport of calcium in the fetal cells, itself the consequence of ischaemia due to anomalous origin of the coronary artery, might again cause an inequality in stress, thus leading to local hypertrophy as described above.2 The wide system of collateral arteries that evolved in both of our patients, and in the others described elsewhere, might facilitate hypertrophy. Angiotensin II produced locally in response to pressure overload may also play a role in the development of cardiac hypertrophy.3 Endothelin-1 is also a potent stimulant of cardiac myohypertrophy, which is again caused by mechanical stress.4
A remote cause for the myohypertrophy seen in these patients, nonetheless, might be the presence of additional genes, such as those producing hypertrophic obstructive cardiomyopathy. The inheritance of hypertrophic obstructive cardiomyopathy is autosomal dominant with variable penetrance. New mutations account for hypertrophic obstructive cardiomyopathy in up to half of all patients.2 It is also possible that an unknown gene accounting for the abnormal morphology of the coronary arteries is causing linkage disequilibrium between the two genes.
In this review, we have analysed the findings from 9 patients, including our own, who presented with left ventricular hypertrophy in various settings of anomalous origin of the left coronary artery. The anomalous coronary arterial perfusion induced by these anomalies unequivocally exposes the myocardium to ischaemia. Any of the mechanisms discussed above may have produced the noted marked myohypertrophy. In 3 of the patients, the left coronary artery arose in anomalous fashion from the pulmonary trunk (Table: cases #1, 2, 3), one of whom had preserved left ventricular function with no hypertrophy, while the other two had hyperactive left ventricular function.5 Another form of the “steal” phenomenon exists in the fourth, eighth and ninth patients (Table), who had fistulas between the coronary and pulmonary arterial trees.6, 7
Table.
The first, second, fifth, eighth and ninth patients had mitral regurgitation of varying severity.8 The third had tricuspid and pulmonary valvar regurgitation. It is likely that the mitral insufficiency can be attributed to left ventricular enlargement, dilation of the mitral valvar annulus, and in particular, the ischaemic changes involving the ventricular septum and the papillary muscles. The improvement in mitral valvar regurgitation in our patients was secondary to surgical revascularization and regression in left ventricular size. An additional beneficial effect was that of treatment by reducing afterload. All patients had relatively mild clinical ischaemic manifestations in the presence of abnormal coronary morphology, thus reducing myocardial perfusion. Conversely we would have expected aggravated clinical ischemia in the presence of left ventricular hypertrophy. Two patients had mild stress related symptoms, which presented at an advanced age (Table: cases #5,6).8, 9 The eighth and ninth patients had ischaemia mainly attributed to their atherosclerosis, and one died unexpectedly, following chest pain (Table: case #7).10 An autopsy did not reveal significant atherosclerosis or myocardial infarction, suggesting that an arrhythmia may have been the cause of death. Patients #2, 4, 5, 6 had electrocardiographic changes indicating ischaemia.
The regression of left ventricular myohypertrophy following surgical correction of the anomalously arising coronary artery in our own patients lends support to the notion that it is this particular lesion itself, and the other morphological anomalies which impair coronary circulation, which induce the left ventricular hypertrophy, rather than there being a coincidence of anomalous origin of the left coronary artery from the pulmonary trunk with hypertrophic obstructive cardiomyopathy.
