Familial hypercholesterolemia is a rare autosomal dominant disorder with diverse clinical presentation. It is characterized by high LDL-cholesterol levels, premature coronary artery disease (CAD), valvar or supravalvar aortic stenosis and cutaneous xanthomas.1-2 Rheumatic heart disease is a common disorder in the developing world. We report an unusual case presenting with a combination of familial homozygous Hypercholesterolemia and rheumatic mitral regurgitation.
A 28 year old woman was referred by her family physician for evaluation of cardiac murmur and symptoms of atypical chest pain. On evaluation, her vitals were normal. She had bilateral tendon xanthomas over the elbows, achillis tendon, lateral margin of the foot (Figure 1) and buttocks. A Grade III/VI ejection systolic murmur was heard in the first right intercostal space and a Grade III/VI pansystolic murmur was heard at the apex. The Electrocardiogram was normal. Her total cholesterol was 509 mg/dl, LDL-cholesterol was 403 mg/dl, VLDL-cholesterol was 63 mg/dl, HDL-cholesterol was 43.3 mg/dl and Triglycerides was 313 mg/dl. Transthoracic echocardiography revealed normal cardiac chamber dimensions and function without any regional wall motion abnormalities. The aortic valve was normal (Figure 2A). There was a discrete narrowing of the aorta, just above the Sino tubular junction with mild post stenotic dilatation (Figure 2A and 2B). The mean gradient across the stenosis was 29/15 mm of Hg. The AML and PML were thickened and the mobility of PML was markedly restricted (Figure 3A and 3B). The chordae and Papillary muscles were likewise thickened suggesting a rheumatic etiology (Figure 3A and 3B). There was moderate mitral valve regurgitation on colour doppler (Figure 3A). In view of the patient’s symptomatology and the high possibility of coronary artery disease a coronary angiogram was performed. The coronary angiogram revealed ostial right coronary artery stenosis of 50%, ostial left main artery stenosis of 20%, and ostial left circumflex artery stenosis of 30%. An LV angiogram in LAO view clearly demonstrated the supravalvular aortic stenosis (Figure 4). A pull back gradient of 21 mm hg was observed across this stenosis. Hence a final diagnosis of familial hypercholesterolemia with premature coronary artery disease, supravalvar aortic stenosis and rheumatic mitral regurgitation was made. Interestingly, the patient’s mother also had tendon xanthomas and Hypercholesterolemia and had died of a myocardial infarction in her fifth decade. Her father had hypercholesterolemia with no other coronary risk factors, and he too had died of a myocardial infarction in his sixth decade. As her coronary lesions were not significant, the patient was advised a conservative management with aspirin, high-dose atorvastatin (40 mg/day), ezetimide, a low cholesterol diet and regular follow-up. She was also advised Benzthine penicllin prophylaxis for the RHD.
Familial hypercholesterolemia is an autosomal dominant disorder of defect in LDL receptor gene resulting in a reduction in the number or function of LDL receptors.3 This leads to high LDL cholesterol levels, formation of xanthomas and increased tendency of atheroma in the vascular structure, preferentially in the coronaries4 and ascending aorta.5 Premature coronary artery disease predominantly involving the ostial/ proximal portion of the coronaries is a well recognized entity in this condition.6-7 Premature CAD develops in the first two decades in homozygotes and in the the early to mid-adulthood in heterozygotes. Supravalvular aortic stenosis is a characteristic feature of homozygous familial hypercholesterolemia.5,8 Despite the association, it still remains to be explained why raised serum cholesterol has a predilection for deposition in the aortic root in familial hypercholesterolemia.9 One of the postulations put forth by summers et al.10 is, that it is due to altered growth of the vessel wall, because the atherosclerosis of HFH occurs at such an early age. High LDL concentrations might repress the expression of genes related to aortic growth. Summers et al.10 found that 41% of their patients had supravalvar aortic stenosis on MRI and 86% of these patients had plaques in the aorta as well. In addition, valvar aortic stenosis has also been described. Degenerative mitral valve involvement has been described by Buja et al. in 11 out of his 21 patients in homozygous familial hypercholesterolemia.11 However, thickening of the chordae, papillary muscles and mitral leaflets; and PML restriction are specific to Rheumatic etiology and not seen in degenerative mitral valve disease. The prevalence of RHD in india is 1-5.4 per 1000 children12-13 and the frequency of FHC is 1 in 1 million individuals in the homozygous form.14-15 The present report of a combination of familial homozygous Hypercholesterolemia and rheumatic heart disease has not been reported earlier. Treatment of FHC is difficult. Weekly/biweekly plasmapharesis forms the cornerstone therapy of FHC.16 However, it is expensive, time consuming and not available to many patients. Despite the deficiency of LDL receptors, high dose statins have been shown to lower LDL-C levels in FHC by upto 15 and 21% in patients with or without plasmapharesis/portocaval shunt respectively by increasing LDL catabolism. Ezetimibe, a cholesterol absorption inhibitor, further reduced LDL-C levels by 20.5% when added to maximal statin therapy. Liver transplantation, by providing functional LDL receptors, has been shown to normalize LDL values.17 A majority of patients with FHC subsequently require percutaneous or surgical intervention for their premature coronary artery disease or aortic stenosis and/or supravalvar valvar aortic stenosis. The added dimension of RHD in our patient further aggravates the clinical complexity. No therapy has till date been shown to regress mitral regurgitation. As MR begets MR, the severity of MR will increase necessitating an intervention in due course. The double burden of FHC and RHD in our patient presents a uniquely challenging clinical scenario.