Ischemic heart disease as deficiency disease.

Four classes of agents capable of producing human illness have been identified: toxicity, heredity, infection and deficiency. The leading paradigm for the etiology and pathophysiology of ischemic heart disease in the 20th century was that of intoxication by too much of the wrong kind of dietary fat. This overemphasis on lipid metabolism persists because important data are neglected and because of inattention to details. For example, heart disease risk does not correlate with fat intake within nations in contrast to between nations. Also development of ischemic heart disease involves inter alia arterial spasm, cardiac rhythm, metabolism of connective tissue, glucose and homocysteine, plus paraoxonase activity and thrombus formation which generally are unaffected by dietary fat. Homocysteine thiolactone accumulates when homocysteine is high. This lactone specifically inhibits lysyl oxidase which depends on copper to catalyze cross linking of collagen and elastin in arteries and bone. The lactone is hydrolyzed by paraoxonase, activity of which can be decreased by copper deficiency. Just as cholesterol was an important focus for heart disease as intoxication, homocysteine can become an excellent focus for a paradigm shift to heart disease as deficiency because supplementation with several nutrients can alter homocysteine metabolism and decrease its plasma concentration. These supplements include betaine, copper, folate, pyridoxine and vitamin B-12. Opportunities for research on ischemic heart disease as deficiency disease are plentiful.     

Anderson-Fabry disease in heart failure

Anderson-Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene that result in deficiency of the enzyme alpha-galactosidase A. The worldwide incidence of Fabry’s disease is reported to be in the range of 1 in 40,000–117,000, although this value may be a significant underestimate given under recognition of symptoms and delayed or missed diagnosis. Deficiency in alpha-galactosidase A causes an accumulation of neutral glycosphingolipids such as globotriaosylceramide (Gb3) in lysosomes within various tissues including the vascular endothelium, kidneys, heart, eyes, skin and nervous system. Gb3 accumulation induces pathology via the release of pro-inflammatory cytokines, growth-promoting factors and by oxidative stress, resulting in myocardial extracellular matrix remodelling, left ventricular hypertrophy (LVH), vascular dysfunction and interstitial fibrosis. Cardiac involvement manifesting as ventricular hypertrophy, systolic and diastolic dysfunction, valvular abnormalities and conduction tissue disease is common in AFD and is associated with considerable cardiovascular morbidity and mortality from heart failure, sudden cardiac death and stroke-related death.     

Copper and ischemic heart disease

Absolute or relative deficiency of copper is hypothesized to be of prime importance in the etiology of ischemic heart disease. According to recent estimates, only 25% of the diets in the United States contain the 2 mg of copper thought to be required daily by adults. Some of these diets have ratios of zinc to copper greater than those that have produced hypercholesteremia in animals. There are many epidemiologic associations between the ratio of zinc to copper and dietary characteristics, organ analyses, clinical status, and environmental features that relate the metabolism of these elements to the anatomy, chemistry, pathology, pharmacology, and physiology of ischemic heart disease. Animals deficient in copper or exposed to a high dietary ratio of zinc to copper, which can produce a relative copper deficiency, are hypercholesteremic and hyperuricemic, and have glucose intolerance and abnormalities of the electrocardiogram. Their hearts and arteries have abnormal connective tissue, lipid deposits, and inflammatory changes; they die suddenly, often with ruptured hearts. Hypercholesteremia and glucose intolerance have been found in men depleted of copper and in children with Menkes’ disease, an inability to absorb copper.     

Beriberi heart disease in London

Haemodynamic measurements before and after treatment are described in two patients with beriberi heart disease. The first patient had severe disease with a cardiac output of 17·3 litres per minute, which had returned to normal a month later. The second patient had moderate disease with a cardiac output of 7·4 litres per minute; a fall in this and a rise in systemic vascular resistance was found one and two hours after the intravenous injection of aneurine hydrochloride. The plasma pyruvate concentration was raised in the first patient but only slightly so in the second, in whom the pyruvate metabolism test was abnormal. The haemodynamic studies in both cases were of considerable help in making the diagnosis. The diagnosis of beriberi should be considered in any patient with heart disease who has a history of alcoholism, especially as prompt vitamin treatment is curative.