224 



HANDBOOK OF PHYSIOLOGY 



CIRCULATION I 



The production of the full-blown syndrome of high- 

 output failure in hiunan beings with beriberi (38) 

 requires both appreciable reduction in myocardial 

 cocarboxylase and peripheral vasodilatation. Under 

 these conditions of increased load and decreased 

 cardiac reserve, congestive failure results. Cardiac 

 catheterization of an alcoholic with high-output 

 failure due to beriberi has revealed the same picture 

 of depressed myocardial carbohydrate oxidation 

 characteristic of the thiamine-deficient dog (176). 

 The administration of thiamine, food, and bed rest 

 usually restores these patients to normal in a few 

 days. 



Diabetes Mellitus 



Insulin lack modifies the metabolic behavior of car- 

 diac muscle without appreciably altering its work ca- 

 pacity. Early studies of the isolated perfused diabetic 

 heart (69) revealed a decreased extraction of glucose 

 without a change in lactate extraction. In cardiac 

 muscle slices from the diabetic rat, Pearson et al. 

 (188) observed a decrease in pyruvate extraction and 

 oxidation below normal. In diabetic human sub- 

 jects studied by Ungar et al. (242) and Goodale 

 et al. (82) a decreased myocardial extraction of 

 glucose, an increased extraction of fatty acids, 

 and a depressed myocardial respiratory quo- 

 tient in the vicinity of 0.70 was noted. The myocardial 

 glucose extraction in diabetes is low despite markedly 

 elevated arterial glucon levels, so that the threshold 

 for glucose extraction is elevated and the whole 

 curve displaced to the right. This defect in glucose 

 uptake is rapidly corrected after insulin administra- 

 tion and is consistent with the permeability hy- 

 pothesis of insulin action (134). Goodale et al. (82) 

 also noted that pyruvate extraction was reduced in 

 diabetes and restored after insulin administration, an 

 observation not entirely consistent witli the per- 

 meability hypothesis. Vester & Stadie (244) noted 

 decreased pyruvate utilization and decreased oxida- 

 tive phosphorylation in liver mitochondria from 

 diabetic cats. On the other hand. Flock and associates 

 (73) found that pyruvate given intravenously was 

 utilized normally in diabetic dogs. The precise 

 change in the diabetic human heart responsible for 

 decreased pyruvate extraction is not evident. The 

 subjects with diabetes show no hemodynamic signs 

 of cardiac failure of metabolic origin. Thus, in 

 diai)ctes mellitus there appears to be no threat to 

 cardiac competence as a result of the defect in carbo- 

 hydrate metabolism per se. The diabetic heart 



probably adapts itself to this biochemical lesion in 

 carbohydrate metabolism by a greater dependence 

 upon fat as a source of energy. 



Hyperthyroidism 



Of various endocrine disorders, only thvTotoxicosis 

 has been identified as the cause of congestive heart 

 failure. With thyrotoxicosis, failure does not usually 

 occur in man unless there is underlying heart disease, 

 although cases without evidence of pre-existing 

 cardiac disorder have been cited (6, 120, 137). 

 The tachycardia, increase in peripheral oxygen 

 consumption, vasodilatation, and the increase in 

 venous return, which accompany hyperthyroidism, 

 may so increase the work of the heart as to precipitate 

 failure at relatively high cardiac outputs of 8 to 12 

 liters per min at rest. Although Bing (19) reported no 

 increase in the oxygen consumption of the myo- 

 cardium in man with hyperthyroidism, convincing 

 evidence that coronary flow and total myocardial 

 oxygen consumption are increased in human thyro- 

 toxicosis has been presented by Rowe and co-workers 

 (204). The sequence of events leading to heart 

 failure in thyrotoxicosis is not thoroughly understood. 

 Until recently, it has been thought, on the basis of 

 older experimental evidence showing a decrease in 

 the concentration of high-energy phosphate com- 

 pounds, ATP, and creatine phosphate (CP) in 

 heart muscle from hyperthyroid animals (37, 152, 

 214), that uncoupling of oxidative phosphorylation 

 was the biochemical lesion leading to congestive 

 heart failure in hyperthyroidism. 



The studies of Maley & Lardy (147, 148) of the 

 effect of in vitro thyroxin addition and in vivo hyper- 

 thyroidism upon oxidative phosphorylation in kidney 

 and liver mitochondria added support to this view of 

 the etiology of thyrotoxic heart failure. Even the 

 finding of Cooper et al. (45) that the action of thyroid 

 hormone in uncoupling oxidative phosphorylation 

 was due to an efi'ect of the hormone upon the in- 

 tegrity of the mitochondrial membrane, rather than 

 the intrinsic reactions of oxidative phosphorylation, 

 did not remove the possibility that thyroid hormone 

 in vivo might uncouple oxidative phosphorylation by 

 altering the properties of the sarcosomal membrane 

 in the heart. Studies by Olson & Piatnek (181), 

 however, have cast grave doubts upon the view that 

 cardiac failure in hyperthyroidism is due to the 

 imcoupling of oxidative phosphorylation. Experi- 

 mental hyperthyroidism was produced liy these 

 workers in dogs (iBi, 193) and rats (192) by feeding 



