L. A. Carlson

ISCHÆMIC HEART-DISEASE IN RELATION TO FASTING VALUES OF PLASMA TRIGLYCERIDES AND CHOLESTEROL: Stockholm Prospective Study

Abstract In a nine-year follow-up of 3168 men in the Stockholm prospective study, the occurrence of new events of ischaemic heart-disease (I.H.D.) has been related to findings at the initial examination in order to identify risk factors for I.H.D. The rate of I.H.D. increases linearly with increasing fasting concentration of plasma-triglycerides and plasma-cholesterol. Plasma triglycerides and cholesterol are risk factors for I.H.D. independent of each other, and a combined elevation of these two plasmalipids carries the highest risk for I.H.D. Smoking, but not an increasing weight/height index, is also a significant risk factor for I.H.D.

Myocardial Lipid and Carbohydrate Metabolism in Healthy, Fasting Men at Rest: Studies During Continuous Infusion of 3H‐Palmitate

Abstract Myocardial metabolism of lipid and carbohydrate substrates was studied in 17 healthy men at rest by measuring the arterial‐coronary sinus [(a—cs)] concentration differences. A continuous intravenous infusion of albumin‐bound 3H‐palmitate was given to provide a tracer for the plasma free fatty acids (FFA) and to produce endogenous labelling of plasma triglycerides (TG).

RELATIONSHIP IN MAN BETWEEN PLASMA FREE FATTY ACIDS AND MYOCARDIAL METABOLISM OF CARBOHYDRATE SUBSTRATES

Abstract Significant negative linear relationships were found between myocardial extraction of glucose, lactate, and pyruvate and arterial free fatty acid (F.F.A.) concentration in 17 healthy resting fasting men. This suggests that F.F.A. can suppress the myocardial uptake of glucose in man as they do in the isolated perfused rat heart, and that this may be due at least in part to inhibition of pyruvate dehydrogenase. These conclusions were supported by the observation in another 10 subjects that reduction of arterial F.F.A. concentration by the administration of nicotinic acid increased myocardial extraction of all 3 carbohydrate substrates.

Comparison between Fractional Turnover Rate of Endogenous Plasma Triglycerides and of Intralipid® (Intravenous Fat Tolerance Test) in Man*

Abstract. The validity of the intravenous fat tolerance test (IVFTT) as a tracer for the fractional turnover rate of endogenous plasma triglycerides (TG) has been studied in 32 fasting men with either normal or elevated plasma TG concentrations. The endogenous plasma TG turnover was determined by sampling arterial and hepatic vein blood, determination of splanchnic net secretion of plasma TG and calculation of fractional TG turnover rate. Later the fractional elimination rate of exogenous TG was determined following a single IV injection of Intralipid® (IVFTT). The TG fractional removal rate constants derived from these two tests were significantly correlated (r= 0. & ‐0.7) but IVFTT gave higher absolute values. A statistical evaluation showed that the error for the determination of the fractional turnover rate of endogenous TG and the IVFTT were about 30–50% and 10% respectively. It is probable that the correlation would have been still better if the error for the estimation of endogenous plasma TG turnover had been lower. A significant negative correlation was found between very low density lipoprotein‐TG concentration and fractional removal rate of both endogenous and exogenous plasma TG (r=−0.7–0.8).

Extraction of endogenous plasma triglycerides by the working human forearm muscle in the fasting state.

The extraction of triglycerides (TG) by the working forearm was determined in eight healthy fasting men, both by the measurement of chemical arterial-deep venous (a-dv) TG differences and by the a-dv differences in TG radioactivity after endogenous labeling with tritiated palmitate. Measurements were made before and then during nicotinic acid infusion. Correction for plasma water shift in the forearm vasculature was made by estimating the (125I)albumin activity after an intravenous injection. The overall mean value +/- S.E.M. without and with nicotinic acid was for TG arterial concentration (mumol/1) 713 +/- 153 and 695 +/- 140, TG a-dv concentration difference (mumol/1)-14 +/- 7 and -6 +/- 4, TG arterial radioactivity (cpm/ml) 1650 +/- 469 and 1471 +/- 342, TG a-dv radioactivity difference 12 +/- 24 and -2 +/- 13. The average standard errors for the determinations of triglycerides were 0.85% and 1.5% for the chemical and the isotope methods, respectively. In conclusion, no significant average a-dv difference in TG concentration as determined by either the chemical or the isotope method was detected. With the standard errors achieved, however, a-dv differences of less than around 20 mumol/lcould not be discovered. Such an extraction of endogenous plasma TG could, if oxidized, account for about 25% of the oxygen extraction by the eercising forearm.

FREQUENCY OF ISCHÆMIC EXERCISE E.C.G. CHANGES IN SYMPTOM-FREE MEN WITH VARIOUS FORMS OF PRIMARY HYPERLIPÆMIA

Abstract Serum cholesterol and triglycerides were measured in approximately 12,000 men attending a screening centre. 130 symptom-free men (aged thirty-five to sixty-five) were selected from the top 2% with the highest lipid values. They, and 59 normolipaemic controls, were studied by recording electrocardiograms (E.C.G.) before and during exercise. The frequency of so-called ischaemic E.C.G. changes (ST-segment depressions Minnesota code 4·1-4·4) increased with age both in controls and in the hyperlipaemic group. Ischaemic E.C.G. changes were significantly more common in all types of hyper-lipaemia (types IIA, IIB, III, and IV) than in controls. The high frequency of the exercise E.C.G. changes in symptom-free hyperlipaemic men reinforces the argument for early treatment of hyperlipaemia to prevent ischaemic heart-disease.

The Role of Fatty Acid and of Hormones in the Determination of Myocardial Carbohydrate Metabolism in Healthy Fasting Men

Abstract. In earlier studies myocardial extraction (MEx) of lipid and carbohydrate substrates was measured in 25 healthy, fasting men under different conditions (rest, exercise, sodium nicotinate infusion). It was found that, at rest, MEx of glucose, lactate, pyruvate and FFA were positively correlated to their respective arterial concentrations. During exercisesuch correlations were found for lactate, pyruvate and FFA. Furthermore MEx, at rest and at exercise, of glucose, lactate and pyruvate were negatively correlated to arterial FFA levels or to MEx of FFA. In the present investigation the role of various hormones in regulating MEx of carbohydrate substrates was analysed by determination of arterial concentrations of hormones in the earlier studies. MEx of glucose was not significantly correlated to arterial concentrations of either insulin, growth hormone or glucocorticoid. MEx of the other two carbohydrate substrates showed weak correlations to growth hormone levels. Furthermore, since the interrelationships which exist in vivo between MEx of a substrate and (1) arterial concentration of the substrate, (2) hormones and (3) extraction of other substrates are complex, simple correlation analysis between these variables may be inadequate. For this reason the relationship of MEx of carbohydrate substrates to the above mentioned factors was examined by multiple regression analysis in order to discover to which factors the extraction was significantly and independently related. This analysis showed that MEx of glucose at rest was negatively related to MEx of FFA and to concentration of glucocorticoid, but positively to insulin levels and not related to arterial glucose concentration. The multiple regression equations suggested that MEx of FFA might affect MEx of carbohydrate substrates in part through inhibition of pyruvate dehydrogenase. Multiple regression analysis has thus permitted the demonstration of the relevance of certain control mechanisms postulated from studies with the isolated perfused heart to the situation in vivo where complex interrelationships often invalidate simple correlations. For example, the dependence of MEx of glucose on FFA extraction, insulin and glucocorticoid is quite consistent with the effects of these factors, one by one, observed tn vitro. The multiple regression equation also gave quantitative estimates. Thus for a 10 per cent increase in either FFA extraction, insulin or glucocorticoid concentrations the equation indicated that such a change in one of the independent variables would alter MEx of glucose by –17%, +24% or –13% respectively.

Release of Immunoreactive Insulin from the Human Heart

Abstract Arterial‐coronary sinus differences in plasma immunoreaetive insulin concentration have been determined in 21 healthy men in the fasting state. Measurements were made both at rest and during prolonged exercise in all subjects and, in 9 of these, during an intravenous infusion of sodium nicotinate. Significant myocardial extraction of insulin could not be detected, but during prolonged exercise and also during the infusion of sodium nicotinate in resting subjects, net release of insulin from the myocardium took place. There was a positive linear relationship between arterial‐coronary sinus difference in insulin concentration and arterial insulin concentration. The most marked release of insulin from the heart occurred at the lowest arterial concentrations.

Differences in heparin-released lipolytic activity in the superficial and deep veins of the human forearm.

Abstract. Various doses of heparin were given as a single injection into the brachial artery of each of twelve fasting healthy males. Plasma lipolytic activity was measured in samples obtained before and at frequent time intervals after heparin injection, in the artery and the deep and superficial veins of the same forearm.

Conversion of Type III Hyperlipoproteinaemia to Type IV Hyperlipoproteinaemia by a Fat-Free, Carbohydrate Rich Diet

Abstract. Hyperlipoproteinaemia type III has been considered a clear cut clinical entity characterized by the presence of cholesterol rich “floating” beta very low density lipoproteins (VLDL) after ultracentri‐fugation. Carbohydrate inducibility is pronounced in type III. This study was undertaken to elucidate the effect of a high carbohydrate diet in type III as an effort to clarify a suggested association between type III and IV hyperlipoproteinaemia. On an isocaloric fat free carbohydrate rich diet the lipoprotein pattern changed as the VLDL triglycerides increased 31 per cent on average and LDL and HDL cholesterol decreased by 40 and 22 per cent. The high ratio cholesterol/triglycerides in VLDL was normalized. The lipoprotein levels in serum after carbohydrate induction showed all characteristics of a type IV with high VLDL triglycerides, normal cholesterol/triglyceride ratio in VLDL, subnormal cholesterol levels in LDL and HDL with changed relation between LDL1 and LDL2. On electrophoresis the floating beta band disappeared. It is probable that depending on the nutritional situation, the metabolic defect in type III may be expressed either as a type III or a type IV. An explanation of the effects of the carbohydrate rich diet on the lipoprotein pattern is suggested.