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• Successful evolutionary adaptation to environmental stress?
  Richard G Fiddian-Green
  Published on: 6 August 2004

• Published on: 6 August 2004

  Successful evolutionary adaptation to environmental stress?

  • Richard G Fiddian-Green, FRCS, FACS

  Dear Editor,

  This sociological study demonstrates associations between exposure to cold in utero and soon after birth, dyslipidaemia and coronary heart disease [1]. The inference that exposure to cold in utero or early in life in disadvantaged homes might increase the risk of coronary artery disease by causing a dyslipidaemia is not supported by all epidemiological studies. Certain indigenous populations, such as t...

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  Dear Editor,

  This sociological study demonstrates associations between exposure to cold in utero and soon after birth, dyslipidaemia and coronary heart disease [1]. The inference that exposure to cold in utero or early in life in disadvantaged homes might increase the risk of coronary artery disease by causing a dyslipidaemia is not supported by all epidemiological studies. Certain indigenous populations, such as the traditional living Inuit, have been relatively spared from ischemic heart disease despite their high fat diet [2]. The implication is that it is a factor or factors other than diet, dyslipidaemia and insulin resistance that causes coronary artery disease.

  The mitochondrial genome in diabetes mellitus is said to be very similar to that in people with the thrifty genome, specifically in regards to insulin resistance [3]. Knockout studies cannot be used to examine the pathogenetic significance of the mitochondrial genome for its absence is incompatible with life. It has been proposed, therefore, that it might be a disorder of mtDNA quality and quantity that is responsible for the dyslipidaemia and insulin resistance in the thifty genome and diabetes mellitus. Before this hypothesis can be addressed it is necessary to consider the mass action effects of substrate availablity, which are a function of dietary composition, and substrate utilisation, which may be a function of metabolic stress such as that imposed by exercise and the cold.

  Let normoxia be a state in which all ATP is being generated by oxidative phosphorylation and there is no oxygen debt present. Let dysoxia be a state in which a portion of ATP rsynthesis is occurring by anaerobic glycolysis the proportion increasing as the % dysoxia increases from 0% to 100% in complete anoxia. Let dysoxia also be a state in which there is an oxygen debt. The oxygen debt may develop with increased activity, such as exercise, and be paid back during rest. The oxygen debt may alternatively or additionally be present at rest and never be repaid. In these pathological circumstances energy supply/demand balance may be maintained by the down regulation of ATP-dependent enzymatic activities in accordance with the Daniel Atkinson energy charge hypothesis. Cardiovascular function but not necessarily myocyte survival may be compromised in these circumstances.

  Let us assume that the sole supply of substrate for oxidative phosphorylation is glucose and that the cardiac output in a healthy resting person is 5 l/min. Let us further assume that the stress hormones released in exercise double the amount of glucose taken up from a unit volume of flowing blood and used to generate ATP by oxidative phosphorylation. If exercise were then to begin and to increase in intensity until it exceeded the anaerobic threshold, that point at which oxygen consumption no longer increases, dysoxia would develop.

  What cardiac output is needed in 0%, 25%, 50%, 75% and 100% dysoxia to increase nutrient delivery to sustain the same rate of ATP resynthesis? My back-of-an-envelope calculations suggsts that it is 5 l/min, 16.2 l/min, 27.6 l/min, 38.9 l/min and 50 l/min respectively.

  It is very clear from these calculations that the maximum cardiac output achieved during supramaximal exercise by healthy amateur soccer players, 10.4 l/min, is reached when the have developed about 10% dysoxia. Higher levels of dysoxia would have greatly exceed their cardiovascular reserves.

  If instead the healthy subjects were to use palmitic acid, one mole of which generates 109 moles ATP relative to the 32 moles generated by each mole glucose metabolised in the Krebs cycle, to the exclusion of all glucose what might the figures be? For 0%, 25%, 50%, 75%, 100% dysoxia the figures are 1.7 L/min, 4.7 l/min, 8.7 l/min. 12.7 l/min, and 16.6 l/min. There is a huge difference because of the greater energy density in fatty acids relative to glucose. Given these circumstances the healthy soccer players could in theory have tolerated some 70% dysoxia without exceeding their cardiovascular capacity.

  Insulin resistance, possibly induced by the release of the stress hormone cortisol, may be an integral part of achieving a fatty acid shift in metabolic stress. Obese children with insulin resistance have a limited tolerance for exercise [4]. Perhaps their insulin resistance is a compensatory metabolic response to an increase in myocardial workload imposed upon their basal physical activity by their excessive weight. In which case their compensatory reserve for cardiovascular physical work can be expected to be limited relative to that of a person without insulin resistance. It would be interesting to know if in reversing their insulin resistance by pharmacological means their tolrance for exercise were to be reduced further.

  Consider the medical implications. By shifting substrate dependence from glucose to fatty acids by endogenous compensatory mechanisms a patient with chronic heart failure might be able to live within his anaerobic threshold if he/she were to have a cardiac output less than 2.0 l/min and even as low as 1.67 l/min. More importantly reversing the fatty acid shift could push a patient over his/her anaerobic threshold at rest. Sudden death is known to have been precipitated by medications administered to patients who have had a very low cardiac output.

  The dyslipidaemic response to cold reported in this study might be a healthy evolutionary metabolic adptation to cold be it one imposed at the gamete level or later in life. It may have nothing whatsoever to do with the associated risk of developing coronary heart disease.

  References

  (1). D A Lawlor, G Davey Smith, R Mitchell, and S Ebrahim Temperature at birth, coronary heart disease, and insulin resistance: cross sectional analyses of the British women’s heart and health study Heart 2004; 90: 381-388

  (2). Kutryk MJ, Ramjiawan B. Plasmid lipid and lipoprotein pattern in the Inuit of the Keewatin district of the Northwest territories. Mol Cell Biochem. 2003 Apr;246(1-2):121-7.

  (3). Lee HK. Method of proof and evidences for the concept that mitochondrial genome is a thrifty genome. Diabetes Res Clin Pract. 2001 Dec;54 Suppl 2:S57-63.

  (4). Crisafulli A, Orru V, Melis F, Tocco F, Concu A. Hemodynamics during active and passive recovery from a single bout of supramaximal exercise. Eur J Appl Physiol. 2003 Apr;89(2):209-16.

  (5). Giordano U, Ciampalini P, Turchetta A, Santilli A, Calzolari F, Crino A, Pompei E, Alpert BS, Calzolari A. Cardiovascular Hemodynamics: Relationships with Insulin Resistance in Obese Children. Pediatr Cardiol. 2003 Sep 4

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  Conflict of Interest:
  None declared.

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