'Cold as ice', why do old coronary arteries pay the price?

Immersing a hand or foot in ice-cold water elicits a powerful sympathetic response. This robust stimulus is detected by cutaneous cold-pain fibres causing centrally mediated reflex increases in sympathetic outflow, which increases peripheral vascular resistance leading to an acute increase in blood pressure (Greene et al. 1965). The coronary vasculature is also on the receiving end of this sympathetic surge, and a myriad of factors ultimately determine whether there is an increase or decrease in coronary vascular resistance (Greene et al. 1965). The physiological response to this simple perturbation has clinical relevance: greater coronary reactivity to the cold pressor test predicts cardiovascular events (Schindler et al. 2003; Nitenberg et al. 2004). The cold pressor test is a long-standing technique developed over 75 years ago by Hines and Brown (1936) to predict subsequent development of hypertension. Subjects with a strong sympathetic response, designated ‘hyperreactors’, had a greater subsequent incidence of hypertension than ‘normoreactors’ (Wood et al. 1984). The cold pressor test can also provoke angina in susceptible individuals (Mudge et al. 1976), highlighting the potent nature of this perturbation on myocardial oxygen supply and demand. In general terms, understanding the nature of ischaemic triggers, particularly as they relate to environmental stressors, is an important area of inquiry. The cold pressor test causes an increase in coronary vascular resistance in patients with coronary artery disease (Mudge et al. 1976). The response of normal versus diseased artery segments is different: normal arteries dilate and diseased arteries constrict during the cold pressor test (Nabel et al. 1988). Cold pressor-induced coronary vasodilation in young adults contrasts with the coronary vasoconstrictor responses observed during other sympatho-excitatory manoeuvres such as static handgrip exercise and simulated orthostatic stress (Momen et al. 2009) Thus, the coronary vascular response to a variety of stressors is influenced by the specific perturbation utilized (i.e. not all sympatho-excitatory manoeuvres have the same result) and the artery segment studied (i.e. healthy vs. diseased). Furthermore, ageing may alter the response as non-painful whole body cooling causes coronary vasoconstriction in older adults but not young adults (Gao et al. 2012). The complexity of the neural and local signalling involved in the regulation of coronary vascular resistance is amplified when considering the multitude of stressors that can alter the myocardial oxygen supply and demand relationship during normal everyday living. In this issue of the Journal of Physiology, Monahan et al. (2013) sought to determine the effect of adrenergic blockade on the coronary vascular response to the cold pressor test in young and older men. They used transthoracic Doppler echocardiography to assess coronary blood velocity and calculate vascular resistance in the left anterior descending artery. Healthy young and older subjects immersed their hand in ice water for 2 min before and after combined systemic alpha- (phentolamine) and beta-adrenergic (propranolol) blockade. As expected, the cold pressor test caused an increase in arterial blood pressure and rate pressure product in all subjects. Adrenergic blockade blunted, but did not abolish, the haemodynamic response to the cold pressor test in the two groups. During the control condition (pre-blockade), coronary vascular resistance decreased in the young subjects during the cold pressor test (i.e. coronary vasodilation) but not in the older subjects. Adrenergic blockade eliminated the decline in coronary vascular resistance in young subjects but had minimal effects in the older subjects, such that the young and old subjects had similar responses during the combined blockade condition. Appropriate consideration was given to the stimulus for the change in coronary vascular resistance by expressing the data relative to the change in the rate pressure product. These data suggest that an adrenergic mechanism underlies the cold pressor-induced decline in coronary vascular resistance (i.e. coronary vasodilation) in young healthy adults, and this response is lost in older healthy adults. There are numerous, redundant mechanisms that underlie a change in coronary vascular resistance with any acute perturbation (Duncker and Bache, 2008), but the key here is that healthy older men lose the ability to dilate the coronary arteries during a powerful sympatho-excitatory stimulus. It is assumed that the healthy older men tested do not have any haemodynamically significant atherosclerotic lesions in their coronary vasculature, but nevertheless subclinical coronary artery disease and/or endothelial dysfunction cannot be ruled out. This does not diminish the findings however, and studies such as this may provide insight into ischaemic triggers during sympatho-excitatory stimuli in older adults. While this work provides insight into age-related changes in coronary vasodilator responses to an environmental stressor, only men were tested so future work will need to include sex comparisons, as limited data exist on the response in older women. Regardless, Monahan et al. (2013) have shown that the cold pressor test has continued utility as a versatile and useful tool to assess coronary reactivity during sympathetic activation in humans. Their key finding, that an adrenergic mechanism may be responsible for the failure of the coronary arteries to dilate in healthy older men, is physiologically relevant and clinically significant. Whether these age-related declines in coronary vascular function are modifiable remains to be tested.