When William Heberden described the Angina Pectoris 250 years ago a member of the public wrote to him describing his symptoms. This honest and detailed clinical history encapsulated the typical symptoms of angina “the first symptom is a pretty full pain in my left arm a little above the elbow; and in perhaps half a minute it spreads across the left side of my breast, and produces either a little faintness, or a thickness in my breathing; at least I imagined so, but the pain generally obliges me to stop”. However, the author of the letter then goes on to state “I have frequently, when in company, borne the pain, and continued my pace without indulging it; at which times it has lasted from five to perhaps ten minutes, and then gone off”. This is the first description of “walk through” also known as “toter punkt” angina. The cause for this reduction in symptom severity despite continued exertion remains uncertain. We investigated it using serial exercise tests and intra-coronary balloon inflations. These attempted to emulate “walk through” using a related form of angina known as “warm-up” or “first hole”; first hole is the term used since symptoms are felt whilst walking whilst playing the first hole of golf but not in subsequent holes. The main purpose of our study was to examine if the recruitment of collaterals after first exercise was responsible for the reduction in symptoms on second exertion and second balloon inflation. We did this using a pressure wire during PCI. Our main finding was that warm up was similar in patients with and without collaterals and may therefore represent an innate form of myocardial resistance to ischaemia akin to ischaemic preconditioning.

 

An example of warm up angina during serial exercise treadmill tests (ETT). At 8 minutes of first exertion (ETT1) there is marked planar ST depression. After resting for 15 mins the patient exercises again (ETT2) and there is less ST segment change at an equivalent time and rate pressure product. After a prolonged rest (ETT3) the angina and ST segment depression reappear as the warm up phenomenon has worn off.

Ischaemic preconditioning and warm up angina share very many common features and may be related. The second half of the talk discussed the intracellular signalling events that underlie ischaemic preconditioning. This research field is large and numerous signalling intermediaries have been shown to be “necessary and sufficient” to the process of protection. The focus of our group’s research is on the activation of p38 MAPK kinase during lethal ischaemia, where it aggravates injury. Unfortunately, short-lived activation of this same kinase during sub-lethal ischaemia and other stresses may actually be protective. We therefore wanted to delve more deeply into the mechanism of p38 activation during lethal myocardial ischaemia. Under this circumstance p38 is activated by an unusual mechanism that does not use an upstream kinase but instead involves an association between p38α and a scaffold protein known as TAB1. This association allows p38 to autophosphorylate its own activation loop. The biophysical basis of this interaction is being investigated with the hope of disrupting it.

I would like to thank the patients for volunteering for the warm up study and the British Heart Foundation, Medical Research Council and the NIHR Comprehensive Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust for their support.

Relevant references

Heberden J. A letter to Dr Heberden, concerning the angina pectoris; and an account of the dissection of one; who had been troubled with that disorder. Medical Transactions, Royal College of Physicians in London. 1785;3:1-11.

Marber MS, Joy MD, Yellon DM. Warm-up in angina: is it ischaemic preconditioning? Br Med J 1994;72:213-215.

Edwards RJ, Redwood SR, Lambiase PD, Tomset E, Rakhit RD, Marber MS. Antiarrhythmic and anti-ischaemic effects of angina in patients with and without coronary collaterals Heart 2002;88:604-610

Lambiase PD, Edwards RJ,Cusack MR, Bucknall CA, Redwood SR, Marber MS. Exercise induced ischemia initiates the second window of protection in humans independent of collateral recruitment. J Am Coll Cardiol 2003;41: 2003;41:1174-82.

Tanno M, Bassi R, Gorog DA, Saurin AT, Jiang J, Heads RJ, Martin JL, Davis RJ, Flavell RA, Marber MS. Diverse mechanisms of myocardial p38-MAPK activation. Evidence for MKK-independent activation by a TAB1 associated mechanism contributing to injury during myocardial ischemia. Circ Res 2003: 93:254-261.

Jacquet S, Nishino Y, Kumphune S, Sicard P, Clark JE, Kobayashi KS, Flavell RA, Eickhoff J, Cotten M, Marber MS. The role of RIP2 in p38 MAPK activation in the stressed heart. J Biol Chem 2008; 283:11964-11971.

Kumphune S, Bassi R, Jacquet S, Sicard P, Clark JE, Verma S, Avkiran M, O'Keefe SJ, Marber MS. A chemical genetic approach reveals that p38alpha MAPK activation by diphosphorylation aggravates myocardial infarction and is prevented by the direct binding of SB203580. J Biol Chem 2010;285:2968-75.