“Well, tell me, how does your research help my patients in the clinic?” This is a question many cardiologists who have undertaken research during their training will remember hearing with a sinking feeling as they dealt with an interview committee. However, the application of basic science research in cardiology now offers the real prospect of neutralising this intentionally hostileinterrogative mantra.
For the past 40 years almost all problems within the heart have been perceived either mechanically or structurally. The unravelling of the whole of valvular and congenital heart disease with the diagnostic developments of cardiac catheterisation and echocardiography and the stunning therapeutic successes of cardiac surgery reinforced the cardiologists' focus on the“mechanical fix.” Ischaemic heart disease yielded less easily to this way of thinking but the technologically driven, mechanically minded cardiologist turned into the interventionalist, and some problems of ischaemic heart disease are yielding under the onslaught. Undoubtedly their patients are helped–but only in part and, often, only temporarily. Winning wars after battles are lost needs a change oftactics, and the change in cardiology is the embracing of basic sciences.
In this article I will show how basic science might influence the management of patients with ischaemic heart disease and examine the real clinical problems of the variability of disease, restenosis after percutaneous transluminal angioplasty, and the shortage of donor hearts for transplantation programmes. Such advances will beimportant since ischaemic heart disease will kill over 150 000 people in the next year in Britain, more than any other single disease process, and cost more than £1.4bn in health care alone.1
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Why do cases of ischaemic heart disease present and progress differently
Coronary angiograms give detail about luminal narrowings in epicardial coronary arteries and, aided byfar from precise tests of inducible ischaemia, cardiologists guess which lesions limit coronary flow reserve and attempt to correlate this with angina. In the most part we get it right, but there is less certainty about the prognostic significance of a lesion. Why does a young man have his life ruined or ended by a 30% narrowing in one coronary artery causing myocardial infarction and another 85year old patient present with severe but stable angina, multiple coronary artery occlusions, and preserved left ventricular function? Ruptured atherosclerotic plaques are seen at necropsy in some patients who have died of non-cardiac causes, and presumably, therefore, the healing of silent ruptures is to some extent normal. Patients who have a myocardial infarction are for some reason unable toheal that plaque rupture, at that moment, at that particular site. But why? The answers are presumably in the genetic make up of the patient, the biology of the plaque causing the luminal narrowing, and the nature of the patient's platelets and coagulation system. How does modern biology help?
Atherosclerosis has an inflammatory component, and many aspects of an individual'sinflammatory response are genetically programmed.2 The plaque contains monocytes, macrophages, and T lymphocytes and is rich in several inflammatory cytokines. Patients with unstable angina who have an unfavourable outcome are characterised by a systemic inflammatory response.2 3 The inflammatory response in any individual is programmed by their genetic composition,4 and such genetic variation may influencethe course of disease–for example, polymorphisms in tumour necrosis factor α predict the development of cerebral malaria.5
Ischaemic heart disease runs in families, but only some of the inherited risk is explicable by known genetic determinants of lipid metabolism or of coagulation. Therefore, many other genes are probably important in either the pathological process itself or in the mode of...