Discovery Of A New Genetic Susceptibility Factor May Improve The Management Of Coronary Heart Disease

June 30, 1997

Coronary heart failure, myocardial infarction and angina pectoris are all due to obstruction of vessels that irrigate the heart. Patients with these diseases can be treated by means of angioplasty, an operation in which the blocked vessels are cleared by inflating small balloons. Unfortunately, the clinical improvement is often transient, as the vessels again become obstructed after a few months.

This complication, known as restenosis, affects more than half the patients treated by angioplasty. The INSERM team headed by Philippe Amouyel (Director of INSERM's Contrat Jeune Formation 95-05, at the Pasteur Institute in Lille), together with clinicians at Lille University Hospital, have made an important contribution to our understanding of how restenosis occurs. In the July 1 issue of Circulation, they report that a particular variant of the angiotensin 1-converting enzyme (ACE) gene is a risk factor for restenosis in certain circumstances.

The role of ACE in cardiovascular disease is well known. This enzyme is crucial for the production of angiotensin II, a growth factor for cells lining the blood vessels. ACE synthesis depends on a gene of which there are two natural variants, known as D and I. The D variant is associated with a higher concentration of ACE and is a recognized risk factor for coronary heart disease.

However, interest in the role of ACE in restenosis declined when it emerged that ACE inhibitors had no preventive effect in clinical trials. This disappointing result was apparently due to the fact that restenosis is related more to vessel shape changes than to cell division in the vessel wall. This "remodeling" is currently prevented by inserting an endovascular prosthesis ("stent") into the stenotic vessel, thereby shoring up the wall and maintaining its normal shape.

What the INSERM team found was that ACE had an important role in restenosis after stenting, a complication that affects about one-quarter of patients treated in this way. Given that vessel remodeling is prevented by stenting, the researchers postulated that vascular cell proliferation became a key event in restenosis after stent insertion, and that the potential role of ACE could be specifically investigated in these patients. The approach they used was to quantify vessel diameter in 146 patients six months after stenting, and to look for correlations with the ACE gene variant. Statistical analysis effectively revealed a close link between the loss of vessel diameter and the ACE genotype: homozygosity for the D variant was associated with a far larger reduction in vessel diameter than ID heterozygosity or II homozygosity. Furthermore, the risk of restenosis after stenting was four times higher in DD homozygotes than in II homozygotes.

This finding has to be confirmed in larger studies, but may already have important implications for the prevention of restenosis. Indeed, it not only provides a means for identifying patients who require closer surveillance after stenting, but also suggests that ACE inhibitors might have an important preventive role in certain circumstances. The combined use of stents and ACE inhibitors, to reduce the risk of restenosis in patients bearing the DD genotype, might be tested.


French National Institute for Health and Medical Research (INSERM)

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