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A Successful Trial of Gene Therapy to Spur Vascular Growth in Heart Disease

One approach to the structural damage that takes place in heart disease is to attempt to spur growth of new blood vessels, to deliver nutrients to heart tissue that is currently poorly supplied. Gene therapy is in principle well suited to this goal, as a range of genes are known to be involved in regulating the processes of blood vessel generation. So far attempts to create a viable treatment haven't gone so well, unfortunately, but here researchers report success in a recent trial. The results seem promising. At the high level, this approach doesn't address the underlying causes of the situation, the various degenerative processes that give rise to heart disease and structural failure of important tissues in the first place, but when effective it might be considerably better than doing nothing, at least in the near term of a few months or years of remaining life expectancy for these patients.

Angina pectoris is the most common symptom of coronary artery disease (CAD). In spite of improved medical and revascularization therapies, 5-10% of patients undergoing coronary angiography have refractory angina (RA), i.e. they are severely symptomatic while on optimal medical therapy and prior revascularization and not amenable to further revascularization procedures. Some patients with CAD develop collateral arteries, which can rescue ischaemic myocardium in spite of significant occlusions in coronary arteries and alleviate ischaemic symptoms. Therapeutic vascular growth stimulates this natural process and offers a potential new treatment for RA. However, most previous cardiovascular proangiogenic trials have been unsuccessful. This is likely due to (i) poor gene transfer efficiency in the myocardium, (ii) tested growth factors may not have been the most optimal ones, and (iii) inability to target therapy into ischaemic, but viable myocardium.

To address these challenges, we used PET perfusion imaging and an electromechanical catheter system for gene transfer to identify ischaemic, hibernating myocardium with the lowest perfusion reserve for the targeted therapy. For the first time, we also used VEGF-DΔNΔC, a new member of the VEGF family that stimulates both angiogenesis and lymphangiogenesis. In addition, because Lp(a) is associated with pro-atherogenic, pro-inflammatory, and pro-thrombotic effects, elevated plasma levels were tested as a potential new biomarker to identify patients who might benefit from the induced therapeutic vascular growth.

Thirty patients with severe RA were randomized 4:1 to VEGF-DΔNΔC therapy (AdVEGF-D group) and placebo (controls) in blocks of five patients. To select optimal sites for gene injections, the left ventricle was mapped to detect areas of viable myocardium with reduced contraction. Coronary angiography and PET imaging were used to confirm viable myocardial segments with impaired myocardial perfusion reserve (MPR). In the AdVEGF-D group, MPR of the treated area increased from 1.00 ± 0.36 at baseline to 1.31 ± 0.46 at 3 months and to 1.44 ± 0.48 at 12 months. Myocardial perfusion reserve of the reference area (myocardium with the highest MPR at baseline) showed no significant change. On the contrary, it tended to decrease by 10.7% at 3 months and 8.8% at 12 months. Myocardial perfusion reserve in the control group showed no significant change from baseline to 3 and 12 months.

A potential impact of elevated Lp(a) was also noted in the response of the RA patients to this therapy, with the most benefit in patients with the highest Lp(a) levels. This is consistent with a recent report that 50% of patients with RA have elevated Lp(a), and in whom Lp(a) lowering achieved by lipid apheresis was associated with objective evidence of myocardial blood flow improvement by MRI and significant relief of RA symptoms.

Link: https://doi.org/10.1093/eurheartj/ehx352

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