Vascular Lesions Induced by Renal Nerve Ablation
Vascular Lesions Induced by Renal Nerve Ablation
This is the first study to evaluate prospectively the morphologic features of RNA-induced renal vascular injury by OCT in patients before and after renal denervation using two different catheter systems, i.e. the Simplicity® catheter and the EnligHTN multi-electrode basket. While the feasibility and effectiveness in reducing blood pressure have been documented in registries and randomized trials using the Simplicity® catheter and to a lesser degree with the EnligHTN multi-electrode basket, little is known about the vascular injury induced by the RNA procedure at the site of ablation. We here, for the first time, demonstrate with OCT that local tissue damage not apparent with angiography occurs, i.e. local and diffuse vasospasm, oedema formation, and endothelial injury with thrombus generation.
An initial observation revealed that catheter-based RNA could be complicated by vascular lesions, i.e. vessel notches, post-procedural vasospasm, dissections, and thrombus formations. Moreover, with the EnligHTN multi-electrode system, more thrombus formation per renal artery occurred than with the Simplicity® catheter.
In this regard, recent animal studies are of interest demonstrating local loss of the endothelial monolayer resulting in thrombus formation even at 6 month follow-up. These observations in patients and animal models suggest that an antithrombotic therapy should be used before and after RNA, possibly for prolonged periods of time. This notion is further supported by the fact that renal artery stenosis may indeed occur after RNA, possibly evolving from such injuries.
In contrast to Steigerwald, we have observed one dissection after RNA in our series with the Simplicity® catheter. In this regard, one patient of the Simplicity® HTN-1 study developed also renal artery dissection. Of note, the true incidence of renal artery dissection could be markedly underestimated in the Simplicity® HTN-1 study, since no intravascular imaging was performed in these patients.
Local notches, which are signs of vessel wall oedema, occurred after RNA with both catheter systems without statistically significant difference between the two. Based on histological analyses of a preclinical study, notches correspond to cellular swelling and connective tissue coagulation within the medial and adventitial layer. This formation of local oedema with water retention within the ablated tissue and an inflammatory response is also known from electrophysiological studies in which radiofrequency ablation is used. It is assumed that such oedemas are only present in the acute phase immediately after RNA and therefore a transient phenomenon of inflammation. Possibly, local oedema may reflect effective renal denervation. Obviously, whether the larger tissue damage really leads to a more effective decrease in blood pressure needs to be elucidated. Furthermore, it is unclear whether the presence of a concomitant atherosclerotic disease in renal arteries has an impact on the success of RNA on arterial blood pressure.
A three-dimensional OCT image reconstruction documented a circumscribed vascular spasm for both catheter systems leading to a 'pearl-of-string' feature with a significant reduction in the mean renal artery diameter as well after RNA. Obviously renal vasospasm can also result from catheter manipulation by the operator; however, the 'pearl-of-string' pattern (encountered along the entire length of the treated renal artery) strongly suggests that such a generalized vasospasm of treated renal arteries most likely results from the mechanical stress induced by the ablation catheter tip or basket, respectively, and/or the applied radiofrequency energy itself rather than from catheter manipulation. The mechanism of such a diffuse vasoconstriction not only at the site of ablation remains unknown, but may involve a reduced nitric oxide release after endothelial damage. However, in the experience of most operators, nitrates and calcium antagonists are not very effective in this context. Possibly, endothelin release, which leads to prolonged vasospasm, may be involved.
It is a limitation of this study that a rather small number of patients has yet been studied and thus these results have to be confirmed in a larger patient population. The comparison of both catheter-based systems is observational and selection bias could have occurred. However, the selection of the system was done by an independent study coordinator who was not involved in the RNA procedure, which would help to alleviate concerns of obvious selection bias. Furthermore, the maximal field of view in OCT is limited to 11 mm; therefore, patients with a large renal artery diameter are difficult to study. Moreover, imaging depth is limited to 0.5–2.0 mm with OCT. Therefore, renal arteries with thick walls cannot be properly evaluated in their entirety. The number of pullbacks excluded due to poor quality is much higher with the Simplicity system when compared with the EnligHTN system. This reflects the real-world practice for which reason we have not excluded the failed cases from our enrolment. However, the imbalance in excluded data could impair the validity of the analysis. Furthermore, no renal artery flow measurements with renal duplex-sonography before and after RNA was performed.
Discussion
This is the first study to evaluate prospectively the morphologic features of RNA-induced renal vascular injury by OCT in patients before and after renal denervation using two different catheter systems, i.e. the Simplicity® catheter and the EnligHTN multi-electrode basket. While the feasibility and effectiveness in reducing blood pressure have been documented in registries and randomized trials using the Simplicity® catheter and to a lesser degree with the EnligHTN multi-electrode basket, little is known about the vascular injury induced by the RNA procedure at the site of ablation. We here, for the first time, demonstrate with OCT that local tissue damage not apparent with angiography occurs, i.e. local and diffuse vasospasm, oedema formation, and endothelial injury with thrombus generation.
An initial observation revealed that catheter-based RNA could be complicated by vascular lesions, i.e. vessel notches, post-procedural vasospasm, dissections, and thrombus formations. Moreover, with the EnligHTN multi-electrode system, more thrombus formation per renal artery occurred than with the Simplicity® catheter.
In this regard, recent animal studies are of interest demonstrating local loss of the endothelial monolayer resulting in thrombus formation even at 6 month follow-up. These observations in patients and animal models suggest that an antithrombotic therapy should be used before and after RNA, possibly for prolonged periods of time. This notion is further supported by the fact that renal artery stenosis may indeed occur after RNA, possibly evolving from such injuries.
In contrast to Steigerwald, we have observed one dissection after RNA in our series with the Simplicity® catheter. In this regard, one patient of the Simplicity® HTN-1 study developed also renal artery dissection. Of note, the true incidence of renal artery dissection could be markedly underestimated in the Simplicity® HTN-1 study, since no intravascular imaging was performed in these patients.
Local notches, which are signs of vessel wall oedema, occurred after RNA with both catheter systems without statistically significant difference between the two. Based on histological analyses of a preclinical study, notches correspond to cellular swelling and connective tissue coagulation within the medial and adventitial layer. This formation of local oedema with water retention within the ablated tissue and an inflammatory response is also known from electrophysiological studies in which radiofrequency ablation is used. It is assumed that such oedemas are only present in the acute phase immediately after RNA and therefore a transient phenomenon of inflammation. Possibly, local oedema may reflect effective renal denervation. Obviously, whether the larger tissue damage really leads to a more effective decrease in blood pressure needs to be elucidated. Furthermore, it is unclear whether the presence of a concomitant atherosclerotic disease in renal arteries has an impact on the success of RNA on arterial blood pressure.
A three-dimensional OCT image reconstruction documented a circumscribed vascular spasm for both catheter systems leading to a 'pearl-of-string' feature with a significant reduction in the mean renal artery diameter as well after RNA. Obviously renal vasospasm can also result from catheter manipulation by the operator; however, the 'pearl-of-string' pattern (encountered along the entire length of the treated renal artery) strongly suggests that such a generalized vasospasm of treated renal arteries most likely results from the mechanical stress induced by the ablation catheter tip or basket, respectively, and/or the applied radiofrequency energy itself rather than from catheter manipulation. The mechanism of such a diffuse vasoconstriction not only at the site of ablation remains unknown, but may involve a reduced nitric oxide release after endothelial damage. However, in the experience of most operators, nitrates and calcium antagonists are not very effective in this context. Possibly, endothelin release, which leads to prolonged vasospasm, may be involved.
Limitations
It is a limitation of this study that a rather small number of patients has yet been studied and thus these results have to be confirmed in a larger patient population. The comparison of both catheter-based systems is observational and selection bias could have occurred. However, the selection of the system was done by an independent study coordinator who was not involved in the RNA procedure, which would help to alleviate concerns of obvious selection bias. Furthermore, the maximal field of view in OCT is limited to 11 mm; therefore, patients with a large renal artery diameter are difficult to study. Moreover, imaging depth is limited to 0.5–2.0 mm with OCT. Therefore, renal arteries with thick walls cannot be properly evaluated in their entirety. The number of pullbacks excluded due to poor quality is much higher with the Simplicity system when compared with the EnligHTN system. This reflects the real-world practice for which reason we have not excluded the failed cases from our enrolment. However, the imbalance in excluded data could impair the validity of the analysis. Furthermore, no renal artery flow measurements with renal duplex-sonography before and after RNA was performed.