Author + information
- Kensuke Nishimiya, MD, PhD,
- Yasuharu Matsumoto, MD, PhD,
- Jun Takahashi, MD, PhD,
- Hironori Uzuka, MD,
- Hongxin Wang,
- Ryuji Tsuburaya, MD, PhD,
- Kiyotaka Hao, MD, PhD,
- Kazuma Ohyama, MD,
- Yuji Odaka, MD,
- Satoshi Miyata, PhD,
- Kenta Ito, MD, PhD and
- Hiroaki Shimokawa, MD, PhD∗ ()
- ↵∗Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, 1-2 Aoba, Sendai 980-8574, Japan
Coronary artery spasm plays important roles in the pathogenesis of a wide range of ischemic heart disease. Recent studies have demonstrated that coronary spasm is frequently noted in Caucasians as in Asians (1). We previously demonstrated that vascular smooth muscle cell hypercontraction through Rho-kinase activation is the key mechanism of the spasm, for which adventitial inflammatory changes may be involved (1). The adventitia has recently attracted much attention as a source of inflammation as it harbors nutrient blood vessels called vasa vasorum (VV). Indeed, VV plays an important role as a supply route of vascular inflammation in the progression of coronary atherosclerotic plaque (2). We recently demonstrated that enhanced VV formation after drug-eluting stents (DES) implantation is associated with coronary hyperconstricting responses through Rho-kinase activation in pigs in vivo (3). We also confirmed the accuracy of optical frequency domain imaging (OFDI) to evaluate VV formation in humans in vivo (4). However, it remains to be elucidated whether the extent of VV is enhanced in patients with vasospastic angina (VSA). In the present study, we thus examined whether VV formation is enhanced in VSA patients by using the OFDI system, and, if so, whether there is any correlation between the extent of VV and that of coronary vasoconstriction.
From April 2013 to February 2015, a total of 115 consecutive patients with suspected VSA symptoms without coronary stenosis ≥75% on coronary angiography (CAG) were enrolled. After control CAG, a coronary spasm provocation test with intracoronary acetylcholine (ACh) was performed. Finally, 63 patients with the diffuse spasm in the left anterior descending coronary artery (LAD) and 26 controls without the spasm were enrolled. Clinical characteristics were comparable between the VSA and the control groups.
Intracoronary OFDI (Lunawave, Terumo, Japan) was performed along the LAD, after administration of intracoronary isosorbide dinitrate (ISDN) (2 mg) after the spasm provocation test. Morphometric analysis of OFDI was performed at every 10-mm by 2 independent investigators. Although the percentage of intimal + medial area tended to be greater in the VSA group compared with the control group, all morphometric parameters were statistically comparable between the 2 groups. Importantly, representative OFDI examination showed that VV formation was markedly enhanced at the spastic LAD in a patient with VSA compared with a control subject (Figure 1). VV area density was calculated by following formula: [VV area/(area outside external elastic lamina within a distance of the thickness of intima plus media − vessel area)] and was significantly greater in the VSA group compared with the control group (control, 0.036 ± 0.004 mm2/mm2 vs. VSA, 0.088 ± 0.004 mm2/mm2; p < 0.001). In the VSA group, there was a significant positive correlation between VV area density and the extent of coronary vasoconstricting responses to ACh (R = 0.553, p < 0.001). Similarly, a significant positive correlation was noted between VV area density and Rho-kinase activity in circulating leukocytes (1) (R = 0.370, p < 0.001).
The major findings of the present study were that VV formation was enhanced at the spastic coronary segments in VSA patients and the extent of VV formation was positively correlated with Rho-kinase activity. We previously demonstrated that the Rho-kinase pathway plays a key role in the pathogenesis of coronary arteriosclerosis and that up-regulation of Rho-kinase is involved in VV formation in pigs after DES implantation (1,3). A similar mechanism may also be involved in VV enhancement in VSA patients. However, the causal relationship between VV formation and coronary spasm remains to be examined in future studies.
In conclusion, the present study demonstrates for the first time that adventitial VV formation is enhanced at the spastic coronary segment in VSA patients with a positive correlation with the extent of coronary vasospastic responses, suggesting the involvement of adventitial VV formation in the pathogenesis of the spasm.
Please note: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- Shimokawa H.
- Taruya A.,
- Tanaka A.,
- Nishiguchi T.,
- et al.