
==== Front
Intern Med
Intern Med
Internal Medicine
0918-2918
1349-7235
The Japanese Society of Internal Medicine

38171873
10.2169/internalmedicine.2917-23
Case Report
Chronic Clinical Findings after RheocarnaⓇ Therapy in a Chronic Limb-threatening Ischemia Patient with Inframalleolar Lesions
Satake Akinori 1
Tokuda Takahiro 2
Niwa Toru 1
Suzuki Akihiro 3
Nakano Yusuke 3
Ando Hirohiko 3
Amano Tetsuya 3
1 Department of Cardiology, Narita Memorial Hospital, Japan
2 Department of Cardiology, Nagoya Heart Center, Japan
3 Department of Cardiology, Aichi Medical University, Japan
Correspondence to Dr.　Akinori Satake, grampus_gamba@yahoo.co.jp

2 1 2024
15 8 2024
63 16 22932296
15 9 2023
13 11 2023
Copyright © 2024 by The Japanese Society of Internal Medicine
https://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).
An 87-year-old man was referred to our hospital for non-healing ulcers on the right third, fourth, and fifth toes. The patient was diagnosed with chronic limb-threatening ischemia. Pre-treatment angiography of the right lower extremity revealed inframalleolar lesions. We failed to perform endovascular treatment because of severe calcification. Therefore, we treated the patient with a novel low-density lipoprotein apheresis device (RheocarnaⓇ; Kaneka, Osaka, Japan). Angiography performed four days after therapy revealed significant improvement in microcirculation. One year after therapy, he managed to avoid major amputation and achieve wound healing. In addition, angiography revealed that the microcirculation was maintained.

RheocarnaⓇ
inframalleolar lesions
chronic limb-threatening ischemia
==== Body
pmcIntroduction

Chronic limb-threatening ischemia (CLTI) is the most advanced form of lower-extremity arterial disease (1). In particular, CLTI with inframalleolar (IM) lesions is often difficult to revascularize and is associated with poor lower limb outcomes (2). Adjuvant therapy plays an important role in such cases.

A novel low-density lipoprotein apheresis (LDL-A) device (RheocarnaⓇ; Kaneka, Osaka, Japan) was developed in Japan for CLTI with refractory ulcers, allowing clinicians to remove the causative agents of CLTI, such as low-density lipoprotein cholesterol (LDL-C) and fibrinogen, using porous cellulose beads containing negatively charged dextran sulfate and hydrophobic tryptophan. Unlike conventional LDL-A (LiposorberⓇ; Kaneka, Osaka, Japan), RheocarnaⓇ usage is not a prerequisite for the presence of treatment-resistant hyperlipidemia. Furthermore, it is approved for insurance reimbursement (maximum of 24 sessions) (3). RheocarnaⓇ therapy improves skin perfusion pressure (SPP), LDL-C levels, fibrinogen levels, and angiographical findings during the acute phase (4-6). However, little is known about the changes induced by RheocarnaⓇ in the chronic phase.

We herein report the chronic clinical findings after using RheocarnaⓇ.

Case Report

An 87-year-old man who underwent hemodialysis for diabetic nephropathy at 79 years old was referred to our hospital for non-healing ulcers on his right third, fourth, and fifth toes as well as rest pain in the past month (Figure a, b). He required wheelchair use. His medical history included cerebral infarction, aortic valve replacement, and coronary artery bypass grafting. His medications included clopidogrel (75 mg/day), rosuvastatin (2.5 mg/day), and alogliptin (12.5 mg/day). Regarding blood sugar management, his HbA1c levels were generally within the 7% range. The right ankle-brachial index was 0.94. The right-sided SPPs were 58 in the dorsal area and 36 in the plantar area. The Rutherford classification score was 5.

Figure. (a, b) Wound before Rheocarna® therapy. (c, d) Angiography images before Rheocarna® therapy. (e, f) Severe calcification on native X-ray of the right foot (white arrows). (g) Wound after 24 sessions of Rheocarna® therapy. (h, i) Angiography images four days after Rheocarna® therapy. (j) Wound status at one year after Rheocarna® therapy. (k, l) Angiography images one year after Rheocarna® therapy.

Electrocardiography at admission revealed a normal sinus rhythm. The left ventricular ejection fraction was 47%. Pre-treatment angiography of the right lower extremity revealed IM lesions (Figure c, d). Owing to non-healing ulcers lasting for more than two weeks, the patient was diagnosed with CLTI (7). As distal bypass surgery (BSX) carried a high risk in this patient, we attempted endovascular treatment (EVT) of the dorsal and plantar arteries. However, the guidewire could not pass through the lesion because of the severe calcification (Figure e, f). Therefore, we decided to treat the patient with RheocarnaⓇ.

The LDL-C and fibrinogen levels immediately before the initiation of RheocarnaⓇ therapy were 78 and 373 mg/dL, respectively. RheocarnaⓇ was used for a total of 24 sessions (maximum); the blood flow was 100-120 mL/min for 2 h for each session (twice a week on non-dialysis days). Apheresis was performed through the arteriovenous fistula used for hemodialysis. No complications occurred with the RheocarnaⓇ therapy.

Post-therapy, although the ulcers were not completely healed, demarcation was visible (Figure g). Angiography performed four days after therapy revealed a significant improvement in microcirculation, and wound blush appeared after completing the RheocarnaⓇ protocol (Figure h, i). After 24 therapy sessions over a period of 3 months, the LDL-C levels decreased from 78 to 30 mg/dL, and the fibrinogen levels decreased from 373 to 228 mg/dL. In addition, his dorsal and plantar SPPs improved to 67 and 71, respectively. Amputation of the right third, fourth, and fifth toes was performed two weeks after the therapy sessions had concluded.

One year after therapy, the patient had managed to avoid major amputation and achieved wound healing (Figure j). At the one-year follow-up, angiography revealed that the microcirculation had been maintained (Figure k, l), and LDL-C and fibrinogen levels were 41 and 271 mg/dL, respectively. Dorsal and plantar SPPs showed minimal changes, with values of 66 and 74, respectively (Table). Furthermore, there were no additions or reductions in oral medications during the one-year period.

Table. Clinical Course of SPP, LDL-C, and Fibrinogen Levels.

	Before Rheocarna®	After 24 sessions of Rheocarna®	At one year after Rheocarna®	
SPP dorsal	58	67	66	
SPP plantar	36	71	74	
LDL-C (mg/dL)	78	30	41	
Fibrinogen (mg/dL)	373	228	271	

Discussion

To our knowledge, this is the first report to assess the effects of RheocarnaⓇ during the chronic phase of CLTI. IM lesions represent a serious clinical issue in patients with CLTI and are associated with a poor lower limb prognosis. Revascularization through BSX or EVT is important to achieve wound healing in patients with CLTI. However, certain CLTI cases with IM lesions, such as the one described above, cannot be revascularized owing to severe anatomical modifications and are called “no-option CLTI” (8,9). Adjuvant therapies are required in such cases.

RheocarnaⓇ, an adjuvant therapy, is a novel LDL-A that removes not only LDL-C but also fibrinogen, unlike conventional LDL-A (LiposorberⓇ), which removes only LDL-C (3,6). Fibrinogen is one of the most important determinants of whole-blood viscosity and affects microcirculation in lower-extremity artery disease (10). A decrease in fibrinogen appears to affect the viscosity of whole blood by reducing erythrocyte aggregation, possibly due to enhanced electrical repulsion among erythrocytes (11).

In the present case, microcirculation in the acute phase was significantly improved after using RheocarnaⓇ. LDL-C and fibrinogen levels decreased, whereas SPP levels increased. These acute-phase changes were consistent with previous reports (5,6). However, during the chronic phase, although the LDL-C and fibrinogen levels were increased compared with the acute phase after using RheocarnaⓇ, the SPP was maintained. In addition, follow-up angiography showed that the microcirculation had also been maintained. SPP measurement is a reliable method for assessing microcirculation and is not affected by arterial calcification (12). SPP measurement can also accurately predict wound healing, and SPP ≥40 mmHg can be a predictor of wound healing (13,14). In this case, wound healing was considered to have occurred because the SPP remained above 40 mmHg, even during the chronic phase.

Although the detailed mechanism underlying the effects of RheocarnaⓇ is unclear, RheocarnaⓇ usage might maintain blood microcirculation in patients with CLTI in the chronic phase and positively influence their outcomes. Further prospective investigations with larger sample sizes are required.

Conclusions

RheocarnaⓇ may be effective in the acute phase and has the potential to contribute to the improvement of microcirculation in the chronic phase.

The authors state that they have no Conflict of Interest (COI).
==== Refs
1. Conte MS , Bradbury AW , Kolh P , et al .; the GVG Writing Group. Global vascular guidelines on the management of chronic limb-threatening ischemia. J Vasc Surg 69 : 3S-125S. e140, 2019.31159978
2. Meloni M , Izzo V , Giurato L , Gandini R , Uccioli L . Below-the-ankle arterial disease severely impairs the outcomes of diabetic patients with ischemic foot ulcers. Diabetes Res Clin Pract 152 : 9-15, 2019.31078668
3. Kobayashi S , Furukawa M , Ichioka S , et al . A novel low-density lipoprotein/fibrinogen apheresis method for chronic limb-threatening ischemia in patients with poor options for revascularization: a multicenter, single-arm clinical trial. Ther Apher Dial 27 : 361-369, 2022.36858047
4. Satake A , Nakano Y , Niwa T , Ando H , Takashima H , Amano T . RheocarnaⓇ as an alternative therapeutic option for patients with chronic limb-threatening ischemia: a case report. SAGE Open Med Case Rep 11 : 1-5, 2023.
5. Kojima S , Nakama T , Obunai K . Angiographic and clinical impact of novel low-density lipoprotein apheresis for no-option chronic limb-threatening ischemia. Ther Apher Dial 27 : 186-187, 2022.35620816
6. Kojima S , Nakama T , Suzuki T , Obunai K , Watanabe H . Clinical impact of a novel lipoprotein apheresis treatment on no-option chronic limb-threatening ischemia: result from the REDUCTION VISCOSITY study. Ther Apher Dial 27 : 960-967, 2023.37056201
7. Aboyans V , Ricco JB , Bartelink MEL , et al . Editors's choice - 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in Collaboration with the European Society for Vascular Surgery (ESVS). Eur J Vasc Endovasc Surg 55 : 305-368, 2018.28851596
8. Tsubakimoto Y , Nakama T , Kamoi D , Andoh H , Urasawa K . Outcomes of pedal artery angioplasty are independent of the severity of inframalleolar disease: a subanalysis of the multicenter RENDEZVOUS registry. J Endovasc Ther 27 : 186-193, 2020.31997714
9. Sato Y , Morishita T , Tan M , et al . Prediction of technical failure of inframalleolar angioplasty in patients with chronic limb threatening ischaemia. Eur J Vasc Endovasc Surg 63 : 852-863, 2022.35659488
10. Paraskevas KI , Baker DM , Vrentzos GE , Mikhailidis DP . The role of fibrinogen and fibrinolysis in peripheral arterial disease. Thromb Res 122 : 1-12, 2008.17669476
11. Ramunni A , Brescia P , Quaranta D , Plantamura M , Ria R , Coratelli P . Fibrinogen apheresis in the treatment of peripheral arterial disease. Blood Purif 25 : 404-410, 2007.17901692
12. Watanabe Y , Onozuka A , Obitsu Y , et al . Skin perfusion pressure measurement to assess improvement in peripheral circulation after arterial reconstruction for critical limb ischemia. Ann Vasc Dis 4 : 235-240, 2011.23555459
13. Yamada T , Ohta T , Ishibashi H , et al . Clinical reliability and utility of skin perfusion pressure measurement in ischemic limbs - comparison with other noninvasive diagnostic methods. J Vasc Surg 47 : 318-323, 2008.18241755
14. Urabe G , Yamamoto K , Onozuka A , Miyata T , Nagawa H . Skin perfusion pressure is a useful tool for evaluating outcome of ischemic foot ulcers with conservative therapy. Ann Vasc Dis 2 : 21-26, 2009.23555352
