Persistent over-dilation of muscle microvasculature may be one reason causing chronic limb-threatening ischemia, recent studies by Kuopio University Hospital and the University of Eastern Finland show. In the future, this surprising finding may offer new avenues for the screening and treatment of patients with chronic limb-threatening ischemia.
Chronic limb-threatening ischemia is known to be caused by peripheral arterial disease in which arterial blockages impair the flow of blood and oxygen to leg muscles. The disease can remain asymptomatic for a long time, but at worst, it can ultimately lead to necrosis and amputation.
“Muscle microvasculature responds to hypoxia by dilating in an attempt to increase the flow of blood and oxygen to the tissues. However, microvascular over-dilation seems to cause also adverse changes,” Research Director, Associate Professor (Docent) Petra Korpisalo of the University of Eastern Finland notes.
Current understanding of microvascular changes in chronic limb-threatening ischemia remains limited, partly because the tissue microvasculature is difficult to study in human patients. However, Korpisalo’s research group has developed imaging methods that are suitable for studying the capillary microvasculature as well.
Recently, the group found that in chronic limb-threatening ischemia, blood flow to the muscles tends not to be reduced despite arterial blockages. On the contrary, blood flow can even increase due to persistent over-dilation of the microvasculature. In the muscle samples studied, more than half of capillaries had transformed to resemble arterioles, exacerbating cellular damage.
The researchers experimentally showed that dilation-induced changes taking place in the capillary wall impair the flow of oxygen from the blood vessel to the tissues.
“Microvascular over-dilation causes hypoxia and cell shrinkage even in healthy muscle,” Korpisalo notes.
In light of the new findings, microvascular over-dilation also plays a significant role in the prognosis of patients with chronic limb-threatening ischemia. Korpisalo’s research group has found that there were more than three times as many negative outcome events, such as hospitalisations, amputations or deaths among patients whose lower limb ischemia was associated with increased capillary flow, compared to controls.
“Patients with chronic limb-threatening ischemia often die of heart and brain diseases. Prolonged microvascular over-dilation may also be linked to this, as changes in muscle blood flow affect the function of the whole circulatory system,” Korpisalo says.
Due to remaining asymptomatic for a long time, timely diagnosis often poses a challenge to the treatment of chronic limb-threatening ischemia. Korpisalo notes that in the future, the disease could potentially be screened by imaging microvascular over-dilation. The development of treatments targeting these transformations could also improve the prognosis for many patients.
Research articles:
Tarvainen S, Wirth G, Juusola G, Hautero O, Kalliokoski K, Sjöros T, Nikulainen V, Taavitsainen J, Hytönen J, Frimodig C, Happonen K, Selander T, Laitinen T, Hakovirta HH, Knuuti J, Laham-Karam N, Hartikainen J, Mäkinen K, Ylä-Herttuala S, Korpisalo P. Critical limb-threatening ischaemia and microvascular transformation: clinical implications. Eur Heart J. 2024 Jan 27;45(4):255-264. https://doi.org/10.1093/eurheartj/ehad562
P Korpisalo, C Frimodig, H Heikkinen, K Happonen, S Tarvainen, G Juusola, G Wirth, Microvascular blood flow disturbances predict poor outcome of revascularization in CLTI patients, European Heart Journal, Volume 45, Issue Supplement_1, October 2024, ehae666.2275, https://doi.org/10.1093/eurheartj/ehae666.2275