Critical limb-threatening ischemia and microvascular transformation: clinical implications
Santeri Tarvainen, Galina Wirth, Greta Juusola, Olli Hautero, Kari Kalliokoski, Tanja Sjöros, Veikko Nikulainen, Jouni Taavitsainen, Jarkko Hytönen, Crister Frimodig, Krista Happonen, Tuomas Selander, Tomi Laitinen, Harri H Hakovirta, Juhani Knuuti, Nihay Laham-Karam, Juha Hartikainen, Kimmo Mäkinen, Seppo Ylä-Herttuala, Petra Korpisalo- Cardiology and Cardiovascular Medicine
Abstract
Background and aims
Clinical management of critical limb-threatening ischemia (CLTI) is focused on prevention and treatment of atherosclerotic arterial occlusions. The role of microvascular pathology in disease progression is still largely unspecified and more importantly not utilized for treatment. The aim of this explorative study was to characterize the role of the microvasculature in CLTI pathology.
Methods
Clinical high-resolution imaging of CLTI patients (n=50) and muscle samples from amputated CLTI limbs (n=40) were used to describe microvascular pathology of CLTI at the level of resting muscle blood flow and microvascular structure, respectively. Furthermore, a chronic, low arterial driving pressure-simulating ischemia model in rabbits (n=24) was used together with adenoviral vascular endothelial growth factor A gene transfers to study the effect of microvascular alterations on muscle outcome.
Results
Resting microvascular blood flow was not depleted but displayed decreased capillary transit time (P<0.01) in CLTI muscles. CLTI muscle microvasculature also exhibited capillary enlargement (P<0.001) and further arterialization along worsening of myofiber atrophy and detaching of capillaries from myofibers. Furthermore, CLTI-like capillary transformation was shown to worsen calf muscle force production (P<0.05) and tissue outcome (P<0.01) under chronic ischemia in rabbits and in healthy, normal rabbit muscle.
Conclusions
These findings depict a progressive, hypoxia-driven transformation of the microvasculature in CLTI muscles, which pathologically alters blood flow dynamics and aggravates tissue damage under low arterial driving pressure. Hypoxia-driven capillary enlargement can be highly important for CLTI outcomes and should therefore be considered in further development of diagnostics and treatment of CLTI.