Critical limb ischaemia is the end stage of peripheral arterial disease before limb loss. Contemporary interventions to restore blood flow have high morbidity and mortality and fail to provide sustained restoration of peripheral circulation. Cell-based therapies designed to promote neovascularisation or angiogenesis have been shown in trials to be safe but clinically ineffective. Notwithstanding endless research in the area, no headway has been made in identifying a successful therapy designed specifically to target muscle disease in critical lower limb ischaemia. Thus, the quest to find an effective, lasting solution for critical lower limb ischaemia continues and requires more innovative therapeutic tactics. Our aim is to highlight the crucially interlinked role of the capillary bed, skeletal muscle mass and mitochondria in critical lower limb ischaemia patients and to identify novel therapeutic mechanisms that the vascular interventionalist can add to their armamentarium.
HausenloyDJYellonDM.Ischaemic conditioning and reperfusion injury. Nat Rev Cardiol2016;
13: 193–209.
3.
HongDMLeeEHKimHJet al.
Does remote ischaemic preconditioning with postconditioning improve clinical outcomes of patients undergoing cardiac surgery? Remote ischaemic preconditioning with postconditioning outcome trial. Eur Heart J2014;
35: 176–183.
4.
MeybohmPBeinBBrosteanuOet al.
A multicenter trial of remote ischemic preconditioning for heart surgery. N Engl J Med2015;
373: 1397–1407.
5.
HausenloyDJCandilioLEvansRet al.
Remote ischemic preconditioning and outcomes of cardiac surgery. N Engl J Med2015;
373: 1408–1417.
6.
ThielmannMKottenbergEKleinbongardPet al.
Cardioprotective and prognostic effects of remote ischaemic preconditioning in patients undergoing coronary artery bypass surgery: a single-centre randomised, double-blind, controlled trial. Lancet2013;
382: 597–604.
7.
CandilioLMalikAAritiCet al.
Effect of remote ischaemic preconditioning on clinical outcomes in patients undergoing cardiac bypass surgery: a randomised controlled clinical trial. Heart2015;
101: 185–192.
8.
CluffKMiserlisDNaganathanGKet al.
Morphometric analysis of gastrocnemius muscle biopsies from patients with peripheral arterial disease: objective grading of muscle degeneration. Am J Physiol Regul Integr Comp Physiol2013;
305: R291–R299.
9.
MakrisKINellaAAZhuZet al.
Mitochondriopathy of peripheral arterial disease. Vascular2007;
15: 336–343.
10.
PipinosIIJudgeARSelsbyJTet al.
The myopathy of peripheral arterial occlusive disease: Part 1. Functional and histomorphological changes and evidence for mitochondrial dysfunction. Vasc Endovascular Surg2008;
41: 481–489.
11.
PipinosIISwansonSAZhuZet al.
Chronically ischemic mouse skeletal muscle exhibits myopathy in association with mitochondrial dysfunction and oxidative damage. Am J Physiol Regul Integr Comp Physiol2008;
295: R290–R296.
12.
PipinosIIJudgeASelsbyJet al.
Basic science review: the myopathy of peripheral arterial occlusive disease: Part 2. Oxidative stress, neuropathy, and shift in muscle fiber type. Vasc Endovascular Surg2008;
42: 101–112.
13.
StewartKJHiattWRRegensteinerJGet al.
Exercise training for claudication. N Engl J Med2002;
347: 1941–1951.
14.
ZakiMElsherifMTawfickWet al.
The role of sequential pneumatic compression in limb salvage in non-reconstructable critical limb ischemia. Eur J Vasc Endovasc Surg2016;
51: 565–571.
15.
TawfickWAHamadaNSoyluEet al.
Sequential compression biomechanical device versus primary amputation in patients with critical limb ischemia. Vasc Endovascular Surg2013;
47: 532–539.
16.
SultanSHamadaNSoyluEet al.
Sequential compression biomechanical device in patients with critical limb ischemia and nonreconstructible peripheral vascular disease. J Vasc Surg2011;
54: 440–446.
17.
SultanSEsanOFahyA.Nonoperative active management of critical limb ischemia: initial experience using a sequential compression biomechanical device for limb salvage. Vascular2008;
16: 130–139.
18.
SultanSTawfickWZakiMet al.
Sequential pneumatic compression biomechanical home therapy device in the management of critical lower limb ischemia for no-option patients. Vas Dis Manag2016;
13: E147–E155.
19.
HammerASteinerS.Gene therapy for therapeutic angiogenesis in peripheral arterial disease – a systematic review and meta-analysis of randomized, controlled trials. Vasa2013;
42: 331–339.
20.
CookeJPLosordoDW.Modulating the vascular response to limb ischemia: angiogenic and cell therapies. Circ Res2015;
116: 1561–1578.
21.
ChargéSBRudnickiMA.Cellular and molecular regulation of muscle regeneration. Physiol Rev2004;
84: 209–238.
22.
WeledjiEPFokamP.Treatment of the diabetic foot – to amputate or not?BMC Surg2014;
14: 83
23.
SongMChenYGongGet al.
Super-suppression of mitochondrial reactive oxygen species signaling impairs compensatory autophagy in primary mitophagic cardiomyopathy. Circ Res2014;
115: 348–353.
24.
KubliDAZhangXLeeYet al.
Parkin protein deficiency exacerbates cardiac injury and reduces survival following myocardial infarction. J Biol Chem2013;
288: 915–926.
25.
LiesaMShirihaiOS.Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab2013;
17: 491–506.
26.
RyanTESchmidtCAGreenTDet al.
Mitochondrial regulation of the muscle microenvironment in critical limb ischemia. Front Physiol2014;
6: 336
27.
GiedtRJYangCZweierJLet al.
Mitochondrial fission in endothelial cells after simulated ischemia/reperfusion: role of nitric oxide and reactive oxygen species. Free Radic Biol Med2012;
52: 348–356.
28.
LejayAMeyerASchlagowskiAIet al.
Mitochondria: mitochondrial participation in ischemia-reperfusion injury in skeletal muscle. Int J Biochem Cell Biol2014;
50: 101–105.
29.
NehlerMRDuvalSDiaoLet al.
Epidemiology of peripheral arterial disease and critical limb ischemia in an insured national population. J Vasc Surg2014;
60: 686.e2–695.e2.
30.
FowkesFGRudanDRudanIet al.
Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet2013;
382: 1329–1340.
31.
TalukderMAJohnsonWMVaradharajSet al.
Chronic cigarette smoking causes hypertension, increased oxidative stress, impaired NO bioavailability, endothelial dysfunction, and cardiac remodeling in mice. Am J Physiol Heart Circ Physiol2011;
300: H388–H396.
32.
ShenoudaSMWidlanskyMEChenKet al.
Altered mitochondrial dynamics contributes to endothelial dysfunction in diabetes mellitus. Circulation2011;
124: 444–453.
33.
IjzermanRGSerneEHVan WeissenbruchMMet al.
Cigarette smoking is associated with an acute impairment of microvascular function in humans. Clin Sci2003;
104: 247–252.
34.
HendersonBCsordasABackovicAet al.
Cigarette smoke is an endothelial stressor and leads to cell cycle arrest. Atherosclerosis2008;
201: 298–305.
35.
DegensHGayan-RamirezGVan HeesHW.Smoking-induced skeletal muscle dysfunction: from evidence to mechanisms. Am J Respir Crit Care Med2015;
191: 620–625.
36.
CardellachFAlonsoJRLópezSet al.
Effect of smoking cessation on mitochondrial respiratory chain function. J Toxicol Clin Toxicol2003;
41: 223–228.
37.
Knight-LozanoCAYoungCGBurowDLet al.
Cigarette smoke exposure and hypercholesterolemia increase mitochondrial damage in cardiovascular tissues. Circulation2002;
105: 849–854.
38.
JudeEBOyiboSOChalmersNet al.
Peripheral arterial disease in diabetic and nondiabetic patients: a comparison of severity and outcome. Diabetes Care2001;
24: 1433–1437.
39.
DeRubertisBGPierceMRyerEJet al.
Reduced primary patency rate in diabetic patients after percutaneous intervention results from more frequent presentation with limb-threatening ischemia. J Vasc Surg2008;
47: 101–108.
40.
ConteMS.Diabetic revascularization: endovascular versus open bypass—do we have the answer?Semin Vasc Surg2012;
25: 108–114.
41.
MalmstedtJLeanderKWahlbergEet al.
Outcome after leg bypass surgery for critical limb ischemia is poor in patients with diabetes: a population-based cohort study. Diabetes Care2008;
31: 887–892.
42.
KelleyDEHeJMenshikovaEVet al.
Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes2002;
51: 2944–2950.
43.
BaumgartnerRNKoehlerKMGallagherDet al.
Epidemiology of sarcopenia among the elderly in New Mexico. Am J Epidemiol1998;
147: 755–763.
44.
EvansWJ.What is sarcopenia?J Gerontol A Biol Sci Med Sci1995;
50: 5–8.
45.
MatsubaraYMatsumotoTAoyagiYet al.
Sarcopenia is a prognostic factor for overall survival in patients with critical limb ischemia. J Vasc Surg2015;
61: 945–950.
46.
PedersenBK.Muscle and their myokines. J Exp Biol2011;
214: 337–346.
47.
PedersenBK.The diseasome of physical inactivity – and role of myokines in muscle – fat cross talk. J Physiol2009;
587: 5559–5568.
48.
FriedLPTangenCMWaltsonJet al.
Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci2001;
56:M146–M156
49.
WongCHWeissDSourialNet al.
Frailty and its association with disability and comorbidity in a community-dwelling sample of seniors in montreal: a cross-sectional study. Aging Clin Exp Res2010;
22: 54–62.
50.
BaggioGDonazzanSMontiDet al.
Lipoprotein(a) and lipoprotein pro-file in healthy centenarians: a reappraisal of vascular risk factors. Faseb J1998;
12: 433–437.
51.
NoconMHiemannTMuller-RiemenschneiderFet al.
Association of physical activity with all-cause and cardiovascular mortality: a systematic review and meta-analysis. Eur J Cardiov Prev Rehabil2008;
15: 239–246.
52.
PetersenAMPedersenBK.The anti-inflammatory effect of exercise. J Appl Physiol2005;
98: 1154–1162.
53.
RajagopalanSMohlerERLedermanRJet al.
Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease: a phase II randomized, double-blind, controlled study of adenoviral delivery of vascular endothelial growth factor 121 in patients with disabling intermittent claudication. Circulation2003;
108: 1933–1938.
54.
CreagerMAOlinJWBelchJJet al.
Effect of hypoxia-inducible factor-1alpha gene therapy on walking performance in patients with intermittent claudication. Circulation2011;
124: 1765–1773.
55.
ChungASLeeJFerraraN.Targeting the tumour vasculature: insights from physiological angiogenesis. Nat Rev Cancer2010;
10: 505–514.
56.
FerraraN.Vascular endothelial growth factor and age-related macular degeneration: from basic science to therapy. Nat Med2010;
16: 1107–1111.
57.
AllenJDMillerEMSchwarkEet al.
Plasma nitrite response and arterial reactivity differentiate vascular health and performance. Nitric Oxide2009;
20: 231–237.
58.
SunLBaiYDuG.Endothelial dysfunction—an obstacle of therapeutic angiogenesis. Ageing Res Rev2009;
8: 306–313.
59.
DelisKTNicolaidesANLabropoulosNet al.
The acute effects of intermittent pneumatic foot versus calf versus simultaneous foot and calf compression on popliteal artery hemodynamics: a comparative study. J Vasc Surg2000;
32: 284–292.
60.
SheldonRDRoseguiniBTLaughlinMHet al.
New insights into the physiologic basis for intermittent pneumatic limb compression as a therapeutic strategy for peripheral artery disease. J Vasc Surg2013;
58: 1688–1696.
61.
ChenLELiuKQiWNet al.
Role of nitric oxide in vasodilation in upstream muscle during intermittent pneumatic compression. J Appl Physiol2002;
92: 559–566.
62.
LiuKChenLESeaberAVet al.
Influences of inflation rate and duration on vasodilatory effect by intermittent pneumatic compression in distant skeletal muscle. J Orthop Res1999;
17: 415–420.
