18F-FDG for imaging microvascular injury
Atherosclerosis is an inflammatory process where oxidation of low-density lipoproteins (LDL) in the arterial wall causes initiation and progression of the atherosclerotic plaque by attracting macrophages.1 The necrotic core of the vulnerable atherosclerotic plaque is rich in free cholesterol crystals derived from apoptotic lipid-laden macrophages and from the membranes of red blood cells which enter the core during intraplaque hemorrhage.2 Vulnerable plaque is more prone to rupture. The plaque rupture triggers macrophage activation, tissue factor release, platelet aggregation, thrombus formation, thromboembolization, cholesterol embolization, arterial obstruction, end organ ischemia and necrosis. Atherosclerosis is a dynamic process and many of its clinical manifestations such as myocardial infarction, ischemic stroke, transient ischemic attack, acute mesenteric ischemia, acute limb ischemia, and renal injury occur as a consequence of rupture of the vulnerable atherosclerotic plaque. So it is very important to understand the various mechanisms behind the distal organ injury caused by acute plaque rupture.
Cholesterol crystal embolization (CCE) is one known mechanism of organ injury from atherosclerotic plaque rupture and it may happen spontaneously or by the endothelial trauma during instrumentation of an artery.3 The prevalence of cholesterol crystal embolism in autopsy studies in unselected patients ranges from 0.7% to 4%.4 This has also been shown to occur spontaneously in 1% of patients with transesophageal echocardiography-confirmed extensive thoracic aortic athersosclerotic disease when followed over 3 years.5 CCE occurs in 3% of patients who underwent infrarenal aortic and infrainguinal vascular surgery or angiographic manipulation,6 in 0.8% of patients undergoing cardiac catheterization,7 and in 0.2% of patients undergoing cardiac surgery.8 CCE causes organ injury by multiple mechanisms. In this issue of the Journal of Nuclear Cardiology, Pervaiz MH et al9 examine the non-obstructive, non-ischemic, direct toxicity of cholesterol crystals as a cause of left thigh muscle inflammation and injury in a controlled animal study after injecting cholesterol crystals, polystyrene microsphere control, or saline control into the left femoral artery of rabbits. Thigh muscle inflammation and injury was assessed by 18F-FDG PET/CT and angiography, which were then correlated with inflammatory markers such as tissue macrophage infiltration density and muscle injury markers such as creatine phosphokinase (CPK) levels. There was more muscle inflammation and injury in the cholesterol crystal group compared to the control groups as demonstrated by high maximum standardized uptake values of the left thigh muscles by PET/CT (0.40 ± 0.16 vs 0.21 ± 0.11 and 0.23 ± 0.06; P = .038 and P = .036, respectively), high CPK levels at 24 hours (7.46 ± 4.32 vs 1.57 ± 0.84 and 1.43 ± 0.57; P = .007 and P = .023, respectively), and high macrophage density in the muscle biopsy.
CCE may cause organ injury by multiple mechanisms such as macrovascular obstruction, microvascular obstruction, direct toxicity to cells by the nature of its physical structure, and by activating inflammatory response. In this study by Pervaiz et al, arterial obstruction by cholesterol crystal or thromboembolism was ruled out by angiography, direct visualization of the blood vessels during autopsy, and histology, and thereby the muscle inflammation and injury were attributed to probable direct toxicity of CCs to the tissue. A physiological intracellular free cholesterol-to-phospholipid ratio is necessary to maintain the normal fluidity of plasma membrane and for maintaining the normal function of integral membrane proteins.10 A high free cholesterol-to-phospholipid ratio can cause cell injury by affecting the integrity of certain cellular proteins like Na+/K+ ATPase, adenylate cyclase, alkaline phosphatase, Na+/Ca++ transporter in the sarcoplasmic reticulum, the ATP-ADP transporter in the inner mitochondrial membrane, and UDP-glucuronosyltransferase.11 Direct cell toxicity of CCs can also be due to intracellular cholesterol crystallization, conversion to oxysterol,12 and inducing apoptosis.13 Intracellular cholesterol crystals can also cause direct cell injury by physically disrupting the integrity of intracellular structures.14 Whether cholesterol crystal tissue injury observed in this study by Pervaiz et al was related to mechanical injury from sharp needle-like structure of cholesterol crystals or due to its direct biochemical toxicity cannot be answered by this study. Perhaps, if some other inert substance like carbon, polystyrene, or silica shaped similar to cholesterol crystal structure had been used instead of the microsphere control, we would have known whether tissue inflammation and injury was caused by the mechanical injury due to the cholesterol crystal or by its biochemical toxicity.
18F-FDG PET/CT is being clinically used as a non-invasive diagnostic tool in cardiovascular medicine to detect myocardial viability, myocardial ischemia, cardiac inflammation, and infections.15-18 PET/CT is also being studied as a tool in demonstrating vascular inflammation in patients with vasculitis19,20 and in identifying vulnerable plaques in atherosclerotic cardiovascular disease.21 This study by Pervaiz et al adds another potential use of 18F-FDG PET/CT for imaging the inflammation and injury to the muscle and possibly other organ systems from CCE.
As the longevity of the population increases, the prevalence of atherosclerotic cardiovascular diseases also increases and is a cause of significant morbidity and mortality. CCE is one of the manifestations of the wide spectrum of atherosclerotic cardiovascular diseases, which is difficult to study and diagnose. Studies focusing on the mechanisms of tissue injury caused by CCE and finding new diagnostic tools to demonstrate tissue injury will help us in understanding more about the pathogenesis of atherosclerotic cardiovascular diseases.
All the three authors do not have any disclosures.
- 7.Fukumoto Y, Tsutsui H, Tsuchihashi M, Masumoto A, Takeshita A. Cholesterol embolism study (CHEST) investigators. The incidence and risk factors of cholesterol embolization syndrome, a complication of cardiac catheterization: A prospective study. J Am Coll Cardiol. 2003;42(2):211-6.CrossRefPubMedGoogle Scholar