The chemical structures of cardiac glycosides
\\n\\n
Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\\n\\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\\n\\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\\n\\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\\n\\nThank you all for being part of the journey. 5,000 times thank you!
\\n\\nNow with 5,000 titles available Open Access, which one will you read next?
\\n\\nRead, share and download for free: https://www.intechopen.com/books
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Preparation of Space Experiments edited by international leading expert Dr. Vladimir Pletser, Director of Space Training Operations at Blue Abyss is the 5,000th Open Access book published by IntechOpen and our milestone publication!
\n\n"This book presents some of the current trends in space microgravity research. The eleven chapters introduce various facets of space research in physical sciences, human physiology and technology developed using the microgravity environment not only to improve our fundamental understanding in these domains but also to adapt this new knowledge for application on earth." says the editor. Listen what else Dr. Pletser has to say...
\n\n\n\nDr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\n\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\n\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\n\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\n\nThank you all for being part of the journey. 5,000 times thank you!
\n\nNow with 5,000 titles available Open Access, which one will you read next?
\n\nRead, share and download for free: https://www.intechopen.com/books
\n\n\n\n
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Cardiac glycosides comprise a large family of naturally derived compounds, the core structures of which contain a steroid nucleus with a five-membered lactone ring (cardenolides) or a six-membered lactone ring (bufadienolides) and sugar moieties [1]. A few widely recognized examples of cardiac glycosides are digoxin, digitoxin, ouabain, and oleandrin. The cardenolides digitoxin and digoxin, two well-known cardiac glycosides, are inhibitors of the plasma membrane Na+/K+-ATPase that are clinically used for the treatment of heart failure. Their positive inotropic effects help suppress the active counter-transportation of Na+ and K+ across the cell membrane, leading to an increase in the intracellular Na+ concentration, a decrease in the intracellular K+ concentration, and a consequent increase in cardiac contraction [2]. Epidemiologic evidence suggests that breast cancer patients who were treated with digitalis have a significantly lower mortality rate, and their cancer cells had more benign characteristics than those from patients not treated with digitalis [3,4]. Interestingly, the concentrations of cardiac glycosides used for cancer treatment are extremely close to those found in the plasma of cardiac patients treated with the same drugs, suggesting that the anticancer effects of these drugs are exerted at non-toxic concentrations [5]. Furthermore, studies have suggested that cardiac glycosides target cancer cells selectively [6]. These encouraging findings have gained considerable attention in the field of anticancer research, and subsequent studies on the anticancer properties of these compounds have been conducted. These studies investigated not only digoxin and digitoxin but also other related cardiac glycosides, such as ouabain, oleandrin, proscillaridin A, and bufalin [7-10]. Several mechanisms of action, including the inhibition of cancer cell proliferation, the induction of apoptosis, and chemotherapy sensitization, have been reported in a large number of published articles that support the potential use of these compounds for cancer treatment [11-14]. However, further clinical studies are still ongoing to better characterize the pharmacological and safety issues associated with these compounds. This chapter provides an overview of the anticancer activities of cardiac glycosides and describes the selectivity of these compounds, which could prove to be promising treatments in cancer therapy.
Cardiac glycosides from both plants and animals have been known for over one hundred years [14]. Major plant-derived cardiac glycosides include digitoxin, digoxin, ouabain, oleandrin and proscillaridin, which are extracted from the plant families Scrophulariaceae, Apocynaceae, and Asparagaceae (Digitalis purpurea, Digitalis lanata, Strophanthus gratus, Nerium oleander and Urginea maritima). These compounds consist of a steroidal nucleus linked with a sugar at position 3 (C3) and a lactone ring at position 17 (C17) (Fig 1) [15]. The various types of sugar moieties and lactones provide a large number of cardiac glycosides that, based on their lactone moieties, can be divided into two sub-groups: cardenolides, which contain a five-membered unsaturated butyrolactone ring, and bufadienolides, which contain a six-membered unsaturated pyrone ring. The core steroidal portion of each molecule has an A/B and C/D cis-conformation, which has significant pharmacological relevance. The attached sugars, such as glucose, galactose, mannose, rhamnose, and digitalose, determine the pharmacodynamic and pharmacokinetic activities of each cardiac glycoside.
Structural characteristics of cardiac glycosides
Cardiac glycosides have been found in animals as well as plants; for example, bufadienolide was isolated from the venom of a toad species [16], and endogenous digitalis-like compounds have been found in mammalian tissues [17,18]. Several studies have reported that ouabain and proscillaridin A are found in human plasma, that digoxin and marinobufagenin are present in human urine, and that 19-norbufalin exists in cataractous human lenses [18-22]. Table 1 presents a list of the cardiac glycosides found in plants and animals along with their chemical structures.
A digitalis preparation from Digitalis purpurea was first used for the treatment of congestive heart failure by William Withering in 1785 [23]. Currently, digoxin is recognized as a primary treatment for patients with heart failure. Its mode of action has been identified as the potent inhibition of Na+/K+-ATPase. Na+/K+-ATPase, a ubiquitous transmembrane enzyme, is a p-type cation transporter that actively drives two K+ ions into the cell and drives three Na+ ions out of the cell using ATP as an energy source. This pump plays a vital role, acting as a secondary transporter of nutrients such as glucose and amino acids and helping to maintain the electrochemical gradient by keeping the intracellular Na+ concentration low [24]. The elevation of the intracellular Na+ level in response to cardiac glycosides stimulates the Na+/Ca2+ exchanger mechanism. As a result, the intracellular Ca2+ concentration is increased, consequently promoting cellular events such as myocardial contractibility, accounting for the positive inotropic effects of the cardiac glycosides.
Accumulating evidence has established that the Na+/K+-ATPase acts as a scaffold for signaling molecules or for the formation of a signalosome complex that activates various signaling cascades. Several signaling molecules, such as caveolin, SRC kinase, epidermal growth factor receptor (EGFR), and the inositol 1,4,5-triphosphate (IP3) receptor, have been investigated [25-27]. The inhibitory effects of cardiac glycosides on Na+/K+-ATPase activity might lead to alterations in these downstream transduction pathways, which could account for the biological properties of these compounds, including their anticancer activities.
Name | \n\t\t\tStructure | \n\t\t
• Digoxin (Cardenolide) • From Digitalis purpurea\n\t\t\t\t • Family: Scrophulariaceae | \n\t\t\t\n\t\t\t\t | \n\t\t
• Digitoxin (Cardenolide) • From Digitalis purpurea\n\t\t\t\t • Family: Scrophulariaceae | \n\t\t\t\n\t\t\t\t | \n\t\t
Ouabain (Cardenolide) From Nerium oleander\n\t\t\t\t Family: Apocynaceae | \n\t\t\t\n\t\t\t\t | \n\t\t
• Oleandrin (Cardenolide) • From Nerium oleander\n\t\t\t\t • Family: Apocynaceae | \n\t\t\t\n\t\t\t\t | \n\t\t
• Proscillaridin (Bufadienolide) • From Urginea maritima\n\t\t\t\t • Family: Liliaceae | \n\t\t\t\n\t\t\t\t | \n\t\t
• Cinobufagin (Bufadienolide) • From Bufo bufo gargarizans\n\t\t\t\t • Family: Bufonidae | \n\t\t\t\n\t\t\t\t | \n\t\t
• Bufalin (Bufadienolide) • From Bufo gargarizans • Family: Bufonidae | \n\t\t\t\n\t\t\t\t | \n\t\t
• Marinobufagenin (Bufadienolide) • From Bufo marinus • Family: Bufonidae | \n\t\t\t\n\t\t\t\t | \n\t\t
The chemical structures of cardiac glycosides
Epidemiologic evidence for the anticancer effects of digitalis was first reported in 1980 by Stenkvist and colleagues. Their study indicated that breast cancer tissue samples from congestive heart failure patients treated with cardiac glycoside therapy exhibited more benign characteristics than cancer tissue samples from control patients who were not treated with the cardiac glycoside regimen [28]. In addition, 5 years after undergoing mastectomy, the recurrence rate for the cardiac glycoside treated-group was 9.6 times lower than that for the control group [28-29]. Four years later, Glodin and colleagues investigated the mortality in 127 cancer patients who received digitalis therapy. These researchers reported that up to 21 patients in the control group died from cancer, whereas only one member of the digitalis-treated group died [30]. Interestingly, the long-term observations of Stenkvist and colleagues also supported the previous finding that digitalis therapy significantly reduces the mortality rate of breast cancer. Among 32 breast cancer patients treated with digitoxin, only two (6%) died, whereas the control group of 143 patients had 48 cancer-related deaths (34%) [4]. Several types of cancer other than breast cancer have also been examined. Recently, Haux and colleagues published an analytical descriptive study on the antineoplastic effects of cardiac glycosides on leukemia and cancers of the kidney/urinary tract [31]. This study indicated that the doses of cardiac glycosides that are active against cancers are similar to the therapeutic plasma concentrations found in cardiac patients treated with these drugs. These clinical observations have established the benificial outcome of cardiac glycosides for cancer therapy. Although these agents seem to be safe at the doses used for the treatment of cardiac disorders, further supporting evidence is still needed before these compounds can be used clinically.
At present, cancer is one of the major causes of death worldwide. Extensive research has been conducted over the last decade in an attempt to identify promising compounds that have anticancer effects. Cardiac glycosides are natural compounds that have been previously documented to be antiarrhythmic agents, and their potential anticancer properties were identified thereafter. Cardiac glycosides have been shown to have anticancer activities during various stages of carcinogenesis. These activities include antiproliferative, pro-apoptotic, and chemotherapy sensitization effects.
Aberrant cell growth is recognized as one hallmark of cancer [32]. Excessive cell replication is the basic characteristic of cancer progression that facilitates tumor formation and expansion. Defects in normal growth signals result in the inadequate regulation of cell division, which drives quiescent cells to proliferate [33]. Cardiac glycosides have been demonstrated to have antiproliferative activities via their regulation of the cell cycle. The extract from the skin glands of Bufo bufo gargarizans, which contains bufalin, is able to induce arrest in human malignant melanoma cells in the G2/M phase of the cell cycle [34]. In lung cancer cells, bufalin upregulates p21 WAF1 and suppresses cyclin D expression in response to the activation of p53 [35]. Because the tumor suppressor p21 WAF1 acts as a potent inhibitor of cell cycle progression [36] and because cyclin D1 is a subunit of cyclin dependent kinase (Cdk)-4 and Cdk-6, which are responsible for cell cycle progression from G1 to S phase [37], these changes prevent cells from entering the next phase of the cycle.
Likewise, digitoxin causes cell cycle arrest in G2/M in a dose-dependent manner, resulting in a large increase in the number of cells in the sub-G0 phase [38]. A synthetic monosaccharide analog of digitoxin, D6-MA, has 5-fold greater potency than digitoxin. The mode of action of D6-MA has been reported to involve the downregulation of key elements required for cell replication, including cyclin B1, cdc2 and survivin. It has been suggested that these events might be downstream signaling events resulting from the modulation of second messengers, such as tyrosine kinase Src, PI3K, phospholipase C and Ras/MAPK pathway components, by cardiac glycoside-bound Na+/K+-ATPase [25-27].
An antiproliferative effect of ouabain against human breast and prostate cancer cells has also been reported [39]. Ouabain mediates the depletion of the Na+/K+-ATPase through endocytosis and a degradation-dependent pathway, which in turn elevates the level of the cell cycle inhibitor p21. It has been suggested that the cellular level of Na+/K+-ATPase plays an important role in determining the rate of cell growth. Additional mechanistic studies have demonstrated that an increase in the intracellular Ca2+ concentration following treatment with digoxin, digitoxin, or ouabain is associated with the antiproliferative effects of these compounds in androgen-dependent and androgen-independent prostate cancer cell lines [40]. Because Ca2+ serves as a mediator in several signaling pathways, the elevation of the Ca2+ concentration may stimulate cellular processes that switch the cells into a growth-retarded state. Several of the antiproliferative effects of cardiac glycosides are summarized in Table 2.
Cardiac glycoside | \n\t\t\tMechanism | \n\t\t
Digitoxin | \n\t\t\tInduction of cell cycle arrest in G2/M phase through the downregulation of cyclin B1, cdc2 and survivin [38] Increase in the intracellular Ca2+ concentration [40] | \n\t\t
Digoxin | \n\t\t\tIncrease in the intracellular Ca2+ concentration [40] Inhibition of DNA topoisomerases I and II and an increase in the intracellular Ca2+ concentration [41] Induction of cell cycle arrest through the upregulation of HIF-1α [42] | \n\t\t
Ouabain | \n\t\t\tDepletion of Na+/K+-ATPase and upregulation of p21 [39] Increase in the intracellular Ca2+ concentration [40] Inhibition of DNA topoisomerases I and II and increase in the intracellular Ca2+ concentration [41] | \n\t\t
Oleandrin | \n\t\t\tAttenuation of NF-kB, JNK and AP-1 (nuclear transcription factors) activation [43,44] | \n\t\t
Bufalin | \n\t\t\tInduction of cell cycle arrest in G2/M phase through the upregulation of p21 WAF1 and p53 and the downregulation of cyclin D [34,35] Inhibition of DNA topoisomerases I and II [45] | \n\t\t
Proscillaridin A | \n\t\t\tInhibition of DNA topoisomerases I and II and an increase in the intracellular Ca2+ concentration [41] | \n\t\t
Antiproliferative effects of cardiac glycosides
Resistance to apoptosis in response to stress conditions is a basic feature of cancer cells and results from the overactivation of survival pathways or the attenuation of cell death mechanisms. The primary readout for screens of anticancer agents is thus usually an apoptosis-inducing effect. Cardiac glycosides have been established as cytotoxic agents that are active against various types of cancers. As mentioned above, the inhibition of Na+/K+-ATPase by cardiac glycosides triggers the formation of the signalosome complex, contributing to the initiation of signaling cascades that favor cell death [25-27].
It is well documented that apoptosis generally occurs through two main pathways: the mitochondrial-dependent and death receptor-dependent pathways [46]. Gan and colleagues have reported that oleandrin induces cervical cell apoptosis through the mitochondrial cell death mechanism [47]. This compound significantly stimulates the caspase-dependent pathway by triggering the cleavage of caspase-3/7, -6, and -9 and by upregulating the proapoptotic factor Bim. Similarly, data reported by Elbaz and colleagues support the hypothesis that digitoxin mediates the induction of the mitochondrial apoptotic pathway via caspase-9 activation [38]. This study demonstrated not only a cell growth inhibitory effect but also an apoptotic induction effect for digitoxin.
Fas and TNF-related apoptosis-inducing ligand (TRAIL) are important mediators of the death receptor pathway, and the deregulation of their expression is a major cause of chemoresistance and immune escape in cancers [48]. Recently, Sreenivasna and colleagues investigated whether oleandrin triggers the expression of the Fas receptor to potentiate apoptosis in cancer cells without affecting normal primary cells [49]. Additionally, oleandrin has been found to be able to attenuate the NF-kB pathway, which is a key pathway with antiapoptosis and pro-proliferative effects. Cardiac glycosides including oleandrin, bufalin, digitoxin, and digoxin also initiate apoptosis through Apo2L/TRAIL by elevating the levels of death receptors 4 and 5 in non-small cell lung cancer cells [50]. Interestingly, both Fas and Apo2L/TRAIL induce apoptosis in cancer cells but have little to no effect on normal cells. Furthermore, our recent work has demonstrated that ouabain was able to increse TRAIL-mediated lung cancer cell death through anti-apoptosis Mcl-1 down-regulation [51]. Because of these results, cardiac glycosides are of great interest in the field of cancer research.
A growing number of studies have indicated that the disruption of the oxidative state inside cancer cells, due to either the suppression of the antioxidant system or the introduction of reactive oxygen species, can lead to cell death [52]. In androgen-independent prostate cancer cells, ouabain triggers apoptosis by interfering with mitochondrial function [53]. Because the mitochondria are a major source of reactive oxygen species, the application of ouabain causes a steady increase in the level of these species, which leads to apoptosis. This study also indicated that a low dose of ouabain was able to upregulate prostate apoptosis response 4, which is required to reach the desired level of apoptotic cell death.
Other mechanisms of cardiac glycoside-induced apoptosis have also been reported (Fig 2). Mitogen-activated protein kinases (MAPKs) have been reported to be targeted in bufulin-induced human leukemia cell apoptosis [54]. JNK and AP-1 are transcription factors that activate the transcription of various genes, including apoptosis-related genes [55,56]. In response to bufalin treatment, the MAPK signaling pathway is triggered, leading to a notable elevation in the activities of c-Jun N-terminal protein kinase (JNK) and AP-1.
Molecular mechanisms of cardiac glycoside-induced apoptosis
The susceptibility of a given cancer to chemotherapy often appears to decrease after several rounds of chemotherapy. Resistance to drug-induced cell death is therefore a critical problem in cancer therapy. Combination therapy may be initiated as an alternative approach to overcome this problem. Furthermore, the use of combination therapy increases the cytotoxicity of anticancer agents and reduces their serious side effects on normal cells by reducing the dosage required for each individual agent. Cardiac glycosides have beneficial effects when used as part of combination therapies. Felth and colleagues have investigated the cytotoxicities of cardiac glycosides alone and in combination with various clinically relevant anticancer drugs [60]. Of the glycosides tested, convallatoxin, oleandrin, and proscillaridin A have been shown to be the most potent inducers of colon cancer cell death. Furthermore, co-treatment with cardiac glycosides, including digoxin, digitoxin, oleandrin, and digitonin, and other anticancer drugs, namely 5-fluorouracil, oxaliplatin, cisplatin, and irinotecan, was shown to result in a substantial increase in cancer cell death. However, this study was only a primary screen of the effects of these compounds, and the mechanisms responsible for these effects have not been elucidated.
It is significant that the members of the ATP binding cassette family of transporters, including ABCC7 (CFTR), ABCB1 (P-glycoprotein), and ABCC1 (MRP1), play critical roles in pumping a broad range of drugs out of cells and that these transporters are obviously overexpressed in several tumors [61]. Ouabain has been identified in a recent study to be able to regulate both the expression and activity of ABCC1 in an embryonic kidney cell line. The impairment of ABCC1 following ouabain treatment suggests that this compound might be able to prevent the reduction of the therapeutic concentration inside target cells.
Radiotherapy is a traditional approach used to destroy localized and unresectable tumor cells and to prevent these cells from metastasizing. The combination of chemotherapy and radiation limits the aggressiveness of cancers and increases the patient survival rate. The basic concept underlying chemoradiation is that chemotherapeutics are administered to make cancer cells more susceptible to radiation. Unfortunately, most cancers develop chemoresistance, and anticancer agents have serious side effects in normal cells. The administration of potent anticancer agents with less toxicity against normal cells to sensitize the tumor cells to readiotherapy is a promising strategy. Cardiac glycosides are substances that exhibit selectivity and significant activity against cancer cell lines; thus, the addition of these compounds to existing chemoradiation regimens has been investigated. Huachansu, which is extracted from the skin glands of Bufo bufo gargarizans, exhibits a radiosensitizing effect on human lung cancer cells [62]. This Chinese medicine contains a group of steroidal cardiac glycosides and substantially increases radiation-mediated cell death via a p53-dependent pathway. The underlying mechanism involves the cleavage of caspase-3 and poly-(ADP-ribose) polymerase (PARP) concurrent with the downregulation of the antiapoptotic protein Bcl-2 and the inhibition of DNA repair.
The ability of ouabain to sensitize cancer cells to radiotherapy has also been established. Transformed fibroblasts and tumor cells exposed to gamma radiation undergo apoptosis in the presence of ouabain [63-65]. In addition, the recovery of cells is clearly delayed when the cells are exposed to ouabain after irradiation. These events are the results of the inhibitory effect of ouabain on the G2/M phase of the cell cycle.
The ideal anticancer agent would not only be effective but also selective against tumor cells. As emphasized above, cardiac glycosides have beneficial anticancer effects but do not affect normal cells. Oleandrin attenuates the activation of nuclear transcription factor-kB and activator protein-1 and mediates ceramide-induced apoptosis [43]. These effects are apparently specific to human tumor cells. Consistent with the above findings, bufalin selectively kills leukemia cells, whereas normal leukocytes remain largely unharmed [66, 67]. Furthermore, cardiac glycosides have also been shown to exhibit selectivity in sensitizing cancer cells to apoptosis during radiation treatment. Large numbers of tumor cells and transformed cells die in response to radiation following ouabain pretreatment, but normal cells do not [63, 65]. These studies support the hypothesis that cardiac glycosides have selective anticancer effects, suggesting that these compounds have potential clinical uses.
This selective killing effect has received attention in the search for the fundamental differences between cancer cells and normal cells that modulate the survival pathway. One attempt to identify such differences demonstrated that the subunit composition of Na+/K+-ATPase is dissimilar in rodent and human cancer cells, affecting the sensitivity to apoptosis induced by cardiac glycosides [68]. The Na+/K+-ATPase consists of two main subunits, the catalytic α subunit and the glycosylated β subunit. It is well known that the α subunit serves as a binding site for cardiac glycosides, Na+, K+ and ATP, whereas the β subunit plays a role in the regulation of heterodimer assembly and insertion into the plasma membrane [69, 70]. Recent data indicate that the α1 and α3 subunits are commonly expressed in human tumor cells, whereas only α1 can be found in rodent tumor cell lines [71,72]. It has also been suggested that the lack of the α3 subunit in rodent cancer cells causes resistance to apoptosis mediated by cardiac glycosides. This finding strengthens the hypothesis that normal cells might have lower α3 subunit expression levels than cancer cells, accounting for the selective anticancer effects of cardiac glycosides. Furthermore, it has been demonstrated that the biological activity of cardiac glycosides results from the binding of these compounds with all α subunits, but the α3 subunit is a favorable target [73]. Ouabain, for example, has a 1000-fold stronger interaction with the α3 isoform than the α1 isoform [74].
Expanding on the above findings, that the expression of the α3 subunit has been shown to increase concurrent with the decrease in α1 subunit expression in human colorectal cancer and colon adenoma cell lines, whereas no significant alteration of α3 subunit expression is detected in normal kidney and renal cells [75]. These results indicate that the overexpression of the α3 subunit is associated with responsiveness to cardiac glycosides. Because all α subunits are commonly expressed at a basal level in cancers, the α3/α1 ratio might be a marker of cell sensitivity to cardiac glycosides, and this ratio could be determined in tumor biopsy samples taken prior to treatment with cardiac glycosides [76]. A lower α3/α1 ratio may indicate unresponsiveness to cardiac glycosides; conversely, cardiac glycoside treatment may improve the clinical outcomes of patients who have tumor tissues with higher ratios.
It has been established that the α1 isoform of the Na+/K+-ATPase plays a critical role in the progression of non-small cell lung cancer. The suppression of α1 subunit expression by RNA interference attenuates the invasiveness of cancer, reducing both migration and proliferation [77]. In addition, an increase the α1 subunit level enhances sensitivity to cardiac glycosides. In more than half of glioblastoma samples, the level of Na+/K+-ATPase α1 mRNA was markedly elevated, up to 10 times greater than that in normal samples [78]. Similarly, significant upregulation of the α1 isoform was observed in metastatic melanoma cell lines and melanoma tissue samples [79, 80]. These results indicate that the responsiveness of either cancer cells or normal cells to cardiac glycosides based on the α3/α1 ratio is tissue specific. It is important to determine the differences in the expression levels of the α subunits between cancer cells and normal cells. Furthermore, the characterization of the specificity of each cardiac glycoside for each enzyme subunit is necessary to identify cancers with the appropriate α3/α1 expression pattern for treatment and to reduce the effect on normal cells, thus optimizing the effectiveness of cardiac glycosides as potent anticancer drugs.
Cancer remains a life-threating disease that is typically characterized by frequently related to dysregulated cell growth and resistance to apoptosis. Within the past decade, cancer research has provided interesting insights with the potential to define the exact causes of cancer and to aid in the development of anticancer agents with enhanced effectiveness against and selectivity for cancer. Several plant-derived compounds were once used as ingredients of treatments for diseases without any established scientific evidence to support the claimed effects. Later, these compounds were found to exhibit relevant biological activities. Numerous studies have screened medicinal plants for compounds with anticancer activity, including cardiac glycosides. Generally, cardiac glycosides are recognized as antiarrhythmic drugs that function by inhibiting Na+/K+-ATPase. These compounds have been reported to be therapeutically beneficial for the treatment of various tumor types because of their antiproliferative effects, ability to induce apoptosis, and ability to sensitize cells to chemo/radiotherapy-induced cell death.
As already emphasized, cardiac glycosides have a narrow therapeutic index, which could cause serious cardiovascular toxicity. Interestingly, it has been observed that the concentration required to treat cancer was lower than of that used to treat cardiac disorders. Furthermore, cardiac glycosides appear to exert a cancer-specific killing activity by targeting the Na+/K+-ATPase α subunit in tumor cells. However, the expression pattern of the enzyme subunits and the target specificity of cardiac glycosides must be optimized. Synthetic cardiac glycosides have been designed to achieve the desired effects; these compounds include UNBS-1450 [81,82] and D6-MA [38 ,83]. Although cardiac glycosides have potential effects on cancer, at present, evidence supporting their usefulness is still needed, and the safety profile of cardiac glycosides as anticancer agents must be determined.
Giant cell arteritis (GCA) is a primary (non-necrotizing granulomatous) vasculitis of autoimmune etiology, which especially affects extra cranial medium-sized arteries (branches of the external carotid arteries-ECAs-particularly the superficial temporal arteries-TAs) and sometimes large-sized arteries (aorta and its major branches). It is also recognized as Horton, temporal, or granulomatous arteritis. It causes narrowing of the artery, leading (by wall thickening) to partial (stenosis) or complete obstruction (occlusion) of local arterial blood flow, its clinical manifestations being expressed by signs of local ischemia [1, 2, 3, 4, 5, 6].
\nGCA is the most common form of vasculitis that occurs in adults and in the elderly, being diagnosed over the age of 50’s. Women are two to three times more affected than men. It is well known that the disease can occur in every racial group but is most common in Caucasians, especially people of northern European descent, and others in northern latitudes. [1, 2, 3, 4, 5, 6].
\nAccording to Hunder [7], and Jennette [8] a complete diagnosis of GCA requires the presence of American College of Rheumatology (ACR) classification modified criteria:
age over 50 years at the onset of the disease;
moderate, bitemporal, recently installed headache;
scalp tenderness, abnormal temporal arteries on inspection and palpation (Figure 1), reduced pulse, jaw claudication (pain in the jaw while/after chewing);
blurred vision or permanent visual loss in one or both eyes (since permanent visual loss due to ischemia is frequent, GCA should be considered an ophthalmic emergency requiring immediate management);
systemic symptoms (fatigue, weight loss, fever, pain in the shoulders and hips: polymyalgia rheumatica);
increased inflammatory markers (erythrocyte sedimentation rate greater than 50 mm/h, C reactive protein greater than 1,5 mg/dl);
representative histologic findings in temporal artery biopsy (TAB): mononuclear cell infiltration or granulomatous inflammation of the vessel wall, usually accompanied with multinucleated giant cells (Figure 2).
Giant cell arteritis (GCA) of the left superficial temporal artery (TA) shows a prominent, tender and nodular artery, that is also hypo pulsating on palpation [9].
The histopathological examination of the left superficial temporal artery biopsy (TAB) noted [10]. (A) Thickened vascular wall with inflammatory infiltration of multinucleated giant cells, (B) epithelioid cells and (C) dissolution of the internal elastic lamina (H&E stain).
Several imaging techniques may be suitable in the diagnosis of GCA. [9] Compared to other imaging techniques, US is considered to be the most suitable in the evaluation of GCA patients, therefor it can easily be performed by the clinician (immediately after the general examination of patient), and it is significantly shortening the waiting period until another investigation is performed. [9, 10, 11, 12, 13, 14, 15, 16].
\nUltrasonography (US) is a safe, noninvasive, without radiations, widespread accessible, fast, and low-cost bedside screening technique which has the unique capacity of studying real-time hemodynamics. It presents the ability to evaluate the anatomy of vessel’s wall, identifying equally parietal abnormalities (wall thickening, hypoechoic plaques, clotting, parietal hematoma, dissections) and the external diameter of the artery; it can rule out both stenosis and occlusion. Therefore, the use of US is widespread in neurological clinical practice, mainly in the evaluation of arterial atherosclerotic process but also for monitoring other diseases such as medium/large-vessel vasculitis. [17, 18, 19].
\nOlah noted that for US imaging of extracranial vessels different modes are being used:
\nB-mode (brightness mode)\n
The strength of the echo is recorded as a bright dot, while the location of different gray dots corresponds to the depth of the target. [17]
\nb. The duplex image\n
It associates a B-mode gray-scale image with pulse-wave (PW) Doppler flow velocities measurements.
The B-mode image represents the anatomical localization of the vessels, indicating the zone of interest where a Doppler sample volume should be placed and where the velocities are measured.
The Doppler angle can be measured correctly when the blood is parallel to the direction of the vessel. [17]
\nc. Color Doppler flow imaging\n
Measure mean frequency shift in each sample volume.
It represents color–coded velocity information, which is superimposed as a color flow map on a B-mode image.
In each sample volume, the color reflects the blood flow velocity in a semi quantitative manner, as well as the flow direction relative to the transducer. Blood flowing toward or away from the transducer is shown by different colors (red and blue). Moreover, fast flow is indicated by a lighter hue and slow flow by a deeper one.
The color flow map indicates the position and orientation of the vessels, as well as the site of turbulent flow or stenosis. Since color flow mapping is based on flow velocity measured by PW technology, aliasing occurs if the frequency shift is higher than half of the pulse repetition frequency (PRF). [17]
\nd. Power Doppler mode\n
Uses the signal intensity of the returning Doppler signal instead of frequency shift.
Power (intensity) of the signal is displayed as a color map superimposed on a B-mode image. Since the Doppler power is determined mainly by the volume rather than the velocity of moving blood, power Doppler imaging is free from aliasing artifacts and much more sensitive to detect flow, especially in the low-flow regions. However, it does not contain information about the flow direction or flow velocity. [17]
The advantages of US over other imaging techniques in GCA are represented by its safety, accessibility, tolerability, fast (may take about 15-20 minutes, if it’s conducted by an experienced sonographer) and the more important, its high resolution (a high –frequency probe offers both an axial and a lateral resolution of 0.1 mm) [19, 20, 21, 22, 23, 24, 25, 26, 27]. The smaller the vessel diameter, the more difficult is to appreciate the vessel wall damages, so that, in this case, the most informative US data are based on Doppler spectral evaluation. This is also valid for the assessment of medium to small vessel inflammation such as intracranial vasculitis. Small vessel vasculitis (the ANCA-associated or the immune complex vasculitis) are not a domain of ultrasound. [19].
\nFurthermore, US has a higher sensitivity than TAB, the last one evaluating only a restricted anatomical region in a systemic disease. Using US, we can reveal pathological characteristics in GCA: non-compressible arteries (compression sign), the wall thickening (“halo” sign), stenosis and vessel occlusion. A normal intima-media complex (IMC) of an artery is represented by US as a homogeneous, hypoechoic or anechoic echo structure delineated by two parallel hyperechoic margins. [19, 20, 21, 22, 23, 24, 25, 26, 27].
\nThere is imperative to underline the importance of establishing the arteries that should be routinely examined in a patient suspected for GCA and these are: the TAs, and axillary arteries. If US of these arteries does not reveal suggestive lesions, in the presence of a clear patient history and of an obvious clinical examination, other arteries should be examined: other branches of the ECAs (the internal maxillary, the facial, the lingual, the occipital arteries), the vertebral, the subclavian, the common carotid arteries-CCAs, and the internal carotid arteries-ICAs. [9, 19, 21].
\nRegarding the adequate US equipment for the diagnosis of GCA, modern high-resolution linear probes providing Doppler mode should be used, especially for examination of TAs. We should take into consideration that tissue penetration increases with lower frequencies and the resolution of US increases with higher frequencies. Probes that provide frequencies >20 MHz allow the clearly visualization of the normal IMC of TAs probes with frequencies ≥15 MHz are usually used for detection of minor wall thickening. [19, 21].
\nIn 2012, during the Chapel Hill Consensus Conference [19, 28], large vascular vasculitis (LVV) was well-defined as a vasculitis involving the aorta and its major branches, although any size of artery may be affected. This definition does not state that LVV mainly affects large vessels because in many patients, the number of medium and small arteries affected is greater than the number of large arteries involvement. For example, in GCA, only few branches of the ECAs may be affected when there is involvement of numerous small branches extending into the eye and orbit (e.g., central retinal artery, posterior ciliary arteries). [29, 30] Less frequently, the CCA and the ICA are also affected (Figures 3 and 4). [9].
\nLarge vessels GCA; CT-angiography- occlusion of the left CCA, ECA, and ICA [9].
Large vessels GCA, color Doppler ultrasound in transverse view of the right CCA. Hypoechoic wall swelling with right CCA occlusion [9].
As Sturzenegger pointed up, angiography is not able to illustrate the vessel wall, so as to diagnose the inflammation of the large cervical and cervico-brachial vessels (aorta and its supra-aortic branches), the US can be very useful, since it can define alterations of the vessel wall with the use of B-mode imaging, while Doppler spectral flow velocity evaluation can help identify the stenosis or occlusion of the vessel. [19].
\nColor Doppler Duplex sonography (CDDS) is an excellent device used in screening the large vessels involvement. Agreeing with different authors, including Sturzenegger, there are two ultra-sonographic hallmarks of large vessels GCA:
Vessel wall thickening, that typically is homogeneous, circumferential and over long segments (Figures 4 and 5);
Stenosis, typically revealing slickly tapered luminal tightening (hour glass like) [19, 20, 21, 22, 23, 24, 25, 26, 27]
Large vessel GCA, color Doppler ultrasound in longitudinal view of the right CCA with hypoechoic wall swelling [4].
Remarkably in some cases [9], the common carotid and the internal carotid arteries are also involved (large-vessel GCA) (Figures 3, 4, and 5).
\nExtracranial Duplex sonography investigates almost completely the whole length of the common superficial TAs, including the frontal and parietal branches, and founds that inflammation is segmental (intermittent arterial involvement) [19, 20, 21, 22, 23, 24, 25, 26, 27]. The common superficial TA derives from the ECA. It divides into the frontal and parietal ramus in front of the ear. The distal common superficial TA and the rami are localized between the two layers of the temporal fascia, which is like a bright band at ultrasound examination. [19, 20, 21, 22, 23, 24, 25, 26, 27].
\nHigh-resolution color Doppler US can illustrate the vessel wall and the lumen of the TAs. One should use linear probes with a minimum gray scale frequency of 8 Mhz. Color frequency should be about 10 Mhz. [19, 20, 21, 22, 23, 24, 25, 26, 27].
\nThe pulse repetition frequency (PRF) should be about 2.5 kHz as maximum systolic velocities are rather high (20-100 cm/s). Steering of the color box and the Doppler beam should be maximal as the rami are parallel to the probe. It is important that the color covers the artery lumen exactly. [19, 20, 21, 22, 23, 24, 25, 26, 27].
\nThe sonographer should perform at least 50 Duplex ultrasound of the TAs of subjects without GCA to be sure about the appearance of normal TAs before starting to evaluate patients with GCA. [19, 20, 21, 22, 23, 24, 25, 26, 27].
\nThe investigation should begin with the TA, using the longitudinal scan. The probe should then be moved along the course of the TA to the parietal ramus. On the way back one should delineate the TA in transverse scans. Using the transverse scan, one can find the frontal ramus, which should then be delineated in both scans (longitudinal and transverse). If the color signal indicates localized aliasing and diastolic flow, one should use the pw-Doppler mode to confirm the presence of stenosis. [19, 20, 21, 22, 23, 24, 25, 26, 27].
\nIn 1997 Schmidt et al. proved that the most specific (almost 100% specificity) and sensitive (73% sensitivity) sign for GCA was a concentric hypo-echogenic mural thickening, dubbed “halo”, which the authors interpreted as “vessel wall edema”. [24].
\nOther positive findings for GCA are the presence of occlusion and stenosis. [19, 20, 21, 22, 23, 24, 25, 26, 27].
\nIn conclusion, there are three important items in the ultrasound diagnosis of temporal arteritis:
“dark halo” sign – a typically homogeneous, hypoechoic, circumferential wall thickening around the lumen of an inflamed TA - which represents vessel wall edema and a characteristic finding in temporal arteritis/GCA. It is well delineated toward the lumen (Figure 6).
stenosis are documented by blood-flow velocities, which are more than twice the rate recorded in the area of stenosis compared with the area before the stenosis, with wave forms demonstrating turbulence and reduced velocities behind the area of stenosis (Figure 7).
acute occlusions, in which the US image is comparable to that of acute embolism in other vessels, showing hypoechoic material in the former artery lumen with absence of color signals. [19, 20, 21, 22, 23, 24, 25, 26, 27]
Color Doppler ultrasonography (CDUS) of the right TA shows a hypoechoic halo around the lumen in transverse view (arrow). The “halo sign” corresponds to edema of the artery wall. [11].
Longitudinal view of the right TA by color Doppler ultrasonography (CDUS) shows a hypoechoic halo of the TA and the presence of turbulent and weak flow, suggesting the presence of stenosis. The PSV is 1 m/s, that is double compared to the segment without stenosis. [11].
Related ultrasound patterns can be found in other arteries: the facial, the internal maxillary, the lingual, the occipital, the distal subclavian and the axillary arteries.
\nThe best time to perform ultrasound investigation is before initiating the corticosteroid treatment, or in the first 7 days of treatment, since with corticosteroid therapy the” halo” revealed by TAs ultrasound disappears within 2-3 weeks. The wall inflammation, stenosis, or occlusions of the larger arteries (CCA, ICA) remain for months, despite corticosteroid treatment. However, the diagnosis process should not postpone the initiation of therapy. Ultrasound may also detect inflamed TAs in patients with clinically normal TAs. Some patients with the clinical image of polymyalgia rheumatica, but with hidden TAs may be diagnosed using ultrasonography. [9, 10, 11, 12, 13, 14, 15, 16, 19, 20, 21, 22, 23, 24, 25, 26, 27].
\nIn 2010, Arida et al. [26] evaluated a number of studies that examined the sensitivity and specificity of the “halo” sign confirmed by TA ultrasound (US) for GCA diagnosis versus the American College of Rheumatology (ACR) 1990 criteria for the classification of this vasculitis (used as a reference standard). Only 8 studies involving 575 patients, 204 of whom received the final diagnosis of GCA, achieved the technical quality criteria for US. This meta-analysis disclosed a sensitivity of 68% and a specificity of 91% for the unilateral “halo” sign, as well as 43% and 100%, respectively, for the bilateral “halo” sign in TA US for GCA diagnosis when the 1990 ACR criteria are used as the reference standard. The authors established that the halo sign in US is of great utility in diagnosing GCA. [19, 20, 21, 22, 23, 24, 25, 26, 27].
\nIn the case of consistent clinical and sonographic results, temporal arteries biopsy (TAB) does not appear to be useful and justified. [19, 27].
\nSturzenegger affirmed that differential diagnosis with arteriosclerosis is important in patients over 50 years, taking into consideration that GCA with large vessels disease disturbs almost exclusively this category of patients. There are some characteristic features of the arteriosclerotic wall: the thickening usually appears less homogeneous; there are calcified arteriosclerotic plaques ulcers; stenosis extends over shorter segments, they are not concentric, not tapering, and location of lesions differs (e.g., mainly bifurcations). [19].
\nBesides, agreeing to Sturzenegger, differential diagnosis with the other LVV, especially Takayasu arteritis, has to be reflected:
Takayasu arteritis usually affects women below the age of 40 years;
symptoms like tender scalp or polymyalgia syndrome are exceptional;
the involvement of CCA is more frequent in Takayasu arteritis, while the involvement of temporal artery in Takayasu arteritis is not known;
US image of wall thickening (“halo”) is brighter in TA than in GCA probably due to a larger mural edema in GCA which is a more acute disease than TA. Reflected. [19, 20, 21, 22, 23, 24, 25, 26, 27]
Approximately 25% of patients with temporal artery biopsy (TAB) - proven GCA have ophthalmologic complications: usually unilateral visual loss (due to the vasculitic involvement of orbital vessels:
of posterior ciliary arteries (PCAs) - represented by arteritic anterior ischemic optic neuropathies (A-AION), or
of central retinal artery (CRA) - represented by central retinal artery occlusion (CRAO). [31, 32, 33, 34, 35]
Schmidt compared the results of TAs-US examinations with the occurrence of visual ischemic complications (A-AION, CRAO, branch retinal artery occlusion, diplopia, or amaurosis fugax) in 222 consecutive patients with newly diagnosed, active GCA. [21, 22, 23, 24].
\nHowever, findings of TAs US did not correlate with eye complications. [21, 22, 23, 24].
\nThis is the reason why we always have to exam the orbital (retrobulbar) vessels in GCA patients or in patients with unilateral abrupt visual loss [9, 10, 11, 12, 13, 14, 15, 16] (Figure 8A,B).
\nColor Doppler imaging (CDI) of orbital (retro-bulbar) vessels: (A). central retinal artery (CRA); (B). posterior ciliary arteries (PCAs) [15].
The ophthalmic artery (OA) branches in several arteries, including (Table 1):
the central retinal artery (CRA) (Figure 8 A), and
the posterior ciliary arteries (nasal and temporal branches-nPCAs, tPCAs) [28, 31, 32] (Figure 8B), (Table 1). [15, 28, 31, 32]
Parameter | \nOA | \nCRA | \nPCA (temporal) | \nPCA (nasal) | \nSOV (superior ophthalmic vein) | \n
---|---|---|---|---|---|
PSV (cm/s) | \n45,3 ± 10,5 | \n17,3 ± 2,6 | \n13,3 ± 3,5 | \n12,4 ± 3,4 | \n10,2 ± 3,8 | \n
EDV (cm/s) | \n11,8 ± 4,3 | \n6,2 ± 2,7 | \n6,4 ± 1,5 | \n5,8 ± 2,5 | \n4,3 ± 2,4 | \n
RI | \n0,74 ± 0,07 | \n0,63 ± 0,09 | \n0,52 ± 0,10 | \n0,53 ± 0,08 | \n\n |
OA finishes in the a. supra-trohlearis and A. dorsalis nasi.
\nStandard neurovascular ultrasound machines equipped with linear-array transducers emitting 6-12 MHz (up to 15 MHz) are adequate for identifying (by Color Doppler sonography), and measuring (by spectral analysis pulsed Doppler sonography) the blood flow in the orbital vessels: the OA, the CRA and central retinal vein (CRV), PCAs, and the superior ophthalmic vein (SOV). [28, 31, 32].
\nThe CRA, a distal branch of the OA, enters the optic nerve (ON) approximately 1-1.5 cm distal from the bulbus coming from the dorsolateral direction. Parallel to this is the CRV.
\nThe PCAs are located near the optic nerve (ON) (the nasal-nPCA and the temporal-tPCA branches). [28, 31, 32].
\nIf the vessels are difficult to display, the power should be elevated for a short time if the clinical question is important. [28, 31, 32].
\nThe optic nerve head (ONH) consists of (from anterior to posterior):
the surface nerve fiber layer - mostly supplied by the retinal arterioles. The cilioretinal artery, when present, usually supplies the corresponding sector of the surface layer. [36, 37, 38, 39, 40]
the prelaminar region - situated anterior of the lamina cribrosa. It is supplied by centripetal branches from the peripapillary choroid. [36, 37, 38, 39, 40]
the lamina cribrosa region - supplied by centripetal branches from the posterior ciliary arteries (PCAs), either directly or by the so-called arterial circle of Zinn and Haller (when is present). [36, 37, 38, 39, 40]
the retrolaminar region - is the part of the ONH that lies immediately behind the lamina cribrosa. It is supplied by two vascular systems: the peripheral centripetal and the axial centrifugal systems. The previous represents the main source of stream for this part. It is formed by recurrent pial branches arising from the peripapillary choroid and the circle of Zinn and Haller (when present, or the PCAs instead). In addition, pial branches from the central retinal artery (CRA) also supply this part. The latter is not present in all eyes. When present, it is formed by inconstant branches arising from the intraneural part of the CRA.
From the description of the arterial supply of the ONH given above, it is obvious that the PCAs are the main source of blood supply to the ONH. [36, 37, 38, 39, 40].
\nThe blood flow in the ONH depends upon [36, 37, 38, 39, 40]:
resistance to blood flow - depends upon the condition and caliber of the vessels supplying the ONH, which in turn are influenced by: the efficiency of auto-regulation of the ONH blood flow, the vascular variations in the arteries feeding the ONH circulation, and the rheological properties of the blood.
arterial blood pressure (BP) - both arterial hypertension and hypotension can influence the ONH blood flow in several ways. In an ONH, a fall of blood pressure below a critical level of auto-regulation would decrease its blood flow. Decrease of BP in the ONH may be due to systemic (nocturnal arterial hypotension during sleep, intensive antihypertensive medication, etc.) or local hypotension.
intra-ocular pressure (IOP) - there is an opposite relationship between intra-ocular pressure and perfusion pressure in the ONH.
The blood flow in the ONH is calculated by using the following formula:
\nPerfusion pressure = Mean BP minus intraocular pressure (IOP).
\nMean BP = Diastolic BP + 1/3 (systolic - diastolic BP) [6, 13].
\nAION is the consequence of an acute ischemic disorder (a segmental infarction) of the ONH supplied by the PCAs. Blood supply interruption can occur with or without arterial inflammation. Therefore, AION is of two types: non-arteritic AION (NA-AION) and arteritic AION (A-AION). The prior is far more common than the last, and they are distinct entities etiologically, pathogenically, clinically and from the management point of view. [36, 37, 38, 39, 40].
\nA history of amaurosis fugax before an abrupt, painless, and severe loss of vision of the involved eye, with concomitant diffuse pale optic disc edema is extremely suggestive of A-AION. None of these symptoms are found in NA-AION patients. [36, 37, 38, 39, 40].
\nIn acute stage, blood flow cannot be detected in the PCAs in the clinically affected eye of any of the GCA patients with A-AION. Low end diastolic velocities (EDV) and high resistance index (RI) are identified in all other orbital vessels (including the PCAs in the opposite eye) of all A-AION patients. [9, 10, 11, 12, 13, 14, 41].
\nOver 7 days, Spectral Doppler analysis of the orbital vessels highlights blood flow alterations in all A-AION patients even with a high-dose corticosteroids therapy. Severely reduced blood flow velocities (especially EDV) in the PCAs of the affected eye (both nasal and temporal branches), compared to the unaffected eye, are observed. An increased RI in the PCAs is noted (the RI is higher on the clinically affected eye as compared to the unaffected eye). [9, 10, 11, 12, 13, 14, 41] (Figure 9A,B).
\nCDI of the PCAs in A-AION: (A). Decreased EDV in the nasal PCAs of the clinically affected right eye, and (B) of the clinically unaffected left eye.
Fewer abnormalities are detected in the CRAs: high RI are measured in both sides, with decreased peak systolic velocities (PSV) in the CRA of the clinically affected eye. [9, 10, 11, 12, 13, 14, 41].
\nSimilar abnormalities are noted in the OAs: high RI are measured in both sides. [9, 10, 11, 12, 13, 14, 41].
\nAt 1 month, after treatment with high-dose corticosteroids, CDI examinations of orbital blood vessels reveals that blood flow normalization is slow in all A-AION patients. [9, 10, 11, 12, 13, 14, 41].
\nIn conclusion, the Spectral Doppler Analysis of the orbital vessels in A-AION indicates (after several days of corticosteroid treatment) low blood velocities, especially EDV, and high RI in all orbital vessels, in both orbits. These signs represent characteristic signs of the CDI of the orbital vessels in A-AION. [9, 10, 11, 12, 13, 14, 41].
\nIn contrast, the patients with NA-AION present the following characteristics in acute stage, and at 1 week of evolution:
minor reduction of PSV in PCAs (nasal and temporal) in the affected eye, compared to the unaffected eye.
slight decrease of PSV in CRA of the affected eye, due to papillary edema. [9, 10, 11, 12, 13, 14, 41]:
in OAs, PSV are variable: normal to decreased, according to ipsilateral ICAs status.
Severe ICA stenosis (≥70% of vessel diameter) combined with an insufficient Willis polygon led to diminish PSV in ipsilateral OA. [9, 10, 11, 12, 13, 14, 41].
\nIn 1 month, CDI examinations of orbital blood vessels reveal that blood flow normalization is reached. The exceptions are the cases with severe ipsilateral ICA stenosis/occlusion. [9, 10, 11, 12, 13, 14, 41].
\nIn conclusion, in NA-AION, blood velocities and RI in PCAs are preserved. Similar results were obtained in other studies. [9, 10, 11, 12, 13, 14, 41].
\nFluorescein angiogram and CDI of the orbital vessels data support the histopathological evidence of involvement of the entire trunk of the PCAs in the A-AION (impaired optic disc and choroidal perfusion in the patients with A-AION). On the other hand, in the NA-AION, the impaired flow to the optic nerve head (ONH) is distal to the PCAs themselves, possibly at the level of the para-optic branches (only 1/3 of the flow of the PCAs). [36, 37, 38, 39, 40].
\nThese branches supply the ONH directly (impaired optic disc perfusion, with relatively conservation of the choroidal perfusion). [36, 37, 38, 39, 40].
\nExtremely delayed or absent filling of the choroid has been depicted as a fluorescein angiogram characteristic of arteritic AION and has been suggested as one useful factor by which A-AION can be differentiated from NA-AION. [36, 37, 38, 39, 40].
\nCRAO is the result of an abrupt diminuation of blood flow in CRA, severe enough to cause ischemia of the inner retina. Due to the fact that there are no functional anastomoses between choroidal (PCAs) and retinal circulation (CRA), CRAO determines severe and permanent loss of vision. Therefore, it is very important to identify the cause of CRAO, in order to protect the contralateral eye. Frequently, the site of the blockage is within the optic nerve substance and for this reason, it is generally not visible on the ophthalmoscopy. The majority of CRAO are caused by thrombus formation due to systemic diseases, including GCA. For this reason, all patients with CRAO should undergo a systemic evaluation. [42, 43, 44].
\nThe patients with an unilateral CRAO present at the Spectral Doppler analysis of the retrobulbar vessels the following aspects [9, 15, 16]:
an elevated RI in the CRAs (the RI is higher on the affected side, than it is on the unaffected side); with severe diminished blood flow velocities (especially EDV) in the CRA.
fewer abnormalities are observed in the PCAs, and in the OAs (Figure 10).
CDI of orbital vessels revealed severely diminished EDV and high RI in both CRAs (a, b) despite the fact that the left eye had the normal aspect at ophthalmoscopy. Fewer abnormalities were observed in the PCAs (c, d). [15].
Other imaging techniques, such as high-resolution magnetic resonance imaging (MRI), magnetic resonance-angiography (MR-A), computer tomography angiography (CT-A), positron emission tomography (PET) provide valuable information regarding the structure of large vessels, highlighting with much greater precision the thoracic aorta, compared with US. [45, 46, 47].
\nThere are few studies that compared US with other imaging techniques. Some of them indicated that there is a good correlation between US and PET, even though PET might have a little more sensitivity for vertebral arteries examination. [45, 46] 18F-fluorodeoxyglucose-positron emission tomography/ computed tomography (FDG-PET/CT) has a higher sensitivity for detection of large arteries and aortic involvement - analysis of the arterial wall. [45, 46] The diagnostic power of high-resolution MRI and color-coded duplex US of extra-cranial arteries in detecting GCA are equivalent [47].
\nThe disadvantages of this techniques are: they are more expensive, hardly accessible, some of them are limited by invasiveness, nephrotoxicity (angiography) and exposure to high radiations (CT,PET), this is why they might be unnecessary (excepting those patients with exclusively thoracic aorta involvement) and are not accepted as diagnostic methods in GCA. They should only be used when interventions are required [45, 46, 47].
\nAll these imaging techniques should always be performed by well-trained specialists, using suitable equipment and operational protocols. [45, 46, 47].
\nNevertheless, US is particularly useful in examining the orbital vessels. [9, 10, 11, 12, 13, 14, 15, 16, 28, 31, 32, 41].
\nThe diagnostic work-up of AION benefits from the combined used of fluorescein angiography and noninvasive multimodal imaging, including CDI of the orbital vessels and structural Optical Coherence Tomography (OCT) of the optic nerve head (ONH) and OCT angiography [10, 48]. They provide very detailed information regarding the structural (retinal nerve fiber layer-RNFL-thickness/optic disc edema) and vascular impairments (microvascular defects-vessel tortuosity, and vessel density reduction) of the ONH, respectively [10, 48].
\nUS should be used as a first-line diagnostic investigation for patients presenting with clinical and biological features suggestive for GCA, taking into consideration that it has a high sensitivity to detect vessel wall thickening (dark hallo sign) in the case of large/medium vessels. In a few cases of our studies, the CCAs and the ICAs were also involved.
\nIn consequence, in our department, CCDS has emerged as a safe and reliable alternative to TAB as a point of care diagnostic tool in the management of temporal arteritis.
\nThe eye involvement in GCA is frequent and consists in A-AIONs or CRAO, with abrupt, painless, and severe loss of vision of the involved eye.
\nBecause findings of TAs US do not correlate with eye complications in GCA, CDI of the orbital vessels is of critical importance, in order to quickly differentiate the mechanism of eye involvement (arteritic, versus non-arteritic). This US tehnique may be helpful to detect the blood flow in the orbital vessels, especially in cases of opacity of the medium, or when the clinical appearance of ophthalmologic complications in temporal arteritis is athypical.
\nThe Spectral Doppler Analysis of the orbital vessels in GCA with eye involvement reveals low blood velocities, especially EDV, and high RI in all orbital vessels, in both orbits, for all patients (especially on the affected side).
\nA huge advantage of CDI of orbital vessels is that it provides immediate information that can be used to inform treatment decisions, including a potential reduction in loss of sight and avoidance of unnecessary long-term steroid treatment by early exclusion of mimics.
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